Holman's Biotech IP Blog

Claim Construction Ruling in Arzerra Infringement Case

2011-10-20T09:42:00.000-05:00

On October 17, a judge in the Southern District of California issued a significant claim construction ruling in the case of Biogen Idec and Genentech v. GlaxoSmithKline. The plaintiffs allege that defendants anti-CD20 monoclonal antibody Ofatumumab (trade name Arzerra) infringes US patent number 7,682,612. Plaintiffs market a competing anti-CD20 antibody, Rituximab (trade name Rituxan).

Based on my understanding of the case, the ruling appears to be a substantial victory for GlaxoSmithKline.

The disputed claim terms are found in claim 1 of the patent, which recites:

1. A method of treating chronic lymphocytic leukemia in a human patient, comprising administering an anti-CD20 antibody to the patient in an amount effective to treat the chronic lymphocytic leukemia, wherein the method does not include treatment with a radiolabeled anti-CD20 antibody.

The court construed the terms "anti-CD20 antibody” and “CD20 binding fragment” as “rituximab and antibodies that bind to the same epitope of the CD20 antigen with similar affinity and specificity as rituximab” and "the portion of the anti-CD20 antibody that binds to the same epitope of the CD20 antigen with similar affinity and specificity as rituximab.” This is significant, because Arzerra does not bind to the same epitope as rituximab, which appears to rule out infringement if this construction of the terms is affirmed on appeal.

The plaintiffs argued for a broader construction, such that the disputed terms would cover any antibody that binds to CD20, even antibodies that bind to different epitopes, such as Arzerra. However, the court found that the prosecution history of the patent established that during prosecution plaintiffs represented that the claims were limited to antibodies binding to the same epitope as rituximab, and the court held them to this more limited construction of the term.

The court also construed the terms "does not include treatment with a radiolabeled anti-CD20 antibody" and "radiation is not used" as "excludes the use of a radiolabeled anti-CD20 antibody or the administration of a separate radiolabeled anti-CD20 antibody," and "no form of radiation (including radiolabeled antibodies) is used," respectively. This construction is significant, because it appears to rule out infringement when Arzerra is used in conjunction with Bexxar or Zevalin, which are both radiolabeled anti-CD20 antibodies.

Thanks to Docket Navigator for making me aware of the ruling.

Pioneer-DuPont Sues Monsanto for Infringing "Low Tech" Agricultural Biotechnology Patents

2011-10-19T11:20:00.000-05:00

Yesterday Pioneer Hi-Bred (a subsidiary of DuPont) sued Monsanto, its rival in the agricultural biotechnology sector, for allegedly infringing its patents directed towards a method of increasing "seed vigor" in maize that entails defoliating maize plants during a specific period after pollination. The lawsuit was filed in the Southern District of Iowa, Pioneer's home territory.

The two companies have been involved in a high-profile patent litigation ever since Pioneer announced its plans to release genetically modified maize comprising Pioneers Optimum GAT trait stacked with Monsanto's Roundup Ready trait. Both traits confer resistance to glyphosate (i.e. Roundup), albeit by different mechanisms - Roundup Ready essentially works by rendering the plant resistant to glyphosate, while Optimum GAT causes the plant to express a protein that breaks down the glyphosate molecule.

Pioneer responded by suing Monsanto for antitrust violations, based on the company’s licensing and enforcement practices with respect to its patents covering the Roundup Ready trait. The patent infringement case is scheduled to go to trial next June, while the antitrust counterclaims are scheduled to go to trial April 2013.

The two patents being asserted by Pioneer in the most recent lawsuit are US patent numbers 5,518,989 and 6,162,974. The ‘989 patent claims a method of increasing seed vigor in maize by defoliating plants during a specific time window after pollination, based upon how long the growing plant has been exposed to warm days. The ‘974 patent claims an "assemblage" of maize seeds produced using the method. Here are a couple of representative claims.

Claim 1 from the ‘989 patent:

1. A method for treating a stand of maize plants, comprising the steps of

(A) reducing functional leaf area in substantially all of said plants, wherein said reducing is effected at between about 600 and about 850 GDDs after pollination of said plants, and then

(B) harvesting said stand, such that a seed assemblage is obtained from said stand that is characterized by a level of seed vigor that is enhanced relative to the level of seed vigor in a seed assemblage harvested from a comparison stand of maize plants not subjected to said reducing of functional leaf area.

Claim 1 from the ‘974 patent:

1. A maize seed assemblage having enhanced seed vigor, wherein said seed assemblage is obtained by the method comprising the steps of:

(a) reducing functional leaf area in substantially all of a stand of maize plants, wherein said reducing is effected at between about 600 and about 850 GDDs after pollination of said plants, and

(b) harvesting said stand to obtain an assemblage of seeds,

wherein said seed assemblage is characterized by a level of seed vigor that is enhanced relative to the level of seed vigor in a seed assemblage harvested from a comparison stand of maize plants not subjected to said reducing of functional leaf area.

According to Wikipedia, “GDD [,which stands for Growing Degree Day, is] a measure of heat accumulation used by horticulturists, gardeners, and farmers to predict plant and pest development rates such as the date that a flower will bloom or a crop reach maturity.” Wikipedia states that "plants grow in a cumulative stepwise manner which is strongly influenced by the ambient temperature. Growing degree days take aspects of local weather into account and allow gardeners to predict (or, in greenhouses, even to control) the plants’ pace toward maturity."

The patents state that "functional leaf area can be reduced" (i.e., the plant can be defoliated) using mechanical or chemical means. "Chemical means" would include treatment with an herbicide such as Roundup (the dependent claims explicitly identify Roundup as an herbicide to be used in the method.

The patents remind me of the patents at issue in In re Cruciferous Sprouts litigation that occurred several years ago. In that case, as I recall, researchers at Johns Hopkins University discovered that cruciferous sprouts (e.g., broccoli sprouts) harvested at a particular point in time after germination (in particular, prior to the "two-leaf stage") contain high levels of certain compounds believed to be useful in preventing cancer.

A representative claim at issue in that case recited " “A method of preparing a food product rich in glucosinolates, comprising germinated cruciferous seeds, with the exception of cabbage, cress, mustard and radish seeds, and harvesting sprouts prior to the 2-leaf stage, to form a food product comprising a plurality of sprouts.”

The Federal Circuit held that the claims were invalid based on inherent anticipation. Although the Johns Hopkins researchers might have been the first to recognize the health benefits of eating cruciferous sprouts harvested prior to the two-leaf stage, in fact people had been eating sprouts harvested at this stage for many years. This was surely the correct result - if the claims were held valid, that would mean that Johns Hopkins would have the right to exclude others from doing something that had long been part of the prior art, i.e., eating broccoli sprouts and the like.

The same sort of issue of inherent anticipation could potentially be raised with respect to Pioneer's patents on methods of defoliating maize plants at a certain time after pollination. It would seem to me that if Monsanto can show that, prior to Pioneers invention, maize plants had been defoliated during this stage of growth (perhaps by treatment with Roundup), a court might come to the conclusion that the claims are inherently anticipated.

The claims also might raise issues of patent eligibility, at least in the minds of people like Justice Breyer. Recall that in his LabCorp dissent Justice Breyer expressed a view that a patent claim that preempts substantially all practical use of a newly discovered natural phenomenon is patent ineligible. Some might characterize Pioneer’s discovery that defoliation of maize at a certain time results in increased seed vigor as the discovery of a "natural phenomenon," and conclude that Pioneer’s claims effectively preempt all substantial practical application of this discovery.

Pioneer's claims directed towards a "maize seed assemblage" might also raise patent eligibility issues. The claimed maize seeds are arguably not genetically modified, in which case they might be considered "products of nature" and not patent eligible under Chakrabarty. In order to be patent eligible, it would seem that a court would have to determine that either the defoliation resulted in a "man-made" seed, or that grouping seeds in an "assemblage" is sufficient human intervention to establish patent eligibility.

Patent Battle over Modified Meganucleases Heats Up

2011-10-05T15:28:00.000-05:00

Meganucleases are endodeoxyribonucleases characterized by a large recognition site (double-stranded DNA sequences of 12 to 40 base pairs); as a result this site generally occurs only once in any given genome. For example, the 18-base pair sequence recognized by the I-SceI meganuclease would on average require a genome twenty times the size of the human genome to be found once by chance. Meganucleases are therefore considered to be the most specific naturally occurring restriction enzymes.

The high specificity of meganucleases gives them a high degree of precision and much lower cell toxicity than other naturally occurring restriction enzymes; they were identified in the 1990s as particularly promising tools for genome engineering.

However, the meganuclease-induced genetic recombinations that could be performed were limited by the repertoire of meganucleases available. Despite the existence of hundreds of meganucleases in nature, and the fact that each one is able to tolerate minor variations in its recognition site, the probability of finding a meganuclease able to cut a given gene at the desired location is extremely slim. Several research laboratories therefore soon began trying to engineer new meganucleases targeting the desired recognition sites.

Cellectis and Precision Biosciences are two competing biotechnology companies, both seeking to commercialize engineered meganucleases for use in genetic engineering.

On March 1, 2011, Cellectis sued Precision Biosciences in the District Court of Delaware for allegedly infringing US patent number 7,897,372, directed to "I-CreI Meganuclease Variants with Modified Specificity.” That case is presently proceeding with discovery, and trial is set for February 2013.

On September 20, 2011, the US patent office issued US patent number 8,021,867, which is directed towards "Rationally-Designed Meganucleases with Altered Sequence Specificity and DNA-Binding Affinity." The named assignee on the patent is Duke University, but according to Celectis the patent is actually owned by Precision.

On September 30, 2011, Cellectis filed another lawsuit against Precision Biosciences, again in the District Court of Delaware, and this time it is a declaratory judgment action seeking a declaration that the Duke/Precision patent is invalid and not infringed by Cellectis.

In the complaint, Cellectis does not allege that it has explicitly been threatened with a lawsuit by Precision. Instead, it argues that declaratory judgment is appropriate because: both patents-in-suit concern the same field of technology, i.e., "modified" or "altered" I-CreI meganucleases; the Cellectis patent is prior art to the precision patent, the parties in both cases are the same, and the discovery in both cases likely would substantially overlap.

Mirus Bio Files Lawsuit Alleging that Roche’s FuGENE 6 Transfection Reagent Infringes Patent

2011-09-13T09:04:00.000-05:00

On September 12, 2011, Mirus Bio sued Fugent, LLC for allegedly infringing its patent entitled "Process of Transfecting a Cell with a Polynucleotide Mixed with an Amphipathic Compound and a DNA-Binding Protein" (U.S. Patent No. 5,744,335). The patent issued in 1998. Claim 1 of the patent recites:

A process of transfecting a polynucleotide into a cell comprising: associating a selected cell with an amphipathic compound, an effective amount of a polynucleotide-binding protein, the polynucleotide-binding protein is selected from the group consisting of histone and histone with a nuclear localizing signal, and a selected polynucleotide, in solution, wherein encapsulation of the polynucleotide by the amphipathic compound is not required for transfection.

Both companies are located in Madison Wisconsin.

The complaint alleges that Fugent infringes the patent, both directly and indirectly (i.e., by inducing its customers to infringe the patent, and/or by contributing to the infringing actions of its customers) by making, using, selling and offering to sell the transfection reagent known as FuGene 6.

FuGene 6 is a Roche product, and appears in the Roche Applied Science catalog. I'm not sure what the relationship is between Fugent and Roche, nor why Roche was not named in the lawsuit.

If you go to Mirus Bio website homepage, this is what you will see:

FuGENE® 6 Supply Problems?
Transfect with TransIT®-LT1
Achieve Comparable Performance
"TransIT-LT1 (MirusBio) has the same performance as FuGENE® 6 (Roche) in our comparison tests."
-The RNAi Consortium (TRC), Broad Institute of MIT and Harvard

Perhaps they are referring to the lawsuit when they suggest people will be having supply problems with FuGENE 6, and might need to switch to the Mirus Bio product TransIT-LT1.

Thanks to Docket Report from Docket Navigator for making me aware of the complaint.

University Sues Makers of Heart-Healthy Cookies

2011-09-09T09:51:00.000-05:00

In a complaint filed September 7 in the Western District of Wisconsin, Brandeis University joins its exclusive licensee (GFA Brands) in suing a number of cookie companies, including Keebler, Famous Amos, Nestlé's and Pillsbury for infringing its patents directed towards methods of "Increasing the HDL Level in the HDL/LDL Ratio in Human Serum by Balancing Saturated and Polyunsaturated Dietary Fatty Acids." As an example, one of the asserted claims is claim 7 of US patent 5,843,497, which recites:

7. A prepared food product, comprising a cholesterol-free fat composition suitable for human or animal ingestion for increasing the HDL concentration and the HDL/LDL concentration ratio in the blood serum, comprising one part by weight polyunsaturated fat and at least one part by weight cholesterol-free saturated fat, where said fat composition comprises linoleic acid and at least one saturated fatty acid selected from the group including lauric acid, myristic acid, and palmitic acid, said linoleic acid constituting between 15% by weight and 40% by weight of the fat in said fat composition and said saturated fatty acid constituting between 20% and 40% by weight of the fat in said fat composition.

Thanks to Docket Report (a service of Docket Navigator) for making me aware of the complaint, which is available here.

One might question the University's decision to patent and exclusively license this discovery, and then proceed to join in a lawsuit against cookie manufacturers apparently employing the fruits of university research in an attempt to make healthier cookies. In an article I published a few years ago with Josh Sarnoff entitled Recent Developments Affecting the Enforcement, Procurement and Licensing of Research Tool Patents (available here), we discussed the policy behind the Bayh-Dole Act, which was primarily intended to increase access to, and the dissemination of, federally-funded University research.

Prior to buy Bayh-Dole, there was a sense that much of the fruits of University research was essentially left sitting on the shelf, due to insufficient incentives for the investment necessary to translate basic University research into useful commercial products. In order to increase the social benefit to be derived from federally funded University research, Bayh-Dole facilitated the ability of universities to patent and license discoveries coming out of such research. But, at least to my understanding, the primary policy justification was not to simply create profit centers for Universities, but rather to permit universities to license patented technologies to companies in the private sector who might only be willing to invest in the commercialization of these technologies if there was some patent protection in place. A good example would be a potentially useful pharmaceutical compound - without a patent in place, few companies would be willing to make the substantial investment the would be required to develop and bring to market a drug based on the compound.

In recent years, there has been much criticism of the manner in which some University technology transfer offices operate, and allegations that university patenting and licensing practices at times impede rather than promote dissemination of the fruits of federally funded University research. For example, in congressional hearings held to address the alleged problem of "gene patents," much of the testimony seemed to suggest that it was University patenting and licensing processes that were more problematic than gene patents per se. In an article I published on human gene patent litigation a few years ago (available here) I found that every gene patent litigation involving genetic diagnostic testing (which is the most controversial use of gene patents) involved gene patents arising out of University research.

In 2007, the trustees of the Association of University Technology Managers (AUTM) published a white paper entitled In the Public Interest: Nine Points to Consider and Licensing University Technology. Point 2 states in part that:

When significant investment of time and resources in a technology are needed in order to achieve its broad implementation, an exclusive license often is necessary and appropriate. However, it is important that technology transfer offices be aware of the potential impact that the exclusive license might have on further research, unanticipated uses, future commercialization efforts and markets. Universities need to be mindful of the impact of granting overly broad exclusive rights and should strive to grant just those rights necessary to encourage development of the technology.

In other words, University technology transfer offices are encouraged to only grant exclusive licenses in technology when a "significant investment of time and resources in a technology are needed in order to achieve its broad implementation." To the extent the patents are licensed exclusively, the University "should strive to grant just those rights necessary to encourage development of the technology."

In this case, the patented technology does not seem to be the type that required a significant investment of time or resources in order to be implemented, as evidenced by the large number of nonlicensed cookie manufacturers who are allegedly employing the suggested "balance of saturated and polyunsaturated dietary fatty acids" in their cookies, presumably in an effort to provide safer products for consumers.

One might question whether the decision of Brandeis University to exclusively license a patent covering these healthy products was the proper decision, or even whether this might be the sort of technology that would be better left unpatented, particularly if one views the University's primary mission as generating and disseminating useful discoveries such as this.

What Does Classen v. Biogen Mean for the Patent Eligibility of Diagnostics and Personalized Medicine?

2011-09-09T08:13:00.000-05:00

In previous posts to this blog, I have discussed three important cases that pertain to the patent eligibility of inventions based on the discovery of medically useful correlations involving patient clinical data - Prometheus v. Mayo, Association for Molecular Pathology v. PTO (AMP) and Classen v. Biogen. Correlations of this type lie at the heart of diagnostics and personalized medicine, so the outcomes of these cases has important ramifications for the patent eligibility of these increasingly important technologies.

Classen v. Biogen was decided on August 31, 2012, so now we have Federal Circuit decisions on all three cases. None of the three cases is necessarily “over” - the Supreme Court has granted certiorari in Prometheus, the parties are petitioning the Federal Circuit for a rehearing of AMP, and the parties in Classen will have the opportunity to do the same. Still, it seems like an appropriate time to step back and assess where we are in light of these three important post-Bilski patent eligibility decisions.

In all three cases, the heart of the underlying invention was a clinically significant correlation between clinical data obtained from patients and a predicted medical outcome. In Prometheus, the inventor discovered a correlation between the level of drug metabolite in an individual patient's body and the optimal drug dosing regimen. In AMP, the inventor isolated the BRCA genes, thus providing a means for testing for the presence of variations in the gene correlated with the likelihood the patient will develop cancer. In Classen, the inventor discovered a correlation between immunization schedule (i.e., the timing at which vaccinations are given to a child) and the likelihood that the immunized patient will develop an autoimmune disorder.

The discoveries forming the basis of these three patents would all appear to be of substantial (and potentially life-saving) clinical significance, but the challenge for the inventor was how to draft a patent claim that would not only be valid, but would also be valuable, in the sense that it would provide meaningful protection from a competitor seeking to commercially exploit the discovery. Clearly, the inventors could have obtained very narrow claims that would be patent eligible, but such claims might be essentially worthless if competitors could easily design around them. Understandably, the inventors chose to claim their inventions in broad terms, which ultimately resulted in allegations that the claims are patent ineligible under 35 USC 101. Note that all three of the patents were drafted years ago, prior to Bilski and the recent tightening of the patent eligibility standard.

Now that all three cases have been decided by the Federal Circuit, we have learned that some of the claims have passed muster, while others have been invalidated for lack of patent eligibility. In Prometheus, the method claims were ruled patent eligible and upheld. In AMP, the diagnostic method claims were ruled patent ineligible and invalidated. And now in Classen, some of the method claims have been upheld, while others have been ruled patent ineligible. Is it possible to reconcile these decisions? I think the Classen majority does a poor job of explaining its decision, but that there are meaningful distinctions between the claims that have been deemed patent ineligible and those that have been deemed patent eligible, and in this article I will discuss those distinctions and attempt, to the extent possible, to reconcile the outcomes in three cases.

The Classen Majority Opinion Rests upon a Gross Misinterpretation of the Claim Language

The Classen claims held to be patent ineligible are essentially directed towards methods of evaluating immunization schedules (i.e., the timing of when immunizations are given to the patient, typically a child) in order to develop an immunization schedule that minimizes the risk of and autoimmunity disorder. Not surprisingly, many people do not like the patent claims, including the district court judge who heard the case at all the Federal Circuit judges who heard the case on appeal. The problem is, the claims explicitly recite a step of "immunizing mammals," which is inherently transformative, and under Prometheus would seem to require a strong presumption of patent eligibility.

The first time the Federal Circuit decided Classen (prior to the Supreme Court's Bilski decision's clarification of the role of the machine or transformation test in the analysis for patent eligibility), it completely ignored the explicit immunization step in the claims, and simply concluded that the claim is patent ineligible because it fails the machine or transformation test. The decision provided absolutely no explanation as to the rationale for ignoring a clearly transformative step, as discussed in a previous post to this blog.

The Supreme Court ordered the Federal Circuit to vacate its earlier decision and re-decide Classen in light of the Supreme Court's Bilski decision, which resulted in the August 31 decision. In this more recent decision, the majority does not ignore the immunization step, but instead grossly misinterprets it in a manner that seems to me entirely inconsistent with the express language of the claims.

The exemplary claim of the ‘283 patent, which was the focus of the court's patent eligibility analysis, recites in full:

1. A method of determining whether an immunization schedule affects the incidence or severity of a chronic immune-mediated disorder in a treatment group of mammals, relative to a control group of mammals, which comprises immunizing mammals in the treatment group of mammals with one or more doses of one or more immunogens, according to said immunization schedule, and comparing the incidence, prevalence, frequency or severity of said chronic immune-mediated disorder or the level of a marker of such a disorder, in the treatment group, with that in the control group.

In attempting to distinguish between this claim and other claims found to be patent eligible, the majority opinion states that "the immunizing in the ‘283 patent refers to the gathering of published data." But the court provides no explanation for how it arrived at its conclusiong that a relatively straightforward word like "immunize" actrually means "gathering published data” (a point raised by Judge Moore in their dissent).

The majority opinion goes on to state that Claim 1 of the '283 patent "is directed to the single step of reviewing the effects of known immunization schedules, as shown in the relevant literature." It also asserts that claim 1 "claims the idea of comparing known immunization results that are . . . found in the scientific literature." By reading the express "immunization" limitation of the claims, the court is able to simply conclude that the claims are directed towards methods of reviewing published data, which woif it were true clearly render the claims ineligible under Prometheus and AMP (i.e., if there actually was no immunization step).

In Prometheus, the Federal Circuit clearly stated that methods of treatment involving administration of drug to patient are inherently transformative because the body is transformed by the drug (and the drug itself is also typically transformed as it is metabolized), and this is clearly the case with respect to immunization of patients. In order to provide a meaningful and principled decision, it was incumbent upon the Federal Circuit to explain why it was that this clearly transformative step was nonetheless insufficient to render the claim patent ineligible. Unfortunately, the majority skirted this important point by reading the immunization step out of the claim. But in fact I think there is a plausible distinction between Classen's patent ineligible claim and the claims held to be patent eligible in Prometheus and Classen, and in the remainder of this article I attempt to articulate that distinction.

The Classen Claims Are Not Directed to Diagnostics or Personalized Medicine

Although the Classen decision is relevant to the patent eligibility of diagnostics and personalized medicine, it is important to point out that the purported inventions claimed by Dr. Classen do not fall into either category. Diagnostics and personalized medicine involve the use of physiological information pertaining to a particular individual patient to diagnose that patient for some clinically significant trait (such as a heightened likelihood of cancer), or discern the optimal therapeutic treatment for that patient (such as whether a particular drug is appropriate for that patient, or the optimal dosage for the patient). Significantly, true personalized medicine and diagnostic claims are directed towards methods of obtaining physiological information from a specific patient and applying that information to the medical treatment of that individual patient.

In contrast, the Classen claims are not directed towards methods of using individual patient data to diagnose or treat that patient. Instead, they are directed towards methods of comparing data derived from two groups of patients, i.e., a control group and a treatment group. This is not personalized medicine - in the words of Judge Moore, Classen is attempting to "claim a monopoly over the scientific method itself.” Classen's method does not involve using information relating to a specific patient to tailor the medical treatment of the patient, but instead involves using information relating to two cohorts of patients (a control group and a treatment group) to arrive at a generally applicable vaccination schedule.

Although none of Classen's claims are directed towards diagnostics or personalized medicine, some of the claims are directed towards methods of treating specific patient, and those claims were deemed patent eligible. This distinction between Classen's patent eligible and patent ineligible claims is clearly reflected in the preambles of the two exemplary claims analyzed by the court. Patent ineligible Claim 1 of the ‘237 patent is directed towards a "method of determining whether an immunization schedule affects the incidence or severity of a chronic immune-mediated disorder in a treatment group of mammals." In contrast, the preamble of patent eligible Claim 1 of the ‘739 patent recites a "method of immunizing a mammalian subject."

In essence, the ’237 patent claims a method of assessing the safety of an immunization schedule applicable to "a treatment group of mammals." Even though the claim explicitly recites immunizing mammals, in the context of the claim the role of the immunization step is to provide data for evaluating an immunization schedule. In contrast, again in the context of the claim, the immunization step of Claim 1 of the ‘739 patent is directed towards the immunization of the specific mammalian subject (e.g., child) recited in the claims preempt all as the intended beneficiary of the claim. Although I don't believe this distinction was never raised by the Federal Circuit judges in their decisions, I think it is a significant distinction that might justify the disparate treatment of the two claims.

In Prometheus, the Federal Circuit basically voiced a policy of treating method of treatment claims as presumptively patent eligible. Fundamentally, the claims held to be patent eligible in Classen are directed towards methods of treating individual patients, while Classen's patent ineligible claims are directed towards methods of analyzing data derived from a group of patients to evaluate and optimize an immunization schedule. Significantly, the immunization schedule being evaluated is a general immunization schedule applicable to a population of patients, such as children, and hence is not diagnostic in nature. I think that if patient data from a specific patient was used to design an optimized immunization schedule for the individual patient, which would I think constitute a form of personalized medicine, the outcome might very well have been different.

When Can a Treatment Step Be Ignored?

In Prometheus, the Federal Circuit stated emphatically that a method of treating a patient with a drug is always transformative, since it transforms the patient's body, and in many cases the drug itself is transformed during the process, and seems to stand for the proposition that any method claim including a step of treating a patient with a drug should be deemed patent eligible. In particular, many of the claims in Prometheus include a step of administering a drug to patient, and the court held that this treatment step was independently sufficient to render the claims patent eligible.

As discussed above, the claims held to be patent ineligible in Classen explicitly recite a step of "immunizing a mammal," which is clearly a form of treatment that results in transformation of the patient's body. Judge Moore in dissent pointed out that this raises an apparent inconsistency; why is the clearly transformative treatment step in these claims insufficient to confer patent eligibility, while in Prometheus it was sufficient (and it was also sufficient in the case of the other Classen claims held to be patent eligible).

The majority dismisses the distinction by reading the "immunizing a mammal" step out of the claims, interpreting "immunized" to mean "gathering data," a clear misinterpretation of the claims as described above. However, there are meaningful distinctions between the treatment step in the patent eligible claims as compared to the patent ineligible claims, which I think arguably justifies the disparate outcomes.

In the patent eligible Classen claims, the immunization step is performed on the individual patient who benefits from the claimed method. Remember, the patent eligible claims are directed to methods of treating patients, and the claims explicitly recite the treatment step, i.e., immunization of the patient. I think that in general, under Prometheus and Classen, a claim directed towards a method of treating a specific patient with a drug will be deemed patent eligible, even if the inventive aspect of the claim is the use of a newly discovered correlation (or other relative information) that informs treatment decision.

Prometheus is a little closer to the edge, because, in the context of the claims, the purpose of the treatment step is to generate data which can be used to infer an optimal dosing regimen for the drug. In particular, the patient is treated with the drug, then the patient is tested for the level of drug metabolites in the body, and the level of drug metabolites is used to determine whether the dosage of the drug should be modified, either up or down. Significantly, the Prometheus claims do not recite a step of treating the patient once the correlation has been used to determine optimal drug dosage, which distinguishes the Prometheus claims from the patent eligible Classen claims, which do explicitly recite immunizing patients according to an improved immunization schedule

Still, I think the critical distinction between the patent ineligible Classen claims and the Prometheus claims is that in Prometheus the individual patient who is the subject of the claim, and the beneficiary of the information, is the same patient that was initially treated with the drug. The Prometheus decision stresses the significance of the fact that the method of treatment is tightly bound up with the overall purpose of the claim, and treats the claim as essentially directed towards a method of optimizing the treatment of an individual patient.

In contrast, the treatment (i.e. immunization) step in the patent ineligible Classen claims is applied to populations of patients (control group and subject group), and then the outcomes of those multiple treatments are used to evaluate a generally applicable immunization schedule, for the benefit of other patients. In the context of these claims, the patient's that are being treated are not the subject or beneficiary the claims, and treatment of individual patients is not the object of the claim. The objective the claim is merely to evaluate a general immunization schedule, and the immunization step is used to generate the data for this evaluation, not to use the improved immunization schedule in the treatment of patient.

In short, in the claims deemed patent eligible the method of treatment step is an integral part of a method claim whose overall goal is to optimize the treatment of the individual receiving the treatment step. In the patent ineligible claims, the treatment step is solely for the purpose of generating data to be used for the more abstract purpose of evaluating a generally applicable immunization schedule. I think the distinction between claims aimed at treating individual patients versus claims directed towards methods of analyzing data for the purpose of identifying medically significant correlations is crucial, and perhaps explains the outcomes in these cases.

When Can a Data Acquisition Step Be Ignored?

In Prometheus, some of the claims did not include a treatment step (i.e., these claims did not explicitly recited administering a drug to a patient), but the Federal Circuit held that even the claims lacking a treatment step were patent eligible because they included a step of "determining" the amount of drug metabolite in the patient's body, and the court held that the determining step inherently involves a physical transformation, and thus constitutes an independent and sufficient basis for patent eligibility under Bilski. The court emphasized that determining drug metabolite levels in a patient's body inherently requires substantial transformative steps, such as physically removing and isolating a sample from the body, and using analytical devices and physically manipulative laboratory processes to make the determination.

Under this rationale, I think it is clear that a method of genetic diagnosis claim that actually requires the analysis of DNA molecules (as opposed to DNA sequence information) inherently involves physically transformative analytical techniques that would necessarily render the claim patent eligible. In AMP, the court explicitly found that the patent ineligible method claims did not require the analysis of DNA molecules, but could be infringed by the mere analysis of genetic information, which explains why the claims were found patent ineligible. If the claims had inherently included a step of physically analyzing DNA molecules (which Myriad argued unsuccessfully was the correct interpretation of the claims), I think the claims should have been, and would have been found patent eligible by the Federal Circuit.

In the Classen claims found to be patent ineligible, the data acquisition step in the claim can be satisfied by merely "comparing the incidence, prevalence, frequency or severity of [a] chronic immune-mediated disorder” in groups of patients that had already been immunized. This determination step does not inherently require the use of transformative analytical processes; one does not necessarily need to use transformative analytical techniques in order to determine whether a patient has developed a chronic immune-mediated disorder. This is I think what the Classen majority was getting at when it complained that the ‘283 patent "claims the idea of comparing known immunization results that are . . . found in the scientific literature. "While the Prometheus claims require the use of transformative analytical methodology to determine the level of drug metabolites, the comparison step in the Classen claim can be satisfied by simply reviewing the incidence of immune-mediated disorders in patients who have been immunized.

How Integral Is a Transformative Step to the Purpose of the Claim?

All of the claims found to be patent eligible in Prometheus and Classen include a transformative step that is central to the purpose of the claim. In Prometheus, all of the claims include a step of determining the level of drug metabolite in a patient's body. Not only is the step transformative, but the purpose behind the step is in furtherance of the claimed method. In other words, the reason a diagnostic test is being performed to determine drug metabolite level is for the purpose of applying the correlation embodied in the claim to determine the optimal drug dosage. Similarly, in the patent eligible Classen claims, the transformative treatment step (immunizing the patient) is integral to the purpose of the claim, which is to immunize the patient according to a safer immunization schedule.

In contrast, in the patent ineligible Classen claim, the "comparing" step is not necessarily transformative, and the "immunizing" step, while clearly transformative of the patient, is not integral to the purpose of the claim. In practice, the patients who are being immunized are doing so for the purpose of obtaining immunity to disease, not for the purpose of generating data for evaluating and immunization schedule. The immunization of these patients is an event that occurs independently of the purpose of the method claim, and would occur regardless of whether or not someone was going to come around later and determine the incidence of autoimmune-mediated disorders that arise in the patients. This is what the majority is getting at I think when it repeatedly asserts that the claims are infringed by someone merely reviewing published data.

As a practical matter, people are immunized for the purpose of obtaining immunity against some disease, and then some level of autoimmune-mediated disorder occurs. This all happens independently of Classen's claimed method. What Classen's claimed method does is analyze this data in order to evaluate the efficacy of immunization schedule used. I think this disconnect between the transformative step and the practical objective of the claimed method likely contributed to the finding of patent eligibility.

The Importance of Specificity

Another attribute of the ‘283 claim that might have contributed to the finding of patent eligibility is a relative lack of specificity. In a previous blog post, I pointed to specificity (or lack thereof) as the most plausible distinction between the claims found patent eligible in Prometheus, compared to the claims found to be patent ineligible in In re Grams (an older case cited with approval in Prometheus). In Prometheus, the Federal Circuit emphasized that the claims at issue recite methods in which correlations between drug metabolite level and optimal dosage are used in "the treatment of a specific disease by administering specific drugs and measuring specific metabolites." In contrast, in Grams the claim found to be patent ineligible was not limited to any particular clinical test, nor to any particular drug.

In Classen, the claims deemed patent eligible are directed towards methods of immunizing a particular "mammalian subject," and specifically recite a step of immunizing the patient. In contrast, the patent ineligible claims recite a "method of determining whether an immunization schedule affects the incidence or severity of a chronic immune-mediated disorder in a treatment group of mammals, relative to a control group of mammals." No particular patient is treated, and the data that is analyzed for determining the immunization schedule is collected from two distinct groups of patients, not an individual patient. Moreover, as complained of by Judge Moore, the claim is not limited to any specific immunogen or any specific immune-mediated disorder.

Patent Eligibility as a Wildcard

In my view, patent eligibility is essentially a doctrinal wildcard that a court can use to dispose of a patent claim deemed unworthy of patent protection; Judge Rader has made the same statement with respect to the Lilly written description requirement. Classen appears to be an example of a court using patent eligibility to dispose of some claims that many people would deem inappropriate, without having to resort to the more established and principled doctrines of patentability.

Because there is no coherent standard for what constitutes patent eligibility, a court faced with claims it doesn't like can pretty easily dispose of them by simply concluding that they are patent ineligible. This is particularly the case where, as was done here, the court misinterprets the claims and ignores explicit claim limitations. Unfortunately, in taking this route court denies the public a rational explanation as to exactly why the claims were deemed patent ineligible, which harms the predictability and coherency of the law.

Where Do We Stand Now?

Now that Classen, Prometheus, and AMP have all been decided by the Federal Circuit, where do we stand with respect to the patent eligibility of personalized medicine diagnostics? I think that with respect to a method claim that recites a physically transformative data acquisition step targeting a specific patient, such as measuring the level of drug metabolite in the patient's body, or analyzing the patient's DNA molecules (as opposed to mere DNA sequence information) for genetic variations, and the data acquired is used in the diagnosis or treatment of that patient, the claim will be deemed patent eligible.

Furthermore, if a method claim recites a physically transformative treatment step directed towards a specific patient, such as administering a specific drug to a patient, or immunizing a patient with a specific vaccine, and the specific patient being treated is the intended beneficiary of the claim process, the claim will likewise be patent eligible. For example, if a claim dictates that a patient be given a particular drug based on the outcome of a genetic test of that patient, the claim should be patent eligible.

However, if the claim lacks any physically transformative step, as was the case with respect to the method of diagnosis claims found to be patent ineligible in AMP, the claim will be found patent ineligible for claiming nothing more than mental processes. Even a claim with a physically transformative step might be found patent ineligible if the claim is not sufficiently specific, such as was the case in In re Grams. Or if the physically transformative step is not integral to the purpose of the claim, as was the case in the patent ineligible Classen claims, they also will be in danger of being ruled patent ineligible.

Overall, inventors of diagnostics and personalized medicine should still be able to claim their inventions, as long as they include an integral physically transformative step. It remains an open question, however, if inclusion of such a step will render the claims too easy to avoid, as Myriad argues in its recent amicus filings in the divided infringement cases to be heard shortly by the Federal Circuit, as discussed on a previous post to this blog.

AMP v. PTO Does Not Appear to Invalidate Very Many Gene Patent Method Claims

2011-08-15T09:27:00.000-05:00

In this post, I explain why my recent analysis of 533 patents identified by Jensen and Murray as "gene patents" (described in a previous post) suggests the Federal Circuit’s recent decision in AMP v. PTO implicates the validity of very few gene patent method claims.

Background

As I pointed out in a blog post last December, the patent eligibility of Myriad's claims to methods of detecting mutations in the BRCA gene by "analyzing" or "comparing" DNA sequences hinged entirely on the court's interpretation of the word "sequence" as it appears in the claims. In the field of molecular biology, the term "sequence" is routinely used not only to refer to the description of the chemical structure of a DNA molecule, but also to the actual DNA molecule as well.

For example, a scientist might say that "I determined the sequence of the BRCA gene." In this context, she is using the word sequence in reference to the abstract description of the order of nucleotides appearing in the gene. But the same scientist might also say that "I cloned the BRCA sequence into an expression vector," in which case she is using the term "sequence" to refer to the DNA molecule itself.

