PTAB

IPR2018-01712

Eli Lilly and Company v. Teva Pharmaceuticals International GmbH

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1. Case Identification

2. Patent Overview

  • Title: Methods for Treating Headache Using Antagonist Antibodies Directed Against Calcitonin Gene-Related Peptide
  • Brief Description: The ’908 patent claims methods for treating or preventing headache, including migraine, by administering a humanized monoclonal anti-Calcitonin Gene-Related Peptide (CGRP) antagonist antibody with specific structural and binding characteristics.

3. Grounds for Unpatentability

Ground 1: Claims 1-18 are obvious over Olesen, Tan, and Queen.

  • Prior Art Relied Upon: Olesen (a 2004 publication in The New England Journal of Medicine), Tan (a 1995 publication in Clinical Science), and Queen (Patent 6,180,370).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of Olesen, Tan, and Queen taught or suggested every limitation of the challenged claims. Olesen established that blocking the CGRP pathway was a clinically proven method for treating migraine. Tan disclosed a murine monoclonal anti-CGRP antagonist IgG antibody (MAb C4.19) that specifically bound CGRP with a high affinity (KD of ~2 nM, well below the claimed ≤10 nM) and was effective in vivo. Queen taught the "gold standard" and widely practiced methods for humanizing a murine antibody, such as Tan's, into a human IgG scaffold suitable for therapeutic use, while maintaining its antigen-binding affinity and specificity. Petitioner contended that the claimed structural features (e.g., IgG heavy and light chains with CDRs and framework regions) were generic to all therapeutic IgG antibodies and taught by the art. Finally, Petitioner asserted that measuring binding affinity using Surface Plasmon Resonance (SPR) at 37°C was a standard, routine technique for therapeutic antibodies by 2005. The limitations of dependent claims 2-18—including formulations, administration routes (intravenous, subcutaneous), specific dosage floors (≥3 µg/kg), IgG subclasses (IgG1, IgG2, IgG4), and binding to C-terminal fragments—were all described as well-known and obvious modifications in the prior art.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would have been motivated to combine the references in a straightforward manner. Olesen’s successful clinical trial provided a clear "proof-of-concept" and a strong motivation to develop a CGRP antagonist to treat migraine. A POSA would select an anti-CGRP antibody, like the one in Tan, as a promising therapeutic agent due to its known advantages over small molecules, such as greater specificity and a longer half-life. Because Tan's antibody was murine and intended for human use, a POSA would have been motivated to humanize it using the well-established methods of Queen to reduce the risk of immunogenicity, a critical step for a drug intended for a chronic condition like migraine.
    • Expectation of Success: A POSA would have had a reasonable expectation of success. Olesen's clinical results confirmed the viability of the therapeutic strategy. Tan demonstrated the in vivo efficacy of an anti-CGRP antibody in a relevant animal model. By 2005, humanization via CDR grafting, as taught by Queen, was a "clinically well-validated technology" routinely used to produce therapeutic antibodies that retained the critical binding properties of the original murine antibody. Therefore, a POSA would have reasonably expected that applying Queen's standard methods to an antibody like Tan's would successfully yield a humanized anti-CGRP antagonist antibody effective for treating migraine.
    • Key Aspects: Petitioner preemptively refuted any argument that Tan "teaches away" from using a full-length antibody. While Tan noted a Fab' fragment was more effective in one short-term experiment, it explicitly explained this was due to the slower distribution of the larger full-length IgG antibody and recommended overcoming this through repeated administration or higher doses—guidance that Teva itself allegedly followed.

4. Key Claim Construction Positions

  • "treating": Petitioner argued this term should be construed broadly as "an approach for obtaining a beneficial or desired clinical result," based on the patent's own lexicography. This construction does not require the achievement of a particular level of efficacy or even a clinical response, thereby lowering the burden for demonstrating a reasonable expectation of success.
  • "effective amount": Relying on the doctrine of claim differentiation from dependent claim 7 (which recites a dose of "at least 3 µg/kg"), Petitioner argued that "an effective amount" in independent claim 1 must encompass doses lower than 3 µg/kg. Further, this term was argued not to require a clinical response, but merely an amount sufficient to produce biochemical or histochemical effects.
  • "specific binding": Petitioner contended this term does not require exclusive binding to a single CGRP target. Based on the patent's disclosure, it would include antibodies that bind to multiple isoforms of CGRP (e.g., α and β) and does not preclude binding to other peptides.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under 35 U.S.C. §325(d) would be inappropriate because the core prior art references—Olesen, Tan, and Queen—were not substantively considered by the Examiner during prosecution. Petitioner stated that while the references were listed in an Information Disclosure Statement, it contained over 450 documents, making it unsurprising the Examiner did not cite or rely on them in any Office Action. Furthermore, the Examiner did not have the benefit of the expert declarations submitted with the petition, which explain the state of the art and the teachings of these references from the perspective of a POSA.

6. Relief Requested

  • Petitioner requested that the Board institute an inter partes review, proceed to trial, and find claims 1-18 of the ’908 patent unpatentable as obvious.