Apotex Inc v. Amgen Inc

1. Case Identification

• Case #: IPR2016-01542
• Patent #: 8,952,138
• Filed: August 5, 2016
• Petitioner(s): Apotex Inc. and Apotex Corp.
• Patent Owner(s): Amgen Inc. and Amgen Manufacturing Limited
• Challenged Claims: 1-24

2. Patent Overview

• Title: Refolding Proteins Using a Chemically Controlled Redox State
• Brief Description: The ’138 patent describes methods for refolding proteins that have been expressed in a non-mammalian system. The process involves contacting a protein solution with a specific refold buffer to form a mixture, incubating the mixture, and then isolating the refolded protein.

3. Grounds for Unpatentability

Ground 1: Obviousness over Schlegl and Hevehan - Claims 1-11 and 13-24 are obvious over Schlegl in view of Hevehan.

• Prior Art Relied Upon: Schlegl (Application # 2007/0238860) and Hevehan (a 1996 article in Biotechnology and Bioengineering).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Schlegl disclosed the claimed three-step protein refolding method, including the use of a non-mammalian expression system, starting with a high protein concentration (16.5 g/L), and using a refold buffer with a redox component, denaturant, and aggregation suppressor. Schlegl's refold buffer inherently disclosed a thiol-pair ratio (2) and redox buffer strength (6 mM) within the claimed ranges. Hevehan was argued to supplement Schlegl by teaching the systematic optimization of refolding proteins at high concentrations (up to 5 g/L) by varying the thiol-pair ratio and redox buffer strength to maximize yield, demonstrating that such optimization was a known strategy.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA) would combine Schlegl’s general high-concentration refolding process with Hevehan’s specific teachings on optimizing redox conditions to improve the efficiency and yield of that process. Petitioner contended that Hevehan's use of a standard model protein (lysozyme) demonstrated the general applicability of its optimization techniques to the type of process disclosed in Schlegl.
  • Expectation of Success: A POSA would have a reasonable expectation of success because both references addressed the known problem of protein aggregation at high concentrations. The successful adaptation of refolding techniques from model proteins to complex therapeutic proteins was well-established in the art, providing confidence that Hevehan's optimization strategies would work with Schlegl's method.

Ground 2: Obviousness over Schlegl, Hevehan, and Inclonals - Claim 12 is obvious over Schlegl and Hevehan in view of Inclonals.

• Prior Art Relied Upon: Schlegl (Application # 2007/0238860), Hevehan (a 1996 article), and Inclonals (a 2009 article in mAbs).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner asserted that Schlegl and Hevehan established the basic refolding method of claim 1, as argued in Ground 1. The additional limitation of claim 12 requires the protein to be an "Fc-protein conjugate." Inclonals taught the production of full-length antibody fusion proteins in E. coli, which is a type of Fc-protein conjugate.
  • Motivation to Combine: A POSA would be motivated to apply the optimized high-concentration refolding methods of Schlegl and Hevehan to the production of Fc-protein conjugates as taught by Inclonals. This was driven by the well-established therapeutic effectiveness of Fc-fusion proteins and the desire to produce them more efficiently.
  • Expectation of Success: Because Inclonals demonstrated the successful production of complex antibody fusion proteins using a bacterial expression system, a POSA would reasonably expect that applying the optimized refolding techniques from Schlegl and Hevehan to such proteins would be successful.

Ground 3: Anticipation by Schlegl - Claims 1-7, 10, 13-17, and 23 are anticipated by Schlegl.

• Prior Art Relied Upon: Schlegl (Application # 2007/0238860).

• Core Argument for this Ground:

  • Prior Art Mapping: Petitioner argued that Schlegl disclosed every element of the challenged claims. Schlegl taught a method of refolding recombinant proteins from non-mammalian systems (e.g., bacteria) starting with a high protein concentration (16.5 g/L). It explicitly disclosed contacting the protein with a refold buffer containing a redox system (GSH/GSSG), a denaturant, an aggregation suppressor, and a protein stabilizer. The example in Schlegl used parameters that resulted in a thiol-pair ratio of 2 and a redox buffer strength of 6 mM, falling squarely within the ranges recited in the ’138 patent claims. Schlegl also disclosed the subsequent incubation and isolation steps.

• Additional Grounds: Petitioner asserted that claims 1-7, 10, 12-17, 19, 22, and 23 are anticipated under 35 U.S.C. §102 by Brady (Application # 2006/0228329), which disclosed a standard dilution method for refolding murine IL-31 ligand starting with a protein concentration of 15.4 g/L and using a refold buffer with parameters that met the claimed ranges.

4. Key Claim Construction Positions

• "a protein ... present in a volume at a concentration of 2.0 g/L or greater": Petitioner argued this phrase should be interpreted to mean "a protein as it exists in a volume before contacting the volume with a refold buffer." This construction, which measures the concentration of the initial protein solution rather than the final refold mixture, was asserted to be consistent with the claim language and specification and was the same construction proposed by the Patent Owner in related district court litigation.
• "a protein": Petitioner argued this term should be given its broad, ordinary meaning and not be limited to "complex proteins." Petitioner contended that such a limitation would be improper under the doctrine of claim differentiation, as dependent claim 10 explicitly adds the limitation "wherein the protein is a complex protein."

5. Relief Requested

• Petitioner requested institution of an inter partes review and cancellation of claims 1-24 of the ’138 patent as unpatentable.