DCT

2:18-cv-03347

Amgen Inc v. Kashiv Biosciences LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:18-cv-03347, D.N.J., 02/07/2019
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey as the Defendant entities are registered to do business in, have their principal places of business in, and maintain regular and established places of business in the state.
  • Core Dispute: Plaintiff alleges that Defendants’ manufacturing process for a proposed biosimilar version of the biological drug NEUPOGEN® (filgrastim) infringes four U.S. patents related to methods for purifying and refolding proteins.
  • Technical Context: The patents relate to industrial-scale manufacturing processes for biologic drugs produced in non-mammalian expression systems, which often require complex purification and protein refolding steps to yield a biologically active product.
  • Key Procedural History: The action arises under the Biologics Price Competition and Innovation Act (BPCIA). The complaint notes that the '878' Patent and '138' Patent have been the subject of prior lawsuits against other parties concerning different biosimilar products, which may have put Defendants on notice of these patents prior to this litigation.

Case Timeline

Date Event
2009-06-22 U.S. Patent No. 8,952,138 Priority Date
2009-06-25 U.S. Patent No. 8,940,878 Priority Date
2015-01-27 U.S. Patent No. 8,940,878 Issued
2015-02-10 U.S. Patent No. 8,952,138 Issued
2017-05-09 U.S. Patent No. 9,643,997 Issued
2017-09-11 Adello provides notice of intent to commercially market its Filgrastim Product
2017-10-01 Adello and Amneal enter into a license and commercialization agreement
2018-01-02 U.S. Patent No. 9,856,287 Issued
2018-03-08 Plaintiff files original Complaint
2018-10-03 Plaintiff files First Amended Complaint
2019-02-07 Plaintiff files Second Amended Complaint

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 8,940,878 - "Capture Purification Processes for Proteins Expressed in a Non-Mammalian System"

The Invention Explained

  • Problem Addressed: The complaint indicates the patent is directed to methods for purifying proteins expressed in non-mammalian systems, such as bacteria (Compl. ¶¶ 69, 70). Such systems often produce proteins in a misfolded, aggregated state (known as inclusion bodies) that must be solubilized and refolded before being purified, a multi-stage process that can be inefficient.
  • The Patented Solution: The patent claims a method that integrates protein refolding with purification by allowing a "refold solution," containing the solubilized and refolding protein, to be "directly" applied to a separation matrix (Compl. ¶69). This approach streamlines the manufacturing process by combining what are often separate, multi-step unit operations into a more integrated capture step.
  • Technical Importance: The complaint does not provide sufficient detail for analysis of the invention's technical importance.

Key Claims at a Glance

  • The complaint asserts independent claim 7 and dependent claims 8, 11-12, 15-19, and 21 (Compl. ¶70).
  • Essential elements of independent claim 7 include (Compl. ¶69):
    • Expressing a protein in a non-native limited solubility form in a non-mammalian cell;
    • Lysing the cell;
    • Solubilizing the protein in a solution containing a denaturant, a reductant, and/or a surfactant;
    • Forming a refold solution that includes the solubilization solution and a refold buffer;
    • Directly applying the refold solution to a non-affinity separation matrix (e.g., ion exchange, mixed mode, or hydrophobic interaction resin);
    • Washing the matrix; and
    • Eluting the protein from the matrix.

U.S. Patent No. 8,952,138 - "Refolding Proteins Using a Chemically Controlled Redox State"

The Invention Explained

  • Problem Addressed: Refolding proteins at high concentrations is a significant manufacturing challenge, as proteins tend to aggregate incorrectly rather than fold into their biologically active conformation when densely packed in a solution (Compl. ¶94, n.2).
  • The Patented Solution: The patent claims a method for refolding proteins at high concentrations (≥ 2.0 g/L) by using a refold buffer with a specific "redox component" (Compl. ¶94, n.2). This component is defined by a "final thiol-pair ratio" and a "redox buffer strength," which creates a chemically controlled environment that facilitates the correct formation of disulfide bonds and prevents aggregation, even at high protein concentrations.
  • Technical Importance: The complaint does not provide sufficient detail for analysis of the invention's technical importance.

