PTAB

IPR2020-00314

Fresenius Kabi USA LLC v. Amgen Inc

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Key Events
Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Refolding Proteins Using a Chemically Controlled Redox State
  • Brief Description: The ’287 patent discloses methods for refolding proteins expressed in non-mammalian cells. The methods involve incubating unfolded proteins in a refold buffer containing specific amounts of an oxidant and a reductant to control the redox state, characterized by a "thiol-pair ratio" and "thiol-pair buffer strength," to achieve a desired yield of properly refolded protein.

3. Grounds for Unpatentability

Ground 1: Anticipation over Vallejo - Claims 1, 4, 8-10, 12, 14-16, 19, 23-26, and 29-30 are anticipated by Vallejo.

  • Prior Art Relied Upon: Vallejo (European Patent Application No. EP 1449848 A1).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Vallejo disclosed every element of the challenged claims in its method for refolding recombinant human bone morphogenetic protein-2 (rhBMP-2) from E. coli inclusion bodies. Vallejo’s "standard renaturation buffer" contained guanidinium hydrochloride (a denaturant), Tris (an aggregation suppressor and protein stabilizer), and a glutathione redox pair (oxidant and reductant). Petitioner asserted that Vallejo’s buffer inherently possessed a thiol-pair buffer strength of 3 mM (meeting the ">2 mM" limitation) and was tested with thiol-pair ratios between 0.004 and 114, which falls within the claimed range of 0.001-100. Furthermore, Vallejo reported an optimized "renaturation yield" of 44%, which satisfies the claim requirement of at least 25-30% properly refolded protein.
    • Key Aspects: Petitioner contended that the equations in the ’287 patent for calculating thiol-pair ratio and buffer strength merely describe inherent properties of the redox buffer disclosed in Vallejo, and their inclusion in dependent claims does not impart novelty.

Ground 2: Anticipation over Ruddon - Claims 16, 19-21, 23-26, and 29-30 are anticipated by Ruddon.

  • Prior Art Relied Upon: Ruddon (International Publication No. WO 95/32216).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Ruddon, which was not cited during prosecution, anticipated the challenged claims by disclosing a method for refolding biologically active glycoprotein hormones (hCG-β) expressed in prokaryotic cells. Ruddon’s refold buffer used a cysteamine/cystamine redox pair, along with urea (a denaturant) and Tris (an aggregation suppressor/protein stabilizer). Petitioner noted that Ruddon expressly calculated a thiol-pair ratio of 11.4 using the same equation as the ’287 patent, which is within the claimed range. The disclosed concentrations in Ruddon’s Example 2 inherently resulted in a thiol-pair buffer strength of 13.6 mM, satisfying the ">2 mM" limitation. The reported "folding efficiency" of 40-60% met the claimed yield limitations.

Ground 3: Obviousness over Ruddon in view of Clark - Claims 1, 4-6, 8-10, 12, 14-16, 19-21, 23-26, and 29-30 are obvious over Ruddon in view of Clark 1998 in light of Schafer or Gilbert.

  • Prior Art Relied Upon: Ruddon (WO 95/32216), Clark 1998 (a 1998 journal article), Schafer (a 2001 journal article), and Gilbert (a 1995 publication).

  • Core Argument for this Ground:

    • Prior Art Mapping: Petitioner asserted that even if not anticipated, the claims were obvious because the claimed method represents nothing more than routine optimization. Ruddon provided a base method for refolding proteins from a non-mammalian system. Clark 1998 explicitly taught that for optimal protein refolding, one must consider and experimentally vary both the ratio of reduced to oxidized glutathione and the total glutathione concentration (i.e., the thiol-pair ratio and buffer strength). Clark’s experiments to optimize the refolding of lysozyme used ratios and buffer strengths within the claimed ranges and achieved yields (>88%) exceeding the claimed minimums.
    • Motivation to Combine: A POSITA would combine the teachings of Ruddon and Clark because both addressed the common problem of optimizing refolding conditions for proteins expressed in bacterial systems. It would have been obvious to apply Clark's systematic, two-variable optimization strategy to the protein refolding process described in Ruddon to improve yields, a well-known goal in the art. Schafer and Gilbert were cited as demonstrating that the equations for calculating these redox parameters were elementary and well-known.
    • Expectation of Success: The success reported in both Ruddon and Clark for refolding different disulfide-containing proteins would have provided a POSITA with a reasonable expectation of success in applying these routine optimization principles.

  • Additional Grounds: Petitioner asserted additional obviousness challenges against dependent claims 8, 9, 14, 15, and 23-25 over Vallejo in combination with Ruddon and Clark, arguing the use of the specific equations recited in those claims was a well-known and obvious choice for a POSITA performing such optimization.

4. Key Claim Construction Positions

  • "Preparation": For the IPR, Petitioner adopted the Patent Owner’s asserted construction that the term means "the refold mixture... prior to contact with the proteins to be refolded."
  • "Is Calculated": Petitioner adopted the Patent Owner’s position that this term requires "an active step of determining" the thiol-pair ratio or buffer strength using an equation as part of the method.
  • "Maintains Solubility": Petitioner argued that in the context of the claims, this phrase should be construed to mean "maintains the solubility of the protein that properly refolds during incubation."

5. Arguments Regarding Discretionary Denial

  • Petitioner argued that the Board should not exercise discretionary denial under the General Plastic factors. A prior IPR had been denied institution because it was found to be duplicative of a then-pending Post-Grant Review (PGR) filed by a third party, Adello. Petitioner asserted that since the Adello PGR was terminated following a settlement, the basis for the prior denial was moot. Petitioner contended that it had no significant relationship with Adello, was not involved in Adello's petition or settlement, and that denying institution would unjustly prejudice Petitioner by allowing the Patent Owner to insulate its patent from a merits review simply by settling with the first challenger.

6. Relief Requested

  • Petitioner requests institution of an inter partes review and cancellation of claims 1, 4-6, 8-10, 12, 14-16, 19-21, 23-26, and 29-30 as unpatentable.