Monday, April 6, 2009

In Re Kubin: Federal Circuit Clarifies Obviousness Standard in Context of cDNA Cloning Invention

In In re Kubin, an important decision for biotechnology, the Federal Circuit affirmed the Patent and Trademark Office’ (PTO’s) rejection of Amgen’s claims directed to the cDNA encoding the human NAIL protein.

The facts of the case are discussed in detail in a previous post, where I pointed out that Kubin provided the Federal Circuit with a good opportunity to address the current significance of In re Deuel, a 1995 Federal Circuit decision. In particular, does Deuel broadly establish that a nucleic acid is only rendered obvious by the disclosure of a structurally similar nucleic acid in the prior art, the position argued by Amgen and others? Many have interpreted Deuel as imposing an extremely low bar to the patentability of cloned cDNA molecules, and indeed biotechnology in general, and have accepted the conventional wisdom that the disclosure of a protein in the prior art does not render the successful cloning and sequencing of the gene encoding the protein obvious. On the other hand, I have felt that Deuel should be read much more narrowly, particularly in view of subsequent developments in the technology of cloning and the law, particularly the Supreme Court's decision in KSR v. Teleflex. I think that in Kubin the Federal Circuit has answered that question pretty emphatically: while not expressly overruling Deuel, it appears to have effectively limited Deuel to the facts of that case.

While many view Kubin as a substantial change in the law of obviousness, I disagree. Kubin basically says that the successful cloning and sequencing of the cDNA encoding a known protein is obvious, and thus unpatentable, if (1) there was some suggestion or motivation in the prior art to clone the cDNA, and (2) there was a “reasonable expectation of success,” based on "detailed enabling methodology" in the prior art. There is nothing remarkable about this standard - it is entirely consistent with the law of obviousness as it is applied outside the context of gene cloning, and it surprises me that people have believed that a very different standard applies to gene cloning. As I pointed out in my previous post, the BPAI has previously seemed to interpret the holding in Deuel as effectively limited to the specific facts of that case. For example, in Ex parte Goldgaber, decided shortly after Deuel, the BPAI affirmed an obviousness rejection of claims directed to newly isolated cDNA sequences based on prior art teaching the encoded protein and general methodologies for cloning and sequencing cDNA, i.e., facts very analogous to both Deuel and Kubin.

Legal presumptions, burdens of proof and the standard of appellate review were critical in the outcome of this case. First off, the Federal Circuit has held that there is a presumption that anything described in issued US patent is enabled, including prophetic examples, i.e., examples that were never actually carried out. See Amgen Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1355 (Fed. Cir. 2003). The PTO relied on this presumption, and Amgen never really argued against it. During oral arguments, the judges on the panel treated this presumption as established law, as it apparently it.

In my view, this presumption that anything asserted in addition patent is enabled makes very little sense. Anybody familiar with actual patents knows that patent specifications are full of wild assertions that are clearly not enabled, and in most cases the patent examiner is in no position to assess the enablement of these assertions. If a prophetic example, or other prophetic assertion in a patent, is not critical to the patentability of the patent claims, there is no reason for the examiner ever to delve into whether the prophetic example could actually be accomplished by one of skill in the art without undue experimentation. Nonetheless, the PTO and courts presume that anything described in a patent application is enabled, and this can be a difficult presumption to overcome in arguing for the patentability of a claim apparently rendered anticipated or obvious by a prophetic disclosure in an issued patent. I have faced this conundrum often in arguing for the patentability of claims with a patent examiner. In my view, a disclosure in a peer-reviewed scientific article is much more likely to be enabled than a prophetic example in a patent, but that is not how the law currently sees things.

