By Kevin E. Noonan --
The Federal Circuit will hear oral argument on Thursday for In re Kubin, a case having great significance for biotechnology patenting. At issue is the question of whether the existence in the prior art of a purified protein, combined with "routine" cloning methods, renders obvious a claim to a nucleic acid encoding the protein. This was the Patent Office position twelve years ago, which was rejected by the Federal Circuit in the In re Bell and In re Deuel decisions. But the Supreme Court's KSR Int'l Co. v. Teleflex Inc. decision emboldened the Patent Office to challenge the Federal Circuit on this issue. As a bonus, the Court will also be asked to opine on how the Office has interpreted its frequently-conflicting written description jurisprudence.
To recap, the case involved an application claiming an isolated cDNA encoding Natural Killer Cell Activation Inducing Ligand (abbreviated as NAIL). The Board determined that all the claims would stand or fall together, since they were not argued separately; accordingly, its analysis was confined to claim 73:
The Board cited three prior art references, including (1) Valiante, which identified the existence of a protein, p38, present on the cell surface of natural killer cells and a monoclonal antibody specific for p38; and (2) Sambrook et al., a standard reference work describing gene cloning techniques (otherwise known as the "Maniatis manual"). The Valiante reference contained a prophetic example to the effect that the gene encoding the p38 protein could be isolated using methods such as those disclosed in Sambrook et al. The Board considered but did not rely upon a reference to Matthews, which disclosed a mouse protein, 2B4, expressed on the cell surface of natural killer cells (2B4 is the mouse ortholog of human p38 although that was not disclosed in the art). The Board stated that it found Matthews "cumulative" of the teachings of Valiante and Sambrook et al.; nevertheless, it used this reference as an "illustration" of how a gene could be isolated. The evidence from the applicants' specification was that their NAIL cDNA clones were produced using an expression library screened with a commercially-available monoclonal antibody against human p38.
The Board based its factual determinations on the notion that the art had progressed since the time Deuel was decided. These differences included:
1. In Kubin, a cell "unambiguously" (see below) expressing the gene was known; in Deuel, the cloned gene was isolated from a cDNA library prepared from placenta, even though the protein encoded thereby was expressed specifically in brain.
2. In Kubin, the art provided an isolated preparation of the cognate protein and a monoclonal antibody that binds to the protein; in Deuel, the art disclosed isolated preparations of three different brain-specific proteins but no antibodies.
3. In Kubin, the art provided a monoclonal antibody specific for the gene product of the desired cDNA and thus providing a specific probe; in Deuel, the probes were a plurality of degenerate oligonucleotides prepared from the partial amino-terminal amino acid sequences.
4. In Kubin, the art has developed expression cloning technology and provided an antibody probe specific for the gene product of the desired clone; in Deuel, the absence of a specific antibody precluded use of expression cloning technology.
Even if the Board was correct in considering these factual distinctions, the Board's decision demonstrated that it did not learn the fundamental lesson from the Federal Circuit's decision in Deuel: that the obviousness of a method for producing a cloned nucleic acid is not sufficient to render obvious the cDNA itself. Rather, the Board attempted to apply the Supreme Court's statements from KSR regarding the obviousness of what is "obvious to try." Expressly citing the Supreme Court's language:
the Board opined, "[t]his reasoning is applicable here." The Board then went on to state:
Using this reasoning as its basis, the Board showed its willingness to continue to conflate whether the method for making a cDNA such as the NAIL cDNA would be obvious with the obviousness of the cDNA itself. This is consistent with the reasoning, and the mistakes, made by the Board in Deuel:
We today reaffirm the principle, stated in Bell, that the existence of a general method of isolating cDNA or DNA molecules is essentially irrelevant to the question whether the specific molecules themselves would have been obvious, in the absence of other prior art that suggests the claimed DNAs. . . . There must, however, still be prior art that suggests the claimed compound in order for a prima facie case of obviousness to be made out; as we have already indicated, that prior art was lacking here with respect to claims 5 and 7. Thus, even if, as the examiner stated, the existence of general cloning techniques, coupled with knowledge of a protein's structure, might have provided motivation to prepare a cDNA or made it obvious to prepare a cDNA, that does not necessarily make obvious a particular claimed cDNA. "Obvious to try" has long been held not to constitute obviousness. In re O'Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1680-81 (Fed. Cir. 1988). A general incentive does not make obvious a particular result, nor does the existence of techniques by which those efforts can be carried out. Thus, Maniatis's teachings, even in combination with Bohlen, fail to suggest the claimed invention.
