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.