In the first example, "sequence" refers to abstract information describing a chemical structure, while in the second "sequence" is used to refer to a physical object, i.e., a specific DNA molecule. Molecular biologists are usually not bothered by the dual meaning of "sequence," because in practice the meaning of the term is understood based on the context in which it is used. However, it can lead to ambiguity, as seen in AMP v. PTO.

In AMP v. PTO, Myriad argued that as used in its claims the term "sequence" refers to an actual DNA molecule, and thus that analyzing or comparing "sequences of the BRCA gene" would involve physically manipulating and processing molecules in a manner that would render the claims patent eligible under Prometheus. I think it is clear that if the court had adopted this interpretation of "sequence" it would have upheld the validity of the claims. The ACLU plaintiffs never argued that a method claim that requires the analysis of physical DNA molecules would be patent ineligible.

Instead, as explained in a previous post, the ACLU's case was based on its argument that the term "sequence" in the claims refers to information, not to a physical molecule, and hence would cover the mental activity of analyzing or comparing genetic information. The court adopted the ACLU's interpretation of "sequence,” and ruled the claims patent ineligible for claiming nothing more than a mental step. This outcome was specifically dictated by the Federal Circuit’s earlier Prometheus decision, where it stated that a claim directed only to mental analysis of information is patent ineligible.

The Federal Circuit based its interpretation of “sequence” on its finding that Myriad's patent specifications implicitly defined “sequence” broadly to cover pure information, as set forth in this excerpt from the case:

The patent specifications make clear that “sequence” does not exclusively specify a DNA molecule, but refers more broadly to the linear sequence of nucleotide bases of a DNA molecule. For example, Figure 10A–10H is described as showing the “genomic sequence of BRCA1.” ′473 patent col.5 l.66. Figure 10 does not show a physical DNA molecule; the figure lists a series of letters (Gs, As, Ts, and Cs) corresponding to the nucleotides guanine, adenine, thymine, and cytosine of a DNA molecule. Similarly, the patent specifications state that “[t]he nucleotide sequence for BRCA1 exon 4 is shown in SEQ ID NO: 11.” Id. col.53 ll.50–53. SEQ ID NO: 11 again lists a series of Gs, As, Ts, and Cs corresponding to the nucleotide sequence of BRCA1 exon 4.

Thus, Myriad’s claims might very well have been found patent eligible if the specification had defined the term "sequence" to refer only the DNA molecule itself. Alternatively, the claim probably would have been found patent eligible if it recited analyzing "DNA molecules" instead of analyzing sequences. If the claims could only be infringed by someone who physically analyzes the DNA molecule, it would certainly be patent eligible under the Federal Circuit's interpretation of Bilski as set forth in Prometheus.

Claims that could be infringed by merely analyzing genetic data appear to be rare in Jensen and Murray dataset

In essence, Myriad’s method claims were patent ineligible because, as interpreted by the court, they could be infringed by analysis of genetic information. However, my research suggests that few if any of the gene patents identified by Jensen and Murray fall into this category. To the contrary, the vast majority of the claims in these patents would appear to be patent eligible.

Of the 533 patents I analyzed in my study, I only found 12 that included a claim reciting a method of analyzing a DNA sequence for a mutation or variation, and most if not all of those claims appear to require a physical manipulation of a patient's DNA in order for there to be infringement.

In 8 of the 12 patents (6,395,482; 6,087,107; 6,458,541; 6,743,579; 5,830,649; 5,840,486; 5,955,265; and 6,410,226) the broadest claims specifically require obtaining a sample from a patient's body, or analyzing for the genetic variation directly in a patient's body.

For example, Claim 1 of US patent number 6,395,482 recites:

1. A method for determining susceptibility in a human subject to schizophrenia wherein the method comprises the steps of:

(a) removing a bodily sample from the subject, wherein the sample comprises a polynucleotide sequence of a PRODH gene;

(b) determining whether the PRODH gene of the bodily sample comprises a DNA sequence comprising a variation in SEQ ID NO:1 consisting of a T to C transition in the first position of codon 497, such that the presence of said variation in said PRODH gene is indicative of said subject's susceptibility to schizophrenia.

These eight claims would all appear to be patent eligible under AMP and Prometheus because they all involve physically manipulating a human sample obtained from patient.

The remaining four of the 12 patents (5,916,748; 6,630,304; 5,989,815; 6,432,644) are a little more ambiguous, and do not explicitly recite obtaining or analyzing a bodily sample. But arguably all of these claims do require physical manipulation of a sample, depending upon how a court interprets the claim, which will depend in part on how the claim terms were used in the patent specification

For example, Claim 1 of 6,432,644 recites:

1. A method for diagnosing the presence of a polymorphism in human KCNE1 (the coding region of which is bases 193-579 of SEQ ID NO:3) which causes long QT syndrome wherein said method is performed by means which identify the presence of said polymorphism, wherein said polymorphism is one which results in the presence of a KCNE1 polypeptide of SEQ ID NO:4 with an altered amino acid, said altered amino acid being selected from the group consisting of: a) a Leu at residue 74.

Note that this claim uses "means plus function" language, and would probably be interpreted to only cover means for identifying polymorphisms (a polymorphism is a genetic variation) that are described in the specification. If the only means for identifying polymorphisms described in the specification rely on physically analyzing DNA molecules, the claim would appear to be so-limited and thus patent eligible.

Similarly, Claim 1 of 6,630,304 recites:

1. A method of diagnosing a susceptibility to osteoporosis in an individual, comprising detecting a polymorphism in a human BMP2 gene of SEQ ID NO: 1, wherein the presence of a "T" at nucleotide position 11980 is indicative of a susceptibility to osteoporosis, compared with an individual having an "A" at nucleotide position 11980.

This claim refers to detecting a genetic variation in a "gene," as opposed to a "sequence" (the language used by Myriad). If a court were to interpret the claim limitation "detecting a polymorphism in the gene" as requiring actual analysis of a DNA molecule (which could depend upon how the term "gene" is using the specification), the claim would appear to be patent eligible. However, if the claim is interpreted to encompass detecting a polymorphism by analyzing genetic sequence data, it would appear to be patent ineligible.

Will Gene Patents Impede Whole Genome Sequencing?: Deconstructing the Myth That 20% of the Human Genome Is Patented

2011-08-08T18:12:00.000-05:00

I am in the process of finalizing an article entitled “Will Gene Patents Impede Whole Genome Sequencing?: Deconstructing the Myth That 20% of the Human Genome Is Patented,” which I think many readers of this blog will find of interest, particularly in light of the recent decision in the Myriad a gene patent case (AMP v. PTO). I will be presenting my work this Thursday at the Intellectual Property Scholars Conference at Depaul Law school in Chicago, and have posted a working draft on SSRN.

In my article, I point out that there is a widely held perception that 20% of human genes are "patented," and that these patents preclude researchers and clinicians from using, studying or even "looking at" the patented genes without obtaining a license or risk being sued for patent infringement. In recent years the basis for this belief has increasingly become obscured.

For example, in AMP v. PTO Judge Lourie states that it “is estimated that . . . By 2005, [the PTO] had granted 40,000 DNA-related patents covering, in non-native form, twenty percent of the genes in the human genome.” In support of this assertion he cites to a law review article: J. Rogers, Can You Patent Genes? Yes and No, 93 J. Pat. & Trademark Off. Soc’y 19, 40 (2010). If you read the article by Rogers, you see that he cites to other secondary sources for the proposition that 20% of human genes are patented. Ultimately, if you trace the string of references back to their primary source, one arrives at the seminal article by Kyle Jensen & Fiona Murray: Intellectual Property Landscape of the Human Genome, 310 Science 239 (2005).

It is no surprise that Judge Lourie believes that 20% of human genes are “patented” - over the years the figure has been quoted so often in so many venues that it has become something of an urban legend. Oftentimes the statement that 20% of human genes are patented is made without any supporting reference (for example, this occurred in a recent article published in Science entitled: The Human Genome (Patent) Project). Other authors, such as Judge Lourie, cite to various secondary sources that parrot the conventional wisdom. But if you trace back through the citations, invariably you will find that the sole basis for the myth that 20% of human genes are patented is the 2005 Science article by Jensen and Murray.

Believing that 20% of human genes are patented, and that a patented gene is effectively off-limits, many have become concerned that whole genome sequencing will result in the infringement of hundreds or even thousands of patents. This specific point was made by Judge Bryson in his dissent to AMP v. PTO. During oral arguments, he asked Myriad's attorney whether Myriad's isolated DNA sequence claims would be infringed by personal whole genome sequencing, to which the attorney essentially responded "no" (the ACLU attorney later voiced his opinion that the patents would cover genome sequencing).

Later during oral arguments, Judge Bryson expressed his concern that whole genome sequencing could result in infringement of thousands of gene patents. His perception that isolated DNA claims create a thicket of patents that will impede personal whole genome sequencing might have contributed to his view that these claims should be declared patent ineligible.

In fact, a careful reading of the supporting online material for the Jensen and Murray article reveals that their study has been grossly misinterpreted by those who claim the 20% of human genes are patented. In fact, those authors only purported to show that, with respect to 20% of human genes known at the time they conducted their study, either (1) the DNA sequence of the gene, or (2) the amino acid sequence encoded by the gene, was mentioned in a US patent claim. The myth that 20% of human genes are “patented” has taken root because too many have incorrectly inferred that the mere “mention” of a gene in a patent claim precludes all uses of the gene.

To better understand the actual implications of Jensen and Murray’s findings, I analyzed the claims from a random sampling of 533 of the 4270 patents identified in their article as “gene patents.” (Jensen and Murray graciously provided me with the entire data set of patents identified in their study). Significantly, I found that, under any reasonable interpretation, 140 of the 533 patents would not be infringed by any form of genetic testing. In fact, many of these patents only claim proteins, or recombinant cells, or methods for using DNA that have nothing to do with DNA sequencing. The implicit assumption that the “gene patents” identified by Jensen and Murray cover all uses of the gene (or in some cases corresponding protein) mentioned in the patent claims is clearly false.

The remaining 393 patents include claims with respect to which I cannot entirely rule out the possibility that at least some form of genetic testing would be found infringing. These claims fall into two categories - products claims directed to polynucleotides (e.g., DNA molecules), and method claims that might cover at least some forms of genetic testing. The language used in these claims is extremely heterogeneous, and it is impossible to predict with any certainty exactly how broadly a court would interpret their scope if they were ever asserted in litigation, but to varying degrees a majority of these patents would appear not to be infringed by at least some, perhaps all, forms of genetic testing.

Perhaps most significantly, few (if any) of these patents would appear likely to be infringed by next-generation whole genome sequencing technologies, particularly those that do not require DNA amplification.

In short, there is absolutely no basis to infer from the Jensen & Murray article that 20% of human genes are off-limits to the patents, nor that whole genome sequencing, and other multiplex genetic diagnostic testing technologies, would result in the infringement of a large number of human gene patents. To the contrary, it appears that a vast majority of these patents were drafted in a manner that would not encompass whole genome sequencing.

AMP v. PTO Casts Doubt on Patent Eligibility of "Purified" (as Opposed to "Isolated") Biomolecules

2011-08-01T09:51:00.000-05:00

On January 5, 2001, the US PTO published Utility Examination Guidelines explaining its long-standing policy of treating "isolated and purified" DNA molecules as patent eligible. Throughout the Guidelines, the PTO consistently refers to these patent-eligible DNA molecules as both isolated and purified, but never explicitly attributes distinct meaning to the two terms. Instead, I think most people have interpreted the terms (as used by the PTO in this context) as essentially redundant, similar to someone referring to a contract provision as "null and void."

If anything, the PTO guidelines might be interpreted as treating "purification" as a more demanding requirement than "isolation." For example, at one point the guidelines state that "an inventor's discovery of a gene can be the basis for a patent on the genetic composition isolated from its natural state and processed through purifying steps that separate the gene from other molecules naturally associated with it,” perhaps implying that mere isolation will not be sufficient unless the DNA molecule is not subsequently purified through processes that separate the gene from other molecules.

In practice, it is my experience that the PTO and most practitioners have interpreted "purification" and "isolation" as essentially redundant. While most "gene patents" recite DNA molecules that are "isolated," "isolated and purified," or "recombinant," there are a substantial number of issued patents that simply recite "purified" DNA molecules. See for example US Patent Nos. 5,780,262, 6,262,247, 6,399,371, 6,448,042 and 6,555,347. The PTO also routinely issues patents on other purified biomolecules, particularly proteins, based no doubt on the assumption that as a general matter purification of a biomolecule from its native environment is sufficient to confer patent eligibility. See for example US Patent Nos. 6,258,556 and 6,284,236.

In the Federal Circuit's recent decision in AMP v. PTO (discussed briefly already on Patently-O and Patent Docs), the two judges in the majority (Lourie and Moore) held that "isolated" DNA molecules are patent eligible, but implied that mere "purification" of a biomolecule is insufficient to render it patent eligible. Writing for the majority, Judge Lourie correctly observes that patent eligibility under 35 USC 101 of purified biomolecules has never been explicitly addressed by the courts. As I pointed out in an earlier blog post:

The cases most commonly cited for the proposition that a purified naturally occurring compound is patent eligible are In re Kratz, 592 F.2d 1169, 1174 (CCPA 1979) (stating that a naturally occurring strawberry constituent compound does not anticipate claims to the substantially pure compound) and In re Bergstrom, 427 F.2d 1394 (CCPA 1970) (stating that a material occurring in nature in less pure form does not anticipate claims to the pure material). The Federal Circuit implicitly seems to support this view, and as recently as 2003 a Federal Circuit panel cited both Kratz and Bergstrom with apparent approval. But it is worth noting that Kratz and Bergstrom dealt specifically with the novelty and nonobviousness of the compounds, not patent eligibility per se. To my knowledge, there is no judicial precedent that has directly addressed the issue of whether isolation of a naturally occurring molecule renders the isolated molecule and eligible under section 101.

Judge Lourie also correctly noted that the Supreme Court's decision in Funk Bros., although often treated as patent eligibility case, was actually decided on the basis of obviousness, a point that Hal Wegner has long made in which I discussed in a previous blog post.

In what might be the most interesting part of the decision, Judge Lourie makes a clear distinction between purification and isolation of DNA. He explicitly states that "isolated DNA is not purified DNA." In his view, “[p]urification makes pure what was the same material, but was previously impure,” while “[i]solated DNA, in contrast, is a free-standing portion of a native DNA molecule, frequently a single gene. Isolated DNA has been cleaved (i.e., had covalent bonds in its backbone chemically severed) or synthesized to consist of just a fraction of a naturally occurring DNA molecule.”

Judge Lourie stresses that unlike a biomolecule that has been merely purified, isolated DNA "has also been manipulated chemically so as to produce a molecule that is markedly different from that which exists in the body." In his view, the test for patent eligibility hinges on whether the claimed molecule is "markedly different" from that which occurs in nature, and differences at the level of chemical structure between synthetic DNA, or genomic DNA that has been excised from the genome, are sufficient to satisfy the test. Implicitly, he seems to suggest that purified DNA molecules that are not structurally distinct from a naturally occurring counterpart would not be patent eligible. This seems to suggest that claims directed towards purified biomolecules, such as proteins, might not be patent eligible.

In its amicus brief, as I recall, the Biotechnology Industry Organization argued that the District Court's decision in AMP v. PTO should be reversed because it implied that a purified natural product, such as Taxol, would be patent ineligible under the logic of the decision. But in fact it seems that even though the Federal Circuit reversed on the patentability of isolated DNA, its decision suggests that a purified natural product is patent ineligible unless it has distinctions in chemical structure sufficient to render it "markedly different" from its naturally occurring counterpart.

Arguably, the Federal Circuit's decision in AMP v. PTO is not inconsistent with the PTO utility examination guidelines. For example, the guidelines provide two examples of patent eligible isolated DNA - DNA that has been chemically synthesized outside of the body, and DNA that has been excised from the chromosome. Judge Lourie explicitly identifies these two forms of DNA as "isolated" and hence patent eligible.

Judge Lourie and Judge Moore get mixed up at times on the nuances of molecular biology, and make some misstatements regarding the nature of genomic DNA and cDNA. However, while a molecular biologist will pick up on these inaccuracies, I don't think they detract from the core of the decision. In a previous blog post, I explained why the amicus brief filed by the DOJ attempting to distinguish between cDNA and genomic DNA missed the mark because it failed to recognize that, in the vast majority of cases, "isolated" DNA refers to DNA that has been synthesized outside of the native context from which it arose in the body. The DOJ brief (which Judge Moore described as being at times “childlike” in its simplicity) assumed wrongly that "isolated" genomic DNA has merely been plucked from the human cell (what Judge Lourie would characterize as purification), when in fact patents on isolated DNA are based on DNA molecules that have been synthesized in the laboratory, either by cloning into a host cell, or by PCR, or something along those lines. I think that at some level Judge Lourie’s decision gets at this distinction between a biomolecule that has merely been purified, and isolated DNA molecules, which are generally the result of human-directed synthesis.

ACLU Responds to Myriad’s Letter Challenging Standing of Dr. Osterer

2011-07-30T12:49:00.000-05:00

On Thursday I posted a letter from Myriad's attorneys to the Federal Circuit judges pointing out that the key plaintiff in the case (Dr. Osterer, the only plaintiff found to have standing in yesterday's decision from the Federal Circuit) has moved from NYU to Albert Einstein College of Medicine. Myriad asserts in the letter that Dr. Osterer will not be able to perform clinical genetic testing at Albert Einstein, and thus will not be because it into start conducting clinical BRCA testing if the Myriad gene patents are invalidated.

Yesterday, the ACLU responded with its own letter to the Federal Circuit, stating that Dr. Osterer will continue to offer clinical genetic testing at his new institution. It would seem to be an important point, since the District Court decision would have been vacated if the Federal Circuit had held that all of the plaintiffs lacked standing to bring suit. The only plaintiff that the Federal Circuit found to have standing was Dr. Osterer, and this was based explicitly on the court's understanding that he intended to begin conducting clinical BRCA testing if the patents could be invalidated. One wonders if this information could have altered the outcome if it had come to light sooner.

Myraid Alerts Federal Circuit Judges that Key Plaintiff in AMP v. PTO Apparently Cannot Perform Clinical BRCA Testing

2011-07-28T13:20:00.000-05:00

During oral arguments in AMP v. PTO (the ACLU/PubPat attack on Myriad Genetic’s BRCA gene patents, previously discussed here), the panel of Federal Circuit judges hearing the case evinced some skepticism as to whether any of the named plaintiffs have standing to bring the lawsuit. For example, many of the plaintiffs are patients who would not appear to be in any real threat of being sued by Myriad for patent infringement.

The plaintiffs most likely to have standing are probably the clinicians who the ACLU argues would engage in BRCA testing were it not for the Myriad patents. However, the declarations by these plaintiffs do not unambiguously state that the plaintiff would begin doing BRCA testing if the patents are invalidated. Instead, they merely declare that the plaintiff has the "capability and desire" to perform the tests, and that the plaintiff "has all the personnel, expertise, and facilities necessary to do various types of sequencing." These declarations were drafted by lawyers, and I think the language used is meaningful, reflecting the fact that these clinicians have not committed to performing BRCA testing if the patents are invalidated.

During oral arguments the Federal Circuit judges pushed the ACLU attorney to clarify whether this language indicated a commitment to perform the tests, implying that a mere "capability and desire" to perform the test might not be sufficient to generate the degree of controversy necessary for standing. In my opinion, the ACLU attorney never provided a clear answer to the question, which suggests that in fact these clinicians have not committed to performing the tests.

Yesterday, Myriad's attorneys sent a letter to the Federal Circuit judges informing them that one of the key clinician plaintiffs who submitted this sort of declaration, Dr. Harry Osterer, has left his position at the NYU Langone Medical Center, and apparently is no longer in a position to offer clinical BRCA genetic testing. Attached to the letter is a printout from the Albert Einstein College of Medicine, identifying Dr. Osterer as a new professor at Albert Einstein. In the letter, Myriad's attorneys state that Albert Einstein does not offer, and is not qualified offer, clinical genetic testing. If this is correct, this seems to further undercut any pretense that he is committed to offering clinical BRCA testing if the patents are invalidated. A copy of the letter is attached here.

Myriad Genetics Files Amicus Briefs in Joint Infringement Cases Akamai and McKesson

2011-07-24T16:14:00.000-05:00

Personalized medicine company Myriad Genetics has filed amicus briefs in Akamai and McKesson, two cases currently pending before the en banc Federal Circuit that address the doctrine of joint infringement (aka divided infringement). These cases have been the subject of much discussion elsewhere, see for example the Patently-O and Patent Docs blogs. In a nutshell, the Federal Circuit seeks to delineate the circumstances under which a party will be held liable for patent infringement when multiple parties perform all steps of the patented method in concert, but no single party performs all of the steps.

In its amicus briefs, which are largely redundant, Myriad points out that while the recent joint infringement cases coming out of the Federal Circuit have tended to involve claims directed towards business methods and software, the decisions have created case law with substantial negative implications for patents on diagnostics and personalized medicine. Molecular diagnostics generally involve the discovery of a correlation between a molecular marker (e.g., a genetic variation, or the level of a metabolite) and a clinically relevant indication (e.g., whether an individual has a predisposition to a disease such as cancer, or would be likely to benefit from a particular drug or course of therapeutic treatment). Patent protection for these discoveries is generally achieved by means of a method claim reciting two steps-(1) detecting the molecular marker in a patient, and (2) recognizing the correlation. As noted in the Myriad briefs, product claims on the molecular markers themselves (e.g., isolated DNA molecules or proteins), and methods of testing for them, are generally precluded in the post-Human Genome Project era by prior art (not to mention efforts by the ACLU and others to render such products unpatentable).

The problem from the perspective of a molecular diagnostic innovator company such as Myriad is that the Federal Circuit's recent joint infringement decisions would seem to dictate that such a method claim would not be infringed under circumstances where one party (e.g., a diagnostic testing laboratory) performs the first step and an independent second party (e.g., a doctor) performs the second. Under recent Federal Circuit case law, assuming that the parties are not in an agency relationship, it seems likely that in most instances no party would be found infringing, and the patent owner would be left without a remedy, even in the face of substantial infringement in competition with its business.

In its briefs, Myriad notes that the Federal Circuit has repeatedly admonished patent owners that problems of divided infringement could have been avoided if the claims have been better drafted, i.e., in a manner such that a single party performs all of the steps of a method claim. However, Myriad argues (correctly I think) that the patent eligibility doctrine effectively forecloses this course of action. The Federal Circuit's recent decision in Prometheus (discussed previously on this blogs), in particular, interprets Bilski as rendering patent ineligible a claim reciting nothing more than the mere recognition of a correlation per se (which the court equates with patenting a mental step). In order to be patent eligible, Prometheus seems to require a diagnostic method claim to explicitly recite a transformative step, such as detecting the marker, or treating a patient. This creates a Catch-22 for the diagnostic inventor. The discovery of the correlation is the core of the invention, providing substantial therapeutic benefits to patients, but under Prometheus and Bilksi a claim to the correlation must also include an additional step which will often render the claim highly susceptible to circumvention by two parties separately performing the steps.

To avoid this problem, Myriad proposes the following as an appropriate test for infringement of method claims by multiple parties:

When a first party performing one or more steps of a method claim actively causes another party to perform the other steps of the same method claim, or when two parties act in a concerted manner to perform all steps of a method claim, then the first party and the parties acting in concert should each be deemed a direct infringer.

District Court Rules That Genencor Products Infringe Novozymes Patent

2011-07-14T11:02:00.000-05:00

On July 7, a federal district court in the Western District of Wisconsin ruled on a motion for summary judgment that a number of Genencor's thermostable alpha-amylase products (sold under trade names such as Spezyme) infringe Novozyme’s US patent number 7,713,723. I have discussed earlier decisions in this case on this blog, including decisions by the District Court denying a motion to invalidate the claims for failure to satisfy the written description requirement (available here) and denying a motion for preliminary injunction (available here).

Claim 1 is representative of the claims found to be infringed:

1. An isolated variant of a parent alpha-amylase, wherein:
(a) the variant has at least 90% sequence identity to SEQ ID NO: 6,
(b) the variant comprises a substitution of serine at position 239 relative to the parent alpha-amylase, using the amino acid sequence of SEQ ID NO: 8 for determining position numbering, and
(c) the variant has increased thermostability relative to the parent
alpha-amylase, wherein thermostability is determined at pH 4.5, 90° C. and
5 ppm calcium and has alpha-amylase activity.

Prior to deciding the issue of infringement, the court had to construe several terms appearing in the claims.

For example, the court had to define what "thermostability" means in the context of the claims. The defendant Genencor argued that the term is so indefinite that the claims should be invalidated, but the judge disagreed and held that the term was not so ambiguous as to render the claims invalid. The court spent a lot of time discussing the ambiguity of the term, noting that it could be the case that a protein variant would have more activity than wild type at some time points after exposing the proteins to elevated temperature, but less activity at other time points, and it was not entirely clear from the patent whether this would constitute increased thermostability. However, the court held that even under a relatively narrow interpretation of the term, pursuant to which the protein variant would have to be more active at all time points under elevated temperature, the Genencor products still infringed because the retained higher activity than wild type at all times after exposing the proteins to high temperature.

Another claim term, which the court spent a lot of time was "isolated." Novozymes argued that "isolated" was not a limitation on the claim scope because it is part of the claims’ preamble. The district court spent some time considering this argument, but ultimately sided with Genencor and held that "isolated" does limit the scope of the claim. In part, it reached this decision because "isolated" did not appear in the claim originally but was introduced during prosecution of the patent application, which the court found implied that the term "isolated" was significant.

The parties disputed the meaning of the term “isolated,” with Novozymes arguing for a broad interpretation that would cover protein existing at a higher concentration in a cell or cell extract than it would naturally, while Genencor argued for a narrower interpretation in which the protein must to some extent be separated from other cellular components. The court adopted the narrower interpretation, but nonetheless found that most Genencor products infringed because they included isolated protein. However, the court did find that some Genencor products are not infringing in which the thermostable alpha-amylase is not separated from other cellular components, which the court referred to as "whole broth" products, because the protein is not isolated.

The proper interpretation of "isolated" in claims such as this has important implications for biotechnology patenting outside the confines of this particular case. For example, the patent office will not issue patents claiming naturally occurring gene sequences unless the claims specifically recite that the DNA molecule is isolated, purified, and/or recombinant, in order to exclude genes as they occur naturally (for example in the human genome). The assumption is that inclusion of the term "isolated" in the claim limits the scope of the claim. I don't think it is even accurate to consider the use of the term "isolated" in claims of this format as preamble, but in any event it should generally be treated as limiting the scope of the claim.

Furthermore, the scope of the term isolated is important in the context of gene patent. As I have discussed elsewhere, the question of whether genetic diagnostic testing or whole genome sequencing infringes gene patents could in many cases dependent on how broadly a court interprets the term isolated in these claims (I have always assumed that "isolated" is a meaningful limitation on claim scope in this context).

In this case, the prosecution history was apparently silent as to why Novozymes amended the claim to include the "isolated" language. It would not seem to be necessarily required in this case if the claim only covers non-naturally occurring variants, because then there would be no danger of the claim reading on a naturally occurring biomolecule. But perhaps Novozymes intended for the claim to cover naturally occurring thermostable variants, in which case limiting the claim to isolated variants would be necessary in order for the claim to be valid.

In any event, the fact that "isolated" was introduced by amendment was significant, because it led the court to rule that under Festo the term could not be expanded beyond its literal scope under the doctrine of equivalents.

Thanks to Docket Navigator for bringing this decision to my attention.

PTO Agrees to Reexamine Broad Codon-Optimization Patents

2011-07-11T12:51:00.000-05:00

Many important applications of biotechnology involve the expression of recombinant genes in heterologous systems. Since the genetic code is degenerate (ie each amino acid can be coded by on average three different codons), the DNA sequence can be modified by synonymous nucleotide substitutions without altering the amino acid sequence of the encoded protein. A biotechnologist might find it useful to make a synonymous substitution for any of a variety of reasons, e.g., to introduce or remove restriction sites, or to remove repeats.

Today genes are also often altered for the specific purpose of optimizing expression, i.e., the entire coding region of the gene is recoded to fit one of a variety of codon optimization schemes. Examples of popular codon optimization schemes used in designing a gene for recombinant expression include:

A) Replace a degenerate codon with the most common codon present in the host chromosome; the rationale being that the most common codon correspond to the most common tRNA results in most protein yield.

B) Reengineer the gene so that it uses the same frequency of codons that are present in the host chromosome; the rationale being that the recombinant gene should have the same codon bias as the host chromosome to fit the translational machinery.

C) Re-code the pattern of rare and common codons found in the wild type by replacing it with the corresponding rare/common codons in the heterologous host; the rationale being that protein folding and expression requires rare (slow) and common (fast) codons distributed according to the folding domains in the protein.

D) Empirically identify codons and other variables that correlate with high protein expression in a systematically varied recombinant gene.

Codon optimization has become standard practice in the recombinant expression of heterologous proteins such as biologic drugs. Gene synthesis companies such as DNA2.0 and Blue Heron assist their customers by providing codon optimization as a part of their services.

Two U.S. patents (both assigned to the Massachusetts General Hospital) include claims directed towards codon optimization, both the method and the resulting codon-optimized gene (US Patent Numbers 5,786,464 and 6,114,148). These patents are very broad, purporting to cover any "synthetic gene encoding a protein normally expressed in an eukaryotic cell wherein at least one non-preferred or less preferred codon . . . has been replaced by a preferred codon encoding the same amino acid, [and wherein the replacement results in at least 10% increase in the level of protein expressed] in an in vitro mammalian cell culture system under identical conditions”

These patents appear to not only cover any successfully codon-optimized recombinant gene, but also many genes that have been reengineered for purposes other than codon optimization. For example, a silent mutation introduced for the purpose of removing a restriction site could easily constitute infringement if it results in the introduction of any of the 17 codons identified in the patent as “preferred,” if it turns out that the substitution results in a modest 10% increase in expression in any in vitro mammalian cell culture system. Rarely would an experimenter test for such an increase in expression at that level of accuracy, and a practical matter it would be virtually impossible to rule out the possibility of a 10% increase in expression in some mammalian cell culture system.

In view of their scope, and the pervasive use of codon replacement in the expression of high-value heterologous proteins (such as biologic drugs), these patents could potentially have sweeping implications for biotechnology. However, although the patents issued in 1998 and 2000, they have never been asserted in court and until recently appear to have received little attention.

However, the patents have recently become a thorny issue for those involved in the business of expressing heterologous proteins, particularly gene synthesis companies providing codon optimized genes for their customers. Last year Geneart (a German gene synthesis company owned by Life Technologies) began sending letters to companies engaged in the expression of heterologous proteins announcing that "we are very pleased to inform you that Geneart has acquired a license under [the Massachusetts General Hospital (MGH) Patents].” The letter goes on to state that under the license “Geneart is in the excellent position to offer a broad range of sublicensing opportunities." The licensing “opportunities” include a royalty-free sublicense to use synthetic genes purchased from Geneart in internal R&D, and a royalty-bearing commercial sublicense for synthetic genes used for purposes other than internal research and development. According to the letter, Geneart has executed a non-prosecution agreement with respect to synthetic genes delivered by Geneart to customers prior to May 30, 2010, so these customers are apparently free to use the genes in any manner without liability for infringement.

The letter goes on to imply that customers who choose to purchase synthetic genes from competing gene synthesis companies could be sued for infringing the MGH Patents, stating that "to Geneart’s knowledge, no other Gene Synthesis Service Provider has obtained a respective license under the MGH Patents."

This poses a problem for any biotechnologist wishing to use a synthetic or partially modified gene. Even slight variations to the wild-type sequence, such as restriction site removal or addition, could infringe.
It certainly poses a problem to other synthetic gene companies, whose customers might switch to Geneart in order to avoid a perceived threat of patent infringement liability for using synthetic genes not purchased from Geneart.

DNA2.0, a leading provider of synthetic genes headquartered in Menlo Park California, has responded to this perceived threat by successfully petitioning for reexamination of both patents, arguing that the broad claims are anticipated and/or rendered obvious by prior art not previously considered by the PTO. The orders granting the ex parte reexamination of the ‘148 and ‘464 patents were issued on December 14, 2010 and January 26, 2011, respectively.

The orders granting reexamination state that a number of references cited by DNA2.0 in the request for reexamination raise substantial new questions of patentability with respect to most of the claims in the patents, particularly the broadest claims. For example, an article published in the Journal of Virology in 1992 by Schwartz et al. describes the characterization of inhibitory RNA elements in the gag region of human immunodeficiency virus type I (HIV-1). This involved replacing many of the codons in the wild type gene with synonymous codons defined as "preferred" in the MGH Patents, resulting in at least a five-fold increase in expression. As another example, the PTO found an article disclosing a computer program for optimizing DNA sequences for protein expression, in combination with another article disclosing the most frequent human codon usage together with preferred codon choice patterns, also raise substantial new questions of patentability for many of the claims.

It is interesting to note that the corresponding codon optimization patent issued to MGH in Europe (EP 0 781 329 B2) is much narrower in scope, claiming a method for preparing a synthetic gene wherein at least 50% of the non-preferred codons and less preferred codons are replaced by preferred codons and resulting in a 10% increase in expression. In contrast, the US patents purport to claim any method that involves replacing even one codon with a preferred codon, and any gene made by such a process.

It is my understanding that, as a practical matter, the European patent only poses a substantial impediment to the “A” form of codon optimization described above, i.e., replacement of all degenerate codons with the most common codon present in the host chromosome. Most other codon optimizations do not require the substitution of 50% of non- or less preferred codons. In contrast, the U.S. patents would appear to cover the majority of recombinant protein expression that has been done in recent years. The patents should expire 2015, but the pending reexamination could be important if it results in cancellation or narrowing of the claims in the US patents, thereby providing assurance that companies will not be sued for expressing recombinant proteins prior to patent expiration.

Organic Seed Growers and Trade Association Et al. v. Monsanto: The Public Patent Foundation Takes on Agricultural Biotechnology

2011-06-01T09:38:00.000-05:00

The Public Patent Foundation (PubPat), housed at the Cardozo School of Law in New York, is probably best known to readers of this blog for its role in the challenge to Myriad gene patents in AMP v. PTO (PubPat is co-counsel, along with the ACLU). PubPat has brought a number of other "public interest" actions against other patents, including reexamination of some of the key University of Wisconsin embryonic stem cell patents.

On March 29 PubPat took on agricultural biotechnology, filing a declaratory judgment action in the Southern District of New York against Monsanto, on behalf of a large contingent of plaintiffs, including agricultural member organizations, farms and farmers, and seed companies. The plaintiffs are primarily, but not entirely, organic, and all have purportedly have disavowed the use of genetically modified seed.

The primary contention of the plaintiffs is that they "are increasingly being threatened by transgenic seed contamination despite using their best efforts to avoid it." The allege that Monsanto "has aggressively asserted [its patents] against literally hundreds of farmers, including those farmers who became contaminated by Monsanto's transgenic seed through no fault of their own." They have asked the court to declare a long list of Monsanto patents invalid, unenforceable, and not infringed, and that Monsanto would not be entitled to any remedies against the plaintiffs even if found to infringe a valid and enforceable patent.

Interestingly, I was talking with someone who works for Monsanto recently and he mentioned that to his knowledge the complaint had never been served upon Monsanto. I checked PACER on June 1, and the docket indicates that PubPat has yet to file notice that the complaint was served on Monsanto, even though the complaint was filed more than two months ago (March 29). For comparison, in the Myriad case notice of service on the plaintiffs was filed within one month after the complaint was filed.

Do the Plaintiffs Have Standing?

Perhaps the biggest stumbling block for PubPat will be establishing that any of the plaintiffs have standing to bring suit (a big issue in the Myriad lawsuit). The standing of the plaintiffs seems even more problematic in this case, since the plaintiffs all avow that they are doing everything they can to avoid infringing Monsanto's patent, and there appears to be no evidence that Monsanto has ever filed suit against an involuntary/inadvertent infringer. The complaint filed by PubPat makes this allegation, but does not document a single example of a case where a party was sued for infringement that was involuntary. The closest it comes is a reference to a 2008 segment of the CBS Evening News, which the complaint alleges described an incident in which farmers (Mr. and Mrs. Runyon), "who never intended to use transgenic seeds," were threatened with a patent infringement suit (but apparently never sued).

The complaint also alleges that Monsanto has litigated patent infringement claims against other farmers who did not want to be contaminated by transgenic seeds, including notably Percy Schmeiser. Schmeiser has become something of a folk hero, a Canadian farmer who was sued by Monsanto for patent infringement in a case that was eventually decided by the Canadian Supreme Court. Critics of Monsanto in the popular media routinely point to Schmeiser as an example of a honest Canadian farmer sued by corporate villain Monsanto for patent infringement that was completely involuntary and inadvertent, while failing to note that the Canadian courts found unambiguously that Schmeiser’s infringement was in fact voluntary, and that he went out of his way to collect and plant transgenic seed incorporating the patented Monsanto trait. Here are some excerpts from the Canadian Supreme Court decision [Monsanto Canada Inc. v. Schmeiser, 2004 SCC 34, [2004] 1 S.C.R. 902]:

The remaining question was how such a pure concentration of Roundup Ready Canola came to grow on the appellants’ land in 1998. The trial judge rejected the suggestion that it was the product of seed blown or inadvertently carried onto the appellants’ land . . .

