PTAB

IPR2015-00415

Boehringer Ingelheim Pharmaceuticals Inc v. Genentech Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Treatment of Autoimmune Diseases
  • Brief Description: The ’161 patent relates to methods of treating autoimmune diseases, particularly rheumatoid arthritis (RA), by administering an anti-CD20 antibody (rituximab) in combination with methotrexate. The claims cover methods comprising administering more than one intravenous dose of rituximab and at least one dose of methotrexate.

3. Grounds for Unpatentability

Ground 1: Obviousness of Combining Rituximab and Methotrexate - Claims 1, 2, 5, 6, 9, and 10 are obvious over Edwards or Gryn in view of O'Dell 1997 or Pincus 1997.

  • Prior Art Relied Upon: Edwards (a 1998 publication on treating RA by killing B-cells), Gryn (a 1998 letter proposing a pilot study of rituximab for RA), O'Dell 1997 (a publication on methotrexate use in RA), and Pincus 1997 (a publication on RA combination therapy).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that all elements of the independent claims were well-known in the art before the patent's priority date. Edwards and Gryn independently taught using rituximab, an anti-CD20 antibody, to treat RA by depleting B-cells. Concurrently, publications like O'Dell 1997 and Pincus 1997 established methotrexate as the undisputed "gold standard" and "cornerstone" of RA therapy, especially in combination regimens for patients who did not fully respond to methotrexate alone.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would have been strongly motivated to combine the promising new biologic agent, rituximab, with the established standard of care, methotrexate. The prior art demonstrated that combination therapy was the prevailing and most effective strategy for managing RA. Furthermore, FDA guidance at the time made it "inevitable" that new RA drugs would be tested and used in combination with methotrexate.
    • Expectation of Success: A POSITA would have had a high expectation of success. Both rituximab and methotrexate were known to be individually effective for RA, and combining them was a logical extension of the well-established paradigm of using methotrexate as the foundation for combination RA therapies. The known mechanisms and safety profiles of both drugs supported a predictable and favorable outcome.

Ground 2: Obviousness of Adding a Glucocorticosteroid - Claims 3, 7, and 11 are obvious over the combination of Edwards/Gryn and O'Dell/Pincus in view of Verhoeven or Kirwan.

  • Prior Art Relied Upon: Edwards (1998 publication), Gryn (1998 letter), O'Dell 1997 (1997 publication), Pincus 1997 (1997 publication), Verhoeven (a 1998 publication), and Kirwan (a 1995 publication).
  • Core Argument for this Ground:
    • Prior Art Mapping: The primary combination of references taught the core method of treating RA with rituximab and methotrexate. The additional references, such as Verhoeven and Kirwan, explicitly taught the widespread use of glucocorticosteroids (e.g., prednisolone) in combination with methotrexate to treat RA. Verhoeven described a "step-down bridge therapy" including corticosteroids that led to "much enhanced efficacy."
    • Motivation to Combine: A POSITA would have been motivated to add a glucocorticosteroid to the rituximab/methotrexate regimen as a standard and obvious component of RA treatment. Glucocorticosteroids were commonly used to manage RA symptoms and were also known to help prevent or mitigate adverse side effects associated with the infusion of biologic agents like rituximab. This was a routine and well-understood clinical practice.

Ground 3: Obviousness of Claimed Dosing Regimens - Claims 2, 4, 6, 8, 10, and 12 are obvious over the primary combinations in view of the 1997 RITUXAN® FDA Label and other art.

  • Prior Art Relied Upon: Edwards (1998 publication), Gryn (1998 letter), O'Dell 1997 (1997 publication), the 1997 FDA-approved RITUXAN® Product Insert (FDA Label), Maloney (a 1994 publication), and Tobinai (a 1998 publication).
  • Core Argument for this Ground:
    • Prior Art Mapping: Dependent claims 2, 6, and 10 recite a rituximab dose range of 250-1000 mg/m². The 1997 FDA Label for rituximab recommended a standard dose of 375 mg/m², which falls within this claimed range. The Maloney 1994 publication detailed a Phase I study that tested doses of 250 mg/m² and 500 mg/m², also within the claimed range. For claims reciting dose escalation (4, 8, and 12), Tobinai disclosed a dose-escalation study that increased the rituximab dose from 250 mg/m² to 375 mg/m².
    • Motivation to Combine: A POSITA would have considered the FDA-approved dose of 375 mg/m² a logical starting point for treating RA. It would have been obvious to perform routine dose-optimization and dose-escalation studies, as taught by Maloney and Tobinai, to determine the optimal therapeutic dose for RA patients. This process of dose finding within known safe ranges was a standard, predictable aspect of clinical practice.
  • Additional Grounds: Petitioner asserted numerous additional obviousness challenges based on various combinations of the primary references with other publications disclosing combination therapies, the benefits of methotrexate, and standard clinical practices in RA treatment.

4. Key Claim Construction Positions

  • Petitioner argued for the broadest reasonable construction of the claims. It contended that the independent claims (1, 5, and 9) require only the administration of (a) two or more intravenous doses of rituximab and (b) at least one dose of methotrexate.
  • Critically, Petitioner asserted that the claims do not specify the timing or order of administration, the method of administration for methotrexate, or that the methotrexate dose must itself be therapeutically effective. This broad construction, Petitioner argued, made the claims more susceptible to invalidation by prior art teaching any concurrent use.

5. Key Technical Contentions (Beyond Claim Construction)

  • Petitioner preemptively refuted the patentability argument of "unexpected results," which Patent Owner had used to overcome rejections during prosecution.
  • Petitioner contended that any synergistic or extended therapeutic effect from combining rituximab and methotrexate was entirely predictable to a POSITA. This predictability was based on the well-known immunological effect of methotrexate, which suppresses the formation of anti-drug antibodies (e.g., HAMA/HACA response) against biologic agents. This known mechanism would lead a POSITA to expect that co-administering methotrexate would enhance the efficacy and duration of action of rituximab.

6. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-12 of Patent 7,820,161 as unpatentable under 35 U.S.C. §103.