In the case of Kubin, the prior art included a patent (Valiante) with a prophetic example essentially describing the cloning of the NAIL cDNA claimed by Kubin. Amgen argued that there was no reasonable expectation that one of skill in the art would have been successful in carrying out Valiante’s prophetic cloning protocol, and they may very well have been correct. Amgen argued that in reality it was much more difficult and complicated then suggested in the prophetic example, and Kubin’s success required a “specific mixture of resting cells, resting NK cells and NK cells stimulated with a very specific cocktail of activators.” But these are technical questions, which Federal Circuit judges are ill-suited to decide de novo. The Federal Circuit was correct to note that the process successfully employed by Kubin to clone the claimed cDNA is irrelevant: the standard is whether one of skill in the art would have had a reasonable expectation of cloning the claimed polynucleotides by any method. In KSR, the Supreme Court correctly chastised the Federal Circuit for considering how difficult the invention was for the alleged inventor (a subjective test), when they should have been considering how difficult the invention would have been for the person having ordinary skill in the art (the correct, objective test). The problem for Amgen was that regardless of the actual difficulties experienced by Kubin, the invention is obvious if one of skill in the art could have cloned a nucleic acid falling within the scope of a claim, by any method. Valiante, a prior art patents, provided a prophetic example purporting to teach just such a method, and because there is a presumption that the example is enabled, the PTO and court presumed that the prior art provided an enabling method for arriving at the claimed nucleic acids with a reasonable expectation of success. Because of the presumption of enablement, the burden was on Amgen to provide evidence that the prophetic example was not actually enabled, and they failed to convince the PTO or the court on this issue.

The standard of review was also important. The Federal Circuit reviews the factual findings of the PTO's Board of Patent Appeals and Interferences for “lack of substantial evidence” to support the findings. In this case, the PTO and Board made a factual determination that the Valiante prophetic example, when combined with other prior art, provided both the motivation to clone the NAIL cDNA and a reasonable expectation of success. As a consequence of the standard of review, the Federal Circuit is required to show a great deal of deference to this factual determination. In effect, if the PTO’s finding of a reasonable expectation of success is at least plausible, based on some substantial evidence, the court will defer to that determination, even if there is also substantial evidence pointing the other direction.

Because the question of whether there was a reasonable expectation of success is a factual finding, Amgen faced a very tough burden to prove that there was no substantial evidence supporting the PTO's decision. When compounded with the presumption that prophetic examples appearing in a patent are enabled, it becomes apparent that Amgen could only prevail by providing compelling evidence that, in fact, the cloning of this particular gene was much more difficult and unpredictable than suggested by the cited prior art, and they appear to have failed to meet this heavy burden.

What about the impact of this case on biotechnology? To quote Patent Docs, “the sky is not falling.” For one thing, Kubin does not mean that any patent claiming a cDNA is necessarily obvious if the encoded protein was known in the prior art. It simply means that we can no longer continue to interpret Deuel as establishing that the cDNA is never rendered obvious under those circumstances. Rather, the inquiry should shift to whether or not there was any kind of suggestion or motivation to clone the cDNA, and if there was, whether there was a reasonable expectation of success. In cases where the patent applicant can bring forth sufficient evidence to show that the cloning of a particular cDNA was more technically challenging, creating a sufficient level of unpredictability with regard to success, the invention should still be patentable under Kubin. After KSR, it should be clear that in many cases it will be necessary for a patent applicant to provide evidence of technical challenges and lack of predictable success to overcome an effective presumption that an invention is obvious, and Kubin simply applies that principle to a cDNA cloning invention.

Of course, the Kubin patent application was prosecuted prior to KSR, and it is unclear whether Amgen could have provided more compelling factual evidence that the cloning of this particular gene was actually more technically challenging and unpredictable than normal. The lesson for biotechnology patent prosecutors might be that this factual support of technical unpredictability of success is more important today than it was pre-KSR.