Invoking the concepts of implied licence and waiver, the appellants argue that this Court should grant an exemption from infringement to “innocent bystanders”. The simple answer to this contention is that on the facts found by the trial judge, Mr. Schmeiser was not an innocent bystander; rather, he actively cultivated Roundup Ready Canola.

Given the issues of standing, one has to wonder why PubPat has chosen the declaratory judgment route to challenge Monsanto's patents. After all, PubPat asserts that Monsanto has aggressively asserted its patents against "literally hundreds of farmers," including farmers whose only offense was to have their crops contaminated by Monsanto's seed. In the Myriad case, the ACLU and PubPat were forced to assemble a group of plaintiffs and file a declaratory judgment action, because for years Myriad has disappointed its critics by never suing anyone for infringing its gene patents. But that is not the case with Monsanto, which I believe has filed patent infringement suits against farms numbering in the hundreds.

Why isn't PubPat defending one of these farmers that has already been sued? This would give PubPat the opportunity to challenge the Monsanto's patents, without any issue of standing. Perhaps they find it is preferable to conduct "public interest litigation" on behalf of recruited plaintiffs rather than actual defendants potentially liable for damages.

In fact, at least one farmer is currently before the Federal Circuit arguing one of the legal theories raised in the PubPat complaint, i.e., that "Monsanto's patent rights in transgenic seed exhaust upon the authorized distribution by Monsanto to its customers." In 2009, a district court in the Southern District of Indiana rejected this very argument in Monsanto v. Bowman, citing earlier Federal Circuit decisions in Monsanto v. Scruggs and Monsanto v. McFarling. Mr. Bowman argued unsuccessfully that he should not be held liable for infringement based on the use of "commodity" soybean seed he had purchased and that inadvertently included seed containing the patented Roundup Ready trait. The district court decision indicates that Mr. Bowman argued the case as a pro se defendant, but the appeal briefs being filed with the Federal Circuit this year indicate that he is currently being represented by Frommer Lawrence & Haug LLP.

Below, I briefly address some of the arguments raised in the PubPat complaint, including moral utility, exhaustion and inadvertent infringement.

Moral Utility

Historically, US law had a doctrine of moral utility, under which a patent could be found invalid if the claimed invention lacks sufficient social or moral use. The doctrine traces its origin to a statement by Justice Story in the 1817 Lowell v. Lewis decision to the effect that inventions that are "injurious to the well-being, good policy, or sound morals of society" are unpatentable. Examples provided by Justice Story included "a new invention to poison people, or to promote debauchery, or to facilitate private assassination."

Although technically still on the books, the doctrine of moral utility has generally been considered moribund in the US since the 1999 Federal Circuit decision in Juicy Whip v. Orange Bang, which essentially held that patent law is not the appropriate legal vehicle for addressing questions of morality. I think this is the proper approach. For example, I would rather not have the patent office deciding whether or not a gambling invention is patentable based on the morality or social utility of gambling. A patent does not confer any positive right to practice in invention, only the right to exclude others from practicing it, so the patent would in no way shields the patent owner from anti-gambling laws, which is the more appropriate way to address morality or social concerns associated with gambling.

European patent law, on the other hand, explicitly provides that inventions that are "immoral and against the public order" are patent ineligible. The European High Court is currently considering a case challenging the patent eligibility of embryonic stem cells based on allegations that the use of viable human embryos in the industrial process of producing cultured embryonic stem cells is immoral. The Court's advocate general has in fact put forth such a position, as discussed recently on the Patent Docs blog.

I cannot imagine PubPat prevailing on this theory. The doctrine of moral utility has generally been considered pretty much irrelevant after Juicy Whip, but even if the doctrine still has some teeth, there is a wealth of data supporting the benefits of transgenic crops, which explains why they have been so widely adopted in the US, and increasingly throughout the world. The PubPat complaint goes to great lengths reciting a host of alleged evils of agricultural biotechnology, and asserts that transgenic crops have failed to provide any benefits, citing authorities such as England's Prince Charles, but I think this flies in the face of a wealth of evidence going the other direction.

Patent Exhaustion

As mentioned above, PubPat alleges that Monsanto's patent rights in transgenic seeds are exhausted by their first authorized sale, presumably relying on the Supreme Court's 2009 Quanta decision. This was one of the main concerns that I raised regarding Quanta, i.e., the potential for the decision to preclude the ability of biotechnology companies to adequately enforce patents covering products capable of self-replication.

Prior to the Supreme Court deciding Quanta, the Federal Circuit held in Monsanto v. Scruggs (2006) that patent exhaustion did not shield from infringement liability a farmer who saved and replanted patented seeds without Monsanto's authorization because (1) the initial sale from Monsanto was not an “unrestricted sale” and (2) the second generation of seeds were never “sold.” Scruggs filed a petition for certiorari with the Supreme Court, which was denied. The case was remanded to the district court, where Scruggs moved for reconsideration in light of the Supreme Court's decision in Quanta. The district court denied the motion, but certified the issue for interlocutory appeal to the Federal Circuit, to resolve the question of whether the Federal Circuit's decision regarding patent exhaustion in Monsanto v. Scruggs was still good law in view of Quanta. But in 2009 the Federal Circuit exercised its discretion and declined to decide the interlocutory appeal, advising Scruggs to appeal the issue after the district court issues a final decision or injunction.

Thus, the question of whether the Federal Circuit decision in Monsanto v. Scruggs regarding patent exhaustion of transgenic seeds survives Quanta has yet to be resolved. The Federal Circuit could address the issue in Monsanto v. Bowman, or perhaps in the PubPat lawsuit if it goes forward.

Inadvertent Infringement

At a doctrinal level, for me perhaps the most interesting argument raised by PubPat is that the plaintiffs are not liable for infringement because any infringement would be involuntary and inadvertent, the result of contamination by transgenic seed used by other farmers. To my knowledge, this issue has never been directly addressed by the courts, and as a practical matter I doubt that Monsanto has sued farmers for legitimate good-faith but inadvertent infringement. As noted above, the PubPat complaint does not appear to identify any specific occurrence of this, and the widely propagated story that Schmeiser was a good-faith inadvertent infringer is contrary to the findings of the Canadian courts.

But how would a court deal with involuntary and inadvertent infringement if the issue ever did arise? It is well-established that, as a general matter, patent infringement is a matter of strict liability, i.e., intent is not an element of patent infringement. However, I am convinced that a court faced with a true case of inadvertent infringement would find some doctrinal loophole to shield the alleged infringer from liability. However, there is to my knowledge no specific doctrinal defense addressing the issue.

For example, in Monsanto v. Schmeiser, the Canadian Supreme Court indicated that if Schmeiser’s infringement had been inadvertent he would not have been liable for infringement, because under such circumstances his mere possession of patented seeds would not lead to a presumption that he had "used" the seeds in an infringing manner.

In the US, the issue of inadvertent infringement was addressed in the fascinating case of SmithKline Beecham v. Apotex, 403 F.3d 1331 (2005), which involved allegations that a generic drug manufacturer would not be able to produce a non-infringing generic drug without inadvertently producing an infringing polymorph of the drug, thus involuntarily infringing the patent. At the district court level, the decision was written by Judge Posner, a famous judge on the Seventh Circuit Court of Appeals, sitting by designation for this case as a district court judge. Judge Posner noted the policy concern attendant to holding an inadvertent infringer liable for patent infringement, and spent a great deal of time grappling with the question of how existing patent doctrine could be interpreted in a manner to arrive at the outcome, i.e. no liability for inadvertent infringement.

Here is an excerpt from Judge Posner's opinion in SmithKline Beecham v. Apotex, 247 F.Supp.2d 1011 (2003):

The reason for excusing the alleged infringement in this case is not that Apotex stole only a little hemihydrate from SmithKline. It stole nothing from SmithKline. It doesn't want hemihydrate, and it derives no value from the hemihydrate that it unavoidably creates and “sells.” If it made hemihydrate deliberately, or if it took advantage of 100 percent conversion to obtain a product that had hemihydrate's superior handling characteristics, that would be theft and it would be nonsense to point out that paroxetine is only 10 percent of the pill by weight. But if the person sitting next to me at dinner spills his soup on my sleeve, I am not a thief even though I cannot remove the stain.

On appeal, the Federal Circuit rendered the question of inadvertent infringement moot by invalidating the SmithKline patent for inherent anticipation. However, in a concurring opinion Judge Gajarsa addressed the issue of inadvertent infringement, in a manner that would probably resonate with PubPat and other opponents of patents on transgenic seeds. Judge Gajarsa essentially advocated a position that the issue of inadvertent infringement could be dealt with in situations such as this by recognizing that any product capable of being "spread and reproduced by natural processes" is patent ineligible under 35 USC 101. I think this assertion is incorrect, and would be inconsistent with the Supreme Court's decision in Diamond v. Chakrabarty, which explicitly found genetically modified living organisms to be patent eligible.

Nevertheless, here are some excerpts from Judge Gajarsa’s concurrence:

The asserted breadth of Claim 1 makes sense only under the erroneous belief that patents may protect products spread and reproduced by natural processes, directly contradicting our well established understanding of the limits imposed by section 101. Given current scientific trends, such a belief could easily lead to misdirected research investments, to inappropriately issued patents, and to a widespread in terrorem effect crippling entire industries whose artisans learn that even their best efforts to respect patent rights may not save them from liability as inadvertent, inevitable infringers. As the district court recognized, the notice function of patents is meaningless in such an environment, SK II, 247 F.Supp.2d at 1028. The lack of suitable notice could easily chill innovation, inquiry, experimentation, and commercial development. The patent law does not sanction the concept of inevitable infringement.
. . .

Consider, for example, what might happen if the wind blew fertile, genetically modified blue corn protected by a patent, from the field of a single farmer into neighboring cornfields. The harvest from those fields would soon contain at least some patented blue corn mixed in with the traditional public domain yellow corn-thereby infringing the patent. The wind would continue to blow, and the patented crops would spread throughout the continent, thereby turning most (if not all) North American corn farmers into unintentional, yet inevitable, infringers.FN7 The implication-that the patent owner would be entitled to collect royalties from every farmer whose cornfields contained even a few patented blue stalks-cannot possibly be correct. The underlying question that engaged the district court, and that led it to develop numerous alternative holdings, is why this implication is incorrect.

FN7. Although intent is not a factor in determining infringement, public notice is required as a predicate to the validity of a patent. Jurgens v. CBK, Ltd., 80 F.3d 1566, 1570 n. 2 (Fed.Cir.1996). The hypothetical causes unavoidable infringement even in situations where the public would, in good faith, want to avoid infringing.

At oral argument, when faced with this hypothetical, SKB expressed its belief that such a blue-corn patent would be “very strong.” Such a belief is misplaced. The implicit concept of “inevitable infringement” stems from the inevitable failure of the patent to provide public notice-which, in turn, stems from the inherently unpatentable nature of the claimed subject matter.

This section 101 problem therefore brings us full circle, back to the impossibility of public notice. Under normal circumstances, inventors other than the patentee will understand how to avoid infringing a patent by avoiding the claimed product. Because products, such as our hypothetical blue corn or SKB's paroxetine hemihydrate, that can be “made” through a natural process of spontaneous conversion imply inevitable infringement, no combination of claim language and written description could possibly teach even one skilled in the art how to avoid infringement. It is unsurprising that a requirement considered so trivial for most patentable products that we are content to let it remain implicit, namely a lesson in infringement avoidance, is effectively impossible for subject matter unpatentable under section 101. In short, patent claims drawn broadly enough to encompass products that spread, appear, and “reproduce” through natural processes cover subject matter unpatentable under section 101-and are therefore invalid.

It will be interesting to see how the PubPat challenge to Monsanto, and the patenting of Arab cultural biotechnology in general, plays out.

Therasense v. Becton Dickinson: Rethinking the Status of Patents as Technical Documents

2011-05-28T11:05:00.000-05:00

Earlier this week the Federal Circuit issued its en banc decision in Therasense v. Becton Dickinson, which essentially made it more difficult to establish inequitable conduct. The decision has been reported and analyzed widely over the Internet, for example on the Patently-O and Patent Docs blogs. This post discusses one aspect of the case I find interesting, which is the problems that can occur when the PTO and courts unjustifiably assume that "legalese" statements appearing in patents constitute technical disclosures. To illustrate, let me begin by summarizing how Therasense (now Abbott Diabetes Care, and referred to in the decision and in this post simply as Abbott) got into trouble in the first place.

Abbott owns US patent number 4,545,382 (the ‘382 patent), which issued in 1985 and is directed towards a sensor comprising an electrode with enzyme bound to its external surface. In the specification, the ‘382 patent includes the following sentence (referred to herein as the "Sentence") which was the root cause of Abbott's alleged inequitable conduct: "Optionally, but preferably when being used on live blood, a protective membrane surrounds both the enzyme and the mediator layers, permeable to water and glucose molecules."

The Sentence refers to a protective membrane, employed to protect the electrode from being "fouled" by components of whole blood, such as red blood cells. As discussed later, it is Abbott's contention that at that time, as a practical matter, one of skill in the art would have considered it necessary to employ such a protective membrane when using the electrode in a whole blood. Nevertheless, as is typical practice in the drafting of patents, whoever drafted the patent (presumably a patent attorney or agent) identified the protective membrane as "optional but preferable" rather than mandatory. This is quite reasonable, in view of all the cases in which patentees have found their rights limited by unnecessarily limiting language appearing in the patent specification. The patent attorney prudently sought to avoid an unnecessarily restrictive interpretation of the scope of the claimed invention, in case it turned out to be possible to practice the invention without a protective membrane. When understood in this context, note that the "optional but preferable" language should not be interpreted as a technical disclosure that use of the electrode in live blood without a protective membrane would have been enabled at the time.

Abbott also prosecuted a counterpart to the ‘382 patent in Europe, containing the same "optionally, but preferably" language. The European Patent Office (EPO) cited as prior art against the application a German reference which required the use of a diffusion-limiting membrane. It is important to recognize that a diffusion-limiting membrane serves a very different purpose than a protective membrane. A diffusion-limiting membrane is used to slow the flow of glucose to the electrode, which was necessary for earlier electrodes that could not deal with a rapid influx of glucose, not to protect the electrode fouling.

In order to distinguish over the German reference, Abbott argued that the membrane mentioned in its patent application is a protective membrane, not a diffusion-limiting membrane. Abbott pointed out that the Sentence specifically notes that the protective membrane must be permeable to glucose molecules, and hence not diffusion-limiting as the membrane in the German reference. The arguments submitted by Abbott to the EPO characterized the protective membrane in their application as optional, parroting the language of the Sentence, but this was really tangential to the argument they were making, which was based on the distinction between protective and diffusion-limiting membranes. Unfortunately for Abbott, the briefs submitted to the EPO in 1994 and 1995 included representations that would come back to haunt them in the US, such as "[i]t is submitted that this disclosure [i.e., the Sentence] is unequivocally clear. The protective membrane is optional . . ..”

A few years later, in 1997, Abbott was prosecuting a different patent application in the US patent office that included claims directed to a sensor that did not require a protective membrane when used in whole blood. The ‘382 patent was cited by the PTO as prior art. To overcome the rejection, Abbott argued that one of skill in the art at the relevant time would have felt that the sensor disclosed in the ‘382 patent required the use of a membrane, notwithstanding the "optionally, but preferably" language appearing in the ‘382 patent specification.

In response to an examiner’s request for evidentiary support, Abbott submitted a declaration by Abbott's Director of Research and Development (Dr. Sanghera) stating that "one skilled in the art would not read [the Sentence] to teach that the use of a protective membrane with a whole blood sample is optionally or merely preferred." In submitting the affidavit, Abbott's patent attorney (Lawrence Pope) represented that "one skilled in the art would not . . . have read the "optionally, but preferably" language . . . as a technical teaching but rather mere patent phraseology." [Emphasis added]

In other words, Abbott argued that the "optionally, but preferably" language did not represent a technical disclosure of the state-of-the-art, but rather was an example of patent legalese inserted by the patent after to avoid unnecessarily limiting the scope of the patented invention. Note that there's nothing wrong with this, it is quite proper under some circumstances for an inventor to obtain patent claims that cover embodiments of her invention that employ after-arising technologies that were not part of the prior art at the time the patent application was filed.

In the declaration and accompanying argument apparently worked, and the application issued as US patent number 5,820,551, (the ‘551 patent), the patent that was ultimately held to be unenforceable for inequitable conduct by the district court based on Abbott's failure to disclose to the PTO the briefs filed to the EPO. The district court was evidently bothered by the appearance that in one forum, to suit its purposes, Abbott asserted that the term “optionally” is mere "patent phraseology" which in fact means "necessarily," while in a different forum it appeared to have argued that the same language is "unequivocally clear," i.e., "optionally" actually means "optionally."

In my view, the representations made to the US and European patent offices are not necessarily inconsistent. The problem is, the district court assumed that the "optional but preferable" language appearing in the patent is a technical disclosure, which it interpreted as a disclosure that one of skill in the art would have been able to use the electrode without a protective membrane. In fact, the language is better understood as patent legalese, or in the words of Abbott's attorney "patent phraseology," not intended as a technical disclosure but as language introduced into the specification to avoid unnecessarily limiting the scope of the patented invention.

The declaration and arguments made to the US PTO essentially made this point, and argued that one of skill in the art would have recognized this as patent legalese rather than a technical disclosure of the state-of-the-art. Before the EPO, Abbott does not appear to have argued that the state-of-the-art would have allowed the use of the electrode without a protective membrane, which is tangential to the argument it did make, which was based on the distinction between protective and diffusion-limiting membranes. Abbott's briefs to the EPO merely parroted the “optionally” language of the specification to make it clear that as a legal matter, Abbott did not intend to disclaim patent protection for electrodes used without a protective membrane, on the eventuality that this might become feasible someday.

In this case, Abbott was faced with a rejection based on patent legalese appearing in one of its own patents. But this sort of thing happens all the time, and often the patent cited as prior art is owned by a third party. In prosecuting patent applications, I have on numerous occasions been frustrated by the patent legalese appearing in patents asserted by examiners as prior art. These patents often include disclosure that is clearly wrong as a technical matter, and evidently was introduced into the patent specification by the patent drafter, but it can be difficult convincing a patent examiner that the disclosure appearing in a patent is inaccurate or not enabled. This is essentially the situation in which Abbott found itself, which required it to submit a declaration to the effect that a facially clear statement that use of a protective membrane is "optional” is inaccurate as a technical matter, and should be dismissed as mere patent phraseology.

Formally, the law treats a patent as a technical document. By statute, the patent specification is supposed to be directed towards a technical audience, i.e., the ubiquitous "person having ordinary skill in the art.” Federal Circuit case law attributes a higher degree of credibility to technical disclosure appearing in US patents than it does to other technical documents, such as peer reviewed journal articles. The Federal Circuit has held that the disclosure appearing in patents is presumptively enabled, apparently based on the rationale that the patent office has examined the patent for compliance with the enablement requirement. Other technical documents, such as articles appearing in technical journals, do not receive the same presumption of enablement.

I am quite skeptical with regard to this presumption favoring the credibility of patents over other technical documents. For one thing, patent examiners are charged with examining the enablement of patent claims, not the specification as a whole, which is a very different thing. The fact that a patent issues in no way implies that a patent examiner has reviewed all of the disclosure in a patent and found it to be technically accurate. As exemplified by the Abbott patent, much of the language appearing in patents is "patent phraseology," introduced by the patent practitioner drafting the patent to achieve certain legal objectives, such as broad scope of protection, or the ability to amend the claims a later date, rather than to provide the most accurate technical disclosure. Some patent attorneys might even disclose hypothetical embodiments simply to create prior art, essentially poisoning the well to prevent others from patenting around their invention. It is quite easy for a patent attorney to come up with hypothetical embodiments and describe them in the specification, and usually little downside to the practice (although it did come back to haunt Abbott in this case). It seems to me that the disclosure appearing in a peer-reviewed journal is much more likely to accurately describe the state-of-the-art than a patent, and that the Federal Circuit's presumption in favor of patents has gotten things backwards.

In fact, I would assert that patent law should recognize the reality that much of the disclosure appearing in patents is not technical in nature, but rather patent legalese introduced into the application by patent practitioners for purposes other than accurately describing the state of technology. In my experience, most scientists and other technical people are well aware of this, and recognize that much of what appears in patents is patent phraseology rather than an accurate and objective disclosure of technology. Patent law would do well if it would acknowledge that patents are often drafted for the primary purpose of furthering the legal and business objectives of the patent owner, not as true technical documents.

Billups-Rothenberg v. ARUP: Genetic Testing Patents Found to Be Anticipated and in Violation of Lilly Written Description Requirement

2011-05-04T12:30:00.000-05:00

Robert Cook-Deegan and I filed an amicus brief in AMP v. US PTO (the Myriad gene patent case) essentially arguing that with respect to gene patents we should not throw out the baby with the bathwater. Some gene patents do appear overly broad and/or overly reaching, particularly in the context of genetic diagnostic testing, but these problematic patents are best addressed by means other than declaring all gene patents patent ineligible, which could have a substantial detrimental effect on biotechnology. For example, we pointed out that other doctrines of patentability, particularly the disclosure requirements of section 112 (written description and enablement) and the requirements of novelty and nonobviousness should be sufficient to address many if not all of the concerns associated with some gene patents. In Billups-Rothenberg v. ARUP, the Federal Circuit has just provided an illustration of what we were talking about, invalidating all of the gene patent claims that have been asserted against companies providing genetic diagnostic testing for mutations in the HFE gene, which are associated with hereditary hemochromatosis.

Gene patents have become quite controversial, based largely on a perception that they impose undue restrictions on the development and availability of genetic diagnostic testing. I have argued that the concerns have been overblown, in part because they assume that gene patent claims are extremely broad in scope (and thus difficult if not impossible to design around), when in fact if interpreted as broadly the claims would be highly susceptible to invalidation under a variety of patentability doctrines. Unfortunately, human gene patents have rarely been litigated in the context of genetic testing, there has been little case law to point to directly on point, and critics of gene patents have assumed the worst.

In fact, in a comprehensive survey of human gene patent litigation in the United States that I conducted in 2007, I found only a handful of lawsuits that had been filed asserting infringement of a human gene patent by a provider of genetic diagnostic testing services, and no substantive judicial decisions arising out of any of these lawsuits, owing to the fact that they all settled shortly after the lawsuit was filed. The Billups-Rothenberg lawsuit was filed shortly after I conducted my survey, and to my knowledge represents the only case in which the courts have actually reached a decision concerning an allegation that a human gene patent was infringed by genetic testing (in the Myriad case, Myriad has not alleged that any of the plaintiffs are infringing its patents)- it is certainly the first time the Federal Circuit has addressed the issue. Consistent with the point we were attempting to make in our amicus brief, the Federal Circuit invalidated the asserted human gene patents for violation of the written description requirement and for lack of novelty. This is a precedential opinion, and I think quite informative as to how the courts will address human gene patents that appear to claim more than was justified by the nature of the inventor's discovery.

Written Description
The asserted claims of US patent 5,674,681 were all held to be invalid for violation of the written description requirement. Claim 2 is representative:
2. A method to identify an individual having or predisposed to having hemochromatosis, comprising the steps of:
providing from the individual a sample containing a gene encoding a nonclassical MHC class I heavy chain and

detecting a mutation in said gene, which mutation results in the reduced ability of said heavy chain to associate with said β2 microglobulin, wherein the presence of said mutation identifies said individual as having or predisposed to having hemochromatosis.

As a sidenote, note that this claim explicitly requires providing a patient sample, and thus would only be infringed by an entity that obtained a physical DNA sample from a patient and analyzed it to detect a mutation in the gene. This sort of limitation appears in most gene patent claims, and is increasingly significant as we move toward whole genome sequencing, since it implies that these sorts of claims will not be infringed in situations where one entity sequences a patient's genome and another entity (for example a doctor) analyzes the genetic data disease-related mutations. On the other hand, the Federal Circuit's recent decision in Prometheus makes clear that a patent claim that could be infringed by merely analyzing genetic data, without physically manipulating DNA molecules, would be invalid based on patent ineligibility. This is part of the reason I believe that gene patents will become less of an issue as personal whole genome sequencing becomes established, and the analysis of DNA molecules becomes decoupled from the analysis of genetic information.

Like most written description decisions coming out of the Federal Circuit, the court is not entirely clear as to exactly why the claims failed the written description requirement, but I see two distinct bases before the court's decision. First, the court found that the specification does not demonstrate possession of the claimed subject matter, and that the inventors had "attempted to preempt the future before has arrived." In other words, the court invoked Lilly written description as a doctrinal "wildcard" (using the language of Judge Rader) to invalidate an "unworthy" patent claim, along the lines seen in cases such as Ariad and Rochester.

The court also based its decision on the failure of the patent to disclose the DNA sequence of the gene recited in the claims, citing Regents of UC v. Lilly and Fiers v. Revel. The patent discloses the general location of the gene in the human genome, but not its exact location, nor its DNA sequence, nor the sequence of any mutations.

The court made the important observation that "this case is like Regents and Fiers, in which the DNA sequences at issue were unknown in the art.” Prior to the Federal Circuit's 2008 decision in Carnegie Mellon v. Hoffman-La Roche, it was my opinion that the only way to reconcile Federal Circuit decisions which invalidated patent claims under Lilly written description for failure to provide DNA sequence information from decisions that upheld the validity of claims failing to provide DNA sequence information was the distinction between previously known and unknown DNA sequences. If the heart of the claimed invention involved identification of a novel DNA sequence (Fiers, Regents of UC, In re Wallach, In re Kubin (a rare precedential BPAI decision), a strict interpretation of Lilly written description has been applied requiring adequate disclosure of DNA sequence. On the other hand, in cases where the heart of the invention involves a novel recombination or modification of a previously known DNA sequence, the court has not required to disclosure of DNA sequence (Amgen v. HMR, Capon v. Eshhar, Invitrogen v. Clontech, and Falko_Gunter Falkner v. Inglis).

In Carnegie Mellon v. Hoffman-La Roche, Roche made the entirely legitimate argument that Lilly written description only requires disclosure of DNA sequence in cases where the invention involves the discovery of a new gene sequence. Since the heart of the claimed invention in that case involved a novel recombination of genetic elements, not the discovery of a new genetic sequence, Roche argued (correctly in my view) that a disclosure of DNA sequence was not necessary to satisfy Lilly written description. But the Federal Circuit rejected Roche's argument, and specifically held that the requirement for compliance with Lilly written description is the same regardless of whether or not an invention is based upon discovery of the new genetic sequence. I thought this was a poor decision, because without that distinction I don't know how you make sense of the disparate outcomes in the previous Federal Circuit written description decisions.

In Centocor, decided earlier this year, the Federal Circuit explicitly held that the requirement for compliance with Lilly written description does depend upon whether or not invention involves a newly discovered molecule. I would say this was the only way it could reconcile its decision to invalidate Centocor's antibody claim for failure to provide adequate disclosure of structure, while running into direct conflict with Noelle v. Lederman, which held that a broad claim directed to antibodies can comply with Lilly written description in the absence of any structural description. Of course, this seems irreconcilable with the court’s statement in Carnegie Mellon that it is irrelevant whether or not the invention involves discovery of a new molecule.

The decision in Billups-Rothenberg adopts the Centocor approach, by emphasizing the distinction between claims directed towards DNA sequences known in the art versus other claims directed towards DNA. I think this distinction is critical in any attempt to reconcile Federal Circuit decisions involving Lilly written description, with the caveat that the Carnegie Mellon University decision is an outlier.

The Billups-Rothenberg decision is I think also illustrates how courts can use the written description requirement to invalidate gene patent claims that seem to be overreaching. For example, even if the patent had disclosed the gene sequence, I can imagine a court invalidating a claim broadly directed towards methods of identifying mutations in the gene for failure to satisfy Lilly written description, because the specification fails to evidence "possession" of all the mutations that might be linked to disease, and because the specification fails to identify the sequence of specific mutations linked to disease.

Novelty
The other patent asserted in the case, US patent number 6,355,425, was found to be invalid based on anticipation by one of the defendant’s patents, 6,025,130. The ‘425 patent claim the method for diagnosing hereditary hemochromatosis by determining the presence of a mutation in exon two of the HFE gene. The patent apparently covers diagnostic testing for the S65C mutation, which has been correlated with the hemochromatosis. The defendants test for this mutation.

The prior art ‘130 patent discloses the S65C mutation, but also states that presence of the mutation in patients "shows no increase in risk of acquiring [hereditary hemochromatosis] and thus may only be a polymorphic variant within the population." In other words, while the prior art patent apparently discloses testing for the S65C mutation, it also explicitly acknowledges that the inventors had not identified any basis to infer that identification of the mutation would be useful for diagnosing risk of hemochromatosis, and thus failed to disclose any practical utility for testing for the mutation.

Billups-Rothenberg argued that prior art disclosing only “a clinically insignificant polymorphism unrelated to disease” did not constitute an anticipatory reference to a claim directed towards a method of testing for the mutation in order to diagnose for disease risk. However, the court rejected this argument, and basically held that the mere disclosure of the mutation and a method of testing for it was sufficient, regardless of whether the reference disclosed a practical utility in testing for the mutation. The court also stressed that disclosure appearing in an issued patent is presumed to be enabled.

This aspect of the decision reminds me of In re Gleave, discussed in an earlier post. The approach adopted by the Federal Circuit in these decisions could have significant implications for the patentability of newly discovered genetic mutations. For example, suppose a researcher identifies a mutation in a known gene of clinical significance, such as correlation with disease. I can imagine a court extending the logic of Billups-Rothenberg and Gleave to conclude that a prior art patent disclosing the gene sequence, and perhaps stating that one could test the gene sequence for mutations, is anticipatory prior art, even though the patent does not disclose the mutations later discovered to be correlated with disease.

A Historical Perspective on the Gene Patent Controversy

2011-04-12T15:35:00.000-05:00

"A page of history is worth a volume of logic”
- New York Trust Co. v. Eisner, 256 US 345, 349 (1921) (Holmes, J.).

Critics postulate that gene patents threaten to impede next-generation genetic testing technologies, such as whole genome sequencing and multiplex genetic testing. We see this concern reflected, for example, in the recent arguments before the Federal Circuit in the Myriad case (Association for Molecular Pathology v. US PTO) where the parties speculated as to whether the challenged patent claims would cover whole genome sequencing. It also seems likely that US governments amicus brief arguing that genomic DNA is patent ineligible was motivated, at least in part, by a desire to clear patents perceived to be an impediment to whole genome sequencing. In considering how to respond to these concerns, we might do well to take the advice of Justice Holmes, and look for guidance to a page of history.

This is not the first time that there has been a call for a prohibition against patenting certain subject matter, based on allegations that patents pose a threat to biomedical research and the public health. In the past, these crusades have often been led by prominent members of the scientific and medical community, who raised alarming concerns that in retrospect seem greatly exaggerated, if not wholly unwarranted.

For example, more than 30 years ago numerous concerned parties filed amicus briefs in Diamond v. Chakrabarty warning that a prohibition against the patenting of genetically modified organisms was necessary to prevent a "gruesome parade of horrible." These briefs quoted a number of scientists, including Nobel laureates, for the proposition that patents on living organisms might pose a serious threat to the human race by encouraging genetic research. In retrospect, the Supreme Court's decision not to follow their advice, and to allow the patenting of genetically modified organisms, is seen as an important milestone that facilitated the growth of biotechnology, thereby facilitating numerous benefits to mankind.

In 1995, a debate raged over the patenting of medical procedures, and the arguments that were raised at that time show striking parallels to today's controversy over gene patents. At that time, the patent office had a long-standing practice of issuing medical procedure patents, but they do not appear to have been the source of any controversy. In fact, the practice had been officially sanctioned by the Board of Patent Appeals and Interferences in 1954, in ex parte Scherer. Apparently, however, most of the public, particularly doctors, were unaware of the practice.

That all changed after a lawsuit was filed in 1993 by a surgeon against a group of doctors alleging infringement of a patent claiming a method of performing cataract surgery. Pallin v. Singer, 36 USPQ2d 1050 (D. Vt. 1995). As described in a leading patent law casebook by Professors Merges and Duffy, "[t]he litigation caused a shudder in the medical community, if only because it called attention to the PTO's practice of allowing surgical patents."

After news of the lawsuit became known, major mainstream media outlets such as the Wall Street Journal, New York Times and Los Angeles Times all published high-profile stories calling attention to the lawsuit. It also became the subject of law review articles decrying the negative effect of these patents on the practice of medicine. The American Medical Association and many physicians raised arguments against medical procedure patents that are highly reminiscent of the claims being made about gene patents today. For example, some doctors argued that medical procedure patents are unethical, and that patents are not needed as financial incentives for doctors to develop better methods for improving patient outcomes. They also argued that patents delay information sharing, and increase the costs patients pay for healthcare. The American Medical Association and many physicians argued patents for medical methods should be prohibited, insisting "that it is impossible to "own" a method of treating patients were performing surgery." Concern was expressed that the medical procedure patents could impede research, forcing researchers to license the patent if they wanted to use the patented technique.

Today, no one is wringing their hands over medical procedure patents. The lawsuit which precipitated the outcry ended in 1996 when the parties stipulated to the patent invalidity due to prior art uses of the claimed technique. Congress intervened in 1996 by enacting 35 USC 287(c), which essentially eliminates the availability of remedies for infringement by medical practitioners. Importantly, Congress did not go along with the suggestion of the American Medical Association and ban the patenting of medical procedures, which can still be patented, and these patents play an important role in incentivizing the development of important innovations such as medical devices.

The limitation on remedies did resolve the concerns that doctors could be sued for performing medical procedures. There appears to be no reported decision in which 35 USC 287(c) has been asserted, and in reality there probably was little threat that the practice of medicine would be harmed by these patents - the lawsuit that triggered all this was probably just an aberration, much like the Myriad suit. Nonetheless, this simple statutory fix addressed the concerns, and since then medical procedure patents have generated little controversy.

In fact, concerns about the gene patent thicket have been with us for more than a decade. Initially, much of the concern was that gene patents would prove an insurmountable obstacle to commercialization of DNA microarrays, based on a perception that since the arrays often comprise DNA sequences representing hundreds or even thousands of unique genes, it would be too difficult to obtain the necessary licenses on the gene patents. In fact, this perceived fear has never come to pass. DNA microarray technology has been the subject of numerous patent infringement lawsuits, but never involving a human gene patent. In a recent book chapter, I discuss possible explanations as to why the postulated gene patent thicket has not presented itself, particularly in the context of microarrays and basic biomedical research. The same rationale would also largely apply to the fears that gene patents will impede the commercialization of whole genome sequencing.

The lesson from all this is that we should be very careful about imposing restrictions on patentability based on perceived fears, when history tells us that in many cases these fears turn out to be vastly overstated. To the extent there are real concerns, there are more targeted solutions than a broad-based attack on patent eligibility, such as the statutory solution to the perceived problem of medical procedure patents.

Upcoming Telebriefing on Centocor and Current Status of Lilly Written Description Requirement

2011-03-28T15:04:00.001-05:00

On March 31, at 12:00PM Pacific Time, I will be speaking during a Law Seminars International TeleBriefing titled "Centocor Ortho Biotech, Inc. v. Abbott Laboratories, discussing the impact of the U.S. Court of Appeals recent ruling.

The panel consists of:

Donald L. Zuhn, Ph.D, Esq., McDonnell Boehnen Hulbert & Berghoff LLP, Chicago, IL

Courteney C. Brinckerhoff, Esq., Foley & Lardner LLP, Washington, DC

Chris Homan, Ph.D., Esq., University of Missouri--Kansas City School of Law, Kansas City, MO

The cost is $125 per caller and $50 each for additional people on the same line who wish to receive continuing education credit. However, Law Seminars International will offer a discounted registration rate of $100 ($25 off of the regular price) to readers of this blog. To take advantage of this discount, please contact LSI by phone at 206-567-4490 to register and request the Holman's Biotech IP Blog rate. Please note that this discount is available by phone registration only and not via web registration.

Click here to view the online brochure:

http://www.lawseminars.com/detail.php?SeminarCode=11CENTB

Centocor v. Abbott: The Federal Circuit Struggles to Articulate a Coherent Standard for Compliance with the Lilly Written Description Requirement

2011-03-15T14:30:00.000-05:00

I have repeatedly pointed out (on my blog, in a law review article, and in an amicus brief filed in Ariad v. Eli Lilly), that the Lilly Written Description Requirement (LWD) lacks any coherent doctrinal foundation, which has led the courts and PTO to flounder in their attempts to apply the doctrine in a principled and consistent manner. The Federal Circuit's recent decision in Centocor v. Abbott underscores and exemplifies some of the points I've been trying to make.

