PTAB

IPR2017-01121

Celltrion, Inc. v. Genentech, Inc.

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1. Case Identification

2. Patent Overview

  • Title: TREATMENT WITH ANTI-ErbB2 ANTIBODIES
  • Brief Description: The ’441 patent claims methods for treating a human patient with a cancer characterized by overexpression of the ErbB2 receptor (HER2-positive). The method involves administering a combination of an anti-ErbB2 antibody (e.g., trastuzumab) and a taxoid (e.g., paclitaxel).

3. Grounds for Unpatentability

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

  • Prior Art Relied Upon: Baselga 1996 (a 1996 clinical oncology journal article on a trastuzumab Phase II study), Seidman 1996 (a 1996 clinical oncology abstract on taxane sensitivity), and the 1995 TAXOL PDR (the 1995 Physicians' Desk Reference entry for paclitaxel). Petitioner also cited Baselga Abstract 53 (a 1994 abstract on preclinical xenograft studies) as reinforcing evidence.
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of references taught all limitations of the challenged claims. Independent claim 1 recites treating a patient with HER2-positive cancer by administering an anti-ErbB2 antibody (trastuzumab) and a taxoid (paclitaxel). Baselga 1996 disclosed the clinical efficacy of trastuzumab as a monotherapy in patients with metastatic HER2-positive breast cancer. Seidman 1996 taught that paclitaxel was also clinically effective in this specific patient population, noting that HER2-overexpression "seems to confer sensitivity" to taxanes. The 1995 TAXOL PDR provided standard, effective dosing regimens for paclitaxel in metastatic breast cancer. Petitioner asserted these references collectively disclosed treating the claimed patient population with the claimed combination of agents. The dependent claims, which add limitations such as the cancer being metastatic breast carcinoma (claims 2-6) or the taxoid being paclitaxel (claims 8 and 12), were argued to be expressly taught by the combination of Baselga 1996 and Seidman 1996.
    • Motivation to Combine (for §103 grounds): A person of ordinary skill in the art (POSA) would have been motivated to combine trastuzumab and paclitaxel based on established principles of combination cancer therapy. The primary motivation was that both agents had demonstrated significant, single-agent clinical efficacy in the target population. The combination satisfied the four well-known principles for developing cancer therapies: (1) each drug has single-agent activity; (2) they have non-overlapping toxicities (trastuzumab's toxicities were minimal, while paclitaxel's known dose-limiting toxicity was myelosuppression, which was not associated with trastuzumab); (3) they have different mechanisms of action (targeted antibody vs. non-specific chemotherapeutic); and (4) they have different resistance mechanisms. Further motivation was provided by Baselga 1996, which explicitly stated that preclinical studies showed trastuzumab "markedly potentiated the antitumor effects of...paclitaxel, without increasing their toxicity" and that "clinical trials of such combination therapy are currently in progress."
    • Expectation of Success (for §103 grounds): A POSA would have had a reasonable expectation of success. This expectation was based on the strong clinical results for each drug individually, their non-overlapping toxicity profiles, and reinforcing preclinical data (cited in Baselga 1996 and detailed in Baselga Abstract 53) demonstrating "major antitumor activity" and "strong synergy" for the combination in xenograft models. The knowledge that clinical trials were already underway would have confirmed to a POSA that the combination was considered safe and promising.

4. Key Claim Construction Positions

  • "Extend the Time to Disease Progression... Without Increase in Overall Severe Adverse Events": Petitioner argued this is a relative term where the proper comparison is between the claimed combination therapy and treatment with the taxoid (paclitaxel) alone. This position was based on the patent's own specification, which presents clinical trial data evaluating the combination of trastuzumab plus paclitaxel (T+H) against paclitaxel alone (T).
  • "Progressing": Petitioner proposed this term means "worsening," based on its use in the specification and expert declaration.
  • Defined Terms: For terms like "Overexpression of ErbB2 Receptor," "Humanized," and "Epitope 4D5," Petitioner adopted the explicit definitions provided within the '441 patent specification.

5. Key Technical Contentions (Beyond Claim Construction)

  • Refutation of Prosecution History Declaration: A central argument of the petition was that the patent was improperly granted based on a flawed declaration by Dr. Sliwkowski, submitted late in prosecution. Petitioner contended the Sliwkowski Declaration made two primary errors that this petition sought to correct with prior art and expert testimony not before the examiner.
    • Cell-Cycle Antagonism: Sliwkowski argued a POSA would have expected an "antagonistic interaction" because trastuzumab arrests the cell cycle at the G1 phase, which would prevent paclitaxel from working at its purported G2/M phase. Petitioner countered that this was technically incorrect, as prior art showed paclitaxel exerts anticancer effects during all phases of the cell cycle, including G1. Furthermore, prior art showed a synergistic, not antagonistic, effect between trastuzumab and cisplatin, another drug that acts at the G2/M phase, directly refuting Sliwkowski's hypothesis.
    • Predictive Value of Xenograft Models: Sliwkowski argued that a POSA would not have been motivated by positive xenograft data because such models were not predictive of clinical success. Petitioner argued this was contrary to the state of the art in 1996, when POSAs routinely relied on such data. Petitioner also noted that Sliwkowski's argument relied on a non-prior art reference from 2001 and was contradicted by Sliwkowski's own later publications.

6. Relief Requested

  • Petitioner requested the institution of an inter partes review and cancellation of claims 1-14 of the ’441 patent as unpatentable under 35 U.S.C. §103.