On April 3, 2009, the U.S. Court of Appeals for the Federal Circuit issued In re Kubin (Fed. Cir., No. 2008-1184), perhaps the most significant patent-law decision affecting the genetic engineering industry in over a decade. At issue was the patentability of isolated genetic sequences, in this case encoding a previously identified, but unsequenced, protein.
Amgen inventors Marek Z. Kubin and Raymond G. Goodwin invented a cDNA molecule encoding a natural killer cell activation-inducing ligand (NAIL) protein involved in an immune response to tumors and viruses. The Federal Circuit held this invention to be obvious in view of knowledge of the protein’s existence and commonly available cloning techniques for obtaining cDNA sequences.
This decision criticized Federal Circuit precedent in cases such as In re Deuel, 51 F.3d 1552 (Federal Circuit 1995), which clearly established patentability of genetic sequences based upon the nonobviousness of the exact chemical structure of the nucleotide sequence, irrespective of the routine means by which the invention may be deduced.
The Kubin case also weakens the art-level distinction of biotechnology inventions generally, which previously were considered merely “obvious to try” but with frequently unpredictable, and hence patentable, experimental outcomes. The commercial significance of this case is highlighted by the number of amicus briefs filed by entities such as Eli Lilly & Co., Amylin Pharmaceuticals, Johnson & Johnson, Novartis, GlaxoSmithKline, and the Biotechnology Industry Organization, in support of Amgen’s position of patentability. Given the momentum for passage of pending legislation for FDA approval of generic and follow-on biologics, the stakes have never been higher for changing the standard for obviousness of genetic sequence patent claims.
Prior Obviousness Developments
The Federal Circuit in Kubin was profoundly influenced by the U.S. Supreme Court’s recent obviousness pronouncements in KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727 (2007) and the implications for inventions that may be obvious to try and result in an expected outcome. In KSR, the Supreme Court rejected a rigid application of the “teaching, suggestion, or motivation” test and mandated an expansive and flexible approach to determine whether a patent is obvious under 35 U.S.C. §103 of the Patent Act.
The Supreme Court stated that an invention may be obvious when there is market pressure to solve a problem and when there are a finite number of identified, predictable solutions, so that a person of ordinary skill has good reason to pursue the known options within his/her technical grasp. If this leads to the anticipated success, according to the Court, it is likely not the product of innovation but of common sense.
However, the invention in KSR did not concern biotechnology, but rather was directed to a mechanical device. The Court’s “obvious to try” and “predicable-result” approach is a workable rationale for addressing the obviousness of combining known physical components to produce a device with predictable features.
But at issue in the patentability or obviousness of claimed genetic sequences is the very nature of the predictability of the result. While it may well be predictable that an accurate nucleic acid structure will result from a particular sequencing methodology, the resulting chemical structure itself (i.e., the cDNA sequence) still cannot be predicted a priori. Moreover, the Federal Circuit had previously recognized that biotechnology is an unpredictable art, and that most often the problems addressed in molecular biology do not have predictable solutions.
Gene Patent Precedents
The Federal Circuit’s ruling in Kubin was a marked departure from settled law controlling the obviousness standard for patenting genes. In In re Bell, 991 F.2d 781 (Fed. Cir. 1993), the Federal Circuit ruled that claims directed to nucleic acids encoding human insulin-like growth factors were not obvious, even though the amino acid sequences for such human growth factors were disclosed in the prior art, as were the general methods for isolating a gene by using degenerate probes corresponding to short amino acid sequences of the known protein.
Following Bell, in Deuel, the Federal Circuit ruled that a combination of a reference disclosing a partial amino acid sequence of a heparin-binding growth factor protein, together with a prior-art reference teaching a method of gene cloning, does not render the claims directed to cDNA molecules encoding the protein obvious.
The Federal Circuit considered the claimed DNA sequences as “new chemical entities in structural terms” and concluded that the obviousness rejection based on the alleged obviousness of a method of making such molecules, not the obviousness of the structurally similar molecules themselves, is improper. In the wake of the Kubin case, however, the reasoning in Deuel and Bell can no longer be relied upon.
