Koios Pharmaceuticals LLC v. Medac Gesellschaft für KLinisChe Spezialpräparate mbH

1. Case Identification

• Case #: IPR2016-01370
• Patent #: 8,664,231
• Filed: July 20, 2016
• Petitioner(s): Koios Pharmaceuticals LLC
• Patent Owner(s): Medac Gesellschaft Fuer Klinische Spezialpräparate MBH
• Challenged Claims: 1-22

2. Patent Overview

• Title: Concentrated Methotrexate Solutions
• Brief Description: The ’231 patent discloses methods for treating inflammatory autoimmune diseases by administering concentrated solutions of methotrexate (MTX) subcutaneously. The purported invention is the use of a higher concentration (e.g., >30 mg/ml) to deliver a standard low dose of MTX in a reduced injection volume, thereby improving patient convenience.

3. Grounds for Unpatentability

Ground 1: Anticipation by Grint - Claims 1, 2, 4-6, 11-13, 17, and 22 are anticipated under 35 U.S.C. §102(b) by Grint.

• Prior Art Relied Upon: Grint (Patent 6,554,504).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Grint, which issued in 2003, explicitly taught every element of the challenged claims. Grint disclosed a method for treating autoimmune diseases, such as rheumatoid arthritis and psoriasis, by administering MTX subcutaneously. Crucially, Grint taught formulating MTX in concentrations "from about 0.1 to about 40 mg/ml of carrier," which expressly discloses and anticipates the ’231 patent's central limitation of a concentration "more than 30 mg/ml." Grint also disclosed the same diseases, pharmaceutically acceptable solvents, and storage containers recited in the dependent claims.
  • Key Aspects: Petitioner contended that because Grint's disclosed range of up to 40 mg/ml overlaps with and teaches the ’231 patent's claimed range, it anticipates. Any argument by the patent owner about the criticality of the claimed range would fail because the ’231 patent specification itself states the invention operates at any concentration above 25 mg/ml, not just above 30 mg/ml.

Ground 2: Anticipation by Wyeth - Claims 1-6, 11-13, 17-18, and 22 are anticipated under §102(b) by Wyeth.

• Prior Art Relied Upon: Wyeth (an FDA-approved package insert for "Methotrexate Sodium for Injection," publicly available as of April 2005).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that the Wyeth product label, an FDA-approved guide for physicians, anticipated the claims. Wyeth explicitly taught reconstituting lyophilized MTX to a concentration of 50 mg/ml for treating inflammatory autoimmune diseases, including rheumatoid arthritis and juvenile rheumatoid arthritis (JRA). Furthermore, Wyeth specifically stated that for children with JRA, MTX may be administered "either intramuscularly or subcutaneously" for better absorption and fewer side effects. A person of ordinary skill in the art (POSITA) would have understood this teaching of subcutaneous administration of a 50 mg/ml solution to apply equally to adults with other autoimmune diseases. Wyeth’s disclosure of a 50 mg/ml concentration directly anticipates claim 1's requirement of "more than 30 mg/ml."

Ground 3: Obviousness over Wyeth and Brooks/Arthur - Claims 1-22 are obvious under §103 over Wyeth in view of Brooks and/or Arthur.

• Prior Art Relied Upon: Wyeth (product label), Brooks (a 1990 journal article), and Arthur (a 2002 journal article).

• Core Argument for this Ground:

  • Prior Art Mapping: Wyeth taught administering a 50 mg/ml MTX solution via intramuscular (IM) injection for treating rheumatoid arthritis. The Brooks and Arthur articles both independently taught that subcutaneous (SQ) administration of MTX is interchangeable with IM administration. Both studies concluded there was no significant difference in safety, efficacy, or bioavailability between the two parenteral routes. Dependent claims related to self-administration devices (e.g., pre-filled syringes, pen injectors) were obvious because Arthur expressly taught patients to "self-administer their methotrexate subcutaneously" using pre-filled syringes.
  • Motivation to Combine: A POSITA would combine these references to improve patient care. Knowing from Wyeth that a 50 mg/ml IM solution was safe and effective, and from Brooks and Arthur that the SQ route was equivalent but more convenient, less painful, and suitable for at-home self-administration, a POSITA would have been motivated to administer the Wyeth formulation subcutaneously to achieve these well-documented benefits.
  • Expectation of Success: A POSITA would have had a high expectation of success because Brooks and Arthur established the bioequivalence and comparable safety profiles of the SQ and IM routes for MTX, removing any uncertainty about whether switching the administration route of the Wyeth product would be effective and safe.

• Additional Grounds: Petitioner asserted additional obviousness challenges, including combinations based on Grint with Arthur or Alsufyani, and a primary combination of Hoekstra and Jørgensen, which relied on the motivation to increase MTX concentration to reduce injection volume for patient comfort.

4. Key Technical Contentions (Beyond Claim Construction)

• Toxicity and Bioavailability are Dose-Dependent, Not Concentration-Dependent: Petitioner argued that the key technical considerations for MTX therapy—toxicity and bioavailability—are dependent on the total dose administered (in mg), not the concentration of the solution (in mg/ml). Therefore, increasing the concentration of an MTX solution to deliver the same dose in a smaller volume was a predictable and routine formulation strategy that would not have been expected to alter the drug's safety or efficacy profile. This contention was used to rebut arguments made by the Patent Owner during prosecution that a POSITA would have been concerned about the safety of higher concentrations.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) would be inappropriate. The petition was distinct from prior IPRs filed by other parties (Antares, Frontier) because Petitioner Koios was not in privity with them. Critically, this petition introduced significant new prior art not previously considered by the Board or the Examiner, including Wyeth, Arthur, and Moitra, and was supported by new expert declarations, presenting different arguments and a stronger case for unpatentability.

6. Relief Requested

• Petitioner requested institution of an inter partes review and cancellation of claims 1-22 of Patent 8,664,231 as unpatentable.