PTAB

IPR2018-01423

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 ’951 patent claims a human or humanized monoclonal anti-Calcitonin Gene-Related Peptide (CGRP) antagonist antibody. The antibody is required to bind to human α-CGRP and inhibit cyclic adenosine monophosphate (cAMP) activation in cells for therapeutic use in treating conditions like migraines.

3. Grounds for Unpatentability

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

  • Prior Art Relied Upon: Tan (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:
    • Prior Art Mapping: Petitioner argued that every element of the challenged claims was disclosed or suggested by the prior art combination. Independent claim 1 recites a human or humanized monoclonal anti-CGRP antibody that binds human α-CGRP and inhibits cAMP activation. Petitioner contended that Tan disclosed a murine monoclonal anti-CGRP antagonist antibody (MAb C4.19) that was proven effective in vitro and in vivo. Wimalawansa, a comprehensive review on CGRP, then explicitly proposed developing "humanized anti-CGRP monoclonal antibodies" for treating human diseases like migraine. Queen provided the well-known and "gold standard" method for humanizing such murine antibodies via techniques like CDR-grafting to reduce immunogenicity while retaining antigen affinity. Finally, Doods demonstrated that inhibiting cAMP activation was a known and expected downstream effect of blocking the CGRP pathway and that using SK-N-MC cells was a standard method for confirming this antagonist activity. Therefore, the combination rendered the subject matter of claim 1 obvious.
    • Petitioner further argued that the limitations of dependent claims 2-6 and 14-19 were also well-known aspects of antibody design. These limitations included binding to the C-terminal region of CGRP (a known critical binding site), using a human IgG2 constant region (a known subclass with weak effector functions desirable for an antagonist), possessing an Fc region with impaired effector function (a known strategy to reduce side effects), being formulated in a pharmaceutical composition (a routine step), and using SK-N-MC cells for the assay (a standard cell line for CGRP research).
    • Motivation to Combine (for §103 grounds): A person of ordinary skill in the art (POSA) would have been motivated to develop a therapeutic for CGRP-mediated diseases, a clear goal in the art. A POSA would start with a known murine anti-CGRP antibody, such as that in Tan, and apply the standard humanization techniques taught by Queen to overcome the known immunogenicity issues of murine antibodies in humans, as explicitly suggested by Wimalawansa. To confirm the resulting humanized antibody was a functional antagonist, the POSA would predictably use a conventional assay, such as the cAMP inhibition assay detailed in Doods. The motivation was to create a safe and effective antibody therapeutic for human use by combining known elements for their predictable results.
    • Expectation of Success (for §103 grounds): Petitioner asserted a POSA would have had a reasonable expectation of success. By 2005, creating anti-CGRP antibodies was established, and antibody humanization was a routine, "clinically well-validated technology" known to preserve the essential binding properties of the original antibody. The ’951 patent itself admits that the methods for making and humanizing antibodies were "known" and "conventional."

4. Key Claim Construction Positions

  • Petitioner argued that for the purposes of the proceeding, the terms "anti-CGRP antagonist antibody" and "humanized antibody" must be construed to encompass antibody fragments, such as Fab and F(ab')2.
  • This construction is based on the ’951 patent’s express definitions in the specification. This position is significant because it ensures that prior art disclosing the activity of antibody fragments (such as Tan's disclosure of a Fab' fragment) is properly considered as teaching key limitations of the claims.

5. Key Technical Contentions (Beyond Claim Construction)

  • Refutation of "Teaching Away": Petitioner contested any argument that Tan taught away from using full-length antibodies. During prosecution, the Patent Owner argued that Tan showed only a Fab' fragment was effective. Petitioner countered that Tan, in fact, demonstrated the full-length antibody was also effective, albeit requiring higher doses or longer administration times to overcome its slower distribution. Petitioner asserted that Tan provided clear guidance for improving the efficacy of full-length IgG antibodies, which the inventors of the ’951 patent appear to have followed.
  • Near-Simultaneous Invention: Petitioner provided evidence of near-simultaneous development of the claimed subject matter by at least two other independent entities (Lilly and Stanford-affiliated researchers) as objective evidence of obviousness. These entities filed their own patent applications for anti-CGRP antagonist antibodies for treating headache within months of the ’951 patent’s priority date, suggesting the invention was the product of ordinary skill at the time, not an inventive leap.

6. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under 35 U.S.C. §325(d) would be inappropriate because the key evidence was not previously considered by the Examiner during prosecution.
  • Specifically, the core prior art combination of Tan, Wimalawansa, Queen, and Doods was never cited or substantively analyzed in any Office Action. While the references were listed in a large Information Disclosure Statement containing over 200 documents, there is no indication the Examiner appreciated their collective significance, warranting a fresh review in an inter partes review (IPR).

7. Relief Requested

  • Petitioner requested the institution of an IPR and cancellation of claims 1-6 and 14-19 of Patent 9,266,951 as unpatentable.