PTAB

IPR2017-01121

Celltrion Inc v. Genentech Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: TREATMENT WITH ANTI-ErbB2 ANTIBODIES
  • Brief Description: The ’441 patent discloses methods for treating patients with cancer characterized by overexpression of the ErbB2 receptor (HER2 protein). The claimed method involves administering a combination of an anti-ErbB2 antibody (e.g., trastuzumab) and a taxoid (e.g., paclitaxel) to extend the time to disease progression without a significant increase in adverse events.

3. Grounds for Unpatentability

Ground 1: Claims 1-14 are obvious over Baselga 1996, Seidman 1996, and the 1995 TAXOL PDR.

  • Prior Art Relied Upon: Baselga 1996 (a March 1996 journal article), Seidman 1996 (a March 1996 clinical oncology abstract), and the 1995 TAXOL PDR (a 1995 entry in the Physicians' Desk Reference).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued the combination of references taught all limitations of the independent claims. Baselga 1996 disclosed the clinical efficacy and good tolerability of trastuzumab (an anti-ErbB2 antibody) in patients with metastatic HER2-positive breast cancer. Seidman 1996, which was not before the examiner, taught that patients with HER2-overexpressing breast cancer were particularly responsive to treatment with paclitaxel (a taxoid). The 1995 TAXOL PDR provided established indications and dosages for paclitaxel in treating metastatic breast cancer. Petitioner asserted that the claim limitation "without increase in overall severe adverse events" was suggested by preclinical data cited in Baselga showing no increased toxicity for the combination, as well as the known non-overlapping toxicity profiles of the two drugs. The limitation "in the absence of an anthracycline derivative" was rendered obvious by the well-known cardiotoxicity of anthracyclines, which would motivate a POSITA to seek safer alternatives.
    • Motivation to Combine: Petitioner asserted that a person of ordinary skill in the art (POSITA) would combine trastuzumab and paclitaxel based on established principles of combination cancer therapy. Both agents had demonstrated individual efficacy in the target patient population. The combination satisfied the four core principles for developing such therapies: (1) each drug is active as a single agent, (2) their toxicities are not significantly overlapping, (3) they have different mechanisms of action, and (4) they have different resistance mechanisms. Further motivation was provided by preclinical data showing synergy and, critically, the explicit statement in Baselga 1996 that clinical trials of the trastuzumab-paclitaxel combination were already "currently in progress."
    • Expectation of Success: Petitioner argued a POSITA would have a reasonable expectation of success in combining the therapies. This expectation was grounded in the known clinical efficacy of each drug as a monotherapy, the promising preclinical data showing synergy without increased toxicity, the favorable non-overlapping toxicity profiles, and the knowledge that other researchers were already actively pursuing the combination in human clinical trials. The preclinical data showing a 93% tumor growth inhibition for the combination, compared to 35% for each drug alone, would have strongly reinforced this expectation.

4. Key Claim Construction Positions

  • Petitioner argued that the claim phrase "extend the time to disease progression... without increase in overall severe adverse events" is a relative term.
  • Based on the clinical trial data presented in the ’441 patent's specification, Petitioner asserted the proper baseline for comparison is treatment with the taxoid (paclitaxel) alone. This construction is critical because it sets a more challenging standard for non-obviousness than the baseline of an "untreated patient," which Patent Owner had argued for during prosecution.

5. Key Technical Contentions (Beyond Claim Construction)

  • A central focus of the petition was refuting the Sliwkowski Declaration, which Patent Owner submitted during prosecution and which was instrumental in securing allowance of the claims.
  • Sliwkowski had argued that a POSITA would have expected an "antagonistic interaction" between trastuzumab and paclitaxel. The theory was that trastuzumab arrests the cell cycle in the G1 phase, which would prevent paclitaxel, purported to act only in the later G2/M phase, from exerting its antitumor effect.
  • Petitioner systematically dismantled this argument as technically flawed. Petitioner contended that a POSITA would have known that: (1) paclitaxel exhibits anticancer effects during multiple phases of the cell cycle, not just G2/M; (2) tumors are heterogeneous, containing cells at all different stages of the cell cycle, allowing both drugs to act simultaneously on different cells; and (3) prior art for a similar combination (trastuzumab and cisplatin) demonstrated synergy, not antagonism, directly contradicting Sliwkowski's hypothesis and showing it was not a generally applicable principle.

6. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-14 of Patent 7,846,441 as unpatentable under 35 U.S.C. §103.