PTAB

IPR2016-01667

Celltrion Inc v. Genentech Inc

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Petition
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1. Case Identification

2. Patent Overview

  • Title: Therapy of Autoimmune Disease in a Patient with an Inadequate Response to a TNF-α Inhibitor
  • Brief Description: The ’838 patent discloses methods for treating rheumatoid arthritis (RA) in patients who have an inadequate response to a tumor necrosis factor-alpha (TNF-α) inhibitor. The claimed method involves administering an anti-CD20 antibody, specifically rituximab, as two intravenous doses of 1000 mg.

3. Grounds for Unpatentability

Ground 1: Anticipation of Claims 1-5 and 7-14 by Edwards 2002

  • Prior Art Relied Upon: Edwards et al., Efficacy and Safety of Rituximab, a B-Cell Targeted Chimeric Monoclonal Antibody (published October 2002) (“Edwards 2002”).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Edwards 2002 expressly disclosed every element of the challenged claims except for treating a patient with an "inadequate response to a TNFα-inhibitor." Edwards 2002 described a clinical trial where RA patients received two 1000 mg intravenous doses of rituximab, often with methotrexate and corticosteroids. Petitioner contended the "inadequate responder" limitation was inherently disclosed.
    • Key Aspects: The core of the argument rested on inherent anticipation. Petitioner asserted that it was well-settled that 30-40% of RA patients are inadequate responders to TNF-α inhibitors. Based on expert statistical analysis, Petitioner argued that in the Edwards 2002 study, which treated at least 92 patients with the claimed regimen, the probability of having at least one inadequate responder was "virtually 100%." Therefore, Edwards 2002 necessarily described treating the claimed patient sub-population with the claimed method, even if not for that express purpose.

Ground 2: Obviousness of Claims 1-14 over Edwards 2002 in view of Tuscano

  • Prior Art Relied Upon: Edwards 2002 and Tuscano, Successful Treatment of Infliximab-Refractory Arthritis with Rituximab (published December 2002).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner asserted that Edwards 2002 taught the specific treatment regimen: two 1000 mg intravenous doses of rituximab, with or without methotrexate and corticosteroids, and demonstrated its effectiveness in treating RA, including achieving ACR50 and ACR70 responses. The only element not expressly taught was the specific patient population of TNF-α inhibitor failures. Tuscano was alleged to explicitly supply this missing element by disclosing the successful treatment of infliximab-refractory (a TNF-α inhibitor) RA patients with rituximab.
    • Motivation to Combine: A POSITA would combine the teachings because Edwards 2002 provided a proven, effective rituximab dosage regimen for RA, and Tuscano provided the explicit suggestion that this therapy would be a "promising agent" for the specific sub-population of patients who had failed TNF-α inhibitor therapy. Applying a known effective treatment to a known patient sub-population needing new options was presented as a straightforward, obvious step.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success because Edwards 2002 demonstrated "substantial clinical benefit" with the regimen in a general RA population, and Tuscano showed positive results for rituximab specifically in TNF-α inhibitor-refractory patients.

Ground 3: Obviousness of Claims 1-14 over Goldenberg, Curd, and De Vita

  • Prior Art Relied Upon: Goldenberg (WO 00/74718), Curd (WO 00/67796), and De Vita (Pathogenic Role of B Lymphocytes in Rheumatoid Synovitis, 2001).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued this combination of prior art, all published before April 9, 2002, rendered the claims obvious. Goldenberg and De Vita taught treating RA patients who had previously failed TNF-α inhibitor therapy with rituximab, showing successful outcomes. Curd and Goldenberg taught the co-administration of rituximab with methotrexate and corticosteroids. The prior art taught a range of successful total rituximab doses (e.g., 1500 mg in Goldenberg, 2550 mg in De Vita), and the claimed 2000 mg dose fell squarely within this known therapeutic window.
    • Motivation to Combine: A POSITA would combine these references to treat the known "hard-to-treat" population of TNF-α inhibitor failures with a combination therapy (rituximab and methotrexate) that was standard for refractory RA. The motivation was to apply known therapeutic agents to a known patient population in a manner consistent with established clinical practice.
    • Expectation of Success: The expectation of success was high, as the individual components of the claimed method—treating TNF-α inhibitor failures with rituximab, combining rituximab with methotrexate, and using doses in the 1500-2550 mg range—were all known to be effective. Petitioner argued the specific claimed dose was merely the result of routine optimization, not an inventive step, as Curd taught that dosing was subject to "a great deal of therapeutic discretion."

4. Key Claim Construction Positions

  • "a patient who experiences an inadequate response to a TNFα-inhibitor": Petitioner argued this phrase should be construed to mean a patient who, due to inherent physiological characteristics, either did not or would not respond to a TNF-α inhibitor, or did or would experience toxicity. This construction does not require the patient to have actually undergone prior treatment with a TNF-α inhibitor and was central to the inherency argument in Ground 1.
  • Result-Oriented Clauses are Not Limiting: Petitioner contended that clauses in claims 2, 10-14 reciting clinical outcomes (e.g., "an amount that is effective to provide an ACR50 response," "wherein the patient has no erosive progression") are not patentable limitations. Because the claims already recited a specific dosage (two 1000 mg doses), these clauses merely stated the intended result of administering that dose and did not further limit the scope of the claimed method.

5. Relief Requested

  • Petitioner requested the institution of an inter partes review and the cancellation of claims 1-14 of Patent 7,976,838 as unpatentable.