Wednesday, September 24, 2008

In re Kubin: Update on the Briefing of This Important Federal Circuit Case Relating to the Application of the Nonobviousness and Written Description

In re Kubin is an appeal of a Board of Patent Appeals and Interferences (BPAI) decision affirming the rejection of claims directed to a genus of isolated nucleic acid molecules. The claim at issue encompasses polynucleotides encoding the human NAIL protein(e.g., cDNA), along with polynucleotides encoding functional variants sharing at least 80% sequence identity with an extracellular domain of the disclosed NAIL protein. The real party in interest is Amgen, a leading biotechnology company.

Kubin involves the classic biotechnology “invention,” i.e., the isolation, cloning and characterization of a human gene (I use quotes because the Patent Office (PTO) has taken the position that the Amgen’s discovery is obvious and thus not a patentable invention.) Essentially, at the time of the alleged invention, the prior art had reported the existence of a protein on the surface of natural killer (NK) cells (which was ultimately identified as the NAIL protein), and the creation of a monoclonal antibody capable of recognizing that protein. The prior art did not describe the purification or isolation of the protein, nor did it teach the protein’s chemical structure, i.e., amino acid sequence. Against this backdrop, Amgen scientists (Kubin and Goodwin) succeeded in cloning and sequencing the cDNA sequence encoding the protein, thereby allowing them to deduce the amino acid sequence of the protein. They also determined that the protein (NAIL) binds to the CD48, a protein expressed on the surface of several types of cells involved in the immune process, including NK cells and various white blood cells such as T cells, B cells, monocytes and granulocytes . According to Amgen, the NAIL-CD48 interaction has important biological consequences, including an increase in natural killer (NK) cells cytotoxicity and stimulation of interferon gamma production. They assert that the isolation and characterization of NAIL and the cDNA encoding it allows for the generation of molecules that can modulate the activation of NK and T cells, with potential therapeutic benefits.

In claiming their invention, Amgen did not limit itself to the specific cDNA sequence encoding NAIL, but instead sought patent coverage for the entire genus of polynucleotides having the ability to encode any polypeptide (protein) sharing at least 80% identical to the extracellular domain of the human NAIL protein and which retains NAILS ability to bind CD48. This sort of broad claiming strategy is standard in biotechnology, and highly desirable in order to provide effective coverage against a competitor designing around a narrow patent limited to the actual cDNA sequence discovered, or to the genus polynucleotides encoding the native NAIL protein. It is generally possible to introduce multiple sequence alterations in at both the polynucleotide and polypeptide level without substantially affecting the protein’s function, e.g., the ability to bind CD 48. (For an extended discussion of genus claiming, the interested reader is directed to my law review article on this point).

The patent examiner rejected the claim for failure to comply with the nonobviousness, enablement and written description requirements, and on appeal the BPAI reversed on the issue of enablement but affirmed on the issues of obviousness and written description. The case is currently on appeal to the Federal Circuit, and many in the biotechnology sector view it as an important opportunity for the Federal Circuit to clarify the proper application of the nonobviousness and written description requirements to this ubiquitous type of biotechnology invention. At this point Amgen and the PTO have filed briefs with the Federal Circuit, along with a number of amicus curiae, including Eli Lilly and the Biotechnology Industry Organization (BIO), Glaxo Smith Kline, Johnson & Johnson and Novartis.

With respect to nonobviousness, a primary question to be addressed is whether, and to what extent, In re Deuel sets the standard for assessing the obviousness of newly isolated genetic sequences. In Deuel, decided in 1995, the Federal Circuit reversed a BPAI decision which had found claims similar to those at issue in Kubin to be obvious. The facts of the two cases are quite analogous. In Deuel, the BPAI found that prior art teaching a partial amino acid sequence for a protein, when combined with standard methodology for cloning a cDNA based on the knowledge of the partial amino acid sequence for a protein encoded by the cDNA, rendered obvious not only the methodology for cloning the cDNA, but also the resulting cDNA. In reversing the BPAI, the Federal Circuit essentially stated that in assessing the obviousness of a biomolecule, it is insufficient to find that the methodology for generating the biomolecule would have been obvious. Instead, it is necessary that the prior art render the biomolecule itself obvious. Many have interpreted Deuel as establishing an extremely low obviousness threshold for the patentability of biotechnology inventions, or more particularly cloning inventions. In particular, Amgen and others would argue that a newly isolated polynucleotide is generally nonobvious unless the prior art discloses a polynucleotide sequence that is sufficiently similar in chemical structure to render the newly isolated polynucleotide obvious.

