Friday, September 9, 2011

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Classen Claims Are Not Directed to Diagnostics or Personalized Medicine

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

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

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

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

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

When Can a Treatment Step Be Ignored?

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

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

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

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

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

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

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

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

When Can a Data Acquisition Step Be Ignored?

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

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

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

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

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

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

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

The Importance of Specificity

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

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

Patent Eligibility as a Wildcard

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

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

Where Do We Stand Now?

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

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

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

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

4 comments:

Tubal Reversal said...

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lorac said...

Whatever happened to the utility standard articulated in Brenner v Manson, that an invention has to be useful in its present form, not just merely useful at some future point after more research. It seems to me that the classen claim is an experiment, not an invention. It's a research intermediate - how to discover a correlation.

www.albacete-3d.com said...

I completely agree with the post.

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