Adello Biologics, LLC v. Amgen Inc

1. Case Identification

• Case #: PGR2019-00001
• Patent #: Patent 9,856,287
• Filed: October 1, 2018
• Petitioner(s): Adello Biologics. LLC, Apotex Inc. and Apotex Corp.
• Patent Owner(s): Amgen Inc. and Amgen Manufacturing Limited
• Challenged Claims: 1-30

2. Patent Overview

• Title: Refolding Proteins Using a Chemically Controlled Redox State
• Brief Description: The ’287 patent relates to methods of refolding proteins expressed in non-mammalian systems. The methods involve contacting the proteins with a preparation containing specific redox components and other ingredients, then incubating the mixture to achieve a specified yield of properly refolded, biologically active protein.

3. Grounds for Unpatentability

Ground 1: Lack of Written Description and Enablement under 35 U.S.C. §112 - Claims 1-30 are invalid for lack of written description and enablement.

• Core Argument for this Ground:
  • Prior Art Mapping: This ground does not rely on prior art but on deficiencies in the patent's specification. Petitioner argued that the ’287 patent and its priority applications fail to provide adequate written description or enablement for the full scope of the claimed refolding yields. Specifically, the limitation "at least about 25% of the proteins are properly refolded" (covering 25-100%) and "about 30-80% of the proteins are properly refolded" are not supported.
  • Key Aspects: Petitioner contended that while the specification provides examples yielding approximately 27-35% and a range of 30-80%, there is no disclosure supporting yields at the higher end of the claimed ranges (e.g., above 80%). Petitioner asserted that achieving higher refolding yields is exceptionally difficult and the specification offers no guidance or examples demonstrating possession or enablement of these higher yields, requiring undue experimentation. This alleged lack of support for the claimed ranges in the priority applications is also Petitioner's basis for asserting the patent is eligible for Post-Grant Review (PGR), arguing the claims contain subject matter not present in pre-AIA applications, thus breaking the priority chain.

Ground 2: Anticipation over Vallejo - Claims 1-4, 7-19, and 22-30 are anticipated by Vallejo under §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 a method for refolding cystine-knot proteins (specifically rhBMP-2) produced in a non-mammalian system (E. coli), which anticipates every element of the challenged claims. Vallejo’s method uses a refolding buffer containing an aggregation suppressor (arginine), a chaotropic agent (Gdn-HCl, a denaturant), and a redox system of reduced and oxidized glutathione (GSH/GSSG), which are the claimed reductant and oxidant. Petitioner asserted that Vallejo's disclosed GSH:GSSG ratios and total glutathione concentration fall within the claimed thiol-pair ratio (0.001-100) and thiol-pair buffer strength (>2 mM). Furthermore, Vallejo reported achieving refolding yields of 33-44%, satisfying the "at least about 25%" and "about 30-80%" limitations.

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 under §103.

• 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 that Ruddon teaches a method for refolding complex, multi-subunit glycoprotein hormones (which share a cystine-knot motif with proteins in Vallejo) expressed in E. coli. Ruddon discloses a refold buffer with a protein stabilizer (Tris-HCl) and a redox system (cysteamine/cystamine) and explicitly provides the equation for the thiol-pair ratio. Ruddon further teaches refolding at low protein concentrations (0.02 to 0.05 mg/ml) and achieves yields of 40-60%.
  • Motivation to Combine: A Person of Ordinary Skill in the Art (POSITA) would have been motivated to combine Ruddon with Vallejo to improve the process. Ruddon expressed a need for methods to produce its proteins in amounts sufficient for clinical applications. Vallejo teaches how to refold similar cystine-knot proteins at much higher concentrations (e.g., 2.1 mg/mL) using a "pulse addition" technique. A POSITA would have looked to Vallejo's successful high-concentration method to solve the problem of low-yield production in Ruddon.
  • Expectation of Success: A POSITA would have had a reasonable expectation of success because both references teach refolding complex, disulfide-bonded, cystine-knot proteins from non-mammalian systems. Applying Vallejo's established high-concentration refolding techniques to the similar proteins in Ruddon would be a predictable optimization of a known process.

• Additional Grounds: Petitioner asserted additional challenges, including anticipation over Schlegl (Application # 2007/0238860) and obviousness over the combination of Schlegl and Vallejo. Petitioner also asserted obviousness over Vallejo in view of Hevehan (a 1997 journal article) to teach adjusting thiol-pair buffer strength in proportion to protein concentration. An indefiniteness challenge under §112 was also raised.

4. Key Claim Construction Positions

• "wherein the thiol-pair buffer strength maintains the solubility of the preparation": Petitioner argued this term is central to the dispute and proposed two possible constructions.
  • The first, which Petitioner asserted is the broadest reasonable interpretation in light of the specification, is that the term means maintaining the solubility of the proteins when they are mixed into the preparation.
  • The second, based on the plain language of the claims, is that the term refers to maintaining the solubility of the preparation itself, before the proteins are added. Petitioner argued this second construction renders claims 1-15 indefinite under §112 because the specification provides no guidance on the "solubility" of the preparation components alone.

5. Arguments Regarding Discretionary Denial

• Petitioner argued that discretionary denial under §325(d) would be inappropriate for several reasons.
  • For the §112 grounds, Petitioner contended that it was presenting new evidence (an expert declaration) not before the Examiner and that the Examiner misapprehended the level of support in the specification for the claimed yield ranges.
  • For the prior art grounds involving Schlegl, Petitioner argued the Examiner did not have the benefit of the Final Written Decision (FWD) from a related case (IPR2016-01542) on the parent ’138 patent, where the Board rejected the same arguments from the Patent Owner regarding Schlegl. Petitioner also asserted it was relying on portions of Schlegl that were not considered during prosecution.

6. Relief Requested

• Petitioner requests institution of post-grant review and cancellation of claims 1-30 of the ’287 patent as unpatentable.