PTAB

IPR2017-01528

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 ’930 patent discloses acidic pharmaceutical formulations of insulin glargine designed for improved stability. The core inventive concept is the addition of a specific class of non-ionic surfactants—esters and ethers of polyhydric alcohols (e.g., polysorbates or poloxamers)—to prevent the known problem of insulin aggregation.

3. Grounds for Unpatentability

Ground 1: Obviousness over LANTUS Label and Lougheed - Claims 1-20 are obvious over the LANTUS® 2000 Label in view of Lougheed.

  • Prior Art Relied Upon: LANTUS® 2000 Label (a 2000 product label) and Lougheed (a 1983 article in Diabetes).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the LANTUS® 2000 Label, a commercially available insulin glargine product, disclosed every element of independent claim 1 except for the required surfactant ("at least one chemical entity chosen from esters and ethers of polyhydric alcohols"). The LANTUS label taught an acidic (pH ~4.0) formulation containing insulin glargine, a preservative (m-cresol), and water. Lougheed taught that non-ionic surfactants, specifically polysorbates like Tween 20 and Tween 80 (which are esters of polyhydric alcohols), effectively inhibit aggregation and increase the stability of insulin formulations.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) knew that insulin, and particularly monomeric insulin glargine in an acidic environment, had a strong tendency to aggregate—a "fundamental obstacle" to its use. The LANTUS label itself warned users to discard the product if particles were visible. Petitioner contended a POSITA would combine the LANTUS formulation with a stabilizer taught by Lougheed to solve this well-known and predictable aggregation problem.
    • Expectation of Success: Because Lougheed demonstrated the effectiveness of polysorbates in stabilizing insulin and these surfactants were widely recognized as safe, a POSITA would have had a reasonable expectation of success in adding them to the LANTUS formulation to inhibit or eliminate aggregation.

Ground 2: Obviousness over LANTUS Label and Insuman Infusat or Grau - Claims 1-18 and 20 are obvious over the LANTUS® 2000 Label in view of Insuman Infusat or Grau.

  • Prior Art Relied Upon: LANTUS® 2000 Label, Insuman Infusat (a 2000 Swedish Drug Formulary entry), and Grau (a 1987 article in Diabetes).
  • Core Argument for this Ground:
    • Prior Art Mapping: Similar to Ground 1, the LANTUS label provided the base insulin glargine formulation. The missing surfactant element was taught by Insuman Infusat and Grau. Insuman Infusat was a commercially available insulin product that contained a poloxamer (an ether of polyhydric alcohols) specifically added as a stabilizer to prevent "precipitation and flocculation of the insulin," particularly for use in insulin pumps. Grau also taught using a poloxamer (Genapol) to stabilize insulin formulations against aggregation.
    • Motivation to Combine: The motivation was to solve the known aggregation problem of the LANTUS formulation. The fact that another commercially available insulin product, Insuman Infusat, already successfully used a poloxamer for this exact purpose would have provided a strong motivation for a POSITA to apply the same class of stabilizers to LANTUS. Grau’s research further confirmed the utility of poloxamers.
    • Expectation of Success: The established commercial use and regulatory approval of Insuman Infusat demonstrated that poloxamers were a safe and effective solution for insulin aggregation. This provided a POSITA with a very high expectation of success.

Ground 3: Obviousness over Owens and Lougheed - Claims 1-20 are obvious over Owens in view of Lougheed.

  • Prior Art Relied Upon: Owens (a 2000 article in Diabetes Care) and Lougheed.
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground substituted the LANTUS label with Owens as the primary reference. Petitioner asserted that Owens disclosed a clinical study formulation of insulin glargine that was nearly identical to the LANTUS product, containing insulin glargine, m-cresol, glycerol, zinc, and water at an acidic pH of 4.0. As with the LANTUS label, Owens taught all elements of claim 1 except the surfactant. Lougheed again provided the teaching of adding polysorbates to prevent aggregation.
    • Motivation to Combine: The rationale was identical to that in Ground 1. A POSITA, aware of the insulin glargine formulation in Owens and the known problem of aggregation, would have looked to known solutions like the surfactants taught in Lougheed.
    • Expectation of Success: The expectation of success was based on the same reasoning as in Ground 1: Lougheed's clear teaching of the effectiveness of polysorbates provided a predictable solution to a known problem.
  • Additional Grounds: Petitioner asserted additional obviousness challenges based on combinations of Owens with Insuman Infusat or Grau, and multi-reference grounds for claim 19, relying on similar theories of combining a known base formulation with a known stabilizer to solve the known problem of aggregation.

4. Key Claim Construction Positions

  • "Esters and Ethers of Polyhydric Alcohols": Petitioner argued this term was critical to the invalidity analysis. Citing the ’930 patent’s specification, Petitioner contended that a POSITA would understand this term to expressly include, among others, polysorbates (e.g., Tween) and poloxamers (e.g., Pluronics). This construction was central to mapping the surfactants disclosed in Lougheed, Insuman Infusat, and Grau directly onto the claim language.

5. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-20 of the ’930 patent as unpatentable.