Kashiv Biosciences LLC v. Amgen Inc

1. Case Identification

• Case #: IPR2019-00797
• Patent #: 9,643,997
• Filed: March 7, 2019
• Petitioner(s): Kashiv Biosciences, LLC
• Patent Owner(s): Amgen Inc.
• Challenged Claims: 9-10, 13-15, 17-21, 23, and 26-30

2. Patent Overview

• Title: Capture Purification Processes for Proteins Expressed in a Non-mammalian System
• Brief Description: The ’997 patent discloses methods for purifying proteins expressed in a non-native, limited solubility form (e.g., inclusion bodies) from non-mammalian expression systems. The claimed process involves solubilizing the protein, forming a refold solution, applying this solution to a separation matrix for capture, and then washing and eluting the purified protein.

3. Grounds for Unpatentability

Ground 1: Anticipation over Ferré - Claims 9-10, 13-14, 17-18, 20-21, 26, 29, and 30 are anticipated by Ferré

• Prior Art Relied Upon: Ferré ("A novel system for continuous protein refolding and on-line capture by expanded bed absorption," Protein Science, 2005).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that Ferré disclosed a complete method for purifying human β2-microglobulin expressed as insoluble inclusion bodies in E. coli, which met every limitation of claim 9. This included: (a) solubilizing the inclusion bodies in 8M urea (a denaturant); (b) forming a refold solution by diluting the solubilized protein with a refold buffer containing Tris-HCl (an aggregation suppressor and protein stabilizer); (c) directly applying the refold solution to an expanded bed adsorption (EBA) column containing an ion-exchange resin; and (d-e) subsequently washing and eluting the captured protein.
  • Key Aspects: Petitioner emphasized that Ferré's system for "continuous protein refolding and on-line EBA capture" explicitly taught the direct application of the refold solution to the separation matrix without any intervening steps like dilution, centrifugation, or dialysis, thereby satisfying even a narrow construction of the "applying" step. Dependent claims were met because Ferré used bacteria, urea as a denaturant, Tris in the refold buffer, and an ion-exchange resin.

Ground 2: Obviousness over Komath - Claims 9-10, 13-14, 17-18, 20-21, 26, 29, and 30 are obvious over Komath

• Prior Art Relied Upon: Komath (WO 2004/001056).
• Core Argument for this Ground:
  • Prior Art Mapping: As an alternative to its anticipation argument, Petitioner contended the claims were obvious over Komath. Petitioner argued Komath disclosed a "simple and cost effective process" for purifying recombinant human G-CSF from E. coli inclusion bodies that taught all steps of claim 9 in the claimed order. This included solubilizing with urea, refolding with a buffer containing polysorbate 20 (a known aggregation suppressor and protein stabilizer), loading the refolded solution onto an ion-exchange column, washing, and eluting.
  • Motivation to Combine: Petitioner argued a POSITA would have been motivated to practice the steps disclosed in Komath in the recited order because they represented the standard, well-established workflow for purifying proteins from inclusion bodies. Komath's goal of a "simple and economical process" with "fewer steps" would have motivated a POSITA to apply the refold solution directly to the chromatography column to achieve higher throughput and yield.
  • Expectation of Success: A POSITA would have reasonably expected success because Komath's process was optimized for maximum recovery. The principles of ion-exchange chromatography (IEX) were well-understood, and the specific components used by Komath (e.g., low concentration urea, non-ionic polysorbate 20) were known to be compatible with IEX matrices, ensuring successful binding and purification.

Ground 3: Obviousness over Ferré, Komath, or Dietrich in view of Rosendahl - Claims 15, 19, 23, 27, and 28 are obvious over the combination

• Prior Art Relied Upon: Ferré, Komath, or Dietrich (Application # 2008/0260684) in view of Rosendahl (Application # 2004/0018586).

• Core Argument for this Ground:

  • Prior Art Mapping: Petitioner argued that while the base references (Ferré, Komath, Dietrich) each disclosed the core method of claim 9, Rosendahl provided specific teachings on reductants and redox components for solubilizing and refolding proteins with disulfide bonds. Rosendahl taught using reductants like cysteine and glutathione in a solubilization buffer and redox mixtures like cysteine/cystine or reduced/oxidized glutathione in a refold buffer.
  • Motivation to Combine: A POSITA seeking to improve the efficiency and yield of protein refolding for proteins with native disulfide bonds (as described in the base references) would combine Rosendahl's teachings. Rosendahl explicitly taught that its preferred reductants/redox components were "useful" and "preferred" for refolding aggregated proteins to a soluble, active form in "high yield." This provided a clear motivation to incorporate these specific, advantageous components into the established purification workflows of Ferré, Komath, or Dietrich.
  • Expectation of Success: A POSITA would have had a reasonable expectation of success in making this combination, as Rosendahl demonstrated that its components resulted in successful refolding of proteins like G-CSF. The combination was a predictable application of known refolding agents to a known purification process to achieve an expected improvement in protein refolding.

• Additional Grounds: Petitioner asserted additional anticipation challenges against various claims based on Komath (Ground 2), Hahm (a 2001 journal article), and Dietrich (’684 application), which each disclosed similar multi-step protein purification processes from inclusion bodies.

4. Key Claim Construction Positions

• Petitioner argued that the term “applying the refold solution to a separation matrix” should be given its plain and ordinary meaning, which encompasses both direct application and application with intervening processing steps (e.g., filtration). Petitioner supported this by citing the patent specification, which describes embodiments with intermediate steps, and the prosecution history, where the Patent Owner distinguished its claims from the parent ’878 patent, which was amended to recite "directly applying." Petitioner noted that even under the Patent Owner's narrower proposed construction ("without intervening steps of dilution, centrifugation, dialysis, or precipitation"), the prior art still rendered the claims unpatentable.

5. Arguments Regarding Discretionary Denial

• In a footnote, Petitioner argued that discretionary denial under §325(d) would be improper. The basis for this argument was that neither the asserted prior art references nor the specific invalidity arguments presented in the petition were previously considered by the Examiner during prosecution of the ’997 patent.

6. Relief Requested

• Petitioner requests institution of an inter partes review and cancellation of claims 9-10, 13-15, 17-21, 23, and 26-30 of the ’997 patent as unpatentable.