PTAB

IPR2018-01422

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 ’614 patent relates to human or humanized monoclonal antibodies that act as antagonists to Calcitonin Gene-Related Peptide (CGRP) for treating CGRP-related conditions like migraines. The independent claim requires the antibody to preferentially bind to human α-CGRP as compared to the related hormone amylin.

3. Grounds for Unpatentability

Ground 1: Claims 1-7 and 15-20 are obvious over Tan 1995, Wimalawansa, and Queen.

  • Prior Art Relied Upon: Tan 1995 (a 1995 journal article), Wimalawansa (a 1996 review article), and Queen (Patent 6,180,370).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the prior art collectively disclosed or suggested every element of the challenged claims. Tan 1995 described a murine monoclonal antibody (MAb C4.19) possessing the key functional properties of claim 1: it was an anti-CGRP antagonist that specifically bound to human α-CGRP but did not bind to amylin, and it demonstrated in vivo efficacy. Wimalawansa, a comprehensive review of CGRP, explicitly proposed that researchers evaluate "humanized anti-CGRP monoclonal antibodies" as therapeutic agents for CGRP-associated diseases like migraine. Finally, Queen taught well-established, "gold standard" methods for humanizing murine antibodies (e.g., by CDR grafting onto a human IgG framework) to reduce immunogenicity in humans while retaining the parent antibody's binding affinity and specificity. Petitioner contended that the limitations of the dependent claims were also well-known aspects of antibody therapeutics, including targeting the C-terminal region of CGRP (claims 2-7), using specific IgG isotypes like IgG2 (claim 15), incorporating an Fc region with impaired effector function (claims 16-17), and formulating for systemic administration (claims 19-20).
    • Motivation to Combine: Petitioner asserted that a person of ordinary skill in the art (POSITA) would be motivated to combine the references for several reasons. Wimalawansa provided the explicit suggestion to develop humanized anti-CGRP antibodies for therapeutic use. Tan 1995 provided an ideal starting point: a murine antibody with proven in vivo antagonistic activity and the desired binding profile (preferential for CGRP over amylin). A POSITA would combine Tan's antibody with the routine humanization techniques of Queen to create a therapeutically viable product, as humanization was the standard approach by 2005 to mitigate the immunogenicity of murine antibodies, a critical step for drugs intended for chronic conditions like migraine that require repeated administration. The desire to create a safe and effective therapeutic for known CGRP-mediated diseases provided a clear motivation to apply these established technologies.
    • Expectation of Success: Petitioner argued a POSITA would have had a reasonable expectation of success. The ’614 patent itself admitted that generating anti-CGRP antibodies and humanizing them were "known" and "conventional" techniques. The prior art demonstrated that creating murine antibodies with the desired binding profile was successful (Tan). Furthermore, the humanization technology described in Queen was considered a "clinically well-validated technology" known to reliably preserve the binding affinity and specificity of the original murine antibody. Therefore, a POSITA would reasonably expect to successfully humanize an antibody like Tan's MAb C4.19 and retain its essential, claimed properties.

4. Key Claim Construction Positions

  • Petitioner argued that the terms “anti-CGRP antagonist antibody” and “humanized antibody” must be construed to encompass antibody fragments (e.g., Fab, Fab', F(ab')2) based on express definitions provided within the ’614 patent's specification. This construction was asserted to be important because Tan 1995 showed that both a full-length murine antibody and its Fab' fragment were effective in vivo, reinforcing the obviousness of the claimed subject matter under a proper construction that includes such fragments.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under 35 U.S.C. §325(d) would be inappropriate. It contended that the core prior art references—Tan 1995, Wimalawansa, and Queen—were not substantively considered by the Examiner during prosecution. Although the references were listed in Information Disclosure Statements, these statements contained over 200 references, making it unsurprising the Examiner did not specifically address this combination in any Office Action.

6. Relief Requested

  • Petitioner requested that the Board institute an inter partes review, proceed to trial, and find claims 1-7 and 15-20 of the ’614 patent unpatentable.