PTAB

IPR2016-01029

Wockhardt Bio AG v. AstraZeneca AB

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1. Case Identification

2. Patent Overview

  • Title: Cyclopropyl-Fused Pyrrolidine-Based Inhibitors of Dipeptidyl Peptidase IV and Method
  • Brief Description: The ’186 patent discloses a large genus of compounds, and related pharmaceutical compositions and treatment methods, that inhibit the dipeptidyl peptidase IV (DP-IV) enzyme. These inhibitors are intended for treating type II diabetes and related conditions by preventing the degradation of glucagon.

3. Grounds for Unpatentability

Ground 1: Obviousness of Saxagliptin and Encompassing Genera - Claims 1, 2, 4, 6-11, 25-28, 32-35, 39, and 40 are obvious over Ashworth, Villhauer, Raag, and Hanessian.

  • Prior Art Relied Upon: Ashworth (a 1996 journal article), Villhauer (WO 98/19998), Raag (a 1991 journal article), and Hanessian (a 1997 journal article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the specific compound of claim 25 ("saxagliptin") and the various genus claims encompassing it were obvious based on a step-by-step modification of a known lead compound. Petitioner asserted that Ashworth identified N-glycyl-2-cyanopyrrolidine analogs as potent DP-IV inhibitors and disclosed Compound 25, having a cyclohexyl group, as a promising lead due to its high potency and stability. Villhauer then taught substituting the cyclohexyl group with larger groups, specifically identifying adamantyl as an "even more preferred" substituent for improving DP-IV inhibitors. Further, Raag taught that adamantane is consistently metabolized to 1-hydroxyadamantane to improve solubility, a known strategy for optimizing lead compounds. Finally, Hanessian described modifying the proline ring via cyclopropanation to create a conformationally constrained, more stable structure, a known technique for improving peptide-based drugs. Petitioner contended that combining these teachings directly yields saxagliptin.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) was motivated to develop more potent and stable DP-IV inhibitors to treat type II diabetes. Petitioner argued that the prior art presented a clear path for drug design: start with Ashworth's potent and stable lead compound, and apply known optimization strategies to further improve its properties. Villhauer and Raag provided a known path to improve the bulky side group for efficacy and solubility, while Hanessian provided a known path to improve the core ring structure for stability.
    • Expectation of Success: Petitioner asserted a POSITA would have had a reasonable expectation of success because the combination involved applying known, predictable chemical modifications to a well-characterized lead compound. The modifications suggested by the prior art were finite and aimed at solving known problems like stability and solubility. For instance, Hanessian taught a limited number of possible cyclopropanations, making it obvious to try them to find the one with the best activity and stability.

Ground 2: Obviousness of Combination Therapy with Metformin - Claims 12-16, 29, 30, 36, 37, 41, and 42 are obvious over Ashworth, Villhauer, Raag, Hanessian, Bachovchin, and the GLUCOPHAGE Label.

  • Prior Art Relied Upon: The references from Ground 1, plus Bachovchin (WO 99/38501) and the GLUCOPHAGE Label (available Jan. 1998).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground builds on the argument that the core DP-IV inhibitor compounds of the ’186 patent were obvious. Bachovchin explicitly taught that DP-IV inhibitors could be advantageously combined with other oral anti-diabetic agents, specifically naming metformin. The GLUCOPHAGE Label confirms metformin was a well-known, approved treatment for type II diabetes. Claims 12-15 are directed to pharmaceutical combinations with an anti-diabetic agent like metformin, and claim 16 recites broad weight ratios for such a combination.
    • Motivation to Combine: The motivation was to provide a more effective and convenient treatment for type II diabetes. Petitioner argued it was common practice and facially obvious to combine different therapeutics that treat the same or related conditions. Bachovchin provided the explicit suggestion to combine a DP-IV inhibitor with metformin. The overlapping dosage ranges disclosed in Villhauer and the GLUCOPHAGE label made the claimed weight ratios obvious to try through routine optimization.
  • Additional Grounds: Petitioner asserted additional obviousness challenges based on similar combination therapy rationales for claims related to co-administration of a DP-IV inhibitor with an anti-obesity agent (orlistat, based on the XENICAL Label) and a lipid-modulating agent (lovastatin, based on the MEVACOR Label), as both obesity and high cholesterol are known comorbidities of type II diabetes.

4. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1, 2, 4, 6-22, 25-30, 32-37, and 39-42 of the ’186 patent as unpatentable under 35 U.S.C. §103.