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.

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.


clinical studies india said...

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clinical studies india said...

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