For example, prior to Centocor the Federal Circuit and PTO had adopted a standard for compliance with LWD for antibodies entirely inconsistent with the standard applied to other biomolecules, including DNA and even other proteins. Strangely, the courts and PTO have refused to acknowledge that antibodies are simply a category of protein, and have never provided any sort of convincing rationale for treating antibodies so differently than other proteins.

Basically, for DNA and other proteins the PTO and courts have held that compliance with LWD requires some adequate level of disclosure of chemical structure, i.e., DNA or amino acid sequence. Although the requirement of structure has not been enforced as stringently as many commentators feared after UC v. Eli Lilly came down in 1997, inadequate disclosure of structure has resulted in claim invalidation in multiple Federal Circuit decisions, such as In re Wallach and Carnegie Mellon University v. Hoffman-La Roche.

However, the PTO has taken the position that a broad genus claim reciting an "isolated antibody capable of binding to [a protein identified as] antigen X” satisfies LWD, even in a case where the specification indicates that not one single antibodies falling within the scope of the claim has never been made, and provides no description of the structural, physical or chemical properties of any antibody falling within the scope of the claim. (See example 13 of the 2008 revised written description training materials; essentially the same example appears in the original 1999 interim guidelines). In other words, an antibody can be purportedly claimed in solely functional terms, without any disclosure of structure for the antibody variable region (the part that binds the antigen), nor even any structural description of the antigen. In Noelle v. Lederman, the Federal Circuit endorsed this approach, characterizing the antibody example in the PTO training materials as "precedent."

In my Ariad v. Eli Lilly amicus brief, I explained why the PTO's attempt to rationalize this dissonant treatment of antibodies under LWD was absolute nonsense as a matter of science.

In Centocor, the Federal Circuit held that a claim reciting a genus of antibodies that bind to a specific epitope of human TNF-alpha was invalid under LWD for failure to disclose sufficient structure. Significantly, the antigen was disclosed, so LWD seemed to be satisfied under the incongruosly permissive approach set forth in Example 13 of the PTO training materials, and endorsed by the Federal Circuit in Noelle. However, the Federal Circuit distinguished the Centocor claim, stating that "while our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly characterized antigens were creation of the claimed antibody is routine." (Emphasis added). The court went on to find that since TNF-alpha was previously characterized, and the production of the claimed antibody "comprising a human constant region" was not routine, the claim failed to satisfy LWD.

I don't necessarily disagree with the court's decision to invalidate the claim, but I do disagree with the court's decision to invalidate the claim under the murky LWD doctrine. This is not an original claim, nothing like it appeared in the priority patent application, and I think traditional written description requirement could have been used to invalidate the claim. The claim also could have been invalidated for lack of enablement, based on the Court's finding that the methodology for producing the claimed antibody was not routine.

Centocor continues the trend of Federal Circuit decisions applying LWD in inconsistent and incoherent manner, lacking any grounding in science, as set forth in greater detail in my Ariad amicus brief. For example, the Centocor panel places great emphasis on the fact that TNF-alpha was not a newly characterized antigen, clearly implying that the requirement for compliance with LWD depends substantially upon whether an invention relates to a newly characterized or previously known biomolecule. But in previous decisions, the Federal Circuit has come to the opposite conclusion, rejecting the argument that the standard for compliance with LWD varies depending upon whether or not the claim involves a newly discovered biomolecule.

For example, in the 2008 Carnegie Mellon University v. Hoffman LaRoche decision, the appellant had argued that LWD’s requirement of structural disclosure only applied to novel DNA sequences, but the Federal Circuit rejected this argument, stating that “nothing in Eli Lilly indicates that that holding was limited to inventions involving novel DNA sequences. Indeed, in University of Rochester, we rejected a similar argument.” (emphasis added)

Another point I have often raised is that the Federal Circuit has failed to articulate any principled distinction between the standard for determining compliance with LWD and the enablement requirement, and this trend continues in Centocor. Recall that the Centocor panel's decision to invalidate the claim under LWD was based on the fact that the antigen had previously been characterized, and the finding that the creation of the claimed antibodies was not "routine." There is nothing in the decision to indicate any distinction between "routine" and "enabled."

For example, the Centocor panel points out that "Centocor simply failed to support its contention that generating fully-human antibodies with the claim properties would be straightforward for a person of ordinary skill in the art given the state of human antibody technology in 1994." (emphasis added). It also found that producing the claimed antibodies "was not possible in 1994
using 'conventional,’ 'routine,' 'well developed and mature' technology."

This is essentially the enablement standard, simply substituting words such as "straightforward," for "without undue experimentation," but failing to articulate any distinction between the level of disclosure necessary to satisfy LWD and enablement.

Neither does the Centocor panel articulate any policy rationale for LWD distinct from that behind the enablement requirement. The panel states that, under LWD, "the scope of Centocor's right to exclude cannot 'overreach the scope of [its] contribution to the field of art as described in the patent specification.’" But this simply paraphrases In re Fisher, a 1970 CCPA decision that held (with respect to the enablement requirement) that the scope of the claim must bear a “reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art.”

I think it would be better for patent law if the court were to use the enablement requirement to address the patentability of claims such as this, instead of continuing to try to muddle through with the highly flawed LWD.

Market exclusivity, data exclusivity and S. 3921

2011-02-16T10:03:00.000-06:00

There has been some confusion lately regarding the distinction between “data exclusivity" and "market exclusivity.” For most newly approved drugs, US law only provides "data exclusivity," five years for small molecule drugs and 12 years under the newly enacted biosimilar legislation. During the period of data exclusivity, generic competitors are prevented from relying on data generated and paid for by the innovator to secure FDA approval for a generic or biosimilar version of the innovator drug. This is not the same as market exclusivity, because a generic company is free to generate all of its data from scratch to obtain marketing approval for their generic version of the drug, although in practice is rarely if ever happens. True market exclusivity would completely preclude generic competition, while data exclusivity simply provides a period of time during which generic competitors are not permitted to rely on innovator's data to obtain marketing approval.

In contrast, the Orphan Drug Act provides a period of true market exclusivity for certain orphan drugs, which precludes FDA from approving a competing version of the same or highly similar drug product to treat the same orphan disease for a period of seven years. The key difference between marketing exclusivity and data exclusivity is that a competitor cannot circumvent marketing exclusivity by generating its own data and submitting a new application for FDA approval, it is an absolute bar to FDA approval of the same drug for the same indication.

Recently, members of Congress sent a letter to the FDA seeking to clarify this point. In the letter, signed by four Senators including Orrin Hatch and John Kerry, the Senators point out that in a recent notice published by FDA seeking comments on the newly enacted biosimilar legislation, FDA incorrectly states that the biosimilar legislation provides a 12 year period of “marketing exclusivity.” The letter quite correctly point out that the biosimilar legislation in fact that does not include any marketing exclusivity period, but rather a 12 year period of data exclusivity.

Perhaps FDA should be excused for the lapse. Reporters and commentators routinely refer to the data exclusivity provided for biologics as "market exclusivity." To see what I mean, just do a Google search for “Obama budget biologic marketing exclusivity,” and you will pull up numerous reports from leading news agencies and bloggers reporting that the Obama budget proposes reducing the market exclusivity period for biologics from 12 years to seven years. In fact, there is no market exclusivity period for biologics, only data exclusivity, they should all read the letter from the Senators and stop propagating the misperception that the biosimilar legislation provides a period of market exclusivity.

I suspect part of the reason people have taken to characterizing data exclusivity as market exclusivity is because it suits the purposes of those who would like to speed to market entry by generic competitors by lowering the barrier to entry of generic competition. When you characterize it as market exclusivity, it sounds like market competition has been completely blocked for 12 years, which is very different from a 12 year period in which competitors cannot free ride on data paid for by the innovator.

For example, in a report on biosimilar legislation prepared by the FTC in 2009, a report of which I've been highly critical, the FTC repeatedly refers to the data exclusivity provisions of biosimilar legislation as marketing exclusivity. FTC's mischaracterization of data exclusivity as marketing exclusivity might have been an attempt to strengthen its argument by implying that no biosimilar product could enter the market during the 12 year data exclusivity period, when in fact this is not the case. But this mischaracterization has spread, apparently leading to confusion even at FDA, and thus necessitating this letter from the Senators.

Related to this debate is the "Ethical Pathway Act of 2010," (S. 3921), a bill introduced into the Senate by Senator Sanders on September 29, 2010, which would effectively eliminate any data exclusivity period for both conventional drugs and biologics. Under this proposed legislation, as I read it, an innovator would be forced to share its clinical and animal data with a competitor, to be used by the competitor to obtain FDA approval for a generic or biosimilar product. The bill includes provisions for a "cost-sharing arrangement," pursuant to which the generic company would be required to compensate the innovator for some of the costs incurred in generating the data. If the innovator and generic company cannot agree on the amount, they are required to submit the matter to an arbitrator who is to determine a "reasonable and fair fee.”

The bill identifies specific factors to be considered in determining the "reasonable and fair fee," including "actual out-of-pocket costs of the applicable clinical investigations, the risk of the investigations, as reflected in the probabilities that similar investigations result in successful applications for marketing, any federal grants, tax credits, or other subsidies that reduce the net cost of the investigations, the expected share of the global market for the product involved, by the party seeking to rely upon the investigations for marketing approval, and the amount of time the holder or holders of the relevant applications for licenses has benefited from exclusive rights, and the cumulative revenue earned on the products that relied upon the regulatory tested at issue."

I think it is reasonable to predict that innovators are highly likely to be undercompensated by this imposed "cost-sharing arrangement." Essentially, after the innovator company has taken on a huge amount of risk bringing a drug to patients, and then establishing a market for the drug, this bill would allow a competitor to free ride off all of this risky investment by simply paying some fraction of the cost for clinical trials. As reported last Monday in Reuters, a survey has found that traditional small molecule drugs have only a 7% chance of making it from phase I through FDA approval. The success rate is even lower for some of the most important drugs-4.7% for cancer drugs, and 5.7% for cardiovascular drugs. There needs to be powerful financial incentives to invest huge amounts of money when there is such a low probability of a payoff, which I think helps explain why we are seeing such a dramatic drop-off in pharmaceutical R&D spending and in the rate of new drug approvals.

When generic competition hits the market, the innovator does not just lose a piece of the pie, the pie shrinks dramatically. Innovators need some substantial period of exclusivity on the market in order to bring in the profits that ultimately drive innovation. Patents play an important role in this regard, but patent protection is unpredictable and not always available, even for important and innovative life-saving drugs, and this is particularly true in the case of biologics.

To me, this is analogous to me going to the racetrack with a friend, and deciding to bet $1000 on a longshot horse. If the horse comes in, and I win $25,000, it is certainly not fair for my friend to wait until the race is won and then demand that I accept $500 (half the price of the bet) in exchange for half of the winnings ($12,500). But this is essentially what the "cost-sharing arrangement" under the proposed legislation would entail. In fact, it's even worse than that, because to take the analogy further, since generic competition reduces profits for everyone, we're not talking about sharing $25,000 anymore, but substantially less than $25,000.

While the legislation would hurt innovators, and ultimately innovation, it is premised upon a quite legitimate ethical concern, i.e., conducting clinical trials on human beings when we presumably already know the product is safe and effective raises substantial ethical issues. While I agree this is an entirely valid concern, I don't think it should be addressed in a manner that substantially reduces incentives for future innovation.

I would suggest that perhaps the best way to deal with these concerns is to provide drug innovators with an actual period of marketing exclusivity, independent of patent rights and independent of data exclusivity. This would give innovators a period of market exclusivity in which to recoup profits that incentivize innovation, without having to worry about patent challenges, and without subjecting human subjects to unnecessary clinical trials.

Does disclosure of laundry list of protein variants provide adequate written description for later claim to specific protein?

2011-02-10T18:03:00.000-06:00

The traditional written description requirement prevents patent applicants from amending their claims during patent prosecution to encompass subject matter not disclosed in the patent specification as filed. Clearly, a patent specification that specifically discloses (without claiming) a small number of protein sequences provides adequate written description to support adding a claim later that recites one of those protein sequences. But what if a patent specification effectively discloses all protein sequences, for example, by generically describing "a protein comprising between 10 and 1000 amino acids, wherein at each position in the sequence the amino acid can be any of the 20 genetically coded amino acids.” It defies common sense to think that such a broad, generic disclosure would be sufficient to satisfy the written description requirement with respect to a claim introduced by amendment specifically reciting any protein of this size, even though the disclosure does literally describe any possible protein of 10 to 1000 amino acids in length.

The question then becomes, at what point do we draw the line? In other words, to what extent is it possible for a patent applicant to satisfy the written description requirement with respect to a later added claim directed towards a specific protein sequence by simply disclosing in the specification as filed an astronomical "laundry list" of protein sequence variants that happens to include the later claimed proteinsequence? This is the question that was presented to a district court recently in the lawsuit brought by Novozymes against Danisco/Genencor, alleging infringement of a patent claiming certain alpha-amylase variants genetically engineered for improved thermostability. (Last September I reported on the district court's denial of a motion for preliminary injunction by Novozymes, available here).

The Federal Circuit (and its predecessor court the CCPA) has addressed this question in the context of traditional small molecules. A seminal case is In re Ruschig, a 1967 CCPA decision that held that the mere disclosure of a large genus of molecules is not necessarily sufficient to satisfy the written description requirement with respect to a later claim directed to some species falling within the genus. Under such circumstances, the Ruschig court held that in order to satisfy the written description requirement, the specification must provide "blaze marks" specifically pointing towards the later claimed species.

In 1996, the Federal Circuit applied the Ruschig "blaze mark standard” in Fujikawa v. Wattanasin, and held that the disclosure of a genus did not provide adequate written description of a later claimed sub-genus, pointing out that "just because a moiety is listed as one possible choice for one position does not mean there is [adequate] support for every species or sub-genus that chooses that moiety. Were this the case, a 'laundry list' disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not 'reasonably lead' those skilled in the art of any particular species."

In the Novozymes v. Danisco, the issue was raised in a motion for summary judgment filed by Danisco, arguing that a disclosure in Novozymes specification of a laundry list comprising an astronomical number of protein variants does not provide adequate written description support for a claim added later directed toward a small subset of those variants. The Novozymes patent specification, filed in 2000, disclosed variants of a specific alpha-amylase (the sequence of which was disclosed in the application) comprising an alteration at one or more positions selected from a list of 33 possible positions. The specification went on to define an alteration as either an insertion downstream of the amino acids which occupies position, a deletion of the amino acid which occupies a position, or a substitution of the amino acid which occupies the position with a different amino acid. So there are multiple variable parameters.

The 33 positions can be independently altered in three different ways. Any number of the 33 positions can be altered independently, and there are 20 different amino acids from which to choose in deletions or substitutions. Genencor did the math, and concluded that this amounted to a “staggering” 8.598 x 1042 different possibilities, a long laundry list indeed. Novozymes did not dispute this calculation. Furthermore, the specification does not specify what effect a specific mutation would have on thermostability, although one passage in the specification discusses "achieving altered stability, in particular improved stability (i.e., higher or lower), at especially high temperatures."

In 2009, nine years after the specification was filed, Novozymes added the claims at issue in the case, directed specifically toward a subset of the proteins on the laundry list that have a substitution at position 239 in amino acid sequence, resulting in increased thermostability. That is, the claim is limited to one of the 33 amino acid positions identified in the specification as filed (position 239), one of the three alterations (substitution), and one of the possible alterations in stability (increased thermostability).

The court discussed applicable precedents such as Ruschig and Fujikawa, but did not really seem to demonstrate a thorough understanding of the principles behind those decisions. Perhaps this is because, as the judge complained in her decision, "a general difficulty in this case has been the party's tendency to argue past each other." Nonetheless, she ultimately concluded that although "I still have doubts that the specification . . provides an adequate written description for the claims, I conclude that the defendants have not met their burden to prove by clear and convincing evidence that the [patent] is invalid as a matter of law." The decision was largely dictated by the cases procedural posture, which imposed a substantial burden of proof on Danisco in attempting to invalidate an issued patent on summary judgment as a matter of law.

The judge explicitly noted that "it is not without hesitation that I'm denying defendant's motion.” It seems clear that she was bothered by the fact that the originally filed specification discloses such an astronomical number of "possible inventions" without seeming to provide any "blaze marks" directing one towards the later claimed variants. But she went on to point out that even if the claims comply with the written description requirement, "to the extent the specification would require undue experimentation before a person of ordinary skill in the art could discover the claimed invention, that may suggest a lack of enablement rather than a problem with the written description." I think she might have a point there.

A copy of the decision is provided here. Thanks to Docket Navigator (www.docketnavigator.com) for making me aware of this case.

Eli Lilly Petitions for Certiorari in Sun v. Eli Lilly

2011-01-30T16:32:00.000-06:00

In a previous post to this blog, I discussed the case of Sun Pharmaceuticals v. Eli Lilly, in which a panel of the Federal Circuit dramatically expanded the scopeof the doctrine of obviousness-type double patenting. I also worked with the Biotechnology Industry Organization (BIO) on an amicus brief supporting Lilly's petition for rehearing en banc, available here. The Federal Circuit denied that petition, over a vigorous dissent by four judges (Newman, Rader, Lourie, and Linn), who argued that "[u]ntil recently the law of double patenting was clear, but it has become distorted by divergent statements, leading to this flawed ruling."

Notably, one of the dissenting judges (Rader) was the author of the Geneva opinion, which created the precedential authority upon which the Sun panel justified its decision. But as noted by the four dissenting judges, "extending Geneva to cover the facts of [Sun] does not further the policy of obviousness-type double patenting."

On Friday, Eli Lilly filed a petition for certiorari asking the Supreme Court to review the Federal Circuit's decision in Sun. The question is presented as "[w]hether the Federal Circuit improperly transformed the doctrine of "double patenting," in conflict with a "vast body of precedent" cited by four dissenting judges, by creating a new bright-line rule that invalidates a subsequent patent on a nonobvious, newly discovered use of the basic invention solely because it was disclosed, but not claimed, in the final text of the earlier basic patent."

Lilly's petition cites extensively to the opinion of the four dissenting Federal Circuit judges, including a statement that the Sun decision "violates a vast body of precedent," and a charge that the majorities refusal to rehear the case en banc to resolve the Court’s conflicting precedent in this area constitutes "an indictment of the ability of [that] court to provide stable law in the areas entrusted to [it]."

Lawsuit Alleging Infringement of Canine Genotyping Patent Raise Interesting Patent Eligibility Issues

2010-12-23T14:12:00.000-06:00

On December 17 Fred Hutchinson Cancer Research Center and its licensees (Argus Genetics and Mars, Inc.) sued MMI Genomics for infringement of a patent directed towards methods of using genetic testing to identify the breed of the dog (US patent 7,729,863). According to the complaint, MMI Genomics is a company based in Davis, California that provides dog breed identification services associated with its Canine Heritage XL Breed Test product.

Some of the claims in the asserted patent raise interesting issues of patent eligibility, particularly in view of the recent Bilski and Prometheus decisions, both discussed extensively on this blog, and the pending appeal of AMP v. PTO (the ACLU challenge to Myriad’s BRCA gene patents). For example, consider claim 1.

1. A method for determining the contributions of canid populations to a canid genome, comprising: (a) genotyping a sample obtained from a test canid to determine the identity of one or both alleles present in the test canid genome for each of a set of markers, wherein the set of markers is indicative of the contributions of canid populations to the genome of the test canid; (b) using a specifically programmed computer comprising an algorithm to compare the identity of one or both alleles for each of the set of markers determined to be present in the test canid genome to a database comprising a plurality of canid population profiles, wherein each canid population profile comprises genotype information for the set of markers in the canid population; and (c) determining the contributions of canid populations to the test canid genome.

The heart of the claimed method seems to reside in applying an algorithm to genotype information using information derived there from to determine the contribution various dog breeds to dog being tested. If that were all the claim covered, I think under Bilski and Prometheus a court would likely find the claim patent ineligible for embodying a fundamental principle. The fundamental principle might be characterized as an abstract idea, or as a natural phenomenon, either would work.

But the claim includes two elements that might be sufficient to render the claim patent eligible: (1) the step of genotyping a sample taken from the dog, and (2) the use of a "specifically programmed computer." In Prometheus, the Federal Circuit relied heavily on the machine or transformation test in arriving at the conclusion that the claims at issue in that case were patent eligible. I believe that even though the Supreme Court clarified in Bilski that the machine or transformation test is not the only test for patent eligibility, it did acknowledge that the test can be a useful and informative tool for assessing patent eligibility, and I predict that the Federal Circuit will continue to rely heavily on the machine or transformation test when faced with claims such as this, as it did in Prometheus.

Under Prometheus and Bilski, I think this one could come out either way. On the one hand, a court could find that genotyping is inherently transformative, because it necessarily involves physical manipulation of biological samples, in the same way that the step of "determining drug metabolite level” was found transformative in Prometheus, and sufficient to render the claim patent eligible. A court could also find that the use of a "specifically programmed computer" satisfies the machine prong of the machine or transformation test.

On the other hand, a court could characterize the genotyping step as mere data-gathering, i.e., "insubstantial extra-solution activity,” and thus ignore it in the analysis. This is what the Federal Circuit did in In re Grams, and as noted in my previous blog post the Federal Circuit explicitly held in Prometheus that Grams is still good law. In Prometheus, the Federal Circuit distinguish the two cases by pointing out that in Grams the focus of the invention is on the algorithm itself, and that the data-gathering step generically covered many different types of clinical diagnostic tests, whereas the Prometheus claims were targeted to specific drugs and specific diseases. The dog breed testing claim seems to fall somewhere in between. I think a court could go either way, by either stressing that the claim focuses on the algorithm and is not limited to any specific genotype or genetic test, in which case the claim is patent ineligible under Grams, or by stressing that the genotyping step is "central to the purpose" of the claim and thus sufficient to render the claim patent eligible under Prometheus.

Regarding the use of a computer, it is important to note that under In re Bilski the machine or transformation test requires the involvement of a "particular" machine, and many have speculated that a general-purpose computer would not satisfy this requirement of "particularity." Whoever drafted the dog breed testing claim wisely specified that the computer used in the method is "specifically programmed," but I'm not sure if that will be sufficient. A court could dismiss the "specifically programmed" language and find that the mere involvement of the computer does not satisfy the "particularity” aspect of the machine or transformation test.

Claim 35 is similar to claim 1, but instead of reciting the use of a computer, includes a step of "applying a computer-implemented statistical model.” This claim could be more vulnerable than claim 1, since it does not appear to explicitly recite the use of a particular machine.

There are also a number of dependent claims limited to specific SNP markers, specific dog breeds, etc., and these claims should face less of a threat of invalidation for lack of patent eligibility. Patent eligibility analysis often hinges on an assessment of whether the claim preempts all substantial practical uses of an abstract idea or natural phenomenon, so logically the narrower a claim is the more likely it is not preemptive, and thus patent eligible. Although in Bilski the Supreme Court apparently rejected this logic, because it held even relatively narrow dependent claims to be patent ineligible even though they clearly did not preempt all uses of risk hedging (the fundamental principle at issue in that case).

Claim 36 appears to be a Beauregard claim, a claim directed toward computer readable medium on which a computer program is inscribed. It would be interesting to see how this claim holds up, it is my understanding that the status of this sort of claim has not been entirely resolved post-Bilski, I saw some posts on this topic on Patently-O a while back.

36. A computer readable medium comprising stored thereon: (a) a data structure stored thereon for use in distinguishing canid populations, the data structure comprising: (i) a marker field, which is capable of storing the name of a marker or of an allele of the marker; and (ii) a genotype information field, which is capable of storing genotype information for the marker in a canid population, wherein a record comprises an instantiation of the marker field and an instantiation of the genotype information field and a set of records represents a canid population profile; and (b) computer-executable instructions for implementing a method for determining the contributions of canid populations to a canid genome, comprising: (i) obtaining the identity of one or both alleles in a test canid genome for each of a set of markers; and (ii) determining the contributions of canid populations to the test canid genome by comparing the alleles in the test canid genome to a database comprising canid population profiles, wherein each canid population profile comprises genotype information for the set of markers in the canid population.

Claim 37 seems even more problematic to me. I don't know that it can be called a Beauregard claim, it appears to basically be directed toward a computer readable medium on which a data structure is stored, which I am guessing is not the same thing as a computer program. I would be particularly interested in seeing how court deals with this claim.

37. A computer-readable medium comprising a data structure stored thereon for use in distinguishing canid populations, the data structure comprising: (a) a marker field, which is capable of storing the name of a marker or of an allele of the marker; and (b) a genotype information field, which is capable of storing genotype information for the marker in a canid population, wherein a record comprises an instantiation of the marker field and an instantiation of the genotype information field and a set of records represents a canid population profile, wherein the marker field comprises a set of markers indicative of the contributions of canid populations to the genome of a test canid.

On Remand, Federal Circuit (Once Again) Decides Prometheus v. Mayo in Favor of Patent Eligibility for Methods of Treatment and Diagnostic Tests

2010-12-17T15:22:00.001-06:00

Today a panel of the Federal Circuit issued a decision in Prometheus v. Mayo, an important case involving the application of the patent eligibility doctrine to biotechnology, and more particularly molecular diagnostic testing and personalized medicine. I have discussed this case in numerous previous blog posts, see for example here.

Background
In a nutshell, the case involves claims directed towards methods for optimizing the amount of drug administered to a specific patient, an example of personalized medicine. The claims are limited to certain categories of thiopurine drugs used to treat immune-mediated gastrointestinal disorders such as Crohn's disease, the use of which is often accompanied by serious adverse side effects, including hepatotoxicity. Because different patients metabolize the drug differently, it had been difficult for doctors to ascertain the proper dosage, and some doctors had reportedly been hesitant to prescribe the drugs at all for fear of toxic side effects.

The challenged claims are directed towards methods that all comprise a step of determining the level of thiopurine drug metabolite in a patient sometime after administering the drug to the patient, and based on the result of that determination recognizing that the dosage of drug administered to the patient should be increased or reduced, i.e.,a determination that the level of drug metabolite exceeds a certain threshold would indicate that the dosage should be decreased, and vice versa. Many of the claims also explicitly recite a step of administering the drug to the patient.

A district court judge, in an opinion clearly influenced by Judge Breyer's provocative dissent in LabCorp, held the claims patent ineligible for allegedly wholly preempting a "natural phenomenon." In its analysis, the judge dismissed the steps of administering drug and determining drug metabolite level as mere "data-gathering steps," irrelevant to the patent eligibility of the claim.

The case was appealed to the Federal Circuit, but before the appeal was decided the Federal Circuit issued its en banc In re Bilski decision (Bilski I) which held the machine or transformation test to be the definitive test for patent eligibility of method claims.

On appeal the Federal Circuit panel reversed and held that the Prometheus claims satisfied applied the newly minted Bilski machine or transformation test. In particular, the panel held that the steps of administering drug to the patient and determining drug metabolite level were both inherently and independently sufficient to satisfy the transformation prong of the machine or transformation test. In contrast with the district court, which dismissed these steps as mere data-gathering, the Federal Circuit characterized the administering and determining steps as central to the purpose of the claim and thus relevant to the question of patent eligibility.

But shortly thereafter, in Bilski v. Kappos (Bilski II), the Supreme Court overturned Bilski I to the extent that it had characterized the machine or transformation test as the definitive test for patent eligibility, and reiterated that the sole and fundamental test for patent eligibility is whether the claim "patents" a fundamental principle, i.e., laws of nature, physical phenomena and abstract ideas. The Supreme Court then vacated the Federal Circuit's decision in Prometheus v. Mayo and remanded the case to the Federal Circuit to decide in a manner consistent with Bilski II.

Today's Post-Bilski II Prometheus Decision
Today's Federal Circuit decision on remand comes to the same conclusion as the first, reversing the district court and holding all of the challenged claims to be patent eligible. The court's analysis is also virtually identical to the original decision, focusing primarily on the transformative nature of the administering and determining steps.

It is important to bear in mind that while Bilski II rejected the notion that the machine or transformation test is the only test for patent eligibility of method claims, it did acknowledge that the machine or transformation test is in many instances highly probative of the fundamental inquiry. Significantly, the Supreme Court did not offer up any other alternative test for determining whether a claim "patents a fundamental principle." As noted by the en banc Federal Circuit in Bilski I, as a practical matter it can be extremely difficult to apply this fundamental test to actual claims, which is why the Federal Circuit tried to institute the use of a definitive machine or transformation test as a more objective and easier to administer proxy for the ultimate inquiry. As a practical matter of expedience, I have predicted that the courts and PTO will continue to rely heavily on the machine or transformation test post-Bilski II.

In today's decision, the Federal Circuit panel pointed out that under Bilski II the scope of patent eligible subject matter remains quite broad, and that while fundamental principles are not patent eligible "particular applications" of fundamental principles are. Applying this standard, the panel held that Prometheus' claims do not preempt the correlations between drug metabolite level and optimal dosage, but rather utilize them in "the treatment of a specific disease by administering specific drugs and measuring specific metabolites."

The panel also emphasized the continuing relevance of the machine or transformation test, pointing out that the Supreme Court had characterize it as a "useful and important clue, an investigative tool" for determining patent eligibility. It then came to the same conclusion as it did in its pre-Bilski II decision, finding that both the administering and determining steps were each inherently and independently sufficient to confer patent eligibility on the claims. In view of this determination, the panel found it unnecessary to address the question of whether the claims satisfy the machine prong of the test.

The panel emphasized that if the claims had not included a step of administering a drug or determining the level of drug metabolite, but had merely recited recognizing the correlation between drug metabolite level and the desirability of modifying the dosage (i.e., the "wherein" clauses of the claims), then the claims would have been patent ineligible for claiming nothing more than "mental steps." But by including a step of administering a drug and/or determining the level of drug metabolite, transformative steps which are "central to the purpose" of the method, the claim is rendered patent eligible.

In effect, Bilski II had essentially on effect on the outcome of the Prometheus appeal. Fortunately, the Supreme Court decided Bilski II in a manner allows a great deal of discretion for the Federal Circuit and lower courts. This panel of the Federal Circuit clearly sees the importance of permitting the patenting of diagnostic methods and methods of treating patients with drugs, and sought to maintain their patent eligiblity by emphatically establishing that method claims reciting a step of administering a specific class of drugs to a patient, or of performing a molecular diagnostic test of the patient, are patent eligible per se.

However, the panel is also emphatic that claims that could be potentially infringed by merely thinking about or recognizing a physiological correlation cannot be patented, a hypothetical scenario that some critics of gene patents and patents on diagnostic tests often point to.

The one aspect of the decision that I found less than entirely convincing was the panel's attempt to distinguish over the holding in In re Grams, a 1989 Federal Circuit decision. Grams was a case involving the patent eligibility of claims reciting methods that basically involved (1) performing a clinical diagnostic test on an individual patient, and (2) applying an algorithm to the data generated by the test in order to determine whether an abnormality exists, and possible causes of the abnormality. In Grams, the data-gathering steps were disregarded in the court's patent eligibility analysis, and the claims held patent ineligible for "in essence" claiming nothing more than a patent ineligible algorithm.

In a sense, the Grams claims are highly analogous to the Prometheus claims. The determining step in the Prometheus claims involves nothing more than performing a clinical diagnostic tests on individual patient, and the step of using the results to determine whether drug dosage should be altered is nothing more than a simple algorithm. According to the Prometheus panel, the distinction lies in the fact that in Grams the "essence" of the claimed process is the algorithm, and that the Gram patent "focused only on the algorithm rather than a clinical test." I'm not sure how convincing this distinction is, perhaps the panel could have been more straightforward and acknowledged the tension between Grams and Prometheus.

However, I have read the Grams decision and think a plausible distinction is that the Prometheus claims are limited to diagnostic tests for a limited number of specified of drug metabolites, while in Gram the claim appears to broadly encompass any of a host of clinical tests to which the algorithm could be applied. This suggests that if the Prometheus claims had been drafted more broadly to encompass any drug and drug metabolite, rather than being restricted to specific classes of thiopurine drugs, the claims could have been found patent ineligible. In effect, the distinction between the Grams and Prometheus claims is a matter of claim scope, something I think would be better addressed using the enablement requirement rather than patent eligibility, as I argued in the amicus brief I filed with Robert Cook-Deegan in the Myriad gene patent case.

Finally, what are the implications of today's Prometheus decision for the patent eligibility of the genetic diagnostic method claims at issue in the Myriad gene patent case (Association for Pathology v. US Patent and Trademark Office)? Today's decision does not alter my previous prediction, which is that the outcome will depend upon how the Federal Circuit interprets the scope of Myriad's patent claims. If the Federal Circuit adopts the ACLU's broad interpretation the claims (which is the interpretation the district court judge accepted for his analysis), pursuant to which the claims broadly cover the purely mental process of analyzing genetic information, then under Prometheus I believe the claims must be found patent ineligible. Alternatively, if the Federal Circuit adopts Myriad’s interpretation of its claims, under which the claims are limited to methods that involve physically isolating and analyzing DNA molecules, I think under Prometheus the claims should be found patent eligible by virtue of comprising a transformative step (highly analogous to the administering step in the Prometheus claims) central to the purpose of the claimed methods.

The American Medical Association et al. File Amici Brief Arguing for Affirmance of AMP v. PTO

2010-12-07T09:46:00.001-06:00

An amici brief was filed yesterday by Professors Lori Andrews and Joshua Sarnoff on behalf of the American Medical Association, American Society of Human Genetics, American College of Obstetricians and Gynecologists, American College of Embryology, and the Medical Society of the State of New York, arguing for affirmance of the district court's decision in AMP v. PTO. Professor Andrews has for years been one of the most outspoken critics of gene patents, and was involved with a bill introduced in Congress in 2007 that if enacted would have broadly prohibited the patenting of DNA-based inventions.

Their brief is more alarmist than the brief submitted by the ACLU/PubPat, arguing that gene patents have cost patient's their lives, and the healthcare system billions of dollars. For example, allege that gene patents are being asserted against physicians across the country, and that physicians have to worry about infringing patents based on nothing more than mere "conscious thoughts." They also contend that gene patents are killing patients. For example, they state that drug companies have used these patents to prevent use of genetic testing to determine whether a drug will help or harm patients, to block the availability of genetic testing (which they allege resulted in the of a 10-year-old patient), and to force patients to use poor quality diagnostic tests rather than improved alternatives (which they allege resulted in a patient undergoing unnecessary removal of ovaries based on erroneous BRC genetic test result).

The AMA et al. adopt a very broad definition of the diagnostic method claims, under which they would be infringed by anyone merely "reading and thinking about the sequence data disclosed in the patent." As discussed in a previous post, this is a much broader interpretation of the claims than Myriad has proffered.

They also argue that patents are not necessary to incentivize the discovery of genetic mutations correlated with disease or the commercialization of diagnostic testing based on these discoveries, citing to the Sec.'s Advisory Committee on Genetics, Health and Society (SACGHS) Report.

In the amici brief submitted by me and Robert Cook-Deegan, we argued that regardless of whether patents are necessary to incentivize the development of genetic diagnostic testing for Mendelian traits, in which mutations in a single gene are highly correlated with a specific disease, they quite likely will be necessary for the optimal development of next-generation genetic diagnostic testing involving much more complex relationships and multiple genes, or if FDA imposes heightened regulation on diagnostic testing. We also argued that a decision broadly rendering gene patents patent ineligible could have serious unintended negative consequences for biotechnology, particularly outside the realm of Mendelian genetic diagnostic testing, and that there are other more focused approaches for dealing with problematic gene patents or gene patent enforcement activities. The AMA brief does not address these points, but rather seems to assume that the only available mechanisms for dealing with problems associated with gene patents is a broad prohibition extending far beyond Myriad and BRCA testing.

Myriad and the ACLU Disagree over Claim Scope, But Apparently Not over Patent Eligibility of Genetic Diagnostic Methods

2010-12-06T15:25:00.000-06:00

After reading the briefs submitted by Myriad and the ACLU/PubPat in AMP v. PTO (the challenge to Myriad’s gene patents, described in previous posts to this blog), one thing that struck me was that the parties do not appear to disagree over the patent eligibility of genetic diagnostic methods. In fact, with respect to these method claims, the only dispute is with respect to the proper interpretation of the claims.

The challenged diagnostic method claims recite processes of either "analyzing" or "comparing" nucleotide sequences. For example, claim 1 of US patent number 6,033,857 claims:

A method for identifying a mutant BRCA2 nucleotide sequence in a suspected mutant BRCA2 allele which comprises comparing the nucleotide sequence of the suspected mutant BRCA2 allele with the wild-type BRCA2 nucleotide sequence, wherein a difference between the suspected mutant and the wild-type sequence identifies a mutant BRCA2 nucleotide sequence.

