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.
Saturday, May 28, 2011
Wednesday, May 4, 2011
Billups-Rothenberg v. ARUP: Genetic Testing Patents Found to Be Anticipated and in Violation of Lilly Written Description Requirement
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.
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.
Tuesday, April 12, 2011
A Historical Perspective on the Gene Patent Controversy
"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.
- 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.
Monday, March 28, 2011
Upcoming Telebriefing on Centocor and Current Status of Lilly Written Description Requirement
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
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
Tuesday, March 15, 2011
Centocor v. Abbott: The Federal Circuit Struggles to Articulate a Coherent Standard for Compliance with the Lilly Written Description Requirement
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.
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.
Wednesday, February 16, 2011
Market exclusivity, data exclusivity and S. 3921
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.
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.
Thursday, February 10, 2011
Does disclosure of laundry list of protein variants provide adequate written description for later claim to specific protein?
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.
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.
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