Also, as noted by Patent Docs, while this sort of invention, based on the successful cloning of a cDNA encoding a protein of known significance, was very important in the early days of biotechnology, it is becoming much less relevant with the passage of time. Today, in the age of high-throughput genomics, it is much more likely that a gene will be discovered prior to the isolation and characterization of the encoded protein. For most known proteins of clinical significance, the corresponding cDNA has already been cloned, in which case it is too late to patent the cDNA. If there are cases where the cDNA as yet to be cloned, that suggests that either there was no motivation or suggestion to do it, or that the cloning has proven unusually difficult technically, in which case it is likely nonobvious under Kubin.
In the early days of biotechnology, the main products were biologic drugs which basically were recombinant versions of naturally occurring human proteins. Patents claiming cloned human cDNA were important in protecting these inventions. But the trend in biotechnology is towards monoclonal antibodies and engineered second-generation proteins bearing less and less structural similarity to naturally occurring proteins. As a result, patents on cloned human genes should be less relevant. This might explain my finding, reported in a recent law review article and Science article, that litigation involving human gene patents has dropped off dramatically in recent years, particularly in the area of biologic drugs. Gene patent filings have also reportedly dropped off in recent years.

In sum will, many in biotechnology will view Kubin as a negative development. I am not so sure it will be that significant, unless investors perceive that it does have serious negative implications for biotechnology. I think we should try to counter that - a perception among investors that biotechnology has been harmed by Kubin could cause more damage to biotechnology than the decision itself.

18 comments:

Anonymous said...

I agree that the decision in In re Kubin brings obviousness of biotechnology inventions back to more rational ground. Even in 1995 (and in the 1980s, the era of the invention in In re Deuel, 51 F.3d 1552 (Fed. Cir. 1995)), biotechnologists considered cloning of a gene based on a protein sequence to be routine, with success given a high probability. However, the point of law on which Kubin was decided ignores the main basis of the decision in Deuel. and thus threatens to create a mismatch between obviousness and written description for biotechnology inventions.

In Deuel (51 F.3d 1552 (Fed. Cir. 1995)) the Federal Circuit reversed a Board of Patent Appeals Interferences decision holding a claim to a specific cDNA sequence obvious over the sequence of the protein encoded by the cDNA and known methods of cloning cDNA molecules using the sequence of the encoded protein. The decision in Deuel was clearly based on the priciple that the cDNA claimed was a chemical compound with a specific structure. The Federal Circuit reasoned that because the cited prior art taught a method of obtaining a cDNA but (according to the court) did not provide any suggestion of the structure of the claimed cDNA, the claimed cDNA could not be obvious. The court in Deuel clearly focused on the lack of teaching in the prior art of any structure of the claimed cDNA. Although the court also mentioned that the prior art method of obtaining the cDNA was "obvious to try" and that "obvious to try" art was insufficient to render a claim obvious, this was not the basis of the decision in Deuel, nor was it the legal principle thereafter applied from Deuel. The lasting legal principle from Deuel was that the structure of a claimed chemical compound could not be described by a mere method of obtaining that chemical (in the absence of a teaching suggesting the structure of the compound).

With amnesiatic sleight of hand, the Federal Circuit in In re Kubin recasts In re Deuel as a case about the “obvious to try” principle in obviousness analysis. In Kubin the court affirms a Board of Patent Appeals and Interferences decision holding a claim to a polynucleotide encoding a protein structurally and functionally related to a cell surface receptor obvious over prior art teaching the same receptor protein and a general method of obtaining the gene encoding the receptor protein.

The court first highlights how obvious the art made it to isolate the gene encoding the receptor protein based on the protein and emphasizing that it was undisputed that the prior art method would almost surely result in obtaining the gene. Thus, the court agreed that there would have been a reasonable expectation of success in obtaining the gene using the method. The court then recognized that affirming the Board decision in Kubin would require the court to address that contrary decision of In re Deuel. To do so, the court notes that the KSR Supreme Court decision has changed the landscape for obviousness determinations. In particular, the court spends some effort highlighting how KSR weakened the status of the “obvious to try” principle in assessing obviousness. The court even suggests that the Supreme Court in KSR was repudiating the obvious to try principle of In re Deuel (“Insofar as Deuel implies the obviousness inquiry cannot consider that the combination of the claim’s constituent elements was “obvious to try,” the Supreme Court in KSR unambiguously discredited that holding.”). The court also noted that the Supreme Court cited In re Deuel as supporting the “obvious to try” principle. However, as noted above, the holding in Deuel does not depend on the “obvious to try” principle. In any case, this repudiation of the holding in Deuel (now apparently based on application of the “obvious to try” principle) allowed the court to hold that the prior art method of obtaining the gene for the receptor protein made the claim to the gene itself obvious, noting that the proper application of the “obvious to try” principle supported a conclusion of obviousness.