Myriad argues for a relatively narrow interpretation of the claims, under which the claims are limited to methods which require actual physical analysis of DNA molecules. Under their interpretation, the term "nucleotide sequence," as used in the claims, refers to actual polynucleotides, i.e., DNA or RNA molecules, and the step of comparing these molecules necessarily requires physically isolating polynucleotides from a patient's tissue sample, and then processing and analyzing the molecules. Myriad argues that these processes are all clearly transformative of physical molecules, and because the transformations are “central to the purpose of the claims,” the claims satisfy the machine or transformation test. They cite to Prometheus for the proposition that transformative steps that are central to the purpose of the claims cannot be disregarded in the analysis as mere "data-gathering steps,” and argue these transformative steps render the claim patent eligible.

The ACLU, on the other hand, argues for a much broader interpretation of the method claims. They argue that the term "nucleotide sequence" in the claims refers to sequence information, not to molecules, and that the claims cover the purely mental process of "comparing" or "analyzing" DNA sequence information. Under this broad interpretation, the claims clearly do not require any sort of physical transformation, and on this basis the ACLU argues they fail the machine or transformation test, which they correctly note remains "a useful and important clue" to patent eligibility (using the language of the Supreme Court).

Interestingly, the ACLU never suggests in their brief that the diagnostic method claims would be patent ineligible if limited to methods involving actual isolation and processing of DNA molecules, i.e., the only processes covered by the claims under Myriad's interpretation of the claims. Conversely, Myriad never argues that a method claim that encompasses purely mental processes for comparing DNA sequence information would be patent eligible. Thus, both parties seem implicitly to agree on a consensus approach under which a claim directed toward a genetic diagnostic method is patent eligible if limited to diagnostic methods that involve actual isolation and manipulation of DNA molecules, but patent ineligible if the claim would also cover merely comparing DNA sequence information.

Notably, the district court adopted the ACLU's broad interpretation of the claims, and held that the claims cover a process of comparing or analyzing DNA sequence information. However, in dicta the district court went even further, stating that "[e]ven if the challenged claims were read to include the transformations associated with isolating and sequencing human DNA, these transformations would constitute no more than ‘data-gathering step[s]’ that are not central to the purpose of the claimed process.. . . . Consequently, even if the method claims-in-suit were construed to include the physical transformations associated with isolating and sequencing DNA, they would still fail the ‘machine or transformation’ test under Section 101 for subject matter patentability."

In my analysis of the district court decision, I pointed out that this dicta seems clearly wrong, and is inconsistent with the Federal Circuit's decision in Prometheus. Clearly, these data-gathering steps are central to the purpose of the claim and should be included in the machine or transformation analysis. I suspect that the ACLU agrees with my assessment, and is not even trying to argue for more extreme position taken by the district court.

It seems to me that the implicit consensus between Myriad and the ACLU is correct, i.e., method of genetic diagnostic claims are patent eligible if they include steps involving the actual physical manipulation of DNA molecules, but patent ineligible if they would cover the wholly mental process of analyzing DNA sequence information.

As a side note, another point of contention regarding claim interpretation exists with respect to whether some of the claims are limited to cDNA molecules. In its amicus brief, the United States government has argued that claims to isolated genomic DNA are patent ineligible, but claims limited to cDNA molecules are patent eligible (as reported in an earlier post to this blog). For some reason, in its brief the ACLU argues that the United States is mistaken, and that none of the challenged claims is limited to cDNA. ACLU seems to be clearly mistaken on this point--for example, Claim 2 of US patent 5,747,282 (one of the challenged claims) recites "DNA [having] the nucleotide sequence set forth in SEQ ID NO:1.” The Sequence Listing section of the patent specification explicitly identifies SEQ ID NO:1 as a cDNA.

Boston Globe Editorial Acknowledges Importance of Gene Patents, and Suggests Issue Should Be Decided by Congress, Not the Courts

2010-11-23T09:59:00.000-06:00

In an apparent shift of position, the Boston Globe has parted company with much of the mainstream media by acknowledging the importance of gene patents to biotechnology, the potential deleterious impact if Judge Sweet's decision finding gene patents ineligible were to be upheld on appeal. The editorial points out that:

Whatever the principle at stake, one practical effect of Judge Sweet’s ruling, if it isn’t reversed, will be to eliminate part of the legal structure upon which the biotechnology industry was founded. The US might leave the company of Japan, Canada, Australia, and the European Union to become the biggest industrialized nation to consider a gene that’s been discovered, characterized, and isolated through scientific inquiry as categorically non-patentable.
. . .
There is still, of course, the very legitimate, and clearly urgent, question of whether gene patents serve the larger goal of advancing medical research and promoting the creation of therapies. But the best answer to this question is unlikely to arrive through a patent challenge. Determining the benefit to society of gene patents involves much more than just the narrow legal consideration of whether DNA isolated through the process of scientific discovery fits the definition of an invention under the US Patent Act.
. . .
Perhaps the best policy would be to simply do away with these patents. But the issue is of such magnitude that it would be best addressed outside the court system, by an act of Congress.

It is good to see that at least some in the mainstream media are waking up to the reality of what is at stake in the ACLU's challenge to gene patents.

Regeneron Sues for Declaratory Judgment That VEGF Trap Does Not Infringe Genentech Patents

2010-11-23T09:33:00.001-06:00

On November 19, Regeneron sued Genentech in the US District Court for the Southern District of New York seeking a declaration that no activities relating to the Regeneron VEGF Trap infringe any claim of US patent numbers 5,952,199; 6,100,071; 6,383,486; 6,897,294; and 7,771,721 (all assigned to Genentech according to the complaint). The complaint is available here, compliments of PriorSmart.com.

Vascular Endothelial Growth Factor, or VEGF, is a protein growth factor which is required for formation of blood vessels, a process known as angiogenesis. According to Wikipedia:

In the adult human, angiogenesis is only consistently active in the gut - however in pathological cases such as cancer, where a solid tumor grows rapidly and therefore requires a blood supply, there is also active angiogenesis. Therefore, the blockade of VEGF is a potentially viable strategy for treating solid tumors.

Regeneron has developed a chimeric (i.e., fusion) protein, which it refers to as VEGF Trap (aflibercept), that comprises the extra-cellular domain of VEGF Receptor (the growth factor's natural receptor). The extra-cellular domain of the receptor is used to bind, or "trap" VEGF, and thereby keep it from binding receptors on the surface of blood vessels. Regeneron is working towards FDA approval to market VEGF Trap for a number of ophthalmologic and oncology indications. According to the complaint, the company intends to submit a Biologic License Application before the end of the second quarter of 2011 to market the product for a wet age-related macular degeneration. Yesterday, Regeneron stock rose 19.7% after the company announced positive Phase 3 clinical trial results for the drug (see here).

Genentech has developed an antibody called Avastin that binds VEGF. Avastin is already approved for the treatment of colon cancer. The five Genentech patents which are the subject of the declaratory judgment action are directed toward chimeric VEGF receptor proteins capable of binding VEGF.

Amicus Brief Filed By Alnylam Pharmaceuticals Argues That Funk Bros. Is About Obviousness, Not Patent Eligibility

2010-11-10T13:07:00.001-06:00

Alnylam Pharmaceuticals is a biopharmaceutical company based in Cambridge, Massachusetts focused on developing synthetic "small interfering RNAs" (SiRNAs) as therapeutic agents. It has filed an amicus curiae brief in the Myriad gene patent case (AMP v. US PTO) that makes a number of insightful points, particularly in attempting to "debunk myths of Funk Brothers Seed Co. v. Kalo Inoculant Co."

Funk Brothers is generally assumed to be a case about patent eligibility. However, Alnylam points out that Funk Brothers was decided by the Supreme Court in 1948, prior to the enactment of the 1952 patent statute and thus prior to 35 USC 101, which is the statutory basis for the patent eligibility doctrine. Prior to 1952, the Court used the term “invention” to refer to "inventiveness," a concept that subsequent to 1952 and the enactment of 35 USC 103 we refer to as "nonobviousness." The Court in Funk Brothers found the claimed subject matter was not the “product of invention,” but Alnylam argues that post-1952 this statement should be interpreted a finding of obviousness, not patent ineligibility.

I have always found it extremely difficult, if not impossible, to find a principled distinction between the inventions claimed in Funk Brothers and Diamond V. Chakrabarty that would justify finding only Dr. Chakrabarty's invention patent eligible. In Funk Brothers, the alleged invention was a novel and useful combination, in a single inoculant, of naturally occurring microorganisms in a combination that did not exist naturally. Chakrabarty’s invention was a novel and useful combination, in a single microorganism, of naturally occurring plasmids in a combination that did not exist naturally. It is important to bear in mind that Chakrabarty's invention did not involve any genetic engineering at the molecular level.

In Funk Brothers, it has been pointed out that while the combination of bacteria in a single inoculant was novel, the bacteria function in the same manner and have the same characteristics as they would have in nature. But the same can be said regarding the plasmids Dr. Chakrabarty introduced into a single microorganism. These were naturally occurring plasmids, and in the claimed microorganism they encoded the exact same proteins, and performed the exact same function as they did in their natural state.

In a nutshell, Funk Brothers was a novel combination of naturally occurring bacteria capable of achieving novel and useful function, with the bacteria functioning in the same manner as they do in nature. Chakrabarty was a novel combination of naturally occurring plasmid DNA capable of achieving novel and useful function, with the plasmid DNA functioning in the same manner as they do in nature. I don't see how one invention can be patent eligible and the other not. However, if Funk Brothers was really decided based on obviousness rather than patent eligibility, as argued by Alnylam, the two decisions are easily reconciled.

Superficial Appeal of DOJ Brief Proves Illusory

2010-11-05T17:46:00.001-05:00

I can understand why many people find the position advanced by the US government in AMP v. PTO (the DOJ amicus brief, discussed in an earlier post) quite appealing. On its face, it seems to offer a reasonable compromise: patent eligibility for "engineered" cDNA, but not for genomic DNA merely "excised" from a human chromosome. However, the distinction is superfical, and does not in my view withstand closer scrutiny.

In particular, the DOJ conveniently ignores the fact that in almost all cases isolation of genomic DNA involves amplification, either through laboratory techniques such as PCR, or by replication in recombinant cells. This distinguishes DNA and RNA from other biomolecules. Prior to the development of recombinant molecular biology in the 1970s, isolation of a naturally occurring biomolecule, such as a protein, involved removing the biomolecule produced in a naturally occurring from other biological constituents. Importantly, all of the purified biomolecule originated in the natural source, and was purified by separating it from other cellular constituents.

In contrast, because DNA can serve as a template for its own replication, DNA is normally isolated by amplifying it many times ("million-fold" is the term used in the amici brief filed by BIO and AUTM). As a result, a typical preparation of "isolated genomic DNA" actually consists primarily of synthetic copies of the genomic DNA molecule.

The DOJ makes much of the fact that a cDNA molecule does not contain the introns, which exist in most human genes, and implies that molecular biologists have "engineered" the introns out. In fact, the introns are naturally removed in the body when genomic DNA is transcribed into mRNA. There is no human engineering involved; production of a cDNA molecule simply entails making a DNA copy of a naturally occurring mRNA and then amplifying it.

In most instances a preparation of isolated genomic DNA comprises synthetic DNA molecules, produced in the laboratory by amplification, that correspond in sequence to a naturally occurring genomic DNA. A preparation of cDNA comprises synthetic DNA molecules, produced in the laboratory by amplification, that correspond in sequence to a naturally occurring mRNA. Considered in this light, I think that the distinction DOJ makes between "excised" genomic DNA versus "engineered" cDNA proves largely illusory.

True, a cDNA molecule has a slightly different chemical structure than the mRNA on which it is based, but the differences are small. The sugar group (ribose) in DNA is lacking an oxygen atom (hence the “deoxy”), and one of the four base groups in RNA (uracil) is slightly different than the corresponding base in DNA (thymine), due to replacement of a methyl group with a hydrogen atom. But mRNA and its corresponding cDNA both encode the same information, and both hybridize to the same complementary strand.

In many instances, a synthetic copy of a genomic DNA molecule is also chemically different from the original. Most naturally occurring genomic DNA is methylated, a form of epigenetic modification, while synthetic copies are often not methylated.

In short, the minor structural difference between cDNA and mRNA is not so qualitatively different than the difference between amplified genomic DNA and genomic DNA of natural origin to warrant using this distinction as the basis for drawing a line between patent eligible and patent ineligible subject matter.

Summary of Myriad Patent Claims Under Attack in AMP v. PTO

2010-11-04T14:36:00.001-05:00

Today I published a short article in Managing IP "discerning" Myriad's patent claims, currently under attack in AMP v. PTO . The article is available here for subscribers to Managing IP, along with other materials relating to the Myriad case.

The substance of my article is as follows:

As a preliminary matter, it bears noting that the precise contours of Myriad's patent claims are not entirely clear. Claim interpretation is a notoriously unpredictable exercise, and no court has ever formally construed the claims, or considered their scope in the context of infringement litigation. In fact, no US court has ever interpreted a human gene patent claim in a case involving genetic diagnostic testing. In an amicus brief filed with the Federal Circuit in AMP v. PTO, the author (Holman) and Robert Cook-Deegan explain that if the claims were ever enforced in an infringement suit there are reasons to believe that the claims would not be interpreted as broadly as many critics of gene patents have assumed. The following analysis is based on a facial reading of the claims in view of the patent specifications, as well as statements made by the district court and by Myriad.

The challenged patent claims recite subject matter falling under general three categories: isolated DNA molecules claimed as compositions of matter, methods of diagnostic testing, and cell-based assay methods. Importantly, none of the claims encompass DNA as it exists naturally in the human body, and none of the claims recite mere genetic information. Thus, popular allegations that the patent claims confer ownership on people's bodies, or can be used to prevent a doctor from communicating the existence of a genetic predisposition to cancer to a patient, would appear to be unfounded.

Isolated DNA claims
All of the composition of matter claims are limited to "isolated" DNA molecules, and hence clearly do not encompass genomic DNA as it exists naturally in the human body. This is consistent with long-standing patent office policy which requires claims directed to naturally occurring DNA molecules to be limited to isolated, purified and/or recombinant embodiments of the molecule, in order to prevent the patent from covering native genes in the human body

There is, however, some uncertainty with respect to exactly how broadly the term "isolated" should be interpreted. Myriad's patent specifications define the term to encompass any DNA sequence that has been “removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analog biologic synthesized by heterologous systems." Many in the biotechnology community have assumed that claims to "isolated" DNA molecules broadly encompass the claimed sequence in any context outside its native environment, such as residing in a recombinant DNA vector, cell or organism. However, there is little US case law directly addressing the proper interpretation of the term "isolated" in this context, and there is reason to believe that if litigated the term might be given a narrower construction, at least in some cases (depending, for example, on how the term "isolated" is used in the patent specification and in communications to the patent office during patent prosecution).

Some of the composition of matter claims encompass any isolated DNA that codes for a full length BRCA1 or BRCA2 protein. These claims are relatively broad in the sense that they would appear to cover any of the astronomical number of redundant DNA sequences that would encode the BRCA1 protein. They also arguably cover genomic DNA coding for the protein, i.e., the isolated gene as it exists in the human body. Assuming the courts gives the term "isolated" an expansive reading, the claims arguably cover very large recombinant molecules that comprise the BRCA coding sequence (i.e., large DNA vectors), as well as recombinant cells or organisms comprising the coding sequence in a non-native context.

Although many have assumed that claims directed towards DNA encoding full-length BRCA proteins can be used to block genetic diagnostic testing, in fact these claims would not appear to be infringed by standard genetic diagnostic testing. In conventional BRCA diagnostic testing, segments of the BRCA gene are amplified and sequenced, not the entire full-length genomic sequence. As a consequence, the full-length coding sequence is not made or used, and thus there would seem to be no infringement (see Holman/Cook-Deegan amici brief). The claim would however appear to cover a recombinant DNA molecule encoding a full-length BRCA protein, which could be used in drug discovery research or, potentially, gene-based therapy.

There are also a variety of narrower isolated DNA claims at issue. For example, some of the isolated DNA claims are limited to a specific cDNA molecule encoding a BRCA protein. These claims are relatively narrow, and could be readily circumvented in many instances by simply using a different DNA sequence that encodes the same protein (which is trivial given the redundancy of the genetic code and the general availability of whole gene synthesis). Although the district court found the cDNA claims patent ineligible, the government argues in its amicus brief that while isolated genomic DNA is patent ineligible, cDNA is patent eligible because it does not exist in nature (cDNA is essentially a DNA version of a naturally existing RNA molecule).

Some of the claims recite any isolated DNA having least 15 nucleotides of a DNA sequence encoding full-length BRCA protein. These claims appear on their face to be extremely broad, encompassing conventional BRCA genetic diagnostic testing (because the testing involves amplification of fragments of the BRCA gene exceeding 15 nucleotides in length). However, a recent bioinformatics study suggests that the breadth of these claims could render them invalid based on anticipation by genetic sequences published in GenBank more than one year before the patents’ filing dates (see Holman/Cook-Deegan amici brief).

Method of diagnosis claims
The method of diagnosis claims are generally directed towards processes of "analyzing" a person's BRCA gene sequence for the existence of a naturally occurring mutation or genetic variation, or “comparing” two BRCA sequences in order to identify the existence of a variation. Critics of gene patents have argued that these method claims broadly cover the mere mental process of analyzing or comparing genetic sequence information, and this was the interpretation of the district court in its summary judgment opinion. However, in their appellant brief Myriad argues for a narrower interpretation, explaining that when the claims are read in light of the specification it is clear that the claims require "extracting, processing and analyzing” DNA molecules, not merely an analysis or comparison of genetic information.

The scope of these method claims could be significant. For example, in the not-too-distant future it is predicted that many people will have their whole genome sequenced. With this information in hand, one could then look for medically significant genetic variations, such as variations in the BRCA gene. Under the district court's broad interpretation, the method claims might be infringed by a doctor or patient merely analyzing the genetic information, which is one of the fears voiced by critics of gene patents. On the other hand, under Myriad's proposed interpretation merely analyzing genetic information would not constitute infringement.

Cell-based assay methods
One of the challenged patent claims recite a method of using recombinant cells engineered to express a BRCA protein to screen for potential cancer drugs. This claim clearly has no implications for genetic testing, and it is unclear why the ACLU chose to challenge its patent eligibility.

Links to Holman/Cook-Deegan and DOJ Amicus Briefs Are Now Operational (I think)

2010-11-01T11:54:00.000-05:00

On Friday I thought I posted links to amicus briefs filed by Holman/Cook-Deegan and DOJ in AMP v. PTO, but turns out they were not operational, I believe the problem has been corrected. Just in case, the link to Holman/Cook-Deegan brief is here. Please let me know if still not working (they work on my computer).

Two Amicus Briefs Filed in ACLU Gene Patent Case: Holman/Cook-Deegan and DOJ

2010-10-29T19:48:00.001-05:00

Robert Cook-Deegan and I just submitted an amicus brief in AMP v. PTO, the ACLU challenge to Myriad's gene patents, available here. The brief was filed on behalf of neither party, but we ask the court to reverse the district court on its determination that the claims at issue are patent ineligible.

Robert Cook-Deegan directs the Center for Public Genomics, Duke University, which conducted eight case studies of the impact of patenting and licensing on genetic testing for ten clinical conditions commissioned by the US Secretary’s Advisory Committee for Genetics, Health and Society, published in April 2010.

A brief submitted by the DOJ on behalf of neither party is available here.

DOJ asks the court to reverse the district court’s invalidation of the composition claims that are limited to cDNAs and similar man-made constructs, but affirm the district court’s conclusion that the claims encompassing isolated human genomic DNA are invalid.

Here are Summaries of the Arguments:

Holman/Cook-Deegan:

In their zeal to address perceived public policy concerns associated with
Myriad’s gene patents, and more particularly Myriad’s controversial business and
patent enforcement practices, plaintiffs have invoked the recently re-invigorated
patent eligibility doctrine in a manner that threatens to wreak substantial collateral
damage on future innovation in genetic diagnostic testing, personalized medicine,
and biotechnology in general. DNA patents have created incentives critical in
attracting the substantial investment necessary to fuel the discovery and
development of life-saving products produced by the biotechnology industry.
Although plaintiffs have identified numerous potential concerns with gene patents
in the context of some types of genetic diagnostic testing, to date there is
insufficient evidence that harms attributable to patents on genes justify broad,
subject matter-based invalidation of all patents made of or based on DNA. More
appropriate and targeted legal and policy solutions to problems associated with
some gene patents and patent enforcement practices are preferable to the blunt
doctrinal instrument of patent eligibility. The decision below should be reversed in
order to prevent substantial unintended negative consequences for innovation in
this increasingly important technology sector, and to enable adjudication of
patentability using other tools that are more appropriate to the task

.

DOJ:

Section 101 marks the “threshold” of the patent system. Bilski v.
Kappos, 130 S.Ct. 3218, 3225 (2010). It not only “defines the subject
matter that may be patented,” ibid., but simultaneously defines what
must remain in “‘the storehouse of knowledge of all men * * * free to all
men and reserved exclusively to none,’” ibid. (quoting Funk Brothers
Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948)); see Bonito
Boats, Inc. v. Thundercraft Boats, Inc., 489 U.S. 141, 151 (1989) (the
patent laws “determine not only what is protected, but also what is free
for all to use”). The boundary between eligible and non-eligible subject
matter is defined, in significant part, by the settled principle that the
patent laws do not embrace laws of nature, physical phenomena, or
abstract ideas. See Bilski, 130 S.Ct. at 3225.
In attempting to apply that principle here, the district court
erroneously cast doubt on the patent-eligibility of a broad range of manmade
compositions of matter whose value derives from the informationencoding
capacity of DNA. Such compositions — e.g., cDNAs, vectors,
recombinant plasmids, and chimeric proteins, as well as countless
industrial products, such as vaccines and genetically modified crops,
created with the aid of such molecules — are in every meaningful sense
the fruits of human ingenuity and thus qualify as “‘human-made
inventions’” eligible for patent protection under section 101. J.E.M. Ag
Supply, Inc. v. Pioneer Hi-Bred Int’l, Inc., 534 U.S. 124, 130 (2001)
(quoting Diamond v. Chakrabarty, 447 U.S. 303, 313 (1980)). The
district court therefore erred in invalidating the challenged composition
claims, such as claim 2 of the ‘282 patent, that are directed solely to
cDNAs.
The district court correctly held, however, that genomic DNA that
has merely been isolated from the human body, without further
alteration or manipulation, is not patent-eligible. Unlike the
genetically engineered microorganism in Chakrabarty, the unique
chain of chemical base pairs that induces a human cell to express a
BRCA protein is not a “human-made invention.” Nor is the fact that
particular natural mutations in that unique chain increase a woman’s
chance of contracting breast or ovarian cancer. Indeed, the relationship
between a naturally occurring nucleotide sequence and the molecule it
expresses in a human cell — that is, the relationship between genotype
and phenotype — is simply a law of nature. The chemical structure of
native human genes is a product of nature, and it is no less a product of
nature when that structure is “isolated” from its natural environment
than are cotton fibers that have been separated from cotton seeds or
coal that has been extracted from the earth.
The scope of Section 101 is purposefully wide and its threshold is
not difficult to cross. See Bilski, 130 S.Ct. at 3225. New and useful
methods of identifying, isolating, extracting, or using genes and genetic
information may be patented (subject to the prohibition against
patenting abstract ideas), as may nearly any man-made transformation
or manipulation of the raw materials of the genome, such as cDNAs.
Thus, the patent laws embrace gene replacement therapies, engineered
biologic drugs, methods of modifying the properties of plants or
generating biofuels, and similar advanced applications of biotechnology.
Crossing the threshold of section 101, however, requires something
more than identifying and isolating what has always existed in nature,
no matter how difficult or useful that discovery may be.

The ACLU Gene Patent Challenge: Analysis of Myriad's Brief

2010-10-26T08:21:00.000-05:00

Yesterday I posted a link to the brief filed last Friday by Myriad Genetics with the Federal Circuit in the case of AMP v. PTO (ACLU and Public Patent Foundation challenge to gene patents). In their brief, Myriad argues that (1) the district court should have dismissed the case for lack of jurisdiction, because there was no evidence of any real or immediate dispute between Myriad in any plaintiff; (2) composition of matter claims directed towards isolated DNA molecules are patent eligible, in part because they have "markedly different characteristics" than their naturally occurring counterparts; and (3) method of diagnosis claims are patent eligible, in part because they all require physical transformation of a DNA sample (i.e., isolation, processing and analysis) that satisfies the Bilski machine-or-transformation test.

Lack of Jurisdiction

Myriad argues that the 20 plaintiffs were all recruited by the ACLU and Public Patent Foundation (referred to herein collectively as ACLU) in order to further those group’s agenda of abolishing gene patents, and that there is no evidence of any current dispute between Myriad and any of the plaintiffs. According to Myriad, only three of the plaintiffs have ever been contacted by Myriad, and those three were contacted more than a decade before the filing of the complaint. Myriad argues that none of the plaintiffs has a controversy "of sufficient immediacy and reality to warrant the issuance of a declaratory judgment" under the MedImmune standard.

Composition of Matter Claims

Myriad begins by arguing that the district court was incorrect in its conclusion that "products of nature" are patent ineligible, pointing out that such a "sweeping exception" would bar the patenting of important inventions like pharmaceuticals derived from natural sources (e.g., Taxol), and would be inconsistent with cases finding isolated natural products patentable that date back nearly 100 years.

Myriad goes on to argue that even if the district court is correct, and isolated products of nature are only patent eligible if they display "markedly different characteristics" compared to the product as exists in nature, Myriad's isolated BRCA gene sequences clearly satisfy the test. Myriad points out that it is inconsistent for plaintiffs to argue on the one hand that the claimed isolated BRCA molecules are necessary for performing BRCA diagnostic testing, while at the same time arguing that the claimed isolated molecules have no "markedly different characteristics" from their naturally occurring counterparts. They note that native DNA is useless for the diagnostic and detection applications for which the isolated molecules must be utilized.

Myriad addresses the much discussed dissent by Judge Dyk in his separate opinion in Intervet, which many have interpreted as signaling his skepticism with respect to the patent eligibility of isolated gene sequences. In his opinion, Judge Dyk suggested that it "would be difficult to argue, for instance, that one could patent a leave of a plant merely because the leaves do not occur in nature in an isolated form." Myriad points out that not only would Judge Dyk’s hypothetical leave likely fail under sections 102 and 103 for lack of novelty and obviousness, it would fail the "markedly different characteristics" test "because the plucked leaf would have exactly the same properties as the unplucked leaf-unlike here, where isolated DNA molecules possess significantly different structural and functional characteristics from native DNA."

Method Claims

Critics of Myriad's gene patents have complained that the claims are much too broad, claiming the information content of the BRCA genes, and totally precluding doctors and patients from looking at or discussing the presence of genetic variations in the BRCA genes. For example, some of the challenged method claims could be interpreted broadly to cover comparing a patient's BRCA sequence with wild-type BRCA in order to identify genetic variations (which could be clinically significant).
However, in their brief Myriad argues for a narrower interpretation, under which all the method claims could only be infringed by a party that isolates and analyzes DNA molecules (as opposed to genetic sequence information). This could be a significant limitation that avoids some of the fears that have been raised with respect to the inability to design around these patent claims. For example, I am reading a book called The $1000 Genome, by Kevin Davies, which describes new technology that is rapidly coming online which will enable people to inexpensively determine the sequence of their entire genome. Salzberg and Pertea recently published an article in Genome Biology called "Do-It-Yourself Genetic Testing,” (described recently on the Patent Docs blog), which purports to allow a person who knows her BRCA sequences to analyze for variations predictive of cancer. It seems to me that in the not-too-distant future method claims such as Myriad’s could be readily circumvented by having one's whole genome sequenced (without asking the sequencer to analyze for BRCA mutations), and then using a computational screen such as the one provided by Salzberg and Pertea to analyze for clinically relevant variations.

Myriad argues that because its method claims all require isolation and processing of DNA molecules, they satisfy the transformation prong of Bilski's machine or transformation test. They correctly note that the Federal Circuit's Prometheus decision explicitly held that diagnostic methods that involve processing a biological sample "necessarily involve a transformation,” and thus pass the machine or transformation test. The Supreme Court in Bilski v. Kappos clarified that the machine or transformation test is not the exclusive test for patent eligibility, but acknowledged that in most instances the existence of a machine or transformation is highly relevant to the question of patent eligibility. The Supreme Court vacated the Federal Circuit's original Prometheus decision, and remanded for the Federal Circuit to reconsider in light of Bilski v. Kappos. I predict that when the Federal Circuit issues a new decision in Prometheus, it will maintain the holding that diagnostic methods involving physical manipulation of biological samples are transformative and generally patent eligible.

Myriad goes on to point out that Bilski v. Kappos "remove any suggestion that the rigid 'machine-or-transformation' test provides the exclusive test for patent eligibility, particularly as applied to "Information Age" technologies like the advanced diagnostic techniques claimed injury and patents." In contrast with the method of hedging claims found to be unpatentable abstract ideas in Bilski, Myriad argues that its methods represent "very real ways of diagnosing and treating cancers."
Interestingly, Myriad does not address the question of whether its method claims impermissibly encompass a natural phenomenon. Supreme Court precedent makes clear that natural phenomena are patent ineligible, and prior to the Federal Circuit's In re Bilski decision most patent eligibility challenges to biological method claims (particularly diagnostic claims) focused on arguments that the method claim preempted the practical use of a natural phenomenon. I have discussed this often on this blog, particularly with respect to the Prometheus and Classen cases, and Justice Breyer's often cited dissent from LabCorp.

Predictions?

I don't have a good sense as to how the Federal Circuit will decide the issue of jurisdiction, it seems to me that the threat of being sued for patent infringement was nonexistent for many of the plaintiffs, and highly speculative for others.

However, I do think that if the Federal Circuit finds jurisdiction it will uphold the validity of isolated polynucleotide claims and methods of diagnosis claims, so long as those method claims require the performance of physically transformative processes (isolation, processing and analysis of molecules).

On the other hand, a broad method claim that could be infringed by the mere analysis of genetic information, without requiring any physically transformative step, would I think face a significant threat of invalidation for patent eligibility under Bilski. I suspect this is why Myriad is arguing for a narrower interpretation.

Myriad Files Brief in AMP v. PTO

2010-10-25T18:44:00.000-05:00

Myriad filed its brief with the Federal Circuit last Friday in its appeal of the district court decision in AMP v. PTO, which found Myriad's gene patents to be patent ineligible. The brief is available here, I will provide some commentary tomorrow.

Yeda Appeals Board Decision Favoring Abbott in TBP-II Interference

2010-10-03T20:22:00.000-05:00

Abbott and the Yeda Research and Development Co. have been involved in a patent interference since 1996 over the right to patent TNF-alpha Binding Protein II (TBP-II, also known as TNF receptor 2). This is a therapeutically and commercially relevant protein. ENBREL (etanercept), a biologic drug developed and marketed by Immunex (now Amgen) for the treatment of autoimmune disease, is a fusion protein comprising the Fc component of human immunoglobulin G1 and TBP-II. I don't know what the specific commercial implications of the patent interference are, but clearly the parties view the patent as sufficiently valuable to justify the cost of a prolonged interference contest. A corresponding patent application claiming the genetic sequence encoding TBP-II was the subject of an important 2004 Federal Circuit decision relating to the written description requirement (In re Wallach).

The interference involves a patent issued to Abbott (5,344,915) and Yeda’s US patent application. The inventor on the Yeda application is Wallach (claiming common priority to the application at issue in In re Wallach). The interference was declared by the patent office in 1996, and resulted in a "Final Decision" by the Board of Patent Appeals and Interferences (the Board). In this decision, the Board invalidated Abbott's patent as anticipated by a prior art reference. Abbott claimed priority to two German applications that would have predated the invalidating prior art reference, but the Board denied Abbott the benefit of these two earlier filing dates. The Board essentially held that the German applications did not satisfy the written description requirement of section 112 with respect to the claimed invention.

The German applications disclosed an isolated protein, defined in terms of its approximate molecular weight and an incomplete N-terminal sequence. The applications also disclosed the source of the protein (the urine of patients with fever) and the method used to purify the protein. Abbott's US patent claims the protein as a "purified and isolated TNF-alpha binding protein which has a molecular weight of about 42,000 daltons and has at the end terminus the amino acid sequence [the specific amino acid sequence of the N-terminus of TBP-II]” The critical difference between the patent claims and the disclosure in the German applications is the N-terminal amino acid sequence. In the German applications, there was some uncertainty about the exact N-terminal sequence, and some amino acids in the sequence were not disclosed. These ambiguities were addressed and resolved in the subsequent filed US patent.

The Board’s decision was based on its determination that the earlier incomplete disclosure failed to adequately describe the more complete amino acid sequence provided in the ultimately issued claims. Abbott argued that the proteins described in the US patent claims and the German applications are the same, as demonstrated by the fact that they have the same molecular weight, bind specifically to TNF-alpha, are isolated from the same source (urine from patients with fever), and isolated and purified using the same methods. In essence, Abbott argued that the German applications inherently disclosed the later claimed protein. However, the Board rejected this argument, finding that the record failed to establish to the necessary degree of certainty that TBP-II was inherently disclosed in the German applications, and noting that "inherency may not be established by probabilities or possibilities."

Abbott appealed the Board decision under 35 USC 146 to the District Court for the District of Columbia. In 2008 the District Court granted Abbott's motion for summary judgment, vacated the Board's final decision and remanded to the Board for further proceedings. The District Court was obliged to review the Board's decision under the "clearly erroneous" standard, but even under this deferential standard of review the court reversed the Board, holding that the German applications inherently disclosed the later claimed protein to a degree of certainty sufficient to satisfy the written description requirement. The court rejected alleged ambiguities raised by Yeda (and accepted by the Board) with respect to the identity of the protein disclosed in the German applications.

Yeda appealed the district court decision to the Federal Circuit, but in 2009 the court dismissed the appeal, holding that they did not have jurisdiction to hear the case prior to a final decision in the interference.

On remand, the Board granted Abbott priority benefit of the German applications, and in May 2010 awarded judgment in the interference to Abbott.

On September 9, 2010, Yeda filed its appeal under 35 USC 146, again in the District of Columbia, challenging the Board's decision. It seems likely the case will continue on for at least several more years, since the District Court's decision will begin be subject to appeal to the Federal Circuit (which should have jurisdiction to hear the case since a final decision will have been rendered in interference).

It interesting to compare this case with Goeddel v. Sugano, a September 7 Federal Circuit decision regarding a patent interference over mature human fibroblast interferon (beta interferon). At issue were claims directed to the mature form of the protein, and the DNA encoding the mature form of the protein.

The mature form of fibroblast interferon is produced by cleaving a 21 amino acid presequence from the N-terminal of precursor fibroblast interferon. Sugano attempted to claim priority to a Japanese application that disclosed the full length precursor protein, and also disclosed the N-terminal sequence of the mature protein. Based on this disclosure, clearly anyone that knows anything about molecular biology would know the sequence of the mature protein - it is simply the portion of the disclosed precursor protein sequence that begins with the N-terminal sequence of mature protein.

However, whoever drafted Sugano’s Japanese patent application (filed more than 30 years ago) apparently did not see the need to point out the obvious, and thus there is no explicit disclosure in the application specifically pointing out the sequence of the mature protein. Because the Japanese application failed to connect the dots, the Federal Circuit held that the Japanese patent application did not satisfy the requirements of section 112 first paragraph (enablement and/or written description), and as a result awarded priority to Goedell.

It seems to me a good argument could be made that the Sugano Japanese application inherently but unambiguously disclosed the sequence of the mature protein. This strict application of the written description requirement is arguably inconsistent with the relatively lenient standard applied by the District Court in reversing the first Board decision in the interference involving Abbott and Yeda.

I say arguably, because even though both interferences involve claims directed to proteins, the facts are quite distinct. In Yeda v. Abbott, the court found that the claimed protein was the same protein disclosed in the priority applications, even though the earlier disclosure provided less detail with respect to the amino acid sequence of the protein. In Goeddel v. Sugano, on the other hand, the priority document provided the full amino acid sequence of the later claimed protein, but failed to explicitly point out the distinction between the mature protein and the precursor protein from which it is derived.

Glaxo Fires Latest Shot in Patent Battle with Genentech over Therapeutic Molecule Antibodies

2010-09-29T22:15:00.000-05:00

On September 20, Glaxo Smith Kline (Glaxo) sued Genentech for infringement of US patent numbers RE40,070 and RE41,555 in the District of Delaware. The patents claim methods of purifying monomeric IgG antibody using hydrophobic interaction chromatography. GSK alleges in its complaint that Genentech's production of therapeutic monoclonal antibody products, specifically Herceptin, infringes the patents. Herceptin is an important monoclonal antibody therapeutic used to treat HER2 positive breast cancer. The complaint is available here.