The problem with the Board's analysis is that KSR requires a "finite number of identified, predictable solutions" (something that does not apply to nucleic acids and which was the basis for the Federal Circuit's decisions in In re Deuel and In re Bell). Such a "finite number" of "identified, predictable" solutions were not known in the prior art cited by the Board.
An important factor discounted by the Board comes from the disclosure of the Matthews reference, relating to the isolation of the mouse ortholog of the human NAIL cDNA. This reference was not considered by the Board, which seemed to recognize that the art did not teach that p38 was the mouse ortholog of NAIL. Moreover, the Matthews reference contained Northern blot experiments (for detecting mRNA expression of NAIL) from human cells and tissues indicating that NAIL expression could not be detected in the immune cell types that applicants used for cloning the human NAIL cDNA. The Board thus ignored evidence in the art that reduced the likelihood that the human NAIL cDNA could be isolated using the methods disclosed in the Sambrook et al. reference, since the art taught that human cells that actually expressed the NAIL cDNA did not do so. This is an important distinction with Deuel: in that case the gene was isolated from a tissue where its expression was not expected, while in Kubin the art taught affirmatively that the gene was not expressed in the tissue source of the cDNA used by applicants.
The other issue to be decided by the Federal Circuit involves the Board's decision to affirm the Examiner's determination that the application failed to satisfy the written description requirement for claims reciting nucleic acids encoding proteins at least 80% identical to the disclosed amino acid sequence of the claimed human NAIL protein. The Board held that Kubin was not entitled to a claim to an isolated nucleic acid encoding a protein having 80% identity to the disclosed amino acid sequence and that bound to CD48. Kubin's specification disclosed the amino acid sequence of the protein encoded by the NAIL gene, as well as domains of the protein (signal peptide, extracellular domain, transmembrane domain, and cytoplasmic domain), including the portion of the protein that bound to CD48 (amino acids 22-221). The specification also disclosed conservative substitutions of these sequences, in addition to deletions, insertions, and fusions. These teachings were generic, however, and no specific amino acid sequence variants were disclosed. The Board held that the absence of any specifically-disclosed variants was a failure to satisfy the written description requirement and upheld rejection on these grounds.
The Federal Circuit's decision on the written description issue may be at least as important as its determination of what is non-obvious, since it presents a question not yet squarely put to the Federal Circuit. The Federal Circuit has developed its written description jurisprudence (in Regents of the University of California v. Eli Lilly & Co., Enzo Biochem, Inc. v. Gen-Probe Inc., and University of Rochester v. G.D. Searle & Co.) generally in the context of patent infringement litigation and, except for dicta in its second Enzo decision, has not had the opportunity to provide guidance to the Office on how (or whether) its Guidelines are properly applying the Court's case law. The Patent Office has applied its Guidelines to effectively preclude an applicant from claiming "conservative substitutions," on the basis that there was no disclosure of a "representative number of species." (Of the 8,367 issued U.S. patents reciting "isolated" and "nucleic acid" in the claims, only 20 contain the term "conservative substitution.") It has become clear that the Office's use of the Guidelines would prevent an applicant from ever disclosing a sufficient number of substitutions that the Office would consider "representative" based on the type of generic disclosure set forth in Kubin's specification, and that it was impractical if not impossible to comply with the Office's requirements. The Office appears to have extended the Federal Circuit's requirement that structural domains important for biological activity be identified, to require that an applicant identify which amino acid residues can be modified and which cannot. This is a clear extension of the analysis set forth in Eli Lilly that has no support in any Federal Circuit decision. Yet, the Office routinely refuses to allow claims containing "conservative substitutions" within their scope. In re Kubin puts the question squarely before the Federal Circuit for the first time.
For information regarding this and other related topics, please see:
• "Docs at BIO: Panel Discusses IP Strategies after KSR," June 26, 2008
• "Docs at BIO: 'Gotcha' Games Continue at USPTO," June 25, 2008
• "Docs at BIO: Representatives from JPO, EPO, SIPO, and USPTO Discuss Recent Developments in Japan, Europe, China, and the U.S.," June 22, 2008
• "Briefs for In re Kubin filed by Amgen and BIO," June 12, 2008
• "USPTO's Bruce Kisliuk Addresses ACI Conference," March 3, 2008
• "DNA Non-obviousness under Ex parte Kubin (It Gets Worse)," October 18, 2007
• "Ex parte Kubin (B.P.A.I. 2007)," July 18, 2007