PTAB

PGR2019-00001

ADello Biologics 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 discloses methods for refolding proteins expressed in a non-mammalian expression system. The methods involve contacting the proteins with a specific refold buffer and incubating the mixture to achieve a desired yield of properly refolded, biologically active protein.

3. Grounds for Unpatentability

Ground 1: Anticipation over Vallejo - Claims 1-4, 7-19, and 22-30 are anticipated by Vallejo under 35 U.S.C. §102(a)(1).

  • Prior Art Relied Upon: Vallejo (European Patent Application No. EP1449848).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner argued that Vallejo discloses every element of the challenged claims. Vallejo teaches a method of refolding recombinant cystine-knot proteins (a type of complex protein) expressed in bacteria by solubilizing inclusion bodies and renaturing the protein in a refolding buffer. Petitioner asserted that Vallejo’s buffer contains the claimed components: an aggregation suppressor (arginine), a denaturant (Gdn-HCl), and a redox system (reduced/oxidized glutathione) comprising an oxidant and reductant. Petitioner calculated the thiol-pair ratio and thiol-pair buffer strength from Vallejo's examples (e.g., a 3 mM total glutathione concentration) to fall within the claimed ranges. Furthermore, Vallejo’s reported refolding yields of 33-44% meet the limitations of "at least about 25%" (claim 1) and "about 30-80%" (claim 10).

Ground 2: Anticipation over Schlegl - Claims 1-4, 8-19, and 23-30 are anticipated by Schlegl under 35 U.S.C. §102(a)(1).

  • Prior Art Relied Upon: Schlegl (Application # 2007/0238860).
  • Core Argument for this Ground:
    • Prior Art Mapping: Petitioner contended that Schlegl teaches a method for refolding recombinant proteins from non-mammalian systems using a customizable refold buffer. This buffer is disclosed to contain a denaturant (GdmHCl), an aggregation suppressor and protein stabilizer (L-arginine, Tris), and an optional redox system like GSH/GSSG. An example in Schlegl uses cysteine and cystine as the redox components, from which Petitioner calculated a thiol-pair ratio of 2 and a thiol-pair buffer strength of 6 mM, both meeting the claim limitations. Petitioner emphasized that Schlegl explicitly discloses final refolding yields of 63% (batch system) and 81-90% (fed-batch system), which directly read on the claimed yield ranges.

Ground 3: Obviousness over Ruddon in view of Vallejo - Claims 1-4, 7-19, and 22-30 are obvious over Ruddon in view of Vallejo.

  • Prior Art Relied Upon: Ruddon (WO 95/32216) and Vallejo (European Patent Application No. EP1449848).

  • Core Argument for this Ground:

    • Prior Art Mapping: Petitioner argued Ruddon discloses refolding complex, cystine-knot glycoprotein hormones using a redox buffer with the claimed components and a thiol-pair ratio within the claimed range (2-40 mM). However, Ruddon teaches performing this refolding at low protein concentrations. Vallejo addresses the problem of low concentration by teaching methods, such as pulse refolding, to increase protein concentration during the refolding of similar cystine-knot proteins for commercial-scale production.
    • Motivation to Combine: A Person of Ordinary Skill in the Art (POSA), seeking to implement Ruddon's method for clinical or commercial applications (a need Ruddon identifies), would have been motivated to look to contemporaneous art like Vallejo for established techniques to increase protein concentration and yield. A POSITA would combine Ruddon's refolding buffer system with Vallejo's pulse addition technique to improve the efficiency and commercial viability of the process.
    • Expectation of Success: A POSITA would have a reasonable expectation of success because both Ruddon and Vallejo address the same technical problem—refolding complex, disulfide-bonded, cystine-knot proteins expressed in non-mammalian systems—using similar buffer components and redox principles.

  • Additional Grounds: Petitioner asserted that claims 1-9 and 16-25 are unpatentable under §112 for lacking written description and that claims 1-30 are unpatentable for lacking enablement. Petitioner also asserted obviousness challenges over Schlegl and Vallejo (claims 7 and 22) and over Vallejo and Hevehan (claims 5, 6, 20, and 21). Finally, claims 1-15 were challenged as indefinite.

4. Key Claim Construction Positions

  • "wherein the thiol-pair buffer strength maintains the solubility of the preparation": Petitioner argued for two possible constructions. The first, based on the specification, is that the phrase means the buffer strength maintains the solubility of the proteins once they are added to the preparation. The second, based on the plain language of claims 1 and 10, is that the buffer strength maintains the solubility of the preparation itself, before the proteins are added. Petitioner argued the second construction renders the claims indefinite and invalid under §112 because the specification provides no support for the "solubility" of the preparation absent the protein.

5. Arguments Regarding Discretionary Denial

  • Petitioner argued against discretionary denial under §325(d), particularly regarding the Schlegl reference. It was contended that while a combination including Schlegl was considered during prosecution, the Examiner did not have the benefit of the Board’s Final Written Decision in a related case involving the parent ’138 patent, where the Board rejected the same arguments Patent Owner made regarding Schlegl. Petitioner also asserted that it was relying on portions of Schlegl (e.g., paragraph [0082] disclosing high yields) that were not considered by the Examiner.

6. Relief Requested

  • Petitioner requested institution of Post-Grant Review and cancellation of claims 1-30 of the ’287 patent as unpatentable.