In Kubin, the BPAI found that a prior art reference disclosing the NAIL protein in an unpurified state and a monoclonal antibody capable of binding the NAIL protein, along with a prophetic example describing how to clone the corresponding cDNA, rendered the claim obvious in view of what it characterized as the routine nature of isolating and sequencing a cDNA molecule once the corresponding protein has been identified and a monoclonal antibody generated. To a large extent, the BPAI is relying on the same sort of rationale that the Federal Circuit rejected in Deuel. Amgen argues that the BPAI’s decision violates precedent established by Deuel and subsequent Fed Cir decisions relating to chemical obviousness, by focusing on the obviousness of the methodology for obtaining the NAIL cDNA rather than the obviousness of the chemical structure of the cDNA. Amgen also argue that the, in any event, the cloning of this particular gene was not routine, and the prior art provided no reasonable expectation of success.

At this point there is some question as to the continuing precedential authority of Deuel, particularly in light of substantial advances in cloning methodology subsequent to date of invention in Deuel, and the Supreme Court's recent decision in KSR which effectively raised the nonobviousness bar for inventions in general. Morevover, 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. Thus, Kubin is an important opportunity for the Federal Circuit to address the current significance of Deuel in light of these developments. Does it broadly establish that a biomolecule is only rendered obvious by the disclosure of a structurally similar molecule in the prior art, as argued by Amgen and others in the biotechnology industry, or should Deuel be read narrowly, as superseded by developments in the technology of cloning and/or by KSR?

With respect to written description, it is noteworthy that the examiner rejected the claims for violating both the enablement and written description requirements, a common rejection in view of the substantial overlap between the enablement and Lilly written description requirements (Note that I am referring to the Lilly written description requirement, not the traditional written description requirement, which is applicable only to amended claims or claims added after the initial filing date.

A couple of years ago I published an article describing the results of an exhaustive search for decisions coming out of the BPAI and federal courts applying the Lilly written description requirement (LWD), and at that time I found only one case in either the BPAI or courts in which a claim was explicitly found to satisfy the enablement requirement but violate LWD. That case was Capon v, Esshar, decided by the BPAI. Significantly, the Federal Circuit subsequently reversed the BPAI on this point, and essentially held that the standards for compliance with the enablement and LWD overlap substantially, and that it will be a rare case in which a claim will satisfy the enablement requirement but fail to satisfy LWD. Other Federal Circuit decisions (e.g., Lizardtech) have also treated enablement and Lilly written description as essentially redundant. Nevertheless, the PTO has recently been pushing for an interpretation of LWD that would it with a role distinct from the enablement requirement. This new expanded interpretation of LWD by the PTO is reflected in Kubin, and also In re Alonso a similar case in which the BPAI found claims directed to an antibody to satisfy the enablement requirement but fail LWD and which is currently on appeal to the Federal Circuit. The PTO’s expanded interpretation of LWD is also reflected in its revised written description guidelines, discussed in a previous post. In the Federal Circuit, Judge Lourie (the architect and main proponent of LWD) recently breathed new life into LWD by affirming a district court’s invalidation of claims directed to genetic constructs for failure to comply with LWD (Carnegie Mellon v. Hoffman-LaRoche, decided 8 September 2008).

Amgen argues that the board’s application of LWD is flawed and inconsistent not only with Federal Circuit precedent, but also with the patent offices own written description guidelines (both the original and revised versions). For example, Amgen points out that example 14 of the original written description guidelines would find a claim valid which is essentially analogous to Amgen's rejected claim, albeit with a 95% identity limitation instead of Amgen’s 80%. The PTO responds that 80% encompasses many more variants than the 95% limitation in the example, but provides no guidance with respect to how one is to determine when a percent identity limitation crosses the threshold between compliance with the written description requirement and invalidity. I think this is a fundamental flaw with LWD jurisprudence – so far, neither the courts nor the PTO have provided any meaningful guidance with respect to the permitted breadth of a polynucleotide genus claim such as this under either the enablement or LWD requirements.

Turning to some of the amicus briefs, BIO, SKB and Novartis all argue in support of Kubin on the question of nonobviousness, but none weigh in on the written description issue (which I consider to be at least as important as the nonobviousness issue). Eli Lilly supports Kubin on nonobviousness, but backs the PTO on written description (not surprising perhaps, since Eli Lilly was directly involved with the creation of LWD in UC v. Eli Lilly).