Key Claims at a Glance

  • The complaint asserts dependent claim 18 (Compl. ¶94). Claim 18 depends on independent claim 1.
  • Essential elements of independent claim 1 include (Compl. ¶94, n.2):
    • Providing a protein expressed in a non-mammalian system at a concentration of 2.0 g/L or greater;
    • Contacting the protein with a refold buffer containing a specific redox component (defined by a final thiol-pair ratio of 0.001 to 100 and a redox buffer strength of 2 mM or greater) and other agents (denaturant, aggregation suppressor, protein stabilizer);
    • Incubating the resulting refold mixture; and
    • Isolating the protein from the refold mixture.
  • Claim 18 adds the limitation that the incubation is performed under "non-aerobic conditions" (Compl. ¶94).

U.S. Patent No. 9,643,997 - "Capture Purification Processes for Proteins Expressed in a Non-Mammalian System"

  • Patent Identification: Issued May 9, 2017 (Compl. ¶56).
  • Technology Synopsis: The patent is directed to methods for purifying proteins expressed in non-mammalian systems. The claimed method involves solubilizing the protein, forming a refold solution with specific components, applying this solution to a separation matrix, and then washing and eluting the protein (Compl. ¶119).
  • Asserted Claims: Independent claim 9 and dependent claims 17-18, 26-27 (Compl. ¶¶ 119-120).
  • Accused Features: The complaint alleges that the process by which Adello manufactures its Filgrastim Product infringes (Compl. ¶120).

U.S. Patent No. 9,856,287 - "Refolding Proteins Using a Chemically Controlled Redox State"

  • Patent Identification: Issued January 2, 2018 (Compl. ¶59).
  • Technology Synopsis: The patent is directed to methods for refolding proteins expressed in non-mammalian systems by contacting them with a preparation containing an oxidant and reductant. The amounts of these components are related through a specific "thiol-pair ratio" (0.001-100) and "thiol-pair buffer strength," and the mixture is incubated until at least 25% of the proteins are properly refolded (Compl. ¶144).
  • Asserted Claims: Independent claim 1 and dependent claims 8-10, 14-16, 23-26, and 30 (Compl. ¶145).
  • Accused Features: The complaint alleges that the process by which Adello manufactures its Filgrastim Product infringes (Compl. ¶145).

III. The Accused Instrumentality

Product Identification

  • The "Adello Filgrastim Product," a proposed biosimilar version of Amgen's NEUPOGEN® (filgrastim) product (Compl. ¶¶ 14, 41).

Functionality and Market Context

  • The complaint alleges, upon information and belief, that Adello will use a "bacterial expression system" to manufacture its Filgrastim Product (Compl. ¶42). The complaint provides a screenshot of Defendant Adello’s online product pipeline, which lists a Filgrastim product manufactured using a bacterial expression system (Compl. ¶42, Ex. 4). The product is intended to copy and compete with Amgen's NEUPOGEN® and is being developed for approval under the BPCIA's abbreviated pathway, which allows reliance on the reference product's safety and efficacy data (Compl. ¶¶ 43, 45).

IV. Analysis of Infringement Allegations

U.S. Patent No. 8,940,878 Infringement Allegations

Claim Element (from Independent Claim 7) Alleged Infringing Functionality Complaint Citation Patent Citation
(a) expressing a protein in a non-native limited solubility form in a non-mammalian cell; Adello's process expresses protein in a non-native limited solubility form in a non-mammalian expression system. ¶70 col. 17:7-10
(b) lysing a non-mammalian cell; In Adello's process, a non-mammalian cell is lysed. ¶70 col. 17:11-12
(c) solubilizing the expressed protein in a solubilization solution comprising one or more of the following: (i) a denaturant; (ii) a reductant; and (iii) a surfactant; In Adello's process, protein is solubilized in a solution comprising one or more of a denaturant, reductant, and surfactant. ¶70 col. 17:13-18
(d) forming a refold solution comprising the solubilization solution and a refold buffer... In Adello's process, a refold solution is formed comprising the solubilization solution and a refold buffer with specified components. ¶70 col. 17:19-27
(e) directly applying the refold solution to a separation matrix... Adello's refold solution is applied to a separation matrix. ¶70 col. 17:28-31
(f) washing the separation matrix; and Adello's separation matrix is washed. ¶70 col. 17:32-33
(g) eluting the protein from the separation matrix... In Adello's process, protein is eluted from the separation matrix. ¶70 col. 17:34-39

