DCