PTAB

IPR2021-01288

Fresenius Kabi USA LLC v. Chugai Seiyaku Kabushiki Kaisha Chugai Pharmaceutical Co Ltd

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Key Events
Petition

1. Case Identification

2. Patent Overview

  • Title: Subcutaneously Administered Anti-IL-6 Receptor Antibody
  • Brief Description: The ’264 patent discloses methods of treating rheumatoid arthritis (RA) by subcutaneously administering a 162 mg fixed dose of the anti-IL-6 receptor antibody tocilizumab either every week or every two weeks.

3. Grounds for Unpatentability

Ground 1: Anticipation of Claims 1-3 and 6-11 by NCT00965653

  • Prior Art Relied Upon: NCT00965653 (a publicly available clinical trial protocol).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that NCT00965653, a clinical trial protocol publicly available on ClinicalTrials.gov since August 2009 (more than one year prior to the patent’s priority date), disclosed every limitation of the challenged claims. The protocol described an open-label study for treating RA in patients with an inadequate response to methotrexate by administering a fixed subcutaneous dose of 162 mg of tocilizumab either "weekly" or "every other week," in combination with methotrexate. This protocol directly taught the method of treating RA (claim 1), the specific fixed dose and subcutaneous route (claim 1), the weekly and bi-weekly schedules (claims 2 and 9), administration to DMARD-inadequate responders (claim 3), and co-administration with an additional drug (claims 6-8 and 11). Petitioner further contended that the specific amino acid sequences of tocilizumab recited in claim 1 were inherently disclosed, as tocilizumab is a well-defined biologic.

Ground 2: Anticipation of Claims 1, 2, 9, and 10 by Ohta 2010

  • Prior Art Relied Upon: Ohta et al., an abstract published in Arthritis and Rheumatism (Oct. 2010) ("Ohta 2010").
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner asserted that Ohta 2010, which disclosed the results of a clinical study, anticipated the core method claims. Ohta 2010 reported that RA patients received 162 mg of tocilizumab subcutaneously either weekly or every other week, and that both regimens were "well tolerated" and associated with a "good clinical response." This disclosed treating RA with a fixed 162 mg subcutaneous dose of tocilizumab on a weekly or bi-weekly schedule, thereby meeting all limitations of independent claims 1 and 10 and dependent claims 2 and 9.
    • Key Aspects: During prosecution, the Examiner initially rejected the claims over Ohta 2010. The applicant overcame this rejection by submitting an inventor declaration to antedate the reference. Petitioner argued the Examiner erred in withdrawing the rejection because the declaration was conclusory, uncorroborated by independent evidence, and thus insufficient to establish prior inventorship. Therefore, Ohta 2010 remained valid prior art.

Ground 3: Obviousness of Claims 1-3 and 6-11 over Maini 2006, Bonilla, and Wang

  • Prior Art Relied Upon: Maini 2006 (a 2006 clinical trial publication), Bonilla (a 2008 publication on immunoglobulin pharmacokinetics), and Wang (a 2009 publication on antibody dosing strategies).

  • Core Argument for this Ground:

    • Prior Art Mapping: Maini 2006 established that intravenous (IV) administration of tocilizumab at 4 mg/kg or 8 mg/kg every four weeks was a safe and effective treatment for RA, including in patients with an inadequate response to methotrexate. The only differences between Maini 2006 and the challenged claims were the route of administration (subcutaneous vs. IV) and the dosing regimen (fixed dose vs. weight-based). Bonilla and Wang supplied the teachings to bridge this gap.
    • Motivation to Combine: A person of ordinary skill in the art (POSITA) would have been motivated to modify the IV therapy in Maini 2006 to a more convenient subcutaneous (SC) formulation. Bonilla taught that SC administration of immunoglobulins was preferable to IV, as it improved convenience and provided more stable serum concentrations with more frequent dosing (e.g., weekly or bi-weekly). Wang taught that for monoclonal antibodies with a wide therapeutic window like tocilizumab, a fixed-dose regimen was preferable to a weight-based one due to better compliance and a lower risk of medical errors.
    • Expectation of Success: A POSITA would have had a reasonable expectation of success in developing the claimed method. It was known how to convert an IV dose to an equivalent SC dose by accounting for bioavailability. Starting from the known effective IV dose in Maini (e.g., 4 mg/kg every four weeks for a 70kg patient), a POSITA would arrive at a bi-weekly SC dose range of approximately 140-195 mg. The claimed 162 mg dose fell squarely within this predictable, optimizable range. The known safety of IV tocilizumab and the established success of other fixed-dose SC biologics for RA would have provided a strong expectation that the resulting treatment would be safe and effective.

  • Additional Grounds: Petitioner asserted an alternative obviousness challenge over NCT00965653, and another over Ohta 2010 in view of Maini 2006 to address dependent claims requiring co-administration with methotrexate.

4. Key Claim Construction Positions

  • Petitioner argued that the preamble phrase “[a] method of treating rheumatoid arthritis in a patient” should not be construed to require that the treatment be effective in any particular patient. Citing the specification and ordinary meaning, Petitioner contended the term means “attempting to cause a therapeutic improvement,” and that treatment occurs regardless of its efficacy. This construction is central to the argument that even if the prior art did not explicitly state the claimed method was effective, it would have been obvious to try.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that discretionary denial under §325(d) would be inappropriate for all asserted grounds.
    • For grounds based on NCT00965653, Petitioner contended that while the reference was listed in an Information Disclosure Statement (IDS), it was never substantively evaluated by the Examiner. Critically, the version submitted to the USPTO omitted the “First Posted” date, meaning the Examiner was never presented with evidence establishing it as a prior art publication.
    • For grounds based on Ohta 2010, Petitioner argued the Examiner committed a clear error by accepting a legally insufficient inventor declaration to antedate the reference.
    • For the ground based on Maini 2006, Bonilla, and Wang, Petitioner noted that these references and the specific combination argument were never before the Examiner, making the challenge entirely new.

6. Relief Requested

  • Petitioner requests institution of an inter partes review (IPR) and cancellation of claims 1-3 and 6-11 of Patent 8,580,264 as unpatentable.