U.S. Patent No. 8,952,138 Infringement Allegations

Claim Element (from Independent Claim 1 & Dependent Claim 18) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of refolding a protein expressed in a non-mammalian expression system... Adello practices a method of refolding a protein expressed in a bacterial expression system. ¶95 col. 23:1-2
...and present in a volume at a concentration of 2.0 g/L or greater... In Adello's process, protein is present in a volume at a concentration of 2.0 g/L or greater. ¶95 col. 23:3-4
(a) contacting the protein with a refold buffer comprising a redox component comprising a final thiol-pair ratio having a range of 0.001 to 100 and a redox buffer strength of 2 mM or greater... In Adello's process, the protein is contacted with a refold buffer comprising a redox component with the claimed properties. ¶95 col. 23:5-15
(b) incubating the refold mixture; and In Adello's process, the refold mixture is incubated. ¶95 col. 23:16-17
...wherein the incubation is performed under non-aerobic conditions. (from Claim 18) The incubation of the refold mixture is performed under non-aerobic conditions. ¶95 col. 23:16-19
(c) isolating the protein from the refold mixture. In Adello's process, the protein is isolated from the refold mixture. ¶95 col. 23:18-19

Identified Points of Contention

  • Evidentiary Questions: The complaint's infringement allegations for all asserted patents are made "upon information and belief" and track the claim language closely without providing specific, publicly available details of Defendants' accused manufacturing process. A central point of contention will be factual: does discovery confirm that Defendants' process uses the specific concentrations, chemical components, ratios, and environmental conditions (e.g., "non-aerobic") required by the asserted claims?
  • Scope Questions: For the ’878 and '997' Patents, the scope of "directly applying" the refold solution to the separation matrix may be a key dispute. This raises the question of whether this term permits any intermediate steps, such as dilution or filtration, between the formation of the refold solution and its application to the purification column.

V. Key Claim Terms for Construction

  • Term: "directly applying" (from Claim 7 of the '878 Patent)

    • Context and Importance: This term's construction is critical because it defines the required relationship between the refolding and purification steps. If Adello's process includes an intermediate step between forming its refold solution and applying it to a chromatography column, a narrow construction of "directly" could support a non-infringement argument.
    • Intrinsic Evidence for Interpretation: The complaint does not provide intrinsic evidence from the patent. Practitioners may focus on this term because the patent specification's description of the process flow and specific embodiments could inform whether "directly" implies immediate temporal succession or simply the absence of intervening substantive purification or chemical modification steps.

  • Term: "non-aerobic conditions" (from Claim 18 of the '138 Patent)

    • Context and Importance: The definition of "non-aerobic" is central to infringement of this claim. The dispute will likely focus on whether this term requires active deoxygenation (e.g., sparging with inert gas) or merely the absence of active aeration, and what level of dissolved oxygen, if any, is permissible.
    • Intrinsic Evidence for Interpretation: The complaint does not provide intrinsic evidence from the patent. Practitioners may focus on this term because the patent specification's examples and definitions will likely be crucial. Evidence for a broader interpretation might include general descriptions of avoiding intentional aeration, while evidence for a narrower interpretation could be found in specific examples that detail steps like purging with nitrogen to achieve a specific, low-oxygen environment.

VI. Other Allegations

Indirect Infringement

  • The complaint alleges that Defendant Adello has induced or will induce Defendants Amneal and New Amneal to offer for sale or sell the Adello Filgrastim Product (Compl. ¶¶ 75, 100, 125, 150). The factual basis for this allegation appears to be the license and commercialization agreement between Adello and Amneal, under which Amneal is responsible for marketing and selling the product that Adello manufactures (Compl. ¶¶ 72, 97, 122, 147).

Willful Infringement

  • The complaint does not contain an explicit count for willful infringement. However, it alleges facts that could support such a claim by asserting Defendants had knowledge of the patents-in-suit. For each asserted patent, knowledge is alleged at least as of the filing of the original complaint (March 8, 2018) (Compl. ¶¶ 73, 98, 123, 148). For the '878 and '138 Patents, the complaint alleges pre-suit knowledge based on prior lawsuits involving those patents against other biosimilar manufacturers (Compl. ¶¶ 73, 98).

VII. Analyst’s Conclusion: Key Questions for the Case

  • A core issue will be one of evidentiary proof: the infringement allegations depend on detailed, quantitative aspects of a confidential manufacturing process. The case will likely turn on whether the specific chemical compositions, concentrations, and process conditions used by Defendants, as revealed in discovery, fall within the numerical ranges and qualitative descriptions required by the asserted claims.
  • A key legal question will be one of claim construction: the dispute may hinge on the scope of procedural terms such as "directly applying" ('878 Patent) and "non-aerobic conditions" ('138 Patent). The court's interpretation of these terms will define the boundaries of the patented methods and could be dispositive of infringement.