PTAB

IPR2014-00676

Phigenix Inc v. Immunogen Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Immunoconjugates and Methods of Use
  • Brief Description: The ’856 patent describes an immunoconjugate for cancer therapy, comprising a specific humanized anti-ErbB2 antibody (huMAb4D5-8, also known as trastuzumab or HERCEPTIN®) chemically linked to a maytansinoid, a highly potent cytotoxic agent.

3. Grounds for Unpatentability

Ground 1: Obviousness over Chari and HERCEPTIN® Label - Claims 1-8 are obvious over Chari 1992 in view of the HERCEPTIN® Label.

  • Prior Art Relied Upon: Chari (a 1992 Cancer Research article) and the HERCEPTIN® Label (published September 1998).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Chari 1992 disclosed all elements of the claimed immunoconjugate except for the specific antibody. Chari taught conjugating a maytansinoid (specifically DM1) to a murine anti-ErbB2 antibody (TA.1) using specified linkers, resulting in a conjugate with 3-5 maytansinoid molecules per antibody. The HERCEPTIN® Label was argued to supply the missing element, explicitly identifying HERCEPTIN® as the humanized antibody huMAb4D5-8 for treating ErbB2-positive breast cancer and disclosing its formulation with a pharmaceutically acceptable carrier.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) would have been motivated to substitute the murine antibody (TA.1) in Chari’s conjugate with the humanized antibody huMAb4D5-8 (HERCEPTIN®). The motivation was to create a therapeutic with reduced immunogenicity for human use, a well-known benefit of humanized antibodies over murine ones. Chari itself noted that developing humanized antibodies would produce less immunogenic conjugates.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success. The combination was a simple substitution of one known anti-ErbB2 antibody for a known, clinically superior anti-ErbB2 antibody to achieve the predictable result of reduced immunogenicity while retaining the targeting and cytotoxic functions demonstrated by the separate references.

Ground 2: Obviousness over Chari and Carter - Claims 1-8 are obvious over Chari 1992 in view of Carter 1992 and common knowledge.

  • Prior Art Relied Upon: Chari (a 1992 Cancer Research article) and Carter (a 1992 PNAS article).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground presented an alternative to using the commercial HERCEPTIN® Label. Petitioner asserted that Chari 1992 taught the base immunoconjugate, as in Ground 1. Carter 1992 was argued to disclose the specific humanized antibody, teaching the creation of the huMAb4D5-8 variant from its murine precursor. Carter explicitly stated that the humanized version was more efficient in antibody-dependent cellular cytotoxicity and was developed to overcome the human anti-mouse antibody response expected from the murine version. Common knowledge would supply the use of a standard pharmaceutically acceptable carrier.
    • Motivation to Combine: The motivation was inherent in Carter’s disclosure. Carter taught that the efficacy of the murine antibody was limited by the human immune response, providing a clear reason to replace it with the disclosed, improved humanized huMAb4D5-8 variant in any therapeutic context, including the immunoconjugate taught by Chari.
    • Expectation of Success: Success was expected because it involved applying a known technique (conjugation from Chari) to an antibody (huMAb4D5-8 from Carter) that was expressly designed and proven to be a superior version of the antibody used by Chari for therapeutic applications.

Ground 3: Obviousness over Liu and HERCEPTIN® Label - Claims 1-5 and 7 are obvious over Liu 1996 in view of the HERCEPTIN® Label.

  • Prior Art Relied Upon: Liu (a 1996 PNAS article) and the HERCEPTIN® Label (published September 1998).

  • Core Argument for this Ground:

    • Prior Art Mapping: Petitioner contended Liu 1996 disclosed a highly effective immunoconjugate comprising maytansinoid DM1 linked to an antibody (C242), demonstrating remarkable anti-tumor efficacy in vivo. While Liu’s antibody targeted a colon cancer antigen, the reference taught the successful composition and use of a maytansinoid immunoconjugate. The HERCEPTIN® Label provided the teaching of using the specific anti-ErbB2 antibody huMAb4D5-8 to target breast cancer.
    • Motivation to Combine: A POSITA would have been motivated to apply the successful maytansinoid conjugate platform from Liu to the well-known and important breast cancer target, ErbB2. The most logical choice for targeting ErbB2 was the FDA-approved, high-affinity humanized antibody HERCEPTIN® (huMAb4D5-8). The goal was to create a potent therapy for breast cancer by combining a proven cytotoxic payload (maytansinoid) with a proven targeting vehicle (HERCEPTIN®).
    • Expectation of Success: A POSITA would expect success because Liu demonstrated the in vivo efficacy and safety of a maytansinoid conjugate, and HERCEPTIN® was known to be a highly effective and specific targeting agent for ErbB2-positive tumors. The conjugation process from Liu would be directly applicable.

  • Additional Grounds: Petitioner asserted additional obviousness challenges, including combinations that added references like Hudziak 1998, Rosenblum 1999, Baselga 1998, Pegram 1999, and Morgan 1990 to provide further motivation regarding the synergistic effects of anti-ErbB2 antibodies with microtubule agents and the benefits of specific chemical linkers. Another distinct ground was based on Cohen 1999 in view of Chari 1992.

4. Key Technical Contentions (Beyond Claim Construction)

  • Rebuttal of Patent Owner’s Prosecution Arguments: Petitioner dedicated a significant portion of the petition to rebutting arguments the Patent Owner made during prosecution to overcome obviousness rejections.
    • Incompatible Mechanisms of Action: The Patent Owner had argued that a POSITA would not have combined HERCEPTIN® and maytansinoid because they have incompatible mechanisms. It was argued that HERCEPTIN® arrests cells in the G1 phase, where they are most resistant to maytansinoid, which is most effective in the M-phase. Petitioner countered that this was an oversimplification, as a tumor contains cells in all phases of the cell cycle. Furthermore, prior art (e.g., Baselga 1998, Pegram 1999) explicitly taught that HERCEPTIN® had additive or synergistic effects with microtubule-directed agents like maytansinoids, providing a strong motivation for the combination.
    • Lack of Expectation of Success: The Patent Owner had argued it was unpredictable whether the conjugate would be safe and effective. Petitioner countered by citing extensive prior art (e.g., Chari 1992, Liu 1996) demonstrating that maytansinoid immunoconjugates showed high, specific cytotoxicity against tumor cells and low systemic toxicity in vivo, establishing a clear expectation of success.

5. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-8 of Patent 8,337,856 as unpatentable under 35 U.S.C. §103.