The Kubin case
Kubin is a pivotal post-KSR obviousness case addressing the classical biotechnology invention involving the cloning and characterization of a human gene encoding an isolated, but not yet sequenced, protein. The human NAIL protein was known to exist on the surface of natural killer (NK) cells and bind to the CD48 protein to elicit an immune response against certain viruses and tumors.
Kubin and Goodwin isolated and cloned a human NAIL protein using an available antibody to the murine version of the protein, and a cDNA expression library generated from pooled mRNAs extracted from human NK cells stimulated with known activators. They became the first to sequence both the cDNA and amino acid sequences of such a protein.
The claims in Kubin are directed to a genus of isolated nucleic acid molecules encompassing an extracellular binding domain of the NAIL protein that binds to CD48. The claims at issue were held invalid as obvious under 35 U.S.C. §103(a), and for lack of enablement and failure to meet the written description requirement under 35 U.S.C. §112, 1st paragraph. The Federal Circuit only discussed the obviousness aspects of the invention. It did not address many issues of fact regarding undefined expression and cloning parameters in the prior art that were necessarily elucidated in order to reveal the cDNA sequence.
Relying on KSR, Judge Randall R. Rader eliminated the effective nonobviousness presumption biotechnology has enjoyed as an unpredictable art. In writing for the Federal Circuit, he stated that “this court cannot deem irrelevant the ease and predictability of cloning the gene that codes for that protein. This court cannot, in the face of KSR, cling to formalistic rules for obviousness, customize its legal tests for specific scientific fields in ways that deem entire classes of prior-art teachings irrelevant, or discount the significant abilities of artisans of ordinary skill in an advanced area of art.”
Rader further stated that KSR limits the Federal Circuit’s reliance on 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,” Rader said. Regarding the proper use of the “obvious to try” standard, Rader noted that the Supreme Court’s admonition against such a formalistic approach to obviousness “actually resurrects this court’s own wisdom in” In re O’Farrell, 853 F. 2d 894 (Fed. Cir. 1988).
O’Farrell acknowledged that the “obvious to try” standard can be erroneously equated with obviousness in two situations. As restated in Kubin, the first situation where an invention might be argued to be “obvious to try”—but the lack of predictability of the result mitigates against obviousness—is “where a defendant merely throws metaphorical darts at a board filled with combinatorial prior-art possibilities.” This was contrasted with KSR obviousness “where a skilled artisan merely pursues ‘known options’ from a ‘finite number of identified, predictable solutions.’”
The second remaining nonobviousness situation, where “obvious to try” does not mitigate toward ultimate obviousness, is when the “obvious to try” was to explore a new technology or general approach that seemed to be a promising field of experimentation—where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it. Kubin indicated that KSR affirmed the inverse of this statement by stating that an invention is obvious unless “the improvement is more than the predictable use of prior-art elements according to their established functions.”
Rader found that neither of the two “obvious to try pitfalls” applied in Kubin, concluding that “the record shows that a skilled artisan would have had a resoundingly ‘reasonable expectation of success’ in deriving the claimed invention in light of the teachings of the prior art.” The Federal Circuit acknowledged that the invention in Kubin was “some minor advance in the art,” but that “granting patent protection to advances that would occur in the ordinary course without real innovation retards progress.”
Kubin’s Impact on Gene Patenting
The Federal Circuit’s decision in Kubin generally means that to the extent a protein has been previously identified, its nucleotide sequence is no longer patentable. The broader application of Kubin will include attempts to reject or invalidate claims directed to biotech inventions that claim an outcome of experimentation from among a range of expected results, even though not expressly predictable.
There will undoubtedly be an increase in invalidity challenges to existing gene patents by those seeking to market generic and follow-on biologics prior to patent expiration, in view of the likelihood that pending regulatory legislation also passes. Clearly, the patentability standard for gene sequences and the commercial exclusivity available for such biotech inventions have been dramatically altered by the Federal Circuit’s In re Kubin decision.