The lawsuit is the latest volley in an ongoing patent war between GSK and Genentech over recombinant monoclonal antibody technology. Most of the patents that have been asserted are directed towards general methodologies used in the production and formulation of monoclonal antibody therapeutics.

For example, in 1999 Glaxo sued Genentech for allegedly infringing US patent numbers 5,545,403 and 5,545,405 (both generally claiming methods of treatment using recombinant antibody glycosylated by Chinese hamster ovary (CHO) cells), and US patent numbers 5,654,403 and 5,792,838 (both directed towards methods of stabilizing antibody formulations using copper chelators). Glaxo alleged that the patents were infringed by Genentech's production of Herceptin and Rituxan, two cancer drugs that target breast cancer whose tumors over express the HER2 protein and CD20 positive, B-cell non-Hodgkin's lymphoma, respectively. A district court held for Genentech, finding all of the asserted Glaxo claims invalid and/or not infringed. The case settled while on appeal to the Federal Circuit.

In 2000, Glaxo sued Genentech for allegedly infringing US patent number 5,633,162, which claims methods of growing CHO cells in a serum-free medium. While the complaint does not specifically identify the allegedly infringing Genentech products, Genentech reported in a filing to SEC that it assumed that the lawsuit was directed towards Herceptin and Rituxan. This case settled early in the litigation.

In 2009, Glaxo received FDA approval to market Arzerra, an anti-CD20 approved for the same indication as Genentech's Rituxan (chronic lymphocytic leukemia). Thus, the two products can be viewed as direct market competitors, perhaps biosimilars (we are still awaiting guidance from FDA as to criteria for biosimilarity under the new biosimilarity legislation passed by Congress as part of healthcare reform).

In 2009, Glaxo filed a declaratory judgment action in the Southern District of Florida seeking a judgment of invalidity, unenforceability and noninfringement with respect to Genentech's patent number 6,331,415. This patent is widely referred to as the “Cabilly II” patent, and came out of a highly publicized interference between Genentech and Celltech. The patent broadly covers the co-expression of immunoglobulin heavy and light genes in a single host cell. Genentech has been quoted as stating that the patent is "the backbone of recombinant antibody production in the biotech industry." Genentech has already asserted the patent against MedImmune and Centocor, alleging that those companies’ production of monoclonal antibodies products Synagis, ReoPro and Remicade infringe the patent. The litigation between Genentech and MedImmune resulted in a Supreme Court decision on standing of a patent licensee to bring a declaratory judgment action action challenging the patent. Genentech successfully moved to have the litigation transfer to the Central District of California, where the Centocor and MedImmune litigations are located.

In 2010, Genentech (along with Biogen Idec, its partner in the marketing of Rituxan) sued Glaxo in the Southern District of California for allegedly infringing US patent number 7,682,612. The patent claims methods of treating chronic lymphocytic leukemia using an anti-CD20 antibody, and thus invalid would appear on its face to be infringed by Arzerra. This case is somewhat noteworthy, since it is the only one in which the patent is specifically directed towards an antibody recognizing a specific antigen (CD20), as opposed to the other patents all relating to general methods of antibody production and formulation.

Jury Finds Scruggs Willfully Infringed Monsanto Patents, Award at Least $9 Million in Damages

2010-09-28T21:03:00.000-05:00

10 years ago Monsanto sued farmers Mitchell and Eddie Scruggs (collectively referred to as "Scruggs") for infringing patents relating to genetically modified Roundup Ready soybean seeds and Bollgard-containing cotton seeds. The case has resulted in numerous judicial decisions, including three Federal Circuit decisions, most notably Monsanto v. Scruggs, 459 F.3d 1328 (Fed. Cir. 2006). Scruggs raised numerous arguments against Monsanto, including first sale/patent exhaustion, implied license, lack of sufficient written description and enablement, as well as allegations of patent misuse and antitrust violations.

Nonetheless, Monsanto has prevailed, and on September 21 a jury in the Northern District of Mississippi found that Monsanto is entitled to $2.6 million for Scruggs unauthorized planting of saved crop seeds contain the patented genes, and $6.3 million for their sale of saved soybean seeds containing the Roundup Ready gene (a practice referred to as "brown bagging"). Not only that, the jury found that the infringement was willful, which means that the court can enhance the damages up to triple the amount found by the jury, or close to $30 million. Based on history, I would not be surprised if Scruggs continues to appeal, perhaps stretching this out a few more years.

District Court Denies Novozymes Motion for Preliminary Injunction in Battle for Control of the Alpha-Amylase Market

2010-09-28T20:58:00.000-05:00

On September 24, 2010, a federal district court in the Western District of Wisconsin denied a motion for preliminary injunction in a patent lawsuit between two of the leading companies in the field of genetically engineered industrial enzymes, Novozymes and Genencor (a division of Danisco). The two companies are essentially the only competitors in the market for alpha-amylases, used to convert corn into fuel ethanol. According to the order (available here) denying preliminary injunction, Genencor dominated the alpha-amylase market until 1999, when Novozymes entered the market with Liquozyme, a genetically engineered thermostable alpha-amylase. At one point, Liquozyme accounted for more than 80% of the alpha-amylase sold in the fuel ethanol market. In 2008, Genencor responded by introducing its own genetically engineered thermostable alpha-amylases (called GC358). Since then, Novozymes market share has dropped approximately 60%.

The patent being asserted by Novozymes, US patent number 7,713,723 (the ‘723 patent) claims priority to a patent application originally filed in 2000. The original patent application was broadly directed toward alpha-amylase mutants having increased stability at “high temperature and/or low pH conditions, in particular at low calcium concentrations.” However, the claims that ultimately issued in the ‘723 patent, which recite thermostable alpha-amylase variants comprising "a substitution of serine at position 239 relative to the parent alpha-amylase," were not added until 2009, apparently in response to Genencor's marketing of GC358, which presumably includes this mutation. Prior to the introduction of these claims in 2009, the patent application contained no disclosure specifically directed towards substitution of serine at position 239.

Importantly, the '723 patent does not cover Liquozyme, over for that matter any Novozymes product. Liquozyme presumably possesses improved thermostability over the wild type enzyme as a result of a different mutation or set of mutations.

In deciding a motion for preliminary injunction, courts essentially consider four factors: (1) the likelihood the patent owner will ultimately prevail on the merits in the case (i.e., the patent will be found infringed and not invalid); (2) the extent to which the patent owner will experience "irreparable harm" if the infringement is not stopped immediately; (3) the balance of the interests of patent owner an accused infringer; (4) and the public interest. In this case, the district court found that all these factors weighed in favor of Genencor, and denied Novozymes’ motion for preliminary injunction.

Irreparable Harm
The district court decision began by addressing the issue of irreparable harm, the factor which the court found likely to be dispositive by itself. Novozymes argued that it would suffer irreparable harm in the form of diminished reputation, loss of market share and price erosion if Genencor's product were allowed to remain on the market during the course of the litigation. However, the court pointed out that Genencor had entered the market with GC358 in 2008, but that the patent did not issue until May 2010, so that most of Novozymes’ loss in market share occurred when it was perfectly legal for Genencor's product to be on the market. The court surmised that most of the customers who would be inclined to switch from Liquozyme to GC358 had probably already done so, and thus most of the alleged harm identified by Novozymes had already occurred prior to issuance of the patent.

In assessing irreparable harm, the district court found the fact that the patent does not cover any product marketed by Novozymes to be quite significant, pointing out that while Novozymes’ argument that sale of GC358 would harm its reputation "could be persuasive if plaintiffs actually sold a product that practiced the ‘723 patent[,] it is difficult for plaintiffs to argue that their good reputation is contingent on their ability ‘to uniquely make and sell [their] patented alpha-amylase’ when they are not even using the claim technology themselves and identify no plans to do so."

The district court went on to speculate that if "plaintiffs are not trying to protect their own right to provide consumers a product that embodies the patent, then it may be that the patent is nothing more than weapon to prevent defendants from competing with them." In other words, the court seems put off by the fact that Novozymes is not practicing the technology claimed in their patent, treating them as something akin to a non-practicing entity (sometimes referred to as a patent troll).

Likelihood of Success on the Merits
The court also expressed doubt with respect to the likelihood that Novozymes would succeed on the merits of the case, based on the court's determination that there was a substantial likelihood that the asserted patent claims are invalid for lack of enablement and lack of sufficient written description. Both the enablement and written description issues arise out of the failure of the originally filed patent application to sufficiently point out and identify the later claimed substitution of serine at position 239. The patent application identified 33 amino acid positions (including position 239) in alpha-amylase which allegedly can be modified by amino acid substitution, deletion or insertion to result in some increased stability under high temperature and/or low pH conditions. It does not, however, particularly point out position 239, nor does it particularly point out substitution with serine (one of 20 amino acids commonly found in proteins), and it does not correlate the specific mutation particularly with thermostability. Genencor pointed out that the patent specification identified 8.589 x 1042 possible amino acid substitutions, deletions and insertions, and now Novozymes was attempting to claim one of those possibilities that had subsequently been shown by Genencor to provide thermostability.

This case illustrates the difficulty the inventors of genetically engineered proteins face when attempting to obtain adequate patent protection for their inventions. Protein sequence space is vast, and in most cases in which a sequence variant of a protein has been found to have some desirable functional characteristic, there are an astronomical number of alternate sequence modifications that will result in the same functional outcome. I have described this problem in a law review article (available here), and more recently in my amicus brief filed in Ariad v. Lilly (available here). Essentially, the written description and enablement requirements limit the ability of protein engineers to claim protein variants in functional terms, resulting in claims limited to enzyme sharing some degree of structural similarity to variants explicitly disclosed in the patent application. This allows competitors to design around the patent by screening for alternate structural modifications to the amino acid sequence that result in the desired function, as exemplified Genencor’s product that apparently shares the desirable functional characteristics of Novozyme’s product but employs a different structural modification to the amino acid sequence.

Balance of Harms
The court found that the balance of harms in this case favored Genencor, finding that if Genencor were forced off the market the company might "very will be crippled and unable to recover even if the injunction is lifted after the trial." On the other hand, the court found that Novozymes was essentially "asking for assistance in maintaining a monopoly at least until the end of trial."

Public Interest
The fact that Novozymes is not marketing a product covered by the asserted patent also counted against them in the court’s analysis of the effect of an injunction on the public interest. The court found that if Genencor's GC358 were taken off the market customers would be deprived of the patented invention entirely for the course of the litigation proceedings, since Novozymes is not marketing any product covered by the patent. The court found it "somewhat inconsistent for plaintiffs to be arguing on one hand that the ‘723 patent represents an important new invention and then argue on the other hand it should make no difference if no one is allowed to actually use it.”

BIO Files Amicus Brief Supporting Eli Lilly Petition for En Banc Rehearing of Sun . Lilly

2010-09-09T14:14:00.000-05:00

Yesterday the Biotechnology Industry Organization filed an amicus brief supporting Eli Lilly in its petition for en banc rehearing of Sun v. Lilly, a recent Federal Circuit decision pertaining to the doctrine of obviousness-type double patenting, and discussed in a previous post. I participated in the drafting of the BIO amicus brief, a copy of which can be found here.

Sun Pharmaceuticals v. Eli Lilly: The Creeping Expansion of the Doctrine of Obviousness-Type Double Patenting

2010-09-02T16:32:00.001-05:00

In Sun v. Eli Lilly, a panel of the Federal Circuit held a Lilly patent claiming use of the drug gemcitabine (GEMZAR) for the treatment of cancer invalid for obviousness-type double patenting, in view of an earlier Lilly patent claiming the drug per se and its originally discovered use as an antiviral agent. The invalidated patent was set to expire on November 7, 2012, 2.5 years after the expiration of the patent claiming the drug active ingredient (May 15, 2010), so this could result in a substantial reduction in Lilly’s period of marketing exclusivity. Lilly is currently seeking en banc reconsideration by the Federal Circuit.

Sun represents the most recent in a series of Federal Circuit decisions expanding the scope of the judge made doctrine of obviousness type double patenting. In this article, I briefly summarize the history of the expansion, and outline why I think the court should take this opportunity to reconsider the implications of these cases en banc.

Eli Lilly's patent prosecution decisions that resulted in a finding of obviousness type double patenting

It is informative to review the facts of the case. In the early 1980s, a Lilly scientist invented a method for synthesizing a genus of chemical compounds including gemcitabine, something others had previously attempted but failed to accomplish. He also showed that the compound had antiviral activity. Lilly filed a patent application disclosing the genus of chemical compounds and their use as antiviral agents.

The original inventor of the compound, along with a second Lilly inventor, then discovered that gemcitabine has anticancer activities, so these inventors filed a second application claiming methods of using the drug to treat cancer. This application did not claim priority to the first application.

On the same day Lilly filed the second application, it also filed a CIP of the first application. In retrospect, this was a critical mistake. The CIP was apparently filed to expand upon the definition of the disclosed genus of compounds, basically by adding to it species wherein certain R groups could be hydrogens. Significantly, this added disclosure was not necessary in order to patent gemcitabine, since gemcitabine was disclosed in the originally filed patent application.

At that time, there was some uncertainty with respect to the extent to which it was necessary to update the best mode when filing a CIP application (this uncertainty was ultimately addressed in 1994 in Transco). In any event, presumably in an attempt to ensure compliance with the best mode requirement, Lilly also added disclosure of the anticancer properties of the chemical compounds in the CIP.

Ultimately, the CIP application resulted in a patent claiming the drug active ingredient as a composition of matter, and also methods of using it as an antiviral agent. Later, the second patent application issued with claims to methods of using the drug to treat cancer. In Sun v. Lilly, it was the disclosure of anticancer activity added to the first patent by means of the CIP application which was used as the basis for invalidating the second patent claiming that use. In the next section, I explain why this represents a significant expansion of the doctrine of obviousness type double patenting.

The creeping expansion of obviousness type double patenting

The Federal Circuit has established a two-step process for analyzing obviousness type double patenting. First, the court construe the claims in the earlier patent and the claims in the later patent, and determines the differences. Second, it determines whether those differences render the claims patentably distinct.

One fundamental distinction between analysis for obviousness under section 103 and obviousness type double patenting is that when analyzing for double patenting only the claims of the two patents are to be considered. As the Federal Circuit stated in 1992 in General Foods v. Studiengesellschaft Kohle, its "precedent makes clear that the disclosure of a patent cited in support of a double patenting rejection cannot be used as though it were prior art.”

However, in the 2002 decision of Geneva v. GSK, the Federal Circuit began chipping away at this prohibition against using the written description of the earlier patent to invalidate the second patent, and embarked upon what has become a creeping expansion of the doctrine. In that case, the earlier patent claimed a drug active ingredient. The written description portion of the earlier patent also describes a method of using the drug to treat a disease, but significantly, this use of the drug is never mentioned in the patent claims. Nonetheless, the panel used this disclosure in the written description of the first patent to invalidate a second patent claiming that method of use.

This seems to fly in the face of General Foods and the controlling case law. However, the Geneva panel justified its decision to go outside the claims of the first patent in its analysis by reasoning that the claim in the earlier patent "is drawn to a compound having a certain physical property," and thus, "[s[tanding alone, that claim does not adequately disclose the patentable bounds of the invention. Therefore, this court examines the specifications of those patents to ascertain any overlap in the claim scope for the double patenting comparison."

Although the Geneva panel states that it needed to refer to the written description of the first patent to determine the extent of overlap between the claims in the two patents, this explanation does not appear to survive close scrutiny. The claims in the first patent broadly recite chemical compound, with absolutely no limitation respecting the use of the compound. It is black letter law that a patent claiming a chemical compound dominates all uses of the compound as defined by the claims, including methods of using the compound that are not disclosed in the patent specification, and methods that were nonobvious and not even contemplated at the time the patent was filed. While it is undoubtedly appropriate to consult the entire specification in construing the scope of a patent claim, it is unnecessary to consult the specification for methods of using a compound when ascertaining the scope of a patent claim directed to the compound as a composition of matter.

Although the Geneva panel’s use of disclosure in the written description as a basis for invalidating the second patent is questionable, at least the panel provided a policy justification for his decision. The panel correctly noted that in order for chemical compound to be patentable, the patent applicant must disclose a utility for the compound. Since the earlier patent only identified a single utility for the claimed drug, the disclosure of that use was necessary for the patentability of the chemical compound. Thus, while it was incorrect for the panel to suggest that the disclosure of the method of use in the written description was relevant to the question of claim scope, it was clearly relevant to the question of patentability.

The Geneva panel stressed that since the earlier patent disclosed only a single utility of the compound, the claims of the second patent reciting nothing more than that disclosed utility as a method was not patentably distinct. In essence, the panel's decision can be rationalized as a policy of not allowing a second patent on a method of use if that method of use was critical to the patentability of the first patent claiming the molecule per se.

Five years later, the Federal Circuit again was faced with an allegation of double patenting involving a first patent claiming a drug active ingredient and a second patent claiming methods of using the drug active ingredient. In Pfizer v. Teva, the panel once again went beyond the language of the patent claims, and invalidated the second patent because the method of use claimed was disclosed in the written description section of the earlier patent.

Significantly, in Pfizer the first patent disclosed multiple uses of the composition, and the invalidated claims encompassed only some subset of those uses. Thus, the facts of Pfizer are distinguishable from those in Geneva, where the method of use claim was directed to the sole utility disclosed in the earlier patent, and thus presumably necessary takedown to the validity of the first patent. Thus the rationale to justify the Geneva decision, i.e., that the claimed method of use was critical to the patentability of the first patent, does not appear to exist in Pfizer. In effect, Pfizer expanded the rule set forth in Geneva, by holding that the disclosure of multiple uses of a molecule in the first patent renders unpatentable later claims directed towards any of those methods.
The Pfizer decision provides no policy justification for this expansion of the Geneva doctrine, and fails to even acknowledge the expansion. Nonetheless, one might justify it on policy grounds by pointing out that by disclosing multiple methods of use in the original patent application, the inventor was able to stake a claim of priority to these multiple uses by securing an early effective filing date. By choosing to avail itself to this earlier effective filing date, the patent applicant (arguably) should be limited to a single term for all of the patents issuing out of this single priority document.

We then come to the Sun v. Lilly decision, in which the panel further expands the holdings in Geneva and Pfizer by interpreting those decisions as creating a bright line rule that any use disclosed in a patent claiming a drug active ingredient precludes the owner of the patent from obtaining any second patent on one of the disclosed method of use, regardless of whether the claimed method of use was disclosed in the original patent application which provides the effective filing date for the first patent. Unlike the earlier cases, the method of use claimed in the second patent was not disclosed in the originally filed application to which the first patent claims priority.

Note that putative policy justifications for the Geneva and Pfizer decisions do not appear to be present in Sun. Unlike Geneva, the second patent does not claim a method of use that was critical to the patentability of the first patent. The first patent disclosed use of the compound as an antiviral agent, and the patent office issued patent claims directed towards use of the compound as an antiviral, raising a presumption that this is a valid practical utility which would confer patentability on the compound, regardless of the later disclosure of the anticancer activity. Furthermore, unlike the case in Pfizer, the later claimed method of use (anticancer) was not disclosed in the originally filed patent application that led to the first patent, so this first patent application was not available to Lilly to provide an effective priority date for the method of treating anticancer.

In fact, Lilly only ran afoul of obviousness type double patenting because it voluntarily chose to update and supplement the disclosure of the first filed patent application with the disclosure of anticancer activity. They could have avoided the problem by simply prosecuting the originally filed patent application to obtain patent claims covering the drug active ingredient, which it seems clear did not require disclosure of the additional material added by amendment to the CIP. If they wanted to expand the genus of chemical compounds, they could have filed the CIP as a divisional, thereby avoiding the need to add disclosure of the anticancer activity to the gemcitabine composition of matter patent.

In short, if Lilly had a crystal ball and could have foreseen the recent expansion of obviousness type patenting, it could have easily avoided obviousness type double patenting by simply altering its patent filing procedure. But this illustrates how the holding in Sun elevates form over substance.

The decision seems to conflict with 35 USC 103(c)

Congress amended the patent statute by introducing 35 USC 103(c), which basically shields companies from having the inventions of a company’s inventors rendered obvious by prior art created by other inventors at the same company. Congress’s intent was to encourage follow-on innovation and intra-company collaboration.

Originally, 103(c) only included 102(f) and 102(g) prior art, but it was subsequently amended to also include 102(e). In effect, Congress explicitly decided that commonly owned inventions should not be subject to invalidation for obviousness based on subject matter disclosed in a commonly assigned earlier filed patent application. Sun stands congressional intent on its head. By ignoring General Foods, it effectively allows the court to invalidate a patent based on a finding that it claims subject matter that is obvious in view of subject matter disclosed in the specification of an earlier filed commonly assigned patent application. But it goes even farther than that, for in Sun invalidity was based on subject matter added after the effective filing date, and thus not available as 102(e) prior art.

The biotech industry would benefit from en banc review of this issue

A number of issues raised by this and decision that would seem to warrant en banc review. There is clearly a tension between General Foods and Sun and its predecessors. While General Foods states that only the patent claims are to be compared, Geneva opened up the door to using the written description of the earlier patent to invalidate a later patent. In Pfizer and Sun, the door has opened wider and wider. The Federal Circuit should acknowledge this expansion of judge made law and consider whether it is justified by public policy considerations. If the court chooses to go down this route, it should delineate the boundaries of the expanded doctrine.

For one thing, it is unfair to patent owners to change the laws of patentability in a manner that invalidates a valuable patent for patent prosecution decisions made based on the case law at the time. In Festo, the Supreme Court stressed the importance of not altering the law in a way that undercuts the investment backed expectations of the inventive community.

Moving forward, some clarity on the issue would be very helpful. Today's inventors should understand the consequences of adding disclosure to a patent application, in order to rationally decide when to file a patent application, what to include in the disclosure, and when to invest in follow-on research.

For example, based on the Sun decision the wisest course for drug companies would be to file their original composition of matter patent application with a minimal disclosure of methods of using the compound sufficient to satisfy the utility requirement. There is an incentive to prioritize follow-on research on uses not disclosed in the original application, because presumably those uses will not be precluded from being patented separately. Companies might be less inclined to pursue research and development of methods of use disclosed in the earlier patent application, but perhaps that is a reason for the court to rethink the course it has embarked upon.

But who is to say for sure that the doctrine will not be expanded in subsequent decisions to cover methods of use that are not even disclosed in the earlier specification? It would certainly be consistent with the progressive expansion we have seen in going from Geneva to Pfizer to Sun. Uncertainty with respect to the availability of patent protection is a disincentive to future investment in innovation, and it would be nice if the en banc Federal Circuit would clarify the boundaries of the obviousness type double patenting doctrine sooner rather than later.

Intervet v. Merial Limited: Judge Dyk Offers His Views on Patent Eligibilty of Isolated DNA Sequences

2010-08-05T11:52:00.000-05:00

A dissenting opinion by Judge Dyk in Intervet v. Merial Limited, decided by the Federal Circuit on August 4, contains interesting ruminations on the patent eligibility of patent claims broadly reciting an isolated, naturally occurring genetic sequence, indicating that at least this Federal Circuit judge is not at all convinced that isolation of a naturally occurring DNA sequence is sufficient to render it patent eligible. The patent eligibility of isolated naturally occurring DNA sequences is one of the key issues at stake in AMP v. USPTO, the ACLU/PubPat challenge to Myriad’s BRCA gene patents, discussed in earlier posts. In AMP, the district court agreed with the ACLU that a product of nature, such as a gene, can only be patent eligible if it has been transformed by human intervention to an extent that confers upon the product "markedly different characteristics from any found in nature,” and that the mere isolation of a gene does not result in the requisite qualitative difference in characteristics. Based on this determination, the court ruled that Myriad’s claims to isolated DNA corresponding in sequence to naturally occurring BRCA sequences were patent ineligible and thus invalid.

Significantly, the question of patent eligibility was not before the court in Intervet. The only issues on appeal to the Federal Circuit related to the district court's interpretation of the claim language and judgment of noninfringement. Judge Dyk, however, in his opinion concurring-in-part and dissenting-in-part with the majority, goes out of his way to point out that the validity of the claims was not before the court on appeal, and to make clear that the court’s decision to construe the claims should not be inferred as implying that the claims are patent eligible.

Judge Dyk acknowledges that the Federal Circuit has upheld the validity of gene patents on a number of occasions, but correctly points out that none of these cases directly address the question of whether the claims satisfy the patent eligibility requirements of section 101. Implicitly, he is suggesting that if the issue of patent eligibility had been raised with respect to gene patent, the Federal Circuit might have ruled that isolation of a naturally occurring DNA sequence does not render it patent eligible.

He goes on to note that "it appears that in order for a product of nature to satisfy section 101, it must be qualitatively different from the product occurring in nature, with "markedly different characteristics from any found in nature," based on his reading of relevant Supreme Court precedent such as Chakrabarty and Funk Brothers. He then concludes that

It is far from clear that an ‘isolated’ DNA sequence is qualitatively different from the product occurring in nature such that it would pass the test laid out in Funk Brothers and Chakrabarty. The mere fact that such a DNA molecule does not occur in isolated form in nature does not, by itself, answer the question. It would be difficult to argue, for instance, that one could patent the leaves of the plant merely because the leaves do not occur in nature in the isolated form.

Clearly the Judge's discussion of the patent eligibility of isolated DNA was prompted by the ACLU gene patent challenge. The validity of the claims at issue in Intervet was never addressed by the district court, and was not at issue in the appeal, let alone patent eligibility. The Federal Circuit has decided numerous cases involving isolated DNA sequences, and to my knowledge has never directly addressed the issue of patent eligibility for isolated, naturally occurring DNA sequences.

However, in 1991 a panel of the Federal Circuit did address the highly pertinent question of whether an isolated naturally occurring protein is patent eligible, and seemed to acquiesce. The case, Scripp’s Clinic v. Genentech, involved the alleged infringement of a Scripps patent claiming isolated Factor VIII:C protein. The defendant, Genentech, never challenged the patent eligibility of isolated naturally occurring protein, not surprising since this position would be entirely inconsistent with its own patenting of isolated proteins and DNA sequences. However, the district court decision included a footnote 6 explicitly concluding that a purified protein is patent eligible under section 101, citing Funk Brothers and In re Bergstrom:

There is no dispute over the patentability of a Factor VIII:C preparation. Although Factor VIII:C molecules occur in nature, a purified and concentrated preparation of Factor VIII:C as claimed in the patent constitutes a new form or combination not existing in nature, and hence is patentable under 35 U.S.C. § 101. See Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 68 S.Ct. 440, 92 L.Ed. 588 (1948); In re Bergstrom, 427 F.2d 1394, 1401 (C.C.P.A.1970).” Scripp’s Clinic v. Genentech, 666 F.Supp. 1379 (1987).

On appeal, the Federal Circuit in Scripp's did not affirmatively state that a purified protein is patent eligible, but merely noted that "judicial attention has on occasion focused on the patentability of claims in this context, see, e.g., In re Bergstrom, 427 F.2d 1394, 166 USPQ 256 (CCPA 1970)," and that Genentech had conceded that the claims were patent eligible. Scripp’s Clinic v. Genentech, 927 F.2d 1565, 1580-81 (Fed. Cir. 1991).

Significantly, the pre-Federal Circuit cases cited in support of the proposition that an isolated naturally occurring biomolecule is patent eligible do not specifically address the issue of patent eligibility under section 101, but are instead based on arguments based on alleged lack of novelty or obviousness, as discussed in a previous post.

In essence, the district court in Scripp’s inferred that because earlier decisions had upheld the patentability of claims to isolated biological molecules, they must be patent eligible. On appeal, the Federal Circuit in Scripp’s simply accepted the patent eligibility of the isolated protein, arguably implicitly accepting the patent eligibility of this sort of invention. I think Judge Dyk raise the issue in Intervet in order to go on record that the Federal Circuit addressed questions of claim construction and infringement should not be taken as tacit endorsement of patent eligibility for isolated biomolecules, an issue that the court will likely address head-on in the appeal of the ACLU lawsuit.

With so many gene patents, and patents claiming naturally occurring proteins and other biomolecules, and so much litigation involving these patents, why has the issue of patent eligibility never been directly addressed before? One explanation is that until the ACLU got involved, the parties to patent litigation have never had an interest in having these sorts of claims found to be patent eligible. Normally, the party arguing that a gene or protein patent claim is invalid is either a biotechnology company, like Genentech, or the patent office in cases like Bell or Deuel , where in a patent applicant is appealing the rejection of a gene patent claim. Biotechnology companies rely heavily on these patents themselves, and the patent office has concluded that isolated DNA and other molecules is patent eligible.

Gene chip company Affymetrix has argued in amicus briefs that isolated genes are patent ineligible, but they have never been sued for infringement of a gene patent, so have never had the opportunity to raise the issue as a party to litigation. The ACLU case is unique in that you have plaintiffs who do not own gene patents, but to the contrary would like to eliminate them.

The fact that Judge Dyk chose to express his thoughts in this manner is somewhat ironic in view of the recent controversy over statements made by Judge Rader at conferences relating to gene patents. The ACLU has moved to have Judge Rader recuse himself from sitting on a panel to decide the ACLU case, based on the ACLU’s assertion that Judge Rader's statements indicate that he believes that isolated DNA sequences appear to be patentable. (Discussed here, for example) Arguably, Judge Dyk has expressed the opposite view, albeit in the form of a formal opinion rather than as a conference speaker.

Judge Dyk speculates that "it is far from clear" that isolated DNA is qualitatively different from the corresponding DNA as it occurs in nature, i.e., having markedly different characteristics from naturally occurring DNA. However, I would point out that the biotechnology revolution has been based in large part on the ability to isolate and manipulate DNA. Biologic drugs such as recombinant human erythropoietin, for example, were only made possible because scientists succeeded in isolating the erythropoietin gene.

Biotechnology is fundamentally based on the ability to do amazing things with isolated genes that cannot be accomplished with the corresponding gene as it exists in the human body. In my view, even if the Federal Circuit decides that an isolated biomolecule is only patent eligible if it has markedly different characteristics from naturally occurring counterpart, isolated DNA sequences (along with isolated forms of proteins and other biomolecules) should clearly satisfy the test.

Monsanto v. Cefetra: EU Court of Justice Limits Scope of Patent Protection Available to Gene Sequences

2010-07-09T16:37:00.000-05:00

A couple of years ago I posted an article (available here) discussing the case of Monsanto v. Cefetra. Essentially, in that case a European court held that Monsanto patents claiming the gene responsible for its Roundup Ready trait were not infringed by the importation of soy meal containing the gene, because the grinding of the soybeans to make the meal rendered the DNA incapable of expressing the encoded protein, and thus unprotectable pursuant to the 1998 European Union Directive on biotechnology.

On Tuesday, July 6, that decision was affirmed by the Court of Justice of the European Union. This is the highest judicial body of the European Union, so there will be no further appeals, and this would appear to be the final word on the subject. The decision was reported in an article posted on IPKat, a respected European IP blog, available here. I am no expert on European law, but here are a few thoughts on the significance of this case.

First, my interpretation of the decision.

In a nutshell, the Court of Justice held that although the so-called Biotech Directive, promulgated by the European Union in 1998, permits the patenting of naturally occurring DNA sequences, the scope of patent protection only extends to products incorporating the DNA if the DNA is capable of performing “the function for which it was patented." Applying this criterion to the facts of the case, the Court held that the patentable function of the gene at issue was to confer glyphosate (i.e., RoundUp) resistance upon a plant, and that since the soy meal is dead and thus incapable of expressing this function, the DNA residing in the soy meal is ineligible for patent protection.

The Court went on to hold that the Biotech Directive supersedes national law, and precludes individual European nations from enacting legislation that would permit patenting of DNA sequence per se. It also held that the prohibition against patenting DNA sequences per se applies retroactively to patents predating the EU’s adoption of Directive in 1998. In short, this unappealable ruling appears to be binding upon all 27 European Union Member States, and all DNA patents, no matter when they were issued.

The ruling could have a substantial impact on biotechnology. Obviously, it provides an opening for growers to circumvent gene patents used to protect genetically modified crops by growing the crops in a country where the gene is not patented, such as Argentina in this case, or in a jurisdiction with weak patent enforcement, and then importing the product into a European Union member wherein the patent is in force with impunity.

According to the logic of the decision, if viable seeds were imported, they would likely be found infringing because the DNA would still be capable of performing the function for which it was patented. But if the product has been processed, and as a result no longer viable, as exemplified by the soy meal at issue in this case, importation should not be found to constitute infringement.

The ruling could also have implications for the scope of protection afforded by gene patents for genetic diagnostic testing. Genetic diagnostic testing, such as by DNA sequencing, typically involves the isolation and/or amplification of the gene sequence being tested. This isolation and amplification might be characterized as the manufacture of the DNA, which could constitute infringement of a patent claiming the DNA sequence. For example, the ACLU challenge to Myriad’s BRCA gene patents is based in part on an assumption that the patent claims reciting isolated BRCA sequences would be infringed by unauthorized testing for mutations in the BRCA genes (which typically involves DNA sequencing).

However, this assumption is premised on the patents covering the isolated DNA sequences per se. But arguably, the isolated and amplified DNA fragments generated in the course of DNA sequencing and testing are not capable of performing their function, and thus after this week’s Court of Justice decision are ineligible for patent coverage in the European Union.

Of course, this would depend upon how one defines the "function of the patented gene. For example, one might argue that one important function of BRCA sequences claimed in Myriad’s patents is for diagnostic testing, and hence isolated DNA sequences generated in the course of genetic testing are performing a function for which they are patented

However, under a more restrictive view the function of the BRCA genetic sequences is to code for the BRCA protein product, i.e., the actual physiological function of the BRCA gene in the human body. Myriad’s patents specifically discuss use of the isolated BRCA gene for production of the BRCA protein in a recombinant cell, which could be a useful research tool in drug discovery. As discussed in earlier posts relating to the ACLU lawsuit, I point out that in practice BRCA testing does not involve the amplification of the full length BRCA coding sequence, but only amplicons representing fragments of the gene. These fragments would not be capable of achieving the function of expressing the full-length protein, and thus arguably lack the requisite functional potential.

I think reasonable minds could go either way on the issue, but given the current level of antipathy towards the use of gene patents to block genetic diagnostic testing, I can envision a European court adopting a restrictive interpretation of what it means for a genetic sequence to be capable of performing its patentable function, and decide that gene patent coverage does not extend to use of the genetic sequence in diagnostic testing.

In a related context, the Court’s decision could have implications for the effect of gene patents on whole genome sequencing. There is much buzz these days regarding the imminent arrival of personal whole genome sequencing, which will permit individuals to have their entire genome sequenced for a relatively small amount of money. Some have worried that a thicket of gene patents might impede the ability of firms to provide whole genome sequencing. However, DNA “manufactured” in the course of whole genome sequencing is unlikely to be found capable of performing the function of individual patented genetic sequences residing therein, in which case genome sequencing would not result in patent infringement liability in Europe.

I personally do not think gene patents will substantially impede whole genome sequencing, in the US or elsewhere. But if I am wrong, and patents on genes pose a substantial impediment to whole genome sequencing in the US, the patents could be circumvented by exporting the process to a place like Europe. The EU court decision could substantially reduce the likelihood that whole genome sequencing in Europe will result in liability for patent infringement.

On the other hand, the ruling should not affect the ability of biotechnology companies to use gene patents to protect their biologic drugs. In this context, the patented gene is performing its primary function of expressing the protein encoded by the gene, and thus satisfies the criterion established by Tuesday's decision of the Court of Justice.

The Impact of Bilski on Biotechnology

2010-07-03T11:22:00.000-05:00

Prior to the Federal Circuit’s 2009 en banc decision in In re Bilski (Bilski I), the Supreme Court had established a test for patent eligibility that was quite straightforward in the abstract, albeit fraught with uncertainty as to how the test should be applied in practice. In a series of decisions, mostly dating from the 1970s and early 1980s, the Court established that essentially any man-made process or product is eligible for patent protection so long as the patent claims do not cover what the court characterized as a "fundamental principle." In these decisions, the Court identified a number of specific categories of patent ineligible fundamental principles, including principles of nature, natural phenomena, abstract ideas and mental processes.

As a practical matter, up until a few years ago patent eligibility was rarely an issue for those attempting to patent inventions relating to biotechnology. So long as there was some element of human intervention, such as isolation of a gene sequence or genetic engineering of a living organism, biotechnology inventions were generally assumed to be eligible for patent protection. Patenting of biotechnology flourished, notwithstanding the protests of many who argued that some inventions based on fundamental biological discoveries, particularly gene patents and patents broadly claiming the practical exploitation of fundamental biological discoveries (such as physiological correlations useful in the diagnosis and treatment of disease), or unsuited for patent protection and should be treated as patent ineligible.

