PTAB

IPR2018-01425

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
  • Brief Description: The ’210 patent relates to humanized monoclonal anti-Calcitonin Gene-Related Peptide (CGRP) antagonist antibodies. The claims cover human IgG antibodies that specifically bind to human CGRP and are intended for the prevention or treatment of CGRP-related conditions, such as migraines.

3. Grounds for Unpatentability

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

  • Prior Art Relied Upon: Tan (K.K.C. Tan et al., a 1995 journal article), Wimalawansa (S.J. Wimalawansa, a 1996 review article), and Queen (Patent 6,180,370).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of these references disclosed all limitations of the challenged claims. Tan disclosed a murine monoclonal anti-CGRP antagonist antibody (MAb C4.19) that was proven to bind human CGRP and block its biological activity both in vitro and in vivo. Wimalawansa, a comprehensive review of CGRP, identified CGRP's role in diseases like migraine and expressly proposed that "humanized anti-CGRP monoclonal antibodies" should be explored as therapeutic agents. Queen taught the then-standard method for humanizing non-human antibodies by grafting their complementarity-determining regions (CDRs) onto a human immunoglobulin scaffold (e.g., IgG) to create a therapeutic antibody that retains binding affinity but avoids immunogenicity in humans. Petitioner asserted that applying Queen’s routine humanization technique to Tan’s known anti-CGRP antibody, for the therapeutic purpose identified by Wimalawansa, would result in the antibody of claim 1.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would combine these references to solve a known problem. By 2005, the art recognized CGRP as a key therapeutic target for diseases like migraine (Wimalawansa). The art also possessed a functional murine anti-CGRP antibody (Tan). However, it was well understood that murine antibodies cause immunogenic reactions in humans, making them unsuitable for therapy. Queen provided the solution: a well-established, "gold standard" technique to humanize such antibodies to make them safe and effective for human use. Wimalawansa explicitly suggested this path, motivating a POSITA to combine Tan’s antibody with Queen’s method to develop a viable human therapeutic.
    • Expectation of Success: Petitioner contended a POSITA would have had a reasonable expectation of success. By the patent's priority date, creating monoclonal antibodies against a known antigen like CGRP was a routine and well-established process. Furthermore, antibody humanization using CDR grafting, as taught by Queen, was considered a "clinically well-validated technology" known to reliably preserve the binding affinity and specificity of the original non-human antibody. Therefore, a POSITA would have reasonably expected to successfully humanize an antibody like Tan’s MAb C4.19 and produce a humanized anti-CGRP antibody with the claimed properties.
    • Key Aspects: The argument for the dependent claims followed from this primary combination.
      • Claims for specific IgG subclasses (IgG1, IgG2, IgG4) were obvious because these were the known, primary options for human antibody scaffolds, each with predictable properties regarding effector function.
      • Claims for binding to the C-terminal region of CGRP were obvious because prior art anti-CGRP antibodies, including those discussed in Tan, were already known to bind to this specific region.
      • Claims requiring CDRs derived from a mouse were directly taught by starting with Tan's murine antibody.
      • Claims reciting a mutation to remove a glycosylation site were obvious because this was a known and routine technique used to reduce or eliminate unwanted effector functions in therapeutic antibodies.

4. Key Claim Construction Positions

  • "specific binding": Petitioner argued that, based on the patent’s own specification, this term should be construed broadly to include antibodies that may bind to more than one isoform of CGRP and are not precluded from binding to other peptides. The term does not require exclusive binding or any particular degree of binding affinity. This broad construction, Petitioner asserted, is important because it means that prior art antibodies which bind human CGRP, even if they also cross-react with other molecules, still meet the claim limitation.

5. Key Technical Contentions (Beyond Claim Construction)

  • Tan 1995 Does Not Teach Away: Petitioner directly rebutted the Patent Owner's prosecution argument that Tan taught away from using full-length antibodies for CGRP blockade. Petitioner argued that while Tan showed a Fab' fragment was more effective under certain short-term, low-dose experimental conditions, it did not discredit the full-length antibody. Instead, Tan explained the result was expected due to slower pharmacokinetics and explicitly recommended strategies to improve the in vivo efficacy of the full-length antibody, such as increasing the dose and using repeated administration—the very strategies later employed and validated in the ’210 patent itself.

6. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under §325(d) would be inappropriate because the evidence and arguments presented in the petition were not previously considered by the USPTO. The Examiner never cited the specific combination of Tan, Wimalawansa, and Queen during prosecution. While the references were listed in a large Information Disclosure Statement with over 450 other documents, they were not substantively evaluated in the applied combination. Furthermore, the Examiner did not have the benefit of Petitioner’s expert declarations explaining the state of the art and the flaws in Patent Owner’s prior arguments.

7. Relief Requested

  • Petitioner requested the institution of an inter partes review and the cancellation of claims 1-15 of the ’210 patent as unpatentable.