PTAB

IPR2018-01424

Eli Lilly Co v. Teva Pharmaceuticals Intl GmbH

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Key Events
Petition

1. Case Identification

2. Patent Overview

  • Title: Antagonist Antibodies Directed Against Calcitonin Gene-Related Peptide and Methods Using Same
  • Brief Description: The ’881 patent claims a human or humanized monoclonal anti-Calcitonin Gene-Related Peptide (CGRP) antagonist antibody. The antibody is functionally defined by its ability to bind human α-CGRP and inhibit its binding to its receptor, as measured by a specific radioligand binding assay in SK-N-MC cells.

3. Grounds for Unpatentability

Ground 1: Obviousness over Tan, Wimalawansa, Queen, and Doods - Claims 1-6 and 14-19 are obvious over Tan 1995, Wimalawansa, Queen, and Doods.

  • Prior Art Relied Upon: Tan 1995 (a 1995 clinical science article), Wimalawansa (a 1996 endocrine review article), Queen (Patent 6,180,370), and Doods (a 2000 pharmacology journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of references taught or suggested every element of the challenged claims. Tan 1995 disclosed a murine monoclonal anti-CGRP antagonist antibody (MAb C4.19) that binds to human α-CGRP and inhibits its biological activity, as confirmed in an in vitro radioligand binding assay. Wimalawansa, a review article on CGRP's clinical potential, explicitly proposed that researchers should evaluate "humanized anti-CGRP monoclonal antibodies" as therapeutic agents for diseases like migraine. Queen disclosed the well-established, "gold standard" methods for humanizing non-human antibodies (like Tan's murine antibody) by grafting their complementarity-determining regions (CDRs) onto a human antibody scaffold to create a therapeutic that is not immunogenic in humans. Finally, Doods established that the specific assay recited in claim 1—a radioligand binding assay using SK-N-MC cells—was a preferred and routinely used method for analyzing whether a compound blocks human CGRP from binding to its human receptors. For the dependent claims, Petitioner asserted that adding features like binding to C-terminal epitopes (claims 2-6), using an IgG2 constant region (claim 14), comprising an Fc region (claim 15), impairing effector function (claim 16), or formulating into a pharmaceutical composition (claims 18-19) were all obvious modifications based on well-known principles in the art.
    • Motivation to Combine (for §103 grounds): Petitioner asserted a clear motivation for a person of ordinary skill in the art (POSA) to combine the references. A POSA would begin with the promising murine anti-CGRP antibody from Tan and, guided by Wimalawansa's express suggestion, seek to create a humanized version for therapeutic use in chronic conditions like migraine. The primary motivation for humanization, taught by Queen, was to reduce the immunogenicity associated with repeated administration of murine antibodies. To confirm the resulting humanized antibody retained its function, a POSA would have logically employed the preferred assay for human CGRP activity described in Doods, which used human SK-N-MC cells.
    • Expectation of Success (for §103 grounds): Petitioner argued a POSA would have had a high expectation of success. By 2005, generating monoclonal antibodies was routine, humanization via CDR grafting as taught by Queen was a "clinically well-validated technology," and the radioligand binding assay in SK-N-MC cells from Doods was a standard, reliable method. The combination represented a predictable application of known techniques to achieve a desired and clearly articulated therapeutic goal.

4. Key Claim Construction Positions

  • "anti-CGRP antagonist antibody" and "humanized antibody": Petitioner argued that, based on express definitions within the ’881 patent's own specification, these terms must be construed to encompass not only intact monoclonal antibodies but also antibody fragments thereof (e.g., Fab, Fab', F(ab')2). This construction was asserted to be critical because prior art, such as Tan 1995, demonstrated the effectiveness of both full-length antibodies and their fragments, bringing such fragments within the scope of the obviousness analysis.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under 35 U.S.C. § 325(d) would be inappropriate because the evidence presented was not previously considered by the USPTO during prosecution. Specifically, the Examiner did not cite Tan 1995, Wimalawansa, Queen, or Doods in any Office Action. Petitioner suggested these key references were overlooked because they were submitted within Information Disclosure Statements containing over 200 other references, preventing a full consideration of their teachings.

6. Relief Requested

  • Petitioner requests that the Board institute an inter partes review, conduct a trial, and find claims 1-6 and 14-19 of the ’881 patent unpatentable.