In Bilski I, a majority of the judges on the Federal Circuit badly misinterpreted Supreme Court precedent and declared the so-called "machine or transformation" test to be the universal and exclusive criterion for determining the patent eligibility of all process claims, including by implication processes relating to biotechnology. In essence, Bilski I shifted the patent eligibility inquiry from whether a claimed biotechnology process covered a fundamental principle (i.e., a natural phenomenon) to whether the process entailed sufficient involvement of a machine or transformation

The machine or transformation test was subsequently used as the basis for invalidating a number of biotechnology process claims, including Myriad’s claims to methods of detecting mutations in BRCA genes. The PTO also began to employ the machine or transformation test to reject biotechnology claims, particularly those relating to diagnostics and personalized medicine. Some commentators, including myself, expressed concern that the machine or transformation test, as mandated by Bilski I, threatened to seriously undermine the ability of companies and researchers engaged in the discovery and commercialization of diagnostics and personalized medicine to obtain adequate patent protection for their inventions, although these concerns were to some extent allayed by the Federal Circuit’s restrained application of the test to a personalized medicine patent claim in Prometheus v. Mayo.

Fortunately, the Supreme Court agreed to hear an appeal of Bilski I, and last Monday the Court decided the case, formally titled Bilski v. Kappos (Bilski II), in a manner that effectively rejected the Federal Circuit's interpretation of the machine or transformation test. The Court held that while the involvement of a machine or transformation in a claimed process is often informative in assessing patent eligibility, it is not a general prerequisite for patent eligibility, and admonished the Federal Circuit that the test for patent eligibility remains whether or not the patent claims encompass a fundamental principle.

In essence, the Supreme Court has turned back the clock, negating Bilski I and the Federal Circuit's ill-conceived experiment with the machine or transformation test. Significantly, however, the Supreme Court provided little if any guidance with respect to what it means for a patent to claim a fundamental principle, and absolutely no guidance with respect to how to apply the test when the fundamental principle is a biological natural phenomenon, leaving it to the lower courts to sort out this important issue
I predict that the issue of patent eligibility for biotechnology inventions, both products and processes, will continue to be actively litigated well into the foreseeable future, as courts and the patent office struggle to figure out just what exactly it means for a patent claim to cover a biological natural phenomenon. In this article, I summarize important developments in the patent eligibility doctrine leading up to and including Bilski II, particularly as they relate to biotechnology, and discuss the issues relating to patent eligibility that will need to be addressed in a post-Bilski world.

Patent Eligibility Prior to LabCorp

There are four requirements of patentability which an invention must satisfy in order to be patentable : patent eligibility, practical utility, novelty and nonobviousness. The first, patent eligibility, has been characterized as the threshold criterion, used to exclude purported inventions that are useful and innovative, but nonetheless unsuited for and hence ineligible for patent protection.

Prior to the advent of modern biotechnology, some biological subject matter, particularly living organisms, were generally considered patent ineligible. This explains why Congress saw fit to enact legislation explicitly creating alternate forms of intellectual property protection for plants (plant patents and plant variety protection certificates). However, with the increasing commercial significance of biotechnology in the 1970s, the question of whether living organisms and other biotechnological inventions of were eligible for patent protection became of increasing importance, and in 1980 the Supreme Court answer to the question in the affirmative in its landmark Diamond v. Chakrabarty decision.

In Chakrabarty, the Supreme Court essentially held that any man-made product or process is patentable, so long as the patent does not purport to claim a "fundamental principle." In Chakrabarty and other Supreme Court decisions relating to the doctrine of patent eligibility, the Court has at various times identify specific categories of fundamental principles, including natural phenomena, physical phenomena, principles of nature, abstract ideas, and mental processes.

As a practical matter, after Chakrabarty patent eligibility was not a major issue for biotechnology. So long as there was some degree of human intervention, biotechnology inventions were generally deemed patent eligible by the patent office and the courts. While living organisms and other biological organisms could not be patented as they exist in nature, genetic engineering of an organism was deemed sufficient to render the non-naturally occurring modified organism patentable. Similarly, isolation of a naturally occurring DNA sequence was deemed sufficient human intervention to render the isolated molecule patentable.

It was not until the Supreme Court granted certiorari in LabCorp v. Metabolite in 2005 that patent eligibility once again took on significance in the context of biotechnology. The patent at issue in lab were was based upon the discovery of a natural correlation between the level of total homocysteine (a naturally occurring metabolite) in the human body and existence of a vitamin B deficiency. Based on this discovery, the patent broadly claimed any method of detecting a vitamin B deficiency that involves assaying a patient's blood for total homocysteine content and correlating elevated total homocysteine with such a deficiency. Although the issue of patent eligibility was never directly addressed in the lower courts, the Supreme Court agreed to hear the case specifically to address the question of whether or not the patent violated the prohibition against the patenting of fundamental principles, i.e., natural phenomena, principles of nature and abstract ideas.

Upon further consideration, however, the Supreme Court had second thoughts about taking the case, and dismissed the LabCorp appeal without deciding it. However, three of the Justices signed on to a dissenting opinion penned by Justice Breyer stating that they considered the claimed process patent ineligible for embodying the natural phenomenon of a correlation between total homocysteine and vitamin B deficiency. Although this dissenting opinion by three of the nine justices has absolutely no binding legal authority, it has proven highly significant because at least established the viability of asserting the doctrine of patent eligibility to challenge patents based on fundamental biological discoveries, particularly patents broadly encompassing the use of natural correlations in a diagnostic method, which had become increasingly common with the emergence of genetic diagnostic testing and personalized medicine.

Patent eligibility after LabCorp

No doubt encouraged by Justice Breyer's dissent, accused infringers began raising the defense of patent ineligibility in patent infringement litigation. Three of these cases, Ariad v. Lilly, Classen v. Biogen, and Prometheus v. Mayo, have been extensively discussed in previous articles on my blog. Significantly, in all three of these cases the case for patent ineligibility was based upon an argument that the challenged claims effectively preempted all practical uses of a biological natural phenomenon, essentially the same rationale propounded by the dissenting justices in LabCorp.

These patent ineligibility-based challenges met with mixed success at the district court level. In Ariad, the district court rejected the challenge, based on a rationale that frankly made absolutely no sense to me. In any event, the issue was rendered moot because the court ruled the claims invalid on the alternate grounds that the claims violated the written description requirement, decision that was ultimately affirmed by the en banc Federal Circuit.

However, in Classen and Prometheus the district court found for the accused infringers and held the asserted claims patent ineligible for broadly preempting the practical exploitation of biological natural phenomena. The patent owners both appealed their cases to the Federal Circuit, but before the Federal Circuit heard the cases issued its en banc decision in Bilski I, which effectively changed the test for patent eligibility, as discussed in the next section.

Patent eligibility in the time between Bilski I and Bilski II

In Bilski I, the Federal Circuit essentially ignored Supreme Court precedent establishing that the test for patent eligibility is based on an inquiry into whether the patent claims a fundamental principle, and announced that the test for patent eligibility of any process claim was whether or not the claimed process included sufficient involvement of a machine or transformation. Bilski I was flawed in a number of regards. For one thing, the holding that no process could be patent eligible without substantial involvement of a machine or transformation was entirely inconsistent with Supreme Court precedent. In attempting to justify its holding, the Bilski I majority pointed to Supreme Court precedent suggesting that a process involving a machine or transformation must be patent eligible, and concluded that this meant that a patent eligible process must include a machine or transformation, a fundamental error in logic that effectively transformed a safe harbor for patentees into an absolute prerequisite for patent eligibility.

As I explained in an earlier article, the machine or transformation test is fundamentally inappropriate for assessing patent eligibility of some processes, especially those involving biotechnology. In crafting the test, the court seemed focused on the perceived problem of so-called business method patents and the like, such as the specific patent claims issue in Bilski I, and erred by declaring the test applicable to all process claims, without adequately considering the implications.

Despite its flaws, Bilski I was an en banc decision of the Federal Circuit, and thus controlling law on the subject absent Supreme Court intervention. Even though Classen and Prometheus were both decided at the district court level prior to Bilski I, based on arguments that focused on alleged preemption of biological natural phenomena, by the time the appeals made it to the Federal Circuit the law had shifted, and as a consequence the parties had to change their arguments to focus upon the involvement (or lack thereof) of a machine or transformation in the claimed processes.

The Federal Circuit decided Classen first, and upheld the district court determination, concluding that the claim, which was originally held invalid or in compassing a natural phenomenon, was invalid for failing to satisfy the machine or transformation test. The decision was only a few sentences in length, and provided absolutely no explanation as to the basis for the court’s decision.

The Federal Circuit then issued a lengthy decision in Prometheus, this time reversing the district court and finding the challenged patent claims to be patent eligible. Specifically, the Federal Circuit found that the steps of administering a drug and determining the level of drug metabolites in a patient's body were both sufficiently transformative to satisfy the machine or transformation test.

The Bilski I machine or transformation test was also the basis relied upon by the district court in invalidating the method claims in the ACLU/Myriad gene patent case, as discussed in previous posts to this blog.

Bilksi II

In Bilski II, the Supreme Court identified the flawed logic in Bilski I, and rejected the Federal Circuit’s machine or transformation test, holding that while the presence of a machine or transformation in a process claim can be relevant in assessing the patent eligibility, there is no general requirement that a patent eligible process include a machine or transformation. The Court reiterated that the test for patent eligibility hinges upon whether or not the claim encompasses a fundamental principle, and held that because the claims at issue were directed towards an abstract idea, one of the fundamental principles expressly identified in earlier Supreme Court decisions, they were patent ineligible.

In essence, Bilski II has voided the Bilski I decision and turned back the clock to where we were prior to Bilski I. The patent eligibility of biotechnological inventions is still very much in play, and there will be much for the courts and patent office to sort out over the next years, but the focus will again be upon figuring out what it means for a patent claim to cover a fundamental principle, not whether it involves a machine or transformation.

The Supreme Court has vacated the Federal Circuit decisions in Classen and Prometheus, and sent those cases back to the Federal Circuit to decide based on Bilski II. Since Bilski II is essentially the law prior to Bilski I, this will require the Federal Circuit to consider the arguments that were actually made a district court level which focused upon preemption of biological natural phenomena, the correct test for patent eligibility. To a large extent, the Federal Circuit will be working on a blank slate. Although the Supreme Court has made clear that the determination of patent eligibility should be based on an inquiry into whether the patent claims encompass a biological natural phenomenon, the Court has provided very little specific guidance as to how this test is to be applied in practice.

An alleged failure to comply with the machine or transformation test was the basis for the invalidation of Myriad’s method claims in the ACLU gene patent challenge. These were the broadest and most relevant of the claims challenged in the case. In my view, Myriad’s product claims directed to polynucleotides are either highly susceptible to invalidation based on prior art (this applies to the fragment claims) or clearly not infringed by BRCA testing (the full-length coding sequence claims). I also think it is highly likely that the Federal Circuit will reverse the lower court’s ruling these product claims are patent ineligible.

However, I thought that the Federal Circuit would probably uphold the finding of patent ineligibility for some of Myriad’s method claims broadly claiming the detection of mutations in the BRCA genes. The processes recited in these claims did not seem to require the use of any machine or transformation, and the district court was probably correct in holding that the claims failed the machine or transformation test.

I think it is pretty apparent that if the district court had decided the case prior to Bilski I, or subsequent to Bilski II, it would have found the method claims patent ineligible for preempting natural phenomena. It just so happened that the district court decided the case during the brief tenure of the machine or transformation test, and thus through no fault of its own conduct the analysis based on the incorrect test. It remains to be seen how the claims will whether a patent ineligibility challenge based on the correct test as set forth in Bilski II.

Bilski II will also force the PTO to alter its examination practices. After Bilski I, the PTO began applying the machine or transformation test as a basis for rejecting patent claims, including claims relating to biotechnology methods, particularly with respect to inventions relating to diagnostics and personalized medicine. Since Bilski I was an en banc decision of the Federal Circuit, the PTO was required to implement it, but now that the Supreme Court has rejected Bilski I rejections based solely on the lack of a machine or transformation are improper. The PTO will need to either forgo rejections based upon a patent ineligibility, or if it chooses to continue on this route, to ground them in a finding of preemption of a fundamental principle, such as a biological natural phenomenon.

Patent eligibility post-Bilski II

I predict that patent eligibility will be a relevant issue for biotechnology in the foreseeable future. Now that the Supreme Court has squashed the red herring of the machine or transformation test, the focus is again upon whether a claim preempts a fundamental principle. For claims like those at issue in Bilski, including claims to so-called business methods, financial methods, and the like, the category of fundamental principle most implicated has been "abstract idea."

Biotechnology inventions do not implicate the claiming of abstract ideas, so much as the patenting of a natural phenomenon. Bilski II provided almost no guidance with respect to what it means for a patent claim an abstract idea, other than pointing out that methods of hedging risk are well known in the economics literature, and concluding that a claim directed to a method of hedging risk improperly encompasses an abstract idea. The Supreme Court has provided even less guidance with respect to what it means to claim a biological natural phenomenon.

Moving forward, the courts, and the PTO if it chooses to base rejections of biotechnology patent claims based on lack of patent eligibility, will need to grapple with two fundamental questions. First, what exactly is a biological natural phenomenon? And second, what does it mean for a patent to impermissibly claim a natural phenomenon?

The first question was addressed in Prometheus. The inventors had discovered that for certain drugs there was a relationship between the level of specific drug metabolites in a patient's body and the optimal dosage of the drug. The patent claimed a method that involved determining the level of the specific drug metabolites in a patient's body and using that information to adjust the dosage of the drug, thereby tailoring the dosage to the physiology of an individual patient, an example of a personalized medicine. The district court held that the relationship between the level of drug metabolites in a person's body and optimal dosage was a patent ineligible "natural phenomenon."

On appeal to the Federal Circuit, I filed an amicus brief arguing that the District Court had erred in this regard, and that the interaction of a man-made, non-naturally occurring molecule (such as a drug metabolite) with the human body is not a natural phenomenon. In my brief, I pointed out that characterizing the interaction of a non-naturally occurring molecule with the human body as a natural phenomenon simply because the interaction is governed by natural principles of chemistry and physiology is akin to characterizing the interaction of an airplane with the atmosphere as a natural phenomenon simply because the interaction of airplane with the air is governed by fundamental scientific principles. I also pointed out that if the interaction of a drug metabolite with the human body is treated as a natural phenomenon, then logically this implied that in general the interaction of drugs with the human body are natural phenomena, which would generally cast doubt upon the validity of many drug patents.

On appeal, the Federal Circuit avoided the issue by simply relying on the machine or transformation test, but now in the wake of Bilski II the Supreme Court has remanded the case to the Federal Circuit, and on remand I think the court needs to address head-on the question of whether or not the interaction of a drug metabolite with the human body is a natural phenomenon.

In contrast, in LabCorp the claim was based on a correlation between a naturally occurring metabolite (homocysteine) and a physiological condition (vitamin B deficiency). This looks much more like a natural phenomenon to me than the correlation between a non-naturally occurring drug metabolite and optimal drug dosage. All of the examples of natural phenomena that have been provided by the Supreme Court involve phenomena that are present absent any human intervention, such as the law of gravity or E=mC2. In Chakrabarty to Supreme Court made clear that for biological inventions human intervention is the key to determining patent eligibility. By drawing a line between biological phenomena that occurs absent human intervention and phenomena that occurs as a result of human intervention, one could have a principled basis for finding the LabCorp claim patent ineligible while upholding the eligibility of the Prometheus claims, and drug patents in general.

This approach could also be a way of dealing with gene patents. Myriad's method claims are directed towards identification of naturally occurring mutations in the BRCA gene. Like a correlation in LabCorp, the correlation between naturally occurring genetic mutation and susceptibility to cancer, or even simply the presence or absence of a national mutation, could plausibly be characterized as a natural phenomena, and therefore a claim preempting the phenomena would be patent ineligible. On the other hand, a patent claim directed towards a correlation between a genetic mutation and a person's optimal medical treatment might be fine because it is not implicate a natural phenomenon. For example, genetic testing is used to identify patients that will benefit from treatment with the cancer drug Herceptin. Since Herceptin is a non-naturally occurring drug, the correlation between genotype and response to Herceptin treatment should not be considered a natural phenomenon, and thus a patent claim directed towards this correlation would not be susceptible to the same sort of challenge that a patent claim directed more broadly simply to the mutation itself.

The benefit of this approach is that would allow some principled means for drawing a line between patent claims broadly encompassing the practical exploitation of a naturally occurring biological phenomenon, which a sizable number of people find objectionable, and patent claims directed towards drugs, personalized medicine, and specific diagnostic applications, which most would agree warrant patent protection. Many people do not like Myriad’s claims broadly directed towards identification of naturally occurring mutations in the BRCA genes, nor did they like claims of the type at issue in LabCorp, which broadly encompass the observation of naturally occurring biological correlations, but would not object to patent protection denied for more targeted protection of methods of treatment or diagnosis, or the combination of the two embodied in personalized medicine

Furthermore, the Supreme Court has failed to articulate what exactly it means to impermissibly patent such a natural phenomena. The admonition could be interpreted as a simple statement of the obvious, i.e., that it is impossible to patent a natural phenomena per se. It is well-established that only products or processes can be claimed in a patent, so inherently it would be impossible to patent a natural phenomenon per se. For example, it would be impossible to simply claim “gravity,” since gravity is neither a product or process. If the prohibition against patenting natural phenomena were interpreted this narrowly, the Supreme Court dictum regarding the patenting of natural phenomena would be entirely gratuitous, and provide absolutely no additional limitation on patenting beyond the statutory limitation of patent protection to products and processes.

However, with all the talk in Supreme Court decisions about the patent ineligibility of natural phenomena, we should assume that the Supreme Court envisions some actual limitation on the scope of patentable subject matter, implying that the prohibition must extend beyond the mere patenting of natural phenomena per se. Clearly Justice Breyer and the other dissenting justices in LabCorp saw its reach in much broader terms. The claim at issue in LabCorp was not directed towards the physiological correlation per se, but rather to a method that involves assaying the blood for total homocysteine level and using that information to diagnose the vitamin B deficiency, thus requiring substantial human and all. Nonetheless, the court concluded that this process amounted to an impermissible attempt to claim the natural phenomenon itself.

On the other hand, it cannot be the case that an invention is patent ineligible simply because it involves a practical application of a natural phenomenon. Indeed, it is difficult to imagine a technology that is not based to some extent on the practical exploitation of natural phenomena, a point made in my Prometheus amicus brief.

If there is indeed a prohibition against the patenting of natural phenomena, and the Supreme Court has repeatedly stated that there is, logically it must go further than simply barring the patent eligibility of natural phenomena per se, but it cannot go so far as to declare all inventions involving the use of a natural phenomena patent ineligible. The line must be drawn somewhere, and there is language from the Supreme Court suggesting that the line is crossed when a patent claim effectively preempts all practical uses of a natural phenomenon. It seems to me this is the most sensible place to draw the line, and this is the criterion that was applied by the district court in Prometheus.

In that case, the district court held that the process claims effectively encompass all practical uses of the natural phenomena at issue, i.e., the correlation between drug metabolite and optimal dosage. In the ACLU gene patent decision, the district court also concluded that the claims at issue effectively encompassed all practical uses of the claimed genes.

If this is correct, a determination of patent eligibility based on the patenting of a natural phenomenon will require two showings: first, a true natural phenomenon will need to be identified, and second, if a natural phenomenon is identified, that must be determination of whether the claim effectively preempts all practical uses of the phenomenon. The impact of the patent eligibility doctrine on biotechnology will depend in large part on how "preemption" is defined. For example, arguably the claim at issue in LabCorp covers any practical method of exploiting the discovery of a correlation between total homocysteine levels and vitamin B deficiency. A court might conclude that this claim is so broad it entirely preempts the practical use of the correlation, thereby preempting a natural phenomenon and thus rendering the claim patent ineligible. However, one could alternatively find that since the claim has no impact on the correlation as it exists and functions naturally in the human body, the phenomenon is not entirely preempted by the claim.

Similarly, some of the Myriad gene patent method claims broadly cover identification of mutations in the BRCA genes. One could consider this preemptive, to the extent it covers any diagnostic use of the information regarding the mutations. On the other hand, the claim does not cover the mutations as they exist in nature, nor the effect of changes in the BRCA sequence on human physiology, so arguably the claim does not preempt the natural phenomenon. Depending on how a court conducts its preemption analysis, patent in eligibility based on preemption of a natural phenomenon could have little impact on these patent claims, or if interpret more restrictively, could constitute a new in substantial obstacle to broad patent claims such as those at issue in Prometheus, Classen in the ACLU patent lawsuit.

Although the natural phenomenon category is probably the most relevant for biological inventions, mental processes has also been identified as a category of patent ineligible fundamental principle, and some biotechnology process patents might be challenged for claiming a thought process. For example, it has been argued that the LabCorp claim, the Prometheus claims, and the Myriad claims directed to methods of detecting mutations all could be infringed by a doctor simply recognizing and thinking about the claimed correlation. Some of the Myriad claims appear to be broadly directed at simply identifying or observing a mutation in a BRCA gene, which could be challenged as improperly covering the mental process of simply noting the existence of the mutation.

Biogen Launches Submarine Patent against Competing Providers of Interferon-Beta Products

2010-06-06T16:07:00.000-05:00

Biogen sells AVONEX, an interferon-beta product used in the treatment of multiple sclerosis. On May 27, Biogen filed a patent infringement lawsuit against Pfizer, Serono, Bayer (formerly known as Berlex) and Novartis for the production and sale of the competing interferon-beta products REBIF, BETASERON and EXTAVIA

Biogen's patent, which issued in 2009 and is not due to expire until at least 2026, claims priority to a British patent application filed in 1980. This is a classic example of what many would refer to as a "submarine patent”: not only does the term of the patent extend nearly 50 years after the original filing date, but the patent application was not published prior to issuance of the patent in 2009, and thus the public had no notice that this potentially blockbuster patent was pending in the US patent office.

In this article, I briefly explore the history of the asserted patent, the history of patent litigation involving the marketing of interferon-beta as a protein therapeutic, and some potentially winning arguments the defendants could raise in their defense.

History of a Biotech Submarine Patent

A submarine patent is an informal term used to describe patents which issue without warning many years after the original filing date of the application. Wikipedia has a page devoted to submarine patents, which explains that they typically arise out of two unique aspects of US patent law: (1) a 17 year term that does not start running until the date the patent is issued (only for patents arising out of an application filed prior to June 8, 1995); and (2) the secret status of patent applications that have not been published.

Prior to November 29, 2000, US patent applications were not published unless and until the application resulted in an issued patent. Even today, an applicant for US patent can choose not to allow the PTO to publish its application so long as the applicant does not seek patent protection outside the US. Without publication, the public has no notice that the application is pending in the patent office, and thus no warning prior to the issuance of the resulting patent. Some have proposed amending US patent law to require publication of all patent applications 18 months after filing, but as of yet this is just a proposal.

Submarine patents are also fostered by relatively loose continuation rules in the US, which permit an applicant to keep a patent application pending virtually indefinitely, and to freely amend the claims to encompass previously unclaimed subject matter (so long as the later claimed subject matter is adequately disclosed in the application as filed). In a previous post, I discussed the relationship between continuation practice and late claiming, and my suspicion that restrictions on continuation practice proposed by the patent office a couple years ago were largely intended to address perceived abuses of continuation practice.

A few years ago, Mark Lemley (Stanford law professor) and Kimberly Moore (currently a judge on the Federal Circuit, but at the time a law professor) wrote a law review article complaining that some patent applicants, particularly pharmaceutical companies, were abusing continuation practice to extend patent protection beyond the statutory term, a practice they refer to as "evergreening." They would likely point to Biogen's patent as an example of what they consider to be abusive continuation practice.

Biogen’s patent, US patent number 7,588,755, arose out of a patent application filed by Walter Fiers in April of 1981 (and claiming priority to a British application filed in April of 1980), which disclosed, among other things, the DNA sequence for the gene encoding interferon-beta, methods of using the gene to produce recombinant interferon-beta protein, and use of the interferon beta protein as a biologic drug for the treatment of cancer and viral conditions. The core claims, directed to the gene itself, became involved in a three-way patent interference, which eventually went before the Federal Circuit and in 1993 resulted in Fiers v. Revel, a seminal biotech patent decision that proved instrumental in the creation of what is often referred to as the "Lilly written description requirement" (the subject of the recent Ariad v. Lilly decision).

In Fiers v. Revel, the Federal Circuit affirmed the board's decision in favor of Sugano, the Japanese party to the interference, and thus denying Fiers a patent on the gene itself. Sugano’s patent on claiming the gene (5,326,859) issued on July 5, 1994, and assuming no patent term extension should expire July 5, 2011, more than 30 years after the patent application was initially filed. In this case, the long pendency between filing date and patent issuance can largely be attributed to the time consumed by the interference proceeding. According to USPTO records, Sugano’s patent is assigned to the Japanese Foundation for Cancer Research, and has never been asserted in a lawsuit.

Although Fiers lost the battle, he did not necessarily lose the war. Denied patent coverage of the gene itself, he took advantage of continuation practice and on May 25, 1995, filed a divisional application claiming priority to the 1980 British patent application. Note that the application was filed just in time to still qualify for a 17 year from date of issuance term; if the application had been filed a few weeks later it would have been subject to a 20 year term from the date the original application was filed, and thus no patent could have issued having a term extending beyond 2001.

The patent ultimately issued on September 15, 2009, with claims essentially reciting methods of using recombinantly produced interferon-beta for “immunomodulation or treating a viral conditions, a viral disease, cancers or tumors." Because the divisional application was filed prior to June 8, 1995, it was granted a 17 year term starting on the date of issuance, resulting in a patent term (assuming no extensions) that will not expire until September 15, 2026, more than 46 years after the patent application was initially filed in Great Britain.

It bears emphasizing that this sort of long delay between filing date and patent expiration is only possible for patent applications filed prior to June 8, 1995. But this case illustrates that some of these applications are still pending, and in cases where the application has not been published there is no public notice of the potential landmine that might explode for companies like Bayer and Novartis at any time.

Note that in some ways the method of treatment patent obtained by Biogen is potentially more valuable than Sugano’s gene patent. The gene patent could be circumvented by producing the interferon-beta product outside of the US, and then importing it into the US. Use of the gene outside of the US, and importation of the protein product, would not infringe a patent limited to the gene itself. In contrast, Fiers method of treatment patent could be infringed by a company selling interferon-beta in the US, regardless of where it is produced.

Furthermore, because of the long delay between the interference and the issuance of Fiers’ method of treatment patent, the term of the patent extends 15 years beyond the term of Sugano’s gene patent. Assuming that the market for interferon-beta as a therapeutic has expanded over time, the 17 years covered by Fiers’ patent is more valuable than Sugano’s 17 year term.

As an aside, note also that Sugano’s gene patent is invalid according to the holding of a recent district court decision in the ACLU challenge to Myriad’s BRCA gene patents, although I feel fairly confident that that decision will not stand (as discussed here).

Previous interferon-beta patent litigation

This is not the first patent infringement lawsuit between these parties involving interferon-beta. On July 3, 1996, Biogen filed a declaratory judgment action against Bayer (at that time Berlex) seeking a declaration that Berlex patents claiming methods for the recombinant production of interferon in Chinese hamster ovary (CHO) cells were not infringed by Biogen's method of producing its interferon-beta product (AVONEX). A district court granted summary judgment in Biogen's favor, finding no infringement.

While the case was on appeal to the Federal Circuit, the parties entered a settlement agreement allowing Biogen to stay on the market, pursuant to which Biogen agreed to pay Berlex $20 million upfront and an additional $55 million if the Federal Circuit reversed the district court’s ruling granting summary judgment in Biogen’s favor (the litigation and settlement are discussed in my article on human gene patent litigation, available here). Ultimately, the Federal Circuit affirmed the lower court's decision that Biogen did not literally infringe Berlex’s patents, but remanded the case to the district court to determine whether there was infringement under the doctrine of equivalents (Biogen v. Berlex, 318 F.3d 1132 (Fed. Cir. 2003)). However, as a result of the settlement the district court never had to decide the issue of eivalent infringement.

Potential Weaknesses in Biogen’s Case

I can imagine a couple of potential avenues by which the defendants in this case might escape liability for infringement of Biogen’s patent. For one thing, the primary use of interferon-beta products is in the treatment of multiple sclerosis. But the only independent claim in the patent recites a "method for immunomodulation or treating a viral conditions, a viral disease, cancers or tumors comprising the step of administering to the patient in need of such treatment a therapeutically effective amount of a composition comprising [recombinantly expressed interferon-beta].” A court would likely only find this claim infringed by use of interferon-beta in the immunomodulation or treatment of "viral conditions, viral diseases, cancers or tumors."

Clearly, MS is not a tumor or cancer, and to my knowledge it has not been established that it is caused by a virus. For example, an article on the website WebMD entitled Multiple Sclerosis: What Causes It? States that “[d]octors still don't understand what causes MS, but there are interesting data that suggest that genetics, a person's environment, and possibly even a virus may play a role.” The patent owner bears the legal burden of proving infringement, and without some fairly persuasive evidence showing that MS is a viral disease, I think that Biogen might have difficulty proving infringement.

There is also the issue of prosecution latches. In Symbol Technologies v. Lemelson, the Federal Circuit affirmed a lower court's determination that certain patents were unenforceable for unreasonable delays in the prosecution of the patent. In that case, the lag between filing date and patent issuance for the patents in suit ranged from 18 to 39 years.

Earlier this year, in Cancer Research Technology v. Barr Laboratories, Inc., 679 F.Supp.2d 560 (D.Del.,2010), a district court cited Symbol Technologies in ruling that a drug patent was unenforceable based on nine years of delay in prosecution.

In this case, Biogen’s patent issued about 28 years after the initial 1981 US filing date. The patent interference was limited to claims directed towards the gene itself, not claims to the method of treatment which ultimately issued in the patent, so I don't think Biogen will be able to point to the interference as an excuse for the 28 year delay. In any event, I think it is likely Biogen will need to provide some justification for the long delay or risk having its patent ruled unenforceable.

The ACLU Gene Patent Decision from an Investor's Perspective: A Black Eye for the US Patent System

2010-04-01T09:01:00.001-05:00

I am trying to put myself into the shoes of a biotechnology investor, and when I do I'm not real happy with the US patent system right now. I'm not well-versed with legal decisions dating back nearly a century dealing with the patentability of citrus fruit treated with mold resistant borax or purified tungsten, the primary case law used by the district court in its decision that the Myriad claims reciting isolated polynucleotides are patent ineligible. I'm not even that sure as to this distinction between "patent eligibility" and patent validity.

However, I do know that for years investors have been willing to invest in biotechnology based in large part upon a belief that patent protection is available for innovation in this important technological sector. For 30 years, the Supreme Court's decision in Diamond v. Chakrabarty, which held that patent protection is available for "anything under the Sun made by man,” including a microorganism modified by the introduction of naturally occurring DNA sequences, had established that in the US patents would be available for biotechnology inventions, including so-called "gene patents."

I know that years ago the US Patent and Trademark Office issued guidelines specifically finding that isolation of a naturally occurring DNA sequence can render it patentable. These guidelines point to a number of earlier decisions in which isolated biomolecules, such as human adrenaline and the molecules responsible for the smell of strawberries, were found to be patentable because the isolation of these biomolecules created a new product with distinct useful properties unavailable absent isolation of the molecules from their native source.

I might also be aware that the controversy over gene patents has been around for many years, and the Federal Circuit has never done anything to indicate that claims such as Myriad's invalidated isolated polynucleotides claims are patent ineligible. In fact, in In re Fisher, decided I believe around 2005, a panel of the Federal Circuit explicitly address the patentability of EST sequences, short segments of naturally occurring genetic DNA. In that case, Affymetrix submitted an amicus brief arguing that naturally occurring genetic sequences are patent ineligible, citing essentially the same case law and rationale as used by the district court in ACLU case. Even though the argument was presented to the Federal Circuit, it never gave any indication in its decision that the argument had any legs.

And look at Europe, which after years of debating the issue has come around to what we thought was the US position, and allowed for the patenting of genetic inventions. Myriad's patents have been challenged in Europe, and the patents have withstood the challenge, albeit the scope has been reduced somewhat, as discussed in a previous post on this blog.

There is something seriously wrong with a patent system that would allow investors to believe for 30 years that these sorts of inventions are patentable, which has resulted in literally thousands of patents and a huge amount of investment, before essentially pulling the rug out from under these investors. That's why it's so important that the Federal Circuit intervene and reverse the district court, at least with respect to most of the claims.

The claims which I think might have trouble in the Federal Circuit are process claims reciting methods for analyzing for genetic mutations in the BRCA genes, without any limitation requiring some physical act of isolating or analyzing the actual DNA molecule. Under the current state of affairs, after Bilski and Prometheus decisions, I think these claims are in trouble. I think Myriad is aware of this problem, which is why they argued to the district court that the claims inherently are limited to processes that involve some physical isolation and the collection of DNA, although I think the district court correctly ruled that the claims do not include such a limitation.

If it turns out these sorts of method claims are not patentable, there are implications as we move into an era of personalized medicine. There is talk about a time in the not-too-distant future when patients will have their entire genome sequence for a reasonable cost. In that case, diagnosis for a genetic mutation would not necessitate any physical transformation of molecular DNA, only analysis of information, so how valuable will method claims be that require some actual physical manipulation of DNA in the United States?

In Case Challenging Myriad Gene Patents, ACLU and Public Patent Foundation Prevail in District Court

2010-03-30T16:49:00.002-05:00

Yesterday, the ACLU and Public Patent Foundation scored a victory in their lawsuit challenging the validity of certain gene patents relating to genetic testing for susceptibility to breast cancer, with a district court judge deciding on summary judgment that product claims reciting isolated polynucleotides comprising naturally occurring genetic sequences, and process claims reciting methods of testing for genetic mutations, are patent ineligible under Section 101 of the patent statute. (The decision is here, courtesy of Public Patent Foundation) The court declined to address the constitutional issues raised by the plaintiffs in the case. This is an important case for biotechnology, discussed in an earlier post, but the implications are hard to assess until the Federal Circuit reviews the case on appeal.

Although the lawsuit was brought to address perceived impediments to innovation and access to genetic diagnostic testing, the decision could potentially implicate the validity of a host of other biotechnology patents, including patents used to protect biologic drugs. The scope of the decision is hard to assess; it could be interpreted as invalidating a host of issued patents claims relating to genetic inventions. Hopefully the Federal Circuit will intervene, and either reverse the decision, or at least limit its reach. But for the time being, it opens a fairly wide door for challenges to biotechnology patents based on allegations of patent ineligibility.

Some of the invalidated patent claims are directed towards isolated polynucleotides encoding BRCA proteins. The court cited to a number of relatively old judicial decisions, all pre-dating Diamond v. Chakrabarty and the Federal Circuit, which held that, at least in some circumstances, the mere isolation of a naturally occurring product does not render it patentable. Although the patent office, the courts and most of the biotechnology community have assumed for years that isolation of a polynucleotide from its native environment renders it patentable, to my knowledge there is no case directly on point to support that position.

Affymetrix, for one, has for years argued that the isolation of naturally occurring DNA does not render it patent eligible. Affymetrix sells DNA hybridization arrays, under the trade name gene chips, and not surprisingly a company whose products can include many thousands of DNA sequences representing naturally occurring genes would prefer the sequences to be unpatentable. The company filed an amicus brief several years ago in In re Fisher (a Federal Circuit case that found EST sequences unpatentable for lack of utility) arguing that isolated naturally occurring DNA sequences are patent ineligible, based in large part on the same rationale and caselaw relied upon by the court in the ACLU lawsuit.

There have been a number of cases upholding the validity of patents claiming isolated naturally occurring molecules, but the issue in those cases has been the novelty and/or nonobviousness of the molecule, not patent eligibility per se, which is a distinct doctrine. The Supreme Court's decision in Diamond v. Chakrabarty in 1980, which upheld the patent eligibility of a recombinantly modified microorganism, arguably supports the patent eligibility of isolated DNA sequences, but the district court did not read Chakrabarty so broadly.

The district court further held that even non-naturally occurring DNA molecules, such as cDNA, is patent ineligible because cDNA corresponds directly to naturally occurring mRNA, and conveys the same information as genomic DNA. The informational attributes of DNA was apparently critical to the court's decision. The court held that DNA is fundamentally different from all other biomolecules because of its primarily informational attributes, and explicitly stated that its decision did not extend to other molecules occurring naturally in the body and capable of conveying information, such as adrenaline. In other words, the decision apparently does not implicate the patent eligibility of isolated naturally occurring proteins and other biomolecules.