Wednesday, September 10, 2008

Federal Circuit Decides Important Biotechnology Written Description Case

In Carnegie Mellon University v. Hoffman-La Roche, decided September 8, 2008, the Federal Circuit affirmed a district court’s holding on summary judgment that claims directed to a recombinant plasmid containing a DNA polymerase I gene, isolated from any bacterial source, under the control of the conditionally controllable foreign promoter were invalid for failure to comply with the written description requirement.

The decision is significant in a number of respects. For one thing, it is the first time the Federal Circuit has invalidated a claim directed to a DNA sequence (or any biological molecule for that matter) in a situation not involving the discovery of a novel DNA sequence. For example, in UC Regents v. Eli Lilly (1997), the first case in which the Federal Circuit applied the written description requirement to invalidate an originally filed, non-amended claim, the invalidated claims were directed towards novel genetic sequences encoding insulin. Likewise, in In re Wallach (2004) the court invalidated claims reciting newly discovered TBP-II genes for failure to comply with what I refer to as the Lilly written description requirement (in contrast with the traditional written description requirement, which is applicable only to amended claims or claims added after the initial filing date).

In Carnegie Mellon, on the other hand, the essence of the invention was the discovery of a means of regulating the expression of the gene encoding DNA polymerase I (polA) to avoid lethality problems associated with over expression of the gene. The polA gene had previously been isolated from three different species of bacteria, and conditionally controllable promoters were also known in the prior art. Carnegie Mellon argued that the holding in Lilly was limited to inventions involving novel DNA sequences, but the Federal Circuit explicitly rejected this argument.

The court also voiced its approval of the USPTO’s 2001 “Written Description Guidelines,” (which were recently superseded by updated guidelines, as discussed in a previous post) finding it to be “persuasive authority” providing guidance in interpreting the written description requirement.

Carnegie Mellon is arguably inconsistent with the Federal Circuit's 2005 decision in Capon v. Eshhar, in which the Federal Circuit reversed a Board of Patent Appeals and Interferences holding that a claim directed to a chimeric DNA sequence failed to satisfy the written description requirement. For example, in Capon the court found that the Board had erred in holding that the written description requirement was not met because the specification failed to recite the structure or formula or chemical name for the DNA sequence components of the claimed chimeric genes. In that case, the court held that it was sufficient that sequences that could function as the segments of the chimeric gene were known in the prior art, and that the applicant was not required to "reiterate" those sequences in the application. In contrast, in Carnegie Mellon the court found it significant that the patent specification only discloses a DNA polymerase gene from a single bacterial species, even though the corresponding gene from two other bacterial species were known at the time of invention.

More striking, the claims in Capon define the chimeric gene in terms of two genetic elements that are defined in much broader, generic terms than the DNA polymerase I gene at issue in Carnegie Mellon. In particular, the Capon claims recite a genus of chimeric genes comprising a first segment encoding some portion of an antibody capable of binding an antigen, and the second segment encoding at least some portion of a protein that (1) is expressed on the surface of cells of the immune system and (2) triggers activation and/or proliferation of the cells. The Carnegie Mellon court distinguished the two cases by noting that in Capon the prior art contained “extensive knowledge of the nucleotide structure of the various and immune-related segments of DNA, including over 785 mouse antibody DNA light chains and 1327 mouse antibody DNA heavy chains,” while only three bacterial DNA polymerase I genes “out of thousands” had been cloned at the time of Carnegie Mellon's invention. However, the court fails to acknowledge the extreme structural variability in antibodies (Capon) compared to DNA polymerases (Carnegie Mellon). Furthermore, the court entirely ignores the extremely broad functional language defining the second element of the Capon chimeric gene, i.e., any segment encoding a protein expressed on the cell surface of cells of the immune system (there are a host of such cells) and capable of triggering activation or proliferation of the cells.

Carnegie Mellon is a significant affirmation of a continuing distinct role for the written description requirement in policing the scope of patent claims, typically in the area of biotechnology. However, it provides little guidance in applying the doctrine, particularly when one considers the seeming inconsistency between the outcomes in this case and Capon. My position is that the court is misguided in its application of the written description requirement in this manner, and the more appropriate tool for policing claim scope is the enablement requirement, but particularly over the last few years Lilly written description is increasingly taking on a life of its own.