By Kevin E. Noonan —

In the excitement of the Federal Circuit's en banc decision in In re Bielski, handed down last Thursday, it could be understandable that another opinion from the Federal Circuit reviewing a Patent Office determination of unpatentability, In re Alonso, might go unnoticed.  Unfortunately, this decision continues the Federal Circuit's practice of expanding the scope of the written description requirement of 35 U.S.C. § 112, first paragraph, as it is applied to biotechnology inventions, and appears to be in direct conflict with the Court's earlier decision in Noelle v. Lederman.

The invention relates to U.S. Patent Application No. 08/469,749 filed by Dr. Kenneth Alonso and relating to antibody reagents and methods for treating neurofibrosarcomas.  The rejected claim recites as follows:

92.  A method of treating neurofibrosarcoma in a human by administering an effective amount of a monoclonal antibody idiotypic to the neurofibrosarcoma of said human, wherein said monoclonal antibody is secreted from a human-human hybridoma derived from the neurofibrosarcoma cells.

(The opinion sets forth in a footnote the evidence in the specification that infusion of a human patient with 100 mg of an expressly-disclosed monoclonal antibody resulted in clearance of lung metastases within 24 hours and regression of the primary brain tumor within seven days.)  The examiner rejected claim 92 on non-enablement and lack of adequate written description grounds; the examiner asserted with regard to the written description rejection:

Applicant is reminded that the disclosure only describes the preparation of a single Mab produced by the hybridoma cell line HB983.  However, the claims are directed toward a much larger genus of molecules (i.e., Mabs that bind to a neurofibrosarcoma), not a specific Mab identified by the deposited hybridoma.  . . .  The crux of the rejection is whether or not applicant has provided sufficient support for the broadly claimed genus of therapeutic antibodies.  As set forth in the rejection, the skilled artisan would reasonably conclude that applicant was clearly not in possession of the claimed genus of compounds.  Applicant should direct the claim language toward the only described embodiment (e.g., a Mab produced by hybridoma HB983).

The Board affirmed rejection on written description grounds, but reversed the enablement rejection, and Dr. Alonso appealed.

The Federal Circuit's decision, heard by Chief Judge Michel, Circuit Judge Mayer, and District Judge Richard G. Stearns from the District of Massachusetts, affirmed the rejection.  In the opinion (curiously, written by Judge Stearns), the Court set forth the familiar litany of Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997); Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555 (Fed. Cir. 1991); Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956 (Fed. Cir. 2002), and Univ. of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916 (Fed. Cir. 2004).  The most relevant citation, however, was In re Gartside, 203 F.3d 1305 (Fed. Cir. 2000), reciting the "substantial evidence" standard (consisting of "relevant evidence that 'a reasonable mind might accept as adequate to support a conclusion'"), since satisfaction of the written description requirement is a question of fact.  The Court cited the analytical basis for the Board's decision:

[W]hether the single monoclonal antibody described in the Specification is representative of the genus of monoclonal antibodies required to practice the claimed treatment method.  That, in turn, depends on whether or not the antibodies (and the antigens they bind) would have been expected to vary substantially within the genus.  The greater the variation in the genus, the less representative any particular antibody would be.

The Board relied on evidence that the genus of antibodies immunologically-reactive to neurofibrosarcoma cells would "vary substantially" throughout the genus, due to "considerable antigenic 'heterogeneity'," both between tumors from different individuals as well as different (metastatic) tumors from the same patient.  In addition, the "efficacy" of antitumor therapy (a fact seemingly more related to operability and enablement than written description) is expected to be related to "idiotypic change in the original tumor" according to a scientific journal article by Dr. Alonso himself.  The Board synthesized this evidence to conclude:

[F]or purposes of satisfying the written description requirement, it is not enough merely to disclose a method of making and identifying compounds capable of being used to practice the claimed invention.  That is, it is not enough to describe[] the procedure for making a human-human hybridoma from neurofibrosarcoma, and teach how to determine whether a given antibody, specific to a patient's neurofibrosarcoma, will function in the claimed method.  We find that the single antibody described in the Specification is insufficiently representative to provide adequate written descriptive support for the genus of antibodies required to practice the claimed invention.