Even if the district court's decision were to be affirmed, the question remains as to the extent to which a DNA molecule corresponding sequence to a naturally occurring gene would have to be modified in order to render it patentable. The modification will presumably need to be sufficient such that the claimed invention has "markedly different characteristics" from the naturally occurring sequence, which is the test articulated by the court. Would a labeled probe, designed to recognize a naturally occurring mutation, be patent eligible? What about a recombinant construct comprising a DNA sequence encoding a naturally occurring protein coupled with a non-naturally occurring regulator of transcription like a promoter? How about genetically engineered cells, or chimeric sequences formed by combining two or more naturally occurring protein coding sequences? A DNA-based vaccine? The impact on biotechnology patenting could potentially be quite significant, although I predict that ultimately the Federal Circuit would not uphold the rule in a form that would so dramatically impact the ability of innovators to protect their inventions.

The district court also found that process claims reciting methods of analyzing a BRCA1 sequence for mutations, or comparing to gene sequences to see if a difference exists, are patent ineligible for failing the Bilski machine-or-transformation test. Myriad argued that the claims implicitly included physically transformative steps of isolating and sequencing DNA, but I think the court correctly rejected these arguments because no such limitation appears in the claims. One could compare two gene sequences without physically isolating or sequencing DNA, for example, if the DNA had already been sequenced by someone else and the reported sequence was being analyzed.

Essentially, Myriad obtained very broad method claims from the patent office, unlimited by any physical analysis step, but this very breadth resulted in their patent in eligibility, even though Myriad unsuccessfully argued for a narrower interpretation of its claims in order to preserve their validity.

Whether or not this is the right outcome, I think it is consistent with current Federal Circuit case law, particularly Prometheus and Bilski, although perhaps this will change after the Supreme Court decides Bilski. In Prometheus, the Federal Circuit stated that the “mental step" of observing a level of drug metabolites indicating a need to adjust the amount of drug subsequently administered is patent ineligible, which I think implies that a claim that would be infringed by merely "comparing” two DNA sequences would likewise be patent ineligible.

Interestingly, the district court went further and posited that even if the claims had specifically recited isolation and sequencing of DNA, these physical steps "would constitute no more than data-gathering steps that are not central to the purpose of the claim process,” and thus would have been insufficient to provide the necessary transformation to render the claims patentable. This is only dicta, because the challenged claims do not include this limitation, but I think the district court is clearly wrong on this one. In Prometheus, the Federal Circuit held that the physical transformation involved in performing analytical procedures to determine the level of drug metabolite in a patient was sufficient to confer patent eligibility, and I don't see how the physical transformation involved in analyzing DNA should be treated any differently.

The district court also found a claim directed to a process for cell-based drug screening, involving using a recombinant cell engineered to express BRCA1 to screen for potential cancer therapeutics, to be patent ineligible. The district court's explanation for this decision was particularly unconvincing. For example, the judge states that the claimed process is "in fact, the scientific method itself, and Claim 20 seeks to patent a basic scientific principle: that a slower rate of cell growth in the presence of a compound indicates that the compound may be a cancer therapeutics.” But the claim is limited to the use of cells recombinantly engineered to express BRCA1, and does not purport to preclude others from using the "scientific method,” or from screening for cancer therapeutics in general. I think the Federal Circuit will have to reverse this decision, because if in fact a method of screening for cancer therapeutics using a recombinantly engineered cell is patent ineligible, the implication might well be that a large percentage of patent claims relating to biotechnology are invalid.

Although clearly the ACLU/Public Patent Foundation lawsuit was motivated by a concern that gene patents impede innovation and impair access to genetic diagnostic testing, ancillary effects might extend to other aspects of biotechnology, including biopharma. In my study on human gene patent litigation, available here, I showed that gene patents have most often been used by biologic innovators to block market access by competitors, functioning as the biotechnology analog of drug patents. Although gene patents have often been the subject of criticism, very few people would argue that gene patents are unjustified when used to protect biologic drugs, thereby providing the necessary incentive for investment in the expensive and risky development of biologics.

Gene patents have played a critical role in providing intellectual property protection for biologic drugs, in part because adequate patent protection for the biologic drug itself has often not been available. For example, the first human gene patent litigation I was able to identify was Amgen v. Chugai, in which Amgen successfully asserted its patent on the erythropoietin gene to block market entry by a competing recombinant erythropoietin product (U.S. Patent No. 4,703,008). The primary claim found to be valid and infringed by the Amgen court was Claim 2, which recites: “A purified and isolated DNA sequence consisting essentially of a DNA sequence encoding human erythropoietin.” Under the district court's ruling in the ACLU case, this claim would clearly be invalid, and thus unavailable to protect Amgen's recombinant erythropoietin drug product, which has been one of the most successful biotechnology drugs and widely acknowledged as a groundbreaking tour de force of applied science.

Of course, there are other types of gene patent claims that might have been available to Amgen to block competition in the market for recombinant erythropoietin. In Amgen v. Chugai, for example, two other patent claims, claims 4 and 6, were also found to be valid and infringed.

Claim 4 recites: “A procaryotic or eucaryotic host cell transformed or transfected with a DNA sequence [consisting essentially of a DNA sequence encoding human erythropoietin] in a manner allowing the host cell to express erythropoietin.”

Claim 6 recites: A procaryotic or eucaryotic host cell stably transformed or transfected with a DNA vector [consisting essentially of a DNA sequence encoding human erythropoietin].”

The question would be whether or not the introduction of the patent ineligible erythropoietin-encoding DNA sequence into a host cell would be sufficient to render the resulting recombinant host cell patent eligible. The question is important, because without the availability of these sorts of patent claims Amgen might have been severely hobbled in its ability to achieve the patent protection warranted by its groundbreaking research. But when I read the district court's decision in the ACLU lawsuit, it seems to suggest that even these claims would be unpatentable.

For example, the decision states that even a synthetic DNA molecule (such as cDNA) is patent ineligible unless it has “markedly different characteristics” from its native counterpart. Similarly, the court found a claim reciting a method of using recombinant cells engineered to include the BRCA1 gene to screen for drug candidates was patent ineligible. If the method is patent ineligible, then one might infer that the recombinant cell itself is patent ineligible, in which case Amgen’s claims 4 and 6 would likely also be invalid.

In previous posts, I have argued that a 12 year data exclusivity period for biologics is warranted, in part because of the uncertainty of whether adequate protection is available for biologic drugs. Even with the passage of the healthcare reform legislation, which includes 12 years of data exclusivity, the issue is far from moot: the generic drug industry is already actively lobbying for new legislation to shorten the period of data exclusivity for biologics. Yesterday's decision illustrates my point, at the very least raising serious questions with respect to the availability of adequate patent protection for biologic drugs, and potentially invalidating many of the patents that biotechnology companies have relied upon to justify their investment in innovation.

Ariad v. Eli Lilly: Pragmatism Prevails over Coherent Patent Doctrine

2010-03-23T11:17:00.002-05:00

Yesterday in Ariad v. Eli Lilly, a majority of the en banc Federal Circuit decided to retain both traditional and Lilly written description as distinct requirements of patentability. I filed an amicus brief in the case arguing against the Lilly written description requirement (LWD), the brief and some of my objections to LWD are available in earlier posts to this blog. Essentially, I have argued that any positive policy aspects of LWD can be better accomplished using the enablement requirement, and that the courts have failed to articulate any coherent standard for compliance with LWD beyond the requirements of enablement. Federal Circuit judges Linn and Rader recognize this problem in their dissents to Ariad.

Still, I was not at all surprised that the majority decided to retain LWD, because it has developed into a useful tool for invalidating clearly objectionable patent claims precisely because it lacks any coherent standard. When faced with a patent such as Ariad's, which I think most people would consider overreaching, instead of having to find by clear and convincing evidence that the claim fails to satisfy one of the more rigorously articulated standards such as nonobviousness or enablement, the court need merely conclude that the application fails to adequately demonstrate the patentee had “possession” of the claimed invention, or, in the alternative, that the application fails to show that the patentee "invented" the invention, and the claim is invalid. No need to go through the more rigorous proofs necessary to show lack of enablement or obviousness.

As noted perceptively by Judge Rader in his dissent, "the courts inadequate description of its written description requirement acts as a wildcard on which the court may rely when it faces a patent that it feels as unworthy of protection.”In other words, the main value of LWD is its lack of any articulated standards for compliance - it provides a pragmatically useful tool for a company like Eli Lilly to dispose of an "unworthy" patent by merely convincing a court of its unworthiness. In the view of many, including myself, Ariad's claim should be found invalid for lack of enablement, but because the criteria for establishing lack of enablement, such as assessment of the Wands factors, are more well defined they can also be more difficult to establish, hence the appeal of an essentially standardless patentability requirement such as LWD.

When the Federal Circuit created LWD in 1997 in Regents of the University of California v. Eli Lilly, it was initially thought of as a serious blow to biotechnology. Typical of the tone of the time, one commentator lambasted Lilly as "an unmitigated disaster that if followed, has the potential for causing untold havoc in the biotechnology field." An article was published in Science predicting that Lilly would have a broad impact on biotechnology, and many feared that LWD would prevent biotechnology inventors from obtaining adequate protection for their inventions. For more discussion of the Lilly decision and response to it, see my 2007 article "Is Lilly Written Description a Paper Tiger?"

In view of the widely held perception that LWD was bad for biotechnology, it might come as surprise to find that major biotechnology companies Amgen, Glaxo Smith Kline, and Abbott all filed amicus briefs in Araid supporting Lilly and retention of LWD. Note that the support comes from major biopharmaceutical companies selling blockbuster drugs, who like Eli Lilly see the pragmatic usefulness of LWD as a tool for invalidating unwarranted and irksome patents such as Ariad’s. Other biotechnology companies, presumably more concerned about the negative impact of LWD on their ability to obtain adequate patent protection for their biotechnology inventions than the threat of being sued for infringing and "unworthy" patent, joined me in arguing against LWD. Universities also filed an amicus brief arguing for elimination of LWD. The Biotechnology Industry Organization (BIO) did not weigh in with an amicus brief, I would guess because their membership, which includes universities, small biotechnology companies, as well as large biopharmaceutical companies like Eli Lilly, was too divided on the issue to take a unified stand.

As a practical matter, I don't think that retaining LWD will have a major impact on biotechnology or patent law in general. As shown in empirical studies conducted independently by me and Dennis Crouch of Patently-O fame, it appears to be very rare for a patent claim to be rejected or invalidated solely based on failure to comply with LWD (both studies are cited in Judge Rader's dissent). In most cases, enablement would be sufficient to handle the job. As shown in my Paper Tiger article, contrary to earlier predictions, LWD has for the most part not prevented biotechnology inventors from obtaining relatively broad scope of protection for their inventions. Its main function is to police claim scope, and in practice patent applicants are routinely granted broad scope of coverage for biomolecule inventions based on a relatively modest disclosure of some relationship between structure and function, or by describing a few representative molecular species falling within the claimed genus. LWD is being used to limit claim scope for some biomolecule inventions, but I would assert that the patent office could achieve the same policy objective using the enablement requirement if it did not have LWD, and in fact my experience looking at many Board of Patent Appeal and Interference decisions involving LWD usually enablement and LWD rejections are raised in tandem.

I also think that “unworthy” claims, such as Ariad's claims asserted against Eli Lilly (and Amgen in a separate case), or the University of Rochester's COX-2 claims asserted against drug companies selling COX-2 inhibitor drugs (and invalidated under LWD in University of Rochester v. G.D. Searle & Co.), could have been invalidated more properly using the enablement requirement. In Rochester, in fact, the district court did find a claims invalid for lack of enablement, but the Federal Circuit did not address the issue as moot. The main problem, as I see it, is that by using LWD instead of enablement to invalidate questionable claims such as Ariad's, the Federal Circuit fails to develop case law articulating the contours of the enablement requirement, which is the appropriate doctrine for addressing these sorts of overly broad claims. In his dissent to the panel decision in Ariad v. Eli Lilly, Judge Linn raised this exact concern.

In the future, I think it will be interesting to watch how the Federal Circuit applies to LWD to antibodies claims. As pointed out in my brief, the Federal Circuit and patent office apply to LWD to antibodies in a manner entirely consistent with how it is applied to other biomolecules. The current practice is to allow extremely broad patent scope covering any antibody recognizing any epitope on an antigen, based on a mere disclosure of the antigen. This is an important issue, because so many of the new biologic drugs, and biologic drugs in the pipeline, are based on antibodies. Recently, Abbott Laboratories was found liable for infringing a broad antibody claim based on its marketing of the biologic drug Humira, with the jury awarding the plaintiff $1.67 billion, reportedly the largest patent verdict in history. Abbott has appealed the decision, and absent a settlement will undoubtedly attempt to convince the Federal Circuit that broad antibody claims of this sort are invalid under LWD, more in line with the way LWD is applied outside the context of antibodies. In fact, Abbott made this very point in the amicus brief it filed in Ariad, available here courtesy of Patent Docs.

A Rare Event for Biotechnology: Two Anjimoto Patents Struck for Violation of the Best Mode Requirement

2010-03-12T12:13:00.001-06:00

In Ajinomoto v. ITC, decided March 8, 2010, the Federal Circuit affirmed the International Trade Commission's determination that two patents claiming methods for producing the amino acid L-Lysine in E. coli are invalid for failure to adequately disclose the best mode of practicing the invention. One of the patents was also found to be unenforceable due to inequitable conduct, based on the Commission’s finding that omission of the best mode was material and made with deceptive intent.

The claimed methods are used to prepare lysine to be sold as a dietary supplement, primarily for animals such as livestock, in what is described in the opinion as a billion-dollar, worldwide market. Both claimed methods recite the use of E. coli strains that have been genetically engineered to produce very high concentrations of lysine, by mutating genes involved in lysine metabolism in order to impair feedback inhibition and lysine degradation, respectively.

The best mode requirement is an anomaly of US patent law, and is not found in other major patent jurisdictions such as Europe and Japan. It essentially requires a patent applicant to adequately disclose what the inventor considers to be the best mode of practicing the claimed invention. In this case, the court found that at the time the original patent applications were filed, the inventors considered certain strains of E. coli to be the best for practicing the invention. These preferred strains included additional genetic alterations besides those recited in the patent claims, including another modified gene involved in lysine metabolism, and genes that allowed the bacterium to utilize sucrose as a carbon source. The patent specifications accompanying the invalidated claims do not disclose these additional genetic alterations, nor the inventor’s preference for use of sucrose as the carbon source, but do include data associated with "fictitious host strains."

This was not the first challenge to an Ajinomoto patent based on an alleged violation of the best mode requirement. In Ajinomoto v. Archer-Daniels-Midland, 228 F.3d 1338 (Fed. Cir. 2000), the Federal Circuit affirmed a district court's determination that a patent owned by Ajinomoto claiming methods of modifying bacteria to increase the production of amino acids was not invalid for failure to disclose the best mode. In that case, the alleged violation was based on the failure of the patent specification to disclose a particular bacterial gene that the inventor considered necessary to practice the best mode of the invention. The court rejected the allegation, and held that even though the patent did not explicitly identify the preferred gene, it disclosed the use of a strain of bacteria that includes the preferred gene, and one of skill in the art would have been aware that the disclosed bacterium included the preferred gene.

Although violation of the best mode requirement is often invoked as a defense in patent litigation, courts rarely invalidate claims for failure to disclose the best mode. In a 2002 Federal Circuit decision, the majority noted that the Federal Circuit and its predecessor courts had only held claims invalid for failure to satisfy the best mode requirement on seven occasions. Bayer AG v. Schein Pharms, 301 F.3d 1306 (Fed. Cir. 2002). To my knowledge, Ajinomoto is the first reported decision wherein a biotechnology patent has been invalidated under the best mode requirement - I have not done an exhaustive search, but I'm sure it has rarely if ever happened before.

The last best mode challenge to a biotechnology patent to make it to the Federal Circuit that I am aware of was in the case of Invitrogen Corp. v. BioCrestMfg., in which the appeal was filed in 2007. The District Court had refused to even submit the issue to the jury. The parties settled prior to the Federal Circuit deciding the issue. In that case, the alleged violation of the best mode requirement also involved the failure to disclose a preferred strain of E. coli for use with the invention. Clearly, patent practitioners should be vigilant to ensure that preferred E. coli strains are disclosed in the specification in order to ward off this common basis for attacking biotechnology patents.

Notably, the best mode violation was the only basis for invalidating either Ajinomoto patent, since the inequitable conduct finding was based solely on the failure to disclose the best mode. The inventors might very well have fully enabled a useful and nonobvious invention, which outside the US would be sufficient to secure a valid patent.

It is perhaps relevant that the best mode violation was based on the failure of the original Japanese patent applications, which were the priority documents for the US patents, to disclose the preferred bacterial hosts and carbon source. Similarly, the Ajinomoto patent which survived the earlier best mode challenge by Archer-Daniels-Midland was based on an application for an Inventor’s Certificate filed in the former Soviet Union. The Inventor’s Certificate was essentially the Soviet analog to a patent under the communist regime. The best mode requirement can be a trap for non-US inventors and patent practitioners unfamiliar with US law, and maybe this played a role in these cases.

There is currently relatively strong support for eliminating the best mode requirement in the US, at least as a basis for invalidating patent claims or rendering patents unenforceable, and some of the recent legislative proposals for patent reform have included provisions to that effect, including the most recent Senate draft that was made publicly available last week (available here).

I am personally of the opinion that the best mode requirement should be eliminated from US law; it seems to me that the rest of the world is doing fine without it, and whatever benefits flow from the doctrine in the form of enhanced disclosure are outweighed by the cost of litigating the issue, the potential for invalidating an objectively valid patent based on the outcome of a litigation-driven inquiry into the inventor’s subjective state of mind many years prior to the litigation, and the potential unfairness to foreign inventors unfamiliar with the best mode requirement.

Inability of Patent Examiner and Board to Correctly Read Prior Art Reference Necessitates Intervention by Federal Circuit

2010-02-25T12:36:00.006-06:00

One of the challenges in prosecuting patent applications is dealing with patent examiners who reject claims based on clearly erroneous misreading of a prior art reference. And sometimes appeal to the Board of Patent Appeals and Interferences does not rectify the situation, forcing the applicant to make a “federal case” out of it. An example of this can be seen in the recently decided case of In re Chapman, where the patent applicants needed to appeal all the way to the Federal Circuit in order to correct an examiner’s misreading of a prior art patent.

Chapman's patent application claims divalent antibody fragments comprising two antibody heavy chains covalently linked by means of a polymer molecule (e.g., polyethylene glycol, or "PEG") through linkage to the sulfur atom in cysteine residues located outside the variable region domain of each chain. The use of the polymer to link the chains increases the antibody fragments’ half-life in the body, which can be beneficial in therapeutic and diagnostic uses of antibody fragments. PEG is often used to extend the half-life of protein biologics, and more generally to modify the pharmacological characteristics of these molecules - Roche's PEGylated version of erythropoietin MIRCERA, the subject of the recently resolved Amgen v. Roche litigation, is a good for example.

The patent examiner rejected Chapman’s claims as obvious in view of a prior art patent (the “Gonzalez" patent) that disclosed, inter alia, linking antibody fragments to a polymer through a cysteine residue in order to increase antibodiy's circulating half-life and thus improve the antibody's therapeutic characteristics. The Federal Circuit vacated this rejection based on its determination that the examiner and the Board of Patent Appeals and Interferences had clearly misread the Gonzalez patent, and this misinterpretation of the reference could have resulted in an erroneous finding of obviousness.

For example, the patent examiner and the B oardboth concluded that Gonzalez described a divalent antibody formed by linking light and heavy antibody chains by means of a polymer linker. In fact, as noted by the Federal Circuit, Gonzalez actually describes attachment of a polymer to either the light or the heavy chain - critically, the polymer is not serving as a link between the chains. Even the government attorney representing the patent office conceded during oral argument that the Board and examiner had misread the reference.

The Board also held that Gonzalez only disclosed three types of antibody fragments, when in fact, as conceded by the government attorney during oral arguments, the reference discloses six different possible antibody fragments. The Federal Circuit held that either of these errors could have led the patent office to erroneously reached its determination of obviousness. Because Gonzalez does not disclose linking the fragments, there is less suggestion of making the linked antibody fragments claimed by Chapman. Particularly since KSR, the number of possible alternate choices presented by the prior art can be critical in assessing the obviousness of invention, so the availability of six types of fragments (rather than the three erroneously cited by the examiner and board) frm which to choose could affect the determination of obviousness.

Biologic Innovator's Lost Profits Won't Necessarily Translate Into Lower Costs for Consumers

2010-02-12T11:14:00.003-06:00

In our recent article on follow-on biologic legislation, David Adelman and I make the somewhat counterintuitive argument that the loss in profits experienced by a biologics innovator due to market entry by a follow-on competitor (as the result of a short data exclusivity period) will not necessarily end up in the pockets of consumers. Some have expressed skepticism on this point. For example, one of our fellow law professors emailed us the following comment:

“I don't understand how you can argue that 12-year data exclusivity won't substantially reduce prices for biologics, and yet is critical for biotech R&D incentives. It either reduces biotech profits substantially, in which case it benefits consumers substantially, or it doesn't have much effect either way.”

On its face, his point seems eminently reasonable, and I'm sure many have had the same thought. However, on closer inspection it becomes apparent that the market for biologic drugs is not that simple. It is not the case that there is a pot of "profits” out there that can either go to "biotech" or to consumers, in a zero-sum game. In fact, it is possible, at least in principle, and probably in fact, for a biologic innovator to experience substantially reduced profits without a concomitant drop in the cost to payers. This is our concern; a short period of data exclusivity could reduce the return on investment for biologic innovators, thus dampening the incentives for innovation, without a compensating benefit to consumers.

Part of the problem with the way the comment is framed is that it focuses on "biotech profits," when in fact the focus should be on the profits of innovators, the companies that take the risk and invest the resources in discovering and commercializing life-saving new biologic drugs. Market entry by a competing follow-on biologic clearly has the potential to divert sales from the innovator, but that does not necessarily mean that consumers will benefit, particularly if the price of the biologic drugs does not drop significantly as a result of competition. In effect, the loss in innovator profits is diverted to the follow-on manufacturer rather than consumers.

To illustrate this point, consider Amgen v. Roche, a case involving Amgen's attempt to block Roche's attempt to enter the US market with MIRCERA. MIRCERA is essentially a pegylated version of recombinant erythropoietin, which would compete with Amgen's erythropoietin products EPOGEN and ARANESP. Although MIRCERA was not approved under an abbreviated follow-on regulatory process, it would compete with Amgen's innovator products in the same manner that follow-on biologics are envisioned competing after passage of FOB legislation.

I wrote several blog posts commenting on the case, but the most relevant for the present discussion was one reporting on the reason the district court decided to enter a preliminary injunction blocking market entry by MIRCERA (post available here) To summarize, the judge initially seriously considered not entering an injunction, based on his perception that the public would benefit from market entry by the competing Roche product. However, ultimately he was persuaded by the expert testimony of an economics professor who studies the economics of drug pricing, to the effect that because of the incentives provided by Medicare compensation, and the manner in which biologic drugs are distributed to patients, market entry by Roche would likely not lead to reduced prices, but would quite likely lead to higher prices for consumers. In other words, while the innovator Amgen would lose profits, the money would shift to Roche rather than drug purchasers. This result, i.e., competition leads to higher prices, is definitely counterintuitive, but I agree with the judge that it is at least plausible, based on the nature of the market.

The FTC Report on follow-on biologics predicts that competition in the market for follow-on biologics will not be based primarily on the price of the drug, as it is for conventional generic drugs. It is my understanding that the introduction of follow-on biologics in the European market has not resulted in any major drop in prices, as has been the experience with conventional generic drugs.

In any event, proponents of a shortened data exclusivity period are fighting hard for it, and thus they must believe it will have an impact on the price of biologic drugs, which will cut into innovator profits. Let us assume this comes to pass. If it does, it will reduce the incentive for investment in innovation, which after all is based on an expectation of profits. Arguably, the current level of investment in biologic innovation is already suboptimal, and it appears to be decreasing, based on the recognition that historically investment in biotechnology has suffered from an overall low rate of return, albeit with a number of notable exceptions. A shortened data exclusivity period will further reduce the incentives for investment, which ultimately translates into a suboptimal pipeline of new biologics.

The point that David Adelman and I are making is that while a shortened data exclusivity period will likely reduce incentives for investment in innovation, it might very well have minimal impact on the cost of healthcare. We argue that more energy should be directed towards finding and implementing other means for reducing the costs of bringing new biologics to market, without unduly harming incentives for innovation.

President Obama Reportedly Seeks to Shorten the Data Exclusivity Period for Biologic Innovators Previously Agreed to by House and Senate

2010-01-16T11:06:00.003-06:00

In recent posts, I have discussed the data exclusivity provision included in pending follow-on biologic legislation, and explained my position that an extended 12 year data exclusivity period for innovators is justified and desirable to promote robust biologic innovation. Others argue in favor of a much shorter period, e.g. five years, including Senator Waxman, the FTC and apparently the Obama administration. Although the healthcare reform bills passed by both the House and Senate include 12 year data exclusivity periods, and one might have thought that this consensus position would have settled the issue for the time being, particularly in view of the numerous and much more pressing issues of controversy currently holding up passage of the bill, today the New York Times reported that Presdent Obama reopened the issue last week in meetings with congressional leaders in which he reportedly pushed for a shorter data exclusivity period.

A link to the New York Times article is provided here. The relevant paragraph reads:

“And even as they tried to resolve their disagreements, Congressional negotiators and the president stirred up a tempest on Friday by reopening an issue on which the House and Senate agreed — establishing procedures for federal approval of generic versions of expensive biotechnology drugs. The House and Senate bills give brand-name companies 12 years to market drugs without fear of generic competition; Mr. Obama wants generics to get to market sooner.”

Jim Greenwood, president and CEO of the Biotechnology Industry Organization (BIO) wasted no time in voicing the chagrin of biotechnology innovators - his blog post is available here.

Misplaced Fears in the Legislative Battle over Biotech Drugs

2010-01-14T16:57:00.002-06:00

In a new article, available here , Professor David Adelman (University of Texas) and I weigh in on the controversial subject of the inclusion of an extended period of data exclusivity in proposed follow-on biologic (FOB) legislation. Both healthcare bills passed by the House and Senate, H.R. 3962 and H.R. 3590 (that is not a typo, the Senate healthcare reform bill was passed as an amendment to House Bill H.R. 3590), include provisions creating an abbreviated approval process for follow on biologics, and both incorporate a 12 year period of data exclusivity for biologic innovators. Some, including the FTC, have argued for a much shorter period of data exclusivity for biologic innovators, and some of the proposed follow-on biologic bills introduced in Congress earlier last year included shorter periods. For example, H.R. 1427 would have provided innovators with only five years of data exclusivity. In an earlier article and post, I challenged the FTC’s conclusion, pointing out what I perceive to be flaws in its arguments purportedly justifying a short-term of data exclusivity for biologic innovators.

One of the primary arguments raised by opponents of an extended 12 year data exclusivity period is that patent protection will be sufficient to provide the necessary incentive for robust investment in innovation on new biologics, rendering data exclusivity unnecessary. Prof. Adelman and I argue that there is substantial uncertainty as to whether patents will be as effective for protecting innovative biologic as they have been for conventional drugs. For example, composition of matter patents claiming the drug active ingredient have generally proven very effective in protecting conventional drugs. Other more attenuated patents covering methods of production or use, specific formulations, etc., have proven much more susceptible to circumvention and/or invalidation. Historically, composition of matter patents on the active ingredient do not have a strong track record of success in the context of biologics, where innovators have more often needed to resort to patents claiming processes and reagents used in production of the biologic, with mixed success. Biologic drugs are fundamentally different than conventional drugs, and the scope of available patent protection for biologics is unclear, particularly in view of uncertainty surrounding the scope of protection available under the enablement and written description requirement (the pending en banc Federal Circuit decision in Ariad v. Eli Lilly for example). All things considered, it would be a mistake to assume patents will be as effective in protecting biologics, and thereby incentivizing innovation, as they have historically been for conventional drugs. And in any event, the 12 year period of data exclusivity would run concurrent with the patent term, and thus should have little impact if strong and robust patent protection is in fact available for biologic.

In our article, Prof. Adelman and I consider the legal, technical and economic context of follow-on biologics and conclude that a shortened period of data exclusivity as endorsed by the FTC would provide at best nominal savings in overall healthcare expenditures in the US. It could, however, substantially impair the likelihood of a biologic innovator recouping a sufficient return on investment to justify the enormous expenditure and high risk associated with bringing a novel biologic to market. In our view, an extended period of data exclusivity, such as the 12 year period included in the current healthcare reform bills, is appropriate. More importantly, the emphasis by the FTC and others on reducing the data exclusivity period is misplaced. Society would be much better served by focusing on the development of technology and regulatory processes that facilitate marketing approval for follow-on biologics subsequent to the expiration of an appropriate period of exclusivity afforded by patents and data exclusivity.

BIO Podcast: The Role of Patents in a Pathway for the Approval of Biosimilars

2009-11-16T16:37:00.002-06:00

I was recently interviewed by Hans Sauer, Associate General Counsel for Intellectual Property at the Biotechnology Industry Organization (BIO), on the role of patents in proposed follow-on biologic legislation currently being considered by Congress. The interview is posted as a podcast here.

Other BIO podcasts can be found at BIOtech NOW.

My Amicus Brief Has Been Filed in Ariad v. Lilly

2009-10-15T15:11:00.003-05:00

I have filed an amicus brief in Ariad v. Lilly in support of neither party but arguing against the Lilly Written Description Requirement (LWD), available here.

My brief essentially argues that LWD has been applied by the courts and PTO in an arbitrary and inconsistent manner that lacks any rational basis in law, science, or policy, and in a manner that can effectively preclude some biotechnological inventors from obtaining adequate patent protection for their inventions, particularly inventions relating to proteins and DNA. My arguments dovetail in large part with those made by Novozymes in the brief they filed a couple days ago.

My colleagues Mark Janis (Indiana University) and Tim Holbrook (Emory University) have filed their own amici brief, arguing that there is no independent written description requirement, and that enablement is the proper and only doctrinal tool for policing claim scope and for determining whether a disclosure supports later added claims.

Law Professor's Debate Impact of Supreme Court's Quanta Decison on Patent Exhaustion and Licensing

2009-10-14T18:07:00.003-05:00

Richard Epstein (Univ of Chicago), Scott Kieff (George Washington Univ, Mark Lemley (Stanford) and Fred von Lohmann (Electronic Frontier Foundation) vigorously debate Quanta. Available here.

Novozymes Files Amicus Brief in Ariad v. Lilly Arguing Against Lilly Written Description

2009-10-13T15:04:00.003-05:00

The brief is attached here. I'll have some commentary and hopefully some more briefs in the next few days.

Ariad v. Lilly Appellant's Brief and Follow-On Biologics

2009-10-06T11:13:00.003-05:00

Ariad's brief in this important Federal Circuit en banc rehearing of Araid v. Lilly, which asks the court to consider revising or perhaps completely eliminating written description as a separate requirement of patentability is available here. I have not had a chance to read it yet, but will post some commentary once I do.

Also, for those interested in the follow-on biologics legislation currently being considered by Congress, here is a short version of the article I posted last week which focuses specifically on the patent provisions of the bills.

A Response to the FTC's Report on Follow-On Biologics

2009-10-01T13:25:00.003-05:00

Congress is considering legislation that would create an abbreviated FDA approval process for follow-on biologics (FOBs), which proponents anticipate will promote competition and lower prices in the market for biologic drugs. In June of 2009 the FTC published a report on FOBs (“the FTC Report”), which attempts to forecast the nature of competition between innovator biologics and FOBs, and offers a number of substantive recommendations regarding specific provisions of the various FOB bills. In particular, the FTC Report concludes that there is essentially no justification for the inclusion of a substantial data exclusivity period (“DEP”) for innovators in pending FOB legislation, and that Congress should not include a pre-approval patent (dispute) resolution process (“PPRP”). The FTC Report bases its conclusion that a substantial DEP is unnecessary to adequately incentivize innovation in biologics in part on a misapplication of the results of a study I conducted in 2007 on the written description doctrine of patent law.

I have written a manuscript that responds to some of the conclusions and recommendations set forth in the FTC Report. In particular, I think it is important to clarify the scope and implications of my study on the written description doctrine, and explain why I believe that the FTC over-interpreted the results of the study to arrive at a conclusion that is unsupported by the data. In my view an extended DEP for innovators is justified and should be included in FOB legislation enacted by Congress.

I also disagree with the FTC's conclusion that a PPRP is unnecessary and unwarranted for biologic drugs; such a process is appropriate and would be important to maintain adequate incentives for innovation. Some of the proposed FOB legislation would discriminate against the developers of innovative biologic drugs, not only with respect to FOB producers, but also in comparison to the treatment currently afforded conventional drug innovators. These discriminatory provisions should be removed or rectified to provide a more balanced approach to promoting competition while maintaining adequate incentives for investment in biotechnology.

The full length manuscript is available as a Working Paper on SSRN (click here for link)

[Added Oct. 6 2009] A short version of the manuscript focusing on the patent provisions is available here.

Prometheus Prevails in a Victory for Biotechnology and Personalized Medicine

2009-09-16T13:48:00.001-05:00

In past posts I have discussed Prometheus v. Mayo, which addresses the issue of whether a diagnostic method for providing personalized therapeutic treatment is patent eligible under Bilski (click here for background on the case). In an amicus brief I filed on behalf of myself and several other law professors, we argued that such claims should be patent eligible, and a contrary decision by the court could adversely impact future innovation in diagnostics and personalized medicine. Today a unanimous panel of the Federal Circuit agreed (click here for opinion).

Claim 1 of US Patent Number 6,355,623 is representative of the claims issue:

1. A method of optimizing therapeutic efficacy for treatment of an immune-mediated gastrointestinal disorder, comprising:

(a) administering a drug providing 6-thioguanine to a subject having said immune-mediated gastrointestinal disorder; and

(b) determining the level of 6-thioguanine in said subject having said immune-mediated gastrointestinal disorder,

wherein the level of 6-thioguanine less than about 230 pmol per 8.times.10.sup.8 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and

wherein the level of 6-thioguanine greater than about 400 pmol per 8.times.10.sup.8 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

In its opinion, the Federal Circuit held that the both the step of administering a drug and the step of determining the level of drug metabolite in the patient are sufficiently transformative to satisfy the transformation prong of the Bilski machine-or-transformation test. The court did not address the issue of whether the claims satisfied the machine prong of the test, since satisfaction of the transformation prong was sufficient to find all of the claims at issue patent eligible.

With respect to the administration step, the court held that administration of the drug to a patient results in “various chemical and physical changes of the drug’s metabolites that enable their concentrations to be determined” is clearly transformative. The court found that “the asserted claims are in effect claims to methods of treatment, which are always transformative when a defined group of drugs is administered to the body to ameliorate the effects of an undesired condition,” and that "the human body necessarily undergoes a transformation" upon the administration of the drug. The court rejected Mayo’s argument that metabolism of a man-made drug is a natural phenomenon merely because it involves natural processes, pointing out that all transformations operate by natural principles.

If the Federal Circuit had stopped there, its holding would have left unresolved the question of whether a diagnostic claim that does not recite an administration step would satisfy the Bilski test. For example, many diagnostic claims simply recite a step of determining the presence of some biomarker, such as a genetic mutation or profile, or the level of a metabolite. In some cases, explicit recitation of an administration step would not be practical for the patentee. For example, if the invention is a method of identifying a genetic mutation which results in a predisposition for cancer, it would be difficult to include a step requiring administration of the drug without rendering the patent highly susceptible to circumvention.

Fortunately, the Federal Circuit went on to hold that determining the level of drug metabolites in the patient's body is also transformative, and would have been independently sufficient to render the claim patent eligible, finding that “[d]etermining the levels of [drug metabolites] in a subject necessarily involves a transformation, for those levels cannot be determined by mere inspection.” Examples of transformation include high-pressure liquid chromatography methods, methods of extracting metabolites from the human body, etc. Thus, it appears that any method of diagnosis that would inherently require some physical manipulation or transformation of a sample should satisfy the transformation prong of Bilski. This is good news for genetic diagnostic companies holding method patents that probably claim methods of identifying genetic mutations of medical significance, without being limited to any particular analytic methodologies or patient treatment steps.

Mayo had argued that the transformations involved in sample analysis are mere data gathering steps amounting to nothing more than "insignificant extra-solution activity." But the Federal Circuit rejected this argument, finding that to the contrary, the “transformation is central to the purpose of the claims, since the determining step is, like the administering step, a significant part of the claimed method treatment . . . , central to the claims rather than merely insignificant extra-solution activity.

Mayo had also argued that the “wherein” clauses at the end of the claims were merely unpatentable mental processes, but the Federal Circuit pointed out that in analyzing a claim for patent eligibility one must consider the claim as a whole. The inclusion of mental process steps in an otherwise patent eligible claim is not render the claim patent ineligible.