PTAB

IPR2019-00971

Fresenius Kabi USA LLC v. Amgen Inc

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Petition
petition

1. Case Identification

2. Patent Overview

  • Title: Refolding Proteins Using a Chemically Controlled Redox State
  • Brief Description: The ’287 patent is directed to 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, related through a "thiol-pair ratio" and "thiol-pair buffer strength," to refold the proteins into their native structure.

3. Grounds for Unpatentability

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

  • Prior Art Relied Upon: Vallejo (European Patent Application EP 1449848 A1).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Vallejo disclosed every element of the challenged claims. Vallejo described a method of refolding a recombinant protein (rhBMP-2) expressed in E. coli, a non-mammalian system. Its refolding buffer explicitly contained a denaturant (Gdn-HCl), aggregation suppressors and protein stabilizers (Tris, CHES), an oxidant (oxidized glutathione, GSSG), and a reductant (reduced glutathione, GSH). Petitioner contended that the thiol-pair ratio and buffer strength described in Vallejo (e.g., 3 mM total glutathione at a 2:1 GSH:GSSG ratio) fell squarely within the ranges claimed in the ’287 patent. Vallejo also reported a refolding yield of up to 44%, satisfying the claimed yield limitations (e.g., at least about 25% or 30-80%).
    • Key Aspects: Petitioner asserted that while Vallejo did not use the terms "thiol-pair ratio" or "thiol-pair buffer strength," a person of ordinary skill in the art (POSA) would understand that Vallejo's disclosure of specific concentrations of GSH and GSSG inherently disclosed these parameters as defined by the equations in the ’287 patent.

Ground 2: Anticipation - Claims 16, 19-21, 23-26, 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) produced in prokaryotic cells. Ruddon's refolding solution contained the protein, a denaturant (urea), an aggregation suppressor/protein stabilizer (Tris), an oxidant (cystamine), and a reductant (cysteamine). Petitioner asserted 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 of 0.001-100. Furthermore, the concentrations disclosed in Ruddon's examples resulted in an inherent thiol-pair buffer strength of 13.6 mM, satisfying the limitation of 2 mM or greater. Ruddon reported a "folding efficiency" of 40-60%, meeting the claimed yield requirements.

Ground 3: Obviousness - Claims 1, 4-6, 8-10, 12, 14-16, 19-21, 23-26, 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 on lysozyme renaturation), Schafer (a 2001 journal article), and Gilbert (a 1995 book chapter).

  • Core Argument for this Ground:

    • Prior Art Mapping: Petitioner argued that Ruddon taught a complete method for refolding proteins within the claimed parameters. To the extent any motivation for optimization was needed, Clark 1998 provided it. Clark investigated the explicit relationship between the thiol-pair ratio and buffer strength ("total glutathione concentration") to optimize refolding yield, concluding that both parameters must be considered. Clark performed experiments varying these parameters within the claimed ranges to achieve high refolding yields (>88%). Petitioner contended that combining Ruddon's general refolding method with Clark's specific teachings on optimizing redox conditions would have rendered the claimed invention obvious. Schafer and Gilbert were cited as evidence that the equations for calculating thiol-pair parameters were basic, well-known principles of redox chemistry.
    • Motivation to Combine: A POSA, seeking to optimize the protein refolding process described in Ruddon, would combine its teachings with a reference like Clark 1998. Both references addressed the same fundamental problem of refolding proteins from inclusion bodies by manipulating redox buffer conditions. Clark's systematic study of optimizing buffer strength and thiol ratios to maximize yield and minimize aggregation represented a routine and logical path for improving the method taught in Ruddon.
    • Expectation of Success: A POSA would have had a reasonable expectation of success in combining these references because both Ruddon and Clark reported successful refolding and optimization of different proteins using the same underlying principles of redox chemistry.

  • Additional Grounds: Petitioner asserted an additional obviousness challenge against claims 8, 9, 14, 15, 23-25, and 30 based on Vallejo in combination with Ruddon and Clark, relying on similar theories that a POSA would have been motivated to combine the teachings of these analogous references to arrive at the claimed invention.

4. Key Claim Construction Positions

  • "Preparation": For the purposes of the IPR, Petitioner adopted the Patent Owner's asserted construction, meaning "the refold mixture comprising an amount of oxidant, an amount of reductant, and one or more of a denaturant, aggregation suppressor, and a protein stabilizer, 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 the specified equation as part of the method.
  • "Maintains Solubility": Petitioner assumed this term to mean "maintains the solubility of the protein that properly refolds during incubation."

5. Relief Requested

  • Petitioner requested 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 of the ’287 patent as unpatentable.