The Federal Circuit found that this conclusion was supported by substantial evidence.  The opinion cites both Noelle v. Lederman and University of Rochester v. G.D. Searle as supporting this conclusion, despite the fact that the Rochester case is most readily distinguished because it (admittedly) disclosed zero members of the genus of specific COX-2 inhibitors necessary to practice the methods claimed in the Rochester patents (indeed, there was no evidence that inhibitors having COX-2 but not — or sufficiently reduced — COX-1 inhibitory activity even existed).  Rather, the opinion here analogizes the assertions in the Rochester opinion that the specification there failed to satisfy the written description requirement because that patent did not disclosed "which peptides, polypeptides, and small organic molecules have the desired characteristics of selectively inhibiting [COX-2]."  The analogy here is Dr. Alonso's failure to disclose the structure of any neurofibrosarcoma-specific antigens, which analogy appears to disregard the significant distinctions between actual antigens expressed by these tumor cells and hypothetical inhibitors specific for COX-2.

The opinion also distinguished Noelle v. Lederman (albeit sub silentio) by noting that Dr. Alonso's specification did not identify or characterize any neurofibrosarcoma cell-specific antigens, merely disclosing the existence of one antigen characterized by its molecular weight.  Dr. Alonso's "specification teaches nothing about the structure, epitope characterization, binding affinity, specificity, or pharmacological properties common to the large family of antibodies implicated by the method," contrasting this "sparse disclosure" with the "detailed method of making the antibodies" that Dr. Alonso disclosed.

Unfortunately for Dr. Alonso, but perhaps fortuitously for the rest of us, there were a number of further distinctions Dr. Alonso raised before the Federal Circuit that the opinion asserts were not raised before the Board, and hence waived.  These include the biological facts that the "well-known correlation between the structure and function of neurofibrosarcoma-specific antibodies," the shared function between members of the subgenus of antibodies raised against a specific patient's tumor, the "well-known correlation between human antibody structure and antibody function," and that monoclonal antibodies are necessarily specific for the neurofibrosarcoma against which they are raised.  The opinion suggests that these factors might satisfy the written description requirement by showing, instead of a representative number of members of a genus, "'relevant identifying characteristics,' such as 'complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics,'" citing Enzo, 323 F.3d at 964 (emphasis in original).

The Federal Circuit's written description jurisprudence has traveled far from the rational bases that founded its decision in Eli Lilly and other early cases.  There, the CAFC rightly found that the inherent uncertainty of isolating genes, being chemical compounds albeit complex ones, necessitated that an applicant show actual possession of the isolated molecule before deserving patent protection for it.  As the case law has developed, however, it has turned more and more surely to requiring a "representative number of species," or its twin, the "relevant identifying characteristics," that in many cases are not justified to the same extent as in the DNA/gene cases.  In those early cases there was not only the uncertainty of possession but the possibility that the results obtained based on, for example, an isolated protein would not predictably yield a nucleic acid encoding it; one ready example is blood clotting Factor VIII, which is encoded by a much larger than predicted transcript because it is produced initially as a preprotein that had not been observed in blood or tissues.

These considerations do not apply to technologies, like monoclonal antibody production, that are well-known and produce predictable results.  And despite the considerations operating in Rochester that preclude a patentable distinction between compound and method claims, the reality is that Dr. Alonso provided a fully characterized plurality of antigens — the neurofibrosarcoma cell, which despite its heterogeneity is a particularly well-characterized type of cancer c
ell — that could be used to reliably produce specific monoclonal antibodies.  The question must be asked whether disclosing two, five, ten, twenty, or one hundred "species" of antibodies would be more readily convincing to the skilled worker that Dr. Alonso was more in "possession" of a method to treat neurofibrosarcomas than is the case based on the one antibody showing such striking results.  A better question is how greatly will innovation be harmed in the therapeutic antibody arts (an area frankly robust in the number of new therapeutics) by decisions like Alonso that impose arbitrary requirements for fulfilling the written description requirement.

In re Alonso (Fed. Cir. 2008)
Panel: Chief Judge Michel, Circuit Judge Mayer, and District Judge Stearns
Opinion by District Judge Stearns

Antibody image: Tom Vickers, Wikipedia Commons