Disclosure of single antibody insufficient to describe genus of related antibodiesNovember 6, 2008

In a recent decision, the Federal Circuit affirmed the decision of the Board of Patent Appeals and Interferences sustaining in part the examiner's final rejection of the broadest claim in an application, directed to methods of treating neurofibrosarcoma using monoclonal antibodies. The Board reversed the examiner's rejection of the claim for lack of enablement, but sustained the rejection for lack of adequate written description. The Board agreed with the examiner that the single example provided of a functional monoclonal antibody for use in treatment and the method of its production did not provide sufficient support for the genus encompassing all such antibodies.The Federal Circuit affirmed, finding the Board's conclusion supported by substantial evidence. The question turned on the level of variability within the claimed genus. There was evidence in the record that the species in the genus "would be expected to vary substantially," based on statements made in scientific literature (including one paper authored by the inventor). As described by the court:

The specification of the '749 Application does not characterize the antigens to which the monoclonal antibodies must bind; it discloses only the molecular weight of the one antigen identified in Example 2. This is clearly insufficient. The 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. While Alonso's claim is written as a method, the antibodies themselves are described in purely structural language – "a monoclonal antibody idiotypic to the neurofibrosarcoma of said human." This sparse description of antibody structure in the claim stands in stark contrast to the detailed method of making the antibodies found in the specification.

Accordingly, the court affirmed the rejection on written description grounds.More detail of In re Alonso after the jump.

On June 6, 1995, Dr. Alonso filed the '749 Application entitled "Method of Producing Human-Human Hybridomas, The Production of Monoclonal and Polyclonal Antibodies Therefrom, and Therapeutic Use Thereof." The claimed invention recites a method for treating neurofibrosarcoma, a rare cancer of the sheath of a peripheral nerve, that uses human monoclonal antibodies targeted at a patient's tumor. Claim 92 of the '749 Application claims:

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.

Example 1 in the Specification described the preparation of a tumor cell suspension from the sample of a tumor and the subsequent sensitization of human spleen cells; example 2 disclosed the results of an experiment conducted by inventor Alonso in treating a patient with neurofibrosarcoma. Adult spleen cells were sensitized with cells from the patient's tumor. The resulting hybridoma secreted monoclonal antibodies, which reacted with a 221 kD tumor surface antigen.The Examiner rejected claim 92 as lacking adequate written description support for the broad genus of antibodies encompassed by the claim language. The Board affirmed the rejection, agreeing Alonso had not adequately described the claimed invention because 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." Alonso appealed.On appeal, the court noted that the determination of whether an applicant has complied with the written description requirement is a finding of fact, to be analyzed from the perspective of one of ordinary skill in the art as of the date of the filing of the application. In making the assessment, the court examines "the record as a whole, taking into account evidence that both justifies and detracts from an agency's decision," to determine whether the Board's decision is supported by substantial evidence. The court noted that even though a fact finder could draw "two inconsistent conclusions from the evidence does not prevent an administrative agency's finding from being supported by substantial evidence." Rather, the Board's decision must be affirmed if any "reasonable fact finder could have arrived at the [same] decision."In its determination, the Board framed the issue raised by the '749 Application as follows:[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 court held that the Board properly characterized the relevant genus as the "genus of antibodies specific to neurofibrosarcoma cells" and that the Board's conclusion of non-compliance with § 112 was supported by substantial evidence. The articles relied upon the Board in its decision confirmed the hypothesis that the antibodies required to perform Alonso's claimed method varied substantially in their composition. In this respect, the court noted its previous decision in a similar context that "a patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."In further support of its decision, the court cited the analogous case of University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 922 (Fed. Cir. 2004). In Rochester, the court affirmed the district court's determination that the inventors had failed to satisfy the written description requirement as they had only hypothetical knowledge of the critical claimed aspect of the method – a compound that selectively inhibits COX-2 activity. The court further noted the specification contained "no disclosure of any method for making even a single 'non-steroidal compound that selectively inhibits activity of the COX-2 gene product,'" and failed to "steer the skilled practitioner toward compounds that can be used to carry out the claimed methods."The court was not persuaded by Alonso's attempt to distinguish his claimed invention from Rochester by emphasizing that he had reduced his method to practice and identified the resulting compound, noting that his "proof of a reduction to practice absent an adequate description in the specification of what is reduced to practice, does not serve to describe or identify the invention for purposes of [the written description requirement]." Moreover, while it was true that Rochester disclosed no compounds that worked with the claimed method, the one compound disclosed by Alonso could not be said to be representative of a densely populated genus.In addition, the court took note that the '749 Application did not characterize the antigens to which the monoclonal antibodies must bind, and taught nothing about the structure, epitope characterization, binding affinity, specificity, or pharmacological properties common to the large family of antibodies implicated by the claimed method.The court refused to consider Alonso's final argument, that the disclosure was sufficient because it specified "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." In this regard, Alonso argued a structure-function relationship between the members of the genus of antibodies directed to a particular patient's tumor sharing the same function, i.e each binding to a patient's neurofibrosarcoma, thereby bolstering the patient's immune mechanism and simulating an attack on the tumor cells. As for structure, Alonso argued that because monoclonal antibodies are secreted from a hybridoma made from a particular neurofibrosarcoma, the antibodies were necessarily specific. However, the court noted Alonso did not raise this structure-function argument before the Board, and was therefore precluded from advancing such legal theories before the court. The court therefore refused to consider this new argument on appeal, but noted in a footnote that even if it did consider the argument, it would not have changed the outcome, as Alonso did not point to any structure for the claimed antibodies, so there was no structure for the function to be correlated to. As a result, the Federal Circuit affirmed the written description rejection.To read the full decision in In re Alonso, click here.

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