PTAB

IPR2015-01093

Coalition for Affordable Drugs II LLC v. NPS Pharmaceuticals Inc

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Key Events
Petition

1. Case Identification

2. Patent Overview

  • Title: GLP-2 Formulations
  • Brief Description: The ’886 patent relates to stable pharmaceutical formulations of glucagon-like peptide-2 (GLP-2) or its analogs. The invention claims formulations comprising a phosphate buffer, L-histidine as a stabilizer, and a bulking agent such as mannitol or sucrose, intended for therapeutic use in treating gastrointestinal disorders.

3. Grounds for Unpatentability

Ground 1: Obviousness of Base Formulation - Claims 1-27, 33-35, 38, and 45 are obvious over Drucker '379 in view of Kornfelt and Osterberg.

  • Prior Art Relied Upon: Drucker '379 (Patent 5,789,379), Kornfelt (Patent 5,652,216), and Osterberg (a 1999 European Journal of Pharmaceutical Sciences article).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that the combination of references disclosed every limitation of the challenged claims. Drucker '379 taught the foundational elements, including therapeutically effective amounts of GLP-2 or its analogs in a phosphate-buffered solution for treating gastrointestinal disorders. However, Drucker ’379 did not explicitly address long-term stability. Kornfelt addressed this known problem for glucagon—a structurally and functionally similar peptide—by teaching the use of L-histidine as a stabilizer and mannitol or sucrose as excipients in a lyophilized formulation. Osterberg further confirmed that L-histidine and sucrose were effective stabilizers for lyophilized protein formulations across a physiologically relevant pH range.
    • Motivation to Combine: Petitioner contended that a person of ordinary skill in the art (POSITA) would be motivated to combine these teachings to solve the well-known problem of peptide instability for therapeutic formulations. Because GLP-2 and glucagon are both members of the glucagon superfamily with significant structural similarity, a POSITA would combine the stable formulation technology for glucagon taught by Kornfelt and Osterberg with the GLP-2 peptides taught by Drucker ’379 to create a stable, therapeutically useful GLP-2 product. This was a straightforward solution to a known design need.
    • Expectation of Success: A POSITA would have a high expectation of success because the functions of the components—phosphate as a buffer, L-histidine as a stabilizer, and mannitol/sucrose as bulking agents—were well-understood and known to be effective for similar peptides. Applying these known ingredients to GLP-2 for the predictable purpose of enhancing stability would have been routine.

Ground 2: Obviousness of Formulated Analogs with Receptor Binding - Claims 31, 32, and 44 are obvious over Drucker '379, Kornfelt, and Osterberg in view of Munroe.

  • Prior Art Relied Upon: Drucker '379 (Patent 5,789,379), Kornfelt (Patent 5,652,216), Osterberg (a 1999 journal article), and Munroe (a 1999 PNAS article).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground built upon the combination in Ground 1 to address claims directed to GLP-2 analogs identified through a screening process for receptor binding activity. While the primary combination taught the stable formulation, Munroe specifically disclosed the creation of a cell line expressing the GLP-2 receptor and its use for screening peptide analogs to identify their binding and biological activity. Munroe demonstrated that specific GLP-2 analogs, such as [Gly-2]GLP-2, bind to the receptor.
    • Motivation to Combine: A POSITA developing formulations of GLP-2 analogs, as taught by Drucker '379, would naturally be motivated to consult prior art like Munroe, which taught the standard and necessary methods for identifying and confirming the activity of such analogs. The desire to formulate a biologically active analog would directly lead a POSITA to incorporate Munroe’s established screening techniques.
    • Expectation of Success: The methods described in Munroe were established scientific procedures for receptor binding assays. A POSITA would have a reasonable expectation of success in applying these standard screening methods to identify active analogs for inclusion in the stable formulation taught by the primary references.

Ground 3: Obviousness of Long-Term Lyophilized Stability - Claims 28-30 and 39-43 are obvious over Drucker '379, Kornfelt, and Osterberg in view of Holthuis.

  • Prior Art Relied Upon: Drucker '379 (Patent 5,789,379), Kornfelt (Patent 5,652,216), Osterberg (a 1999 journal article), and Holthuis (Patent 5,496,801).
  • Core Argument for this Ground:
    • Prior Art Mapping: This ground targeted claims reciting specific long-term stability metrics (e.g., <5% degradation over 6 months at ambient temperature) and low residual water content (<5% or <2%) for lyophilized formulations. The base formulation was taught by the primary combination. Holthuis provided the specific missing link by teaching a lyophilization process for another peptide hormone (PTH) that explicitly resulted in the claimed stability and low moisture levels. Holthuis disclosed that its lyophilized formulations were stable for at least 9 months and had a water content below 2%.
    • Motivation to Combine: A POSITA tasked with creating a commercially viable, shelf-stable product would be motivated to optimize the lyophilization process to achieve long-term stability and low water content, which are standard FDA requirements. Holthuis provided an exemplary and successful method for achieving these exact properties in a similar peptide hormone formulation, making it an obvious resource to consult and apply.
    • Expectation of Success: Holthuis provided a detailed, successful protocol for achieving the claimed stability results. A POSITA would reasonably expect that applying this established lyophilization technique to the GLP-2 formulation—already known to be stabilizable with the same types of excipients—would yield a similarly stable product.
  • Additional Grounds: Petitioner asserted an additional obviousness challenge against claims 36-37 based on the combination of Drucker '379, Kornfelt, Osterberg, and Drucker '574, which specifically taught GLP-2 receptor antagonists.

4. Key Claim Construction Positions

  • "analog" of GLP-2: Petitioner argued this term should be construed to mean a peptide that incorporates one or more amino acid substitutions, deletions, additions, or modifications into a natural GLP-2 peptide while retaining biological activity. This construction, supported by the patent’s specification and prosecution history, was asserted to be broad enough to read on the various modified GLP-2 peptides disclosed in the prior art, including those taught by Drucker '379.

5. Key Technical Contentions (Beyond Claim Construction)

  • Structural Similarity of GLP-2 and Glucagon: A central pillar of Petitioner's obviousness argument was the asserted structural and functional relationship between GLP-2 and glucagon. Petitioner argued that both are members of the glucagon superfamily, share approximately 50% amino acid sequence similarity, and possess a similar alpha-helical structure. This close relationship, it was contended, would have made it obvious to a POSITA to apply the known and successful stabilization techniques for glucagon formulations (taught by Kornfelt) directly to GLP-2 formulations to achieve the predictable result of improved stability.

6. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1-45 of Patent 7,056,886 as unpatentable.