PTAB

IPR2017-01526

Mylan Pharmaceuticals Inc v. Sanofi Aventis Deutschland GmbH

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1. Case Identification

2. Patent Overview

  • Title: Acidic Insulin Preparations Having Improved Stability
  • Brief Description: The ’652 patent discloses pharmaceutical formulations of insulin glargine, an insulin analog, with improved stability against aggregation. The invention is the addition of a non-ionic surfactant, specifically a polysorbate or poloxamer, to an acidic insulin glargine solution that also contains a preservative and water.

3. Grounds for Unpatentability

Ground 1: Obviousness over LANTUS Label and Lougheed - Claims 1-25 are obvious over the LANTUS® 2000 Label in view of Lougheed.

  • Prior Art Relied Upon: LANTUS® 2000 Label (a commercial product label for insulin glargine published by Dec. 2000) and Lougheed (a May 1983 article in Diabetes on insulin formulation stability).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the LANTUS® 2000 Label, a commercially available insulin glargine product from the Patent Owner’s assignee, disclosed every element of the challenged claims except for the required surfactant. The label taught a formulation containing insulin glargine, the preservative m-cresol, glycerol, zinc, water, and an acidic pH of approximately 4.0. Lougheed was cited to remedy this deficiency, as it explicitly taught that adding non-ionic surfactants, including polysorbate 20 and polysorbate 80 (recited in claim 1), to insulin formulations inhibits aggregation and increases stability. Lougheed also disclosed concentration ranges for these surfactants that overlap with or suggest the ranges recited in dependent claims 17-19.
    • Motivation to Combine: A POSITA would combine Lougheed's teachings with the LANTUS formulation to solve the well-known and long-standing problem of insulin aggregation. This problem was known to be particularly acute for monomeric insulin formulations at an acidic pH, precisely the characteristics of the LANTUS product. The LANTUS label itself warned against using the product if any particle aggregation was visible, directly pointing to the problem Lougheed aimed to solve.
    • Expectation of Success: A POSITA would have a high expectation of success because Lougheed demonstrated that polysorbates were effective at stabilizing insulin. Furthermore, polysorbates were widely used, generally regarded as safe (GRAS), and known to be effective excipients in other protein-based pharmaceutical products.

Ground 2: Obviousness over LANTUS Label and Insuman Infusat - Claims 7 and 24 are obvious over the LANTUS® 2000 Label in view of the FASS Insuman Infusat Entry.

  • Prior Art Relied Upon: LANTUS® 2000 Label (a 2000 commercial product label) and Insuman Infusat (a Jan. 2000 entry in the Swedish Drug Formulary for a commercial human insulin product).
  • Core Argument for this Ground:
    • Prior Art Mapping: As in Ground 1, the LANTUS® 2000 Label provided the base insulin glargine formulation. The Insuman Infusat entry was introduced to supply the missing surfactant element for independent claims 7 and 24, which broadly recite a "polysorbate or poloxamer." Insuman Infusat was a commercially available insulin product that already contained a poloxamer (poly(oxyethylene, oxypropylene)glycol) as a stabilizer.
    • Motivation to Combine: The motivation was to improve the stability of the LANTUS formulation by incorporating a solution that was already proven and in commercial use in another insulin product. The Insuman Infusat entry explicitly stated that the addition of its stabilizer "prevents precipitation and flocculation of the insulin," making it "particularly suited for use in insulin pumps." A POSITA seeking to prevent aggregation in LANTUS would look to other successful commercial insulin formulations for known solutions.
    • Expectation of Success: Success was reasonably expected because the use of a poloxamer was not a theoretical suggestion but an established practice in a commercially available insulin product, demonstrating its safety and efficacy for the intended purpose.

Ground 3: Obviousness over Owens and Lougheed - Claims 1-25 are obvious over Owens in view of Lougheed.

  • Prior Art Relied Upon: Owens (a June 2000 article in Diabetes Care on insulin glargine pharmacokinetics) and Lougheed (a May 1983 article in Diabetes).

  • Core Argument for this Ground:

    • Prior Art Mapping: Petitioner presented Owens as an alternative primary reference to the LANTUS label. Owens described the exact formulation used in clinical trials for insulin glargine (HOE 901), disclosing insulin glargine, m-cresol, glycerol, zinc, water, and a pH of 4.0. This formulation taught all limitations of the independent claims except for the surfactant. The teachings of Lougheed, as described in Ground 1, were then applied to supply the missing polysorbate 20 or polysorbate 80.
    • Motivation to Combine: The motivation was identical to that in Ground 1: to solve the known aggregation problem inherent in the acidic, monomeric insulin glargine formulation described by Owens. A POSITA would apply Lougheed’s well-known solution (adding polysorbates) to the base formulation disclosed in Owens.
    • Expectation of Success: The expectation of success was similarly high, as Lougheed’s experiments provided a clear roadmap and empirical support for using polysorbates to enhance the stability of insulin formulations like the one detailed in Owens.

  • Additional Grounds: Petitioner asserted additional obviousness challenges for claims 7 and 24 based on combining the LANTUS label or Owens with Grau (a 1987 article teaching the use of the poloxamer Genapol to stabilize insulin) and combining Owens with the Insuman Infusat entry. These grounds relied on similar theories of adding a known surfactant to a known base formulation to solve the known problem of insulin aggregation.

7. Relief Requested

  • Petitioner requests institution of inter partes review and cancellation of claims 1-25 of Patent 7,476,652 as unpatentable under 35 U.S.C. §103.