As noted above, the decision in In re Kubin brings obviousness of biotechnology inventions back to more rational ground. Although the facts and difficulties differ for the cloning of each gene (and changed over time), biotechnologists have long considered cloning of a gene based on a protein sequence to be reasonably routine, with success given a high probability. Thus, the decision in In re Deuel was greeted with some disbelief by those knowledgeable in biotechnology. The Deuel decision was pro-inventor, but the true basis of the holding in Deuel was soon applied to reach a significantly anti-inventor decision in the realm of written description that followed directly from the true principle of the Deuel holding.

In Regents of the University of California v. Eli Lilly (119 F.3d 1559 (Fed. Cir. 1997)), the Federal Circuit addressed the question of whether a method of obtaining a gene provided a sufficient written description of the gene to satisfy the requirements of 35 U.S.C. § 112, first paragraph. A specific human cDNA was claimed in patents at issue in Eli Lilly but the patent specification provided only the sequence of the rat version of the cDNA and a method of using the rat cDNA sequence to obtain the human cDNA sequence. It was agreed by the court and the parties that the method of obtaining the human cDNA was enabling and would (and did) result in the human cDNA when it was performed. However, neither the rat cDNA nor the method suggested the structure of the human cDNA. Citing the reasoning in Deuel, the court held that an enabled method of obtaining a gene did not provide an adequate written description of the gene because it did not provide sufficient information about the structure of the gene. There was no doubt that the method/structure aspect of Deuel was the basis for the holding in Eli Lilly:

"We had previously held that a claim to a specific DNA is not made obvious by mere knowledge of a desired protein sequence and methods for generating the DNA that encodes that protein. See, e.g., In re Deuel, 51 F.3d 1552, 1558, 34 USPQ2d 1210, 1215 (1995) ("A prior art disclosure of the amino acid sequence of a protein does not necessarily render particular DNA molecules encoding the protein obvious because the redundancy of the genetic code permits one to hypothesize an enormous number of DNA sequences coding for the protein."); In re Bell, 991 F.2d 781, 785, 26 USPQ2d 1529, 1532 (Fed.Cir.1993). Thus, a fortiori, a description that does not render a claimed invention obvious does not sufficiently describe that invention for purposes of § 112, ¶ 1. Because the '525 specification provides only a general method of producing human insulin cDNA and a description of the human insulin A and B chain amino acid sequences that cDNA encodes, it does not provide a written description of human insulin cDNA. Accordingly, the district court did not err in concluding that claim 5 is invalid for failure to provide an adequate written description.

* * *

A written description of an invention involving a chemical genus, like a description of a chemical species, "requires a precise definition, such as by structure, formula, [or] chemical name," of the claimed subject matter sufficient to distinguish it from other materials."

Eli Lilly, 119 F.3d at 1567-68.

Thus, the court in Eli Lilly applied the scientifically questionable principle from Deuel—that an enabled and predictable biotechnology method of obtaining a biological molecule does not provide an adequate description of the biological molecule because the structure of the biological molecule cannot be determined a priori—to establish what is and is not an adequate written description of such biological molecules. The problem with this reasoning is that, in biotechnology and molecular biology, most biological molecules can be discovered and used without any need to know their structure (antibodies are an example). This view of the error of Eli Lilly (and of In re Deuel) has not gotten much traction in the last decade. However, the view of the biotechnological arts by the court in In re Kubin is now more in line with the scientific and practical realities of biotechnology and molecular biology. It is to be hoped that the this same rationality will now filter into written description decisions involving biotechnological inventions. However, the fact that the Federal Circuit did not mention or deal with the true principle of In re Deuel makes it more likely that this issue will be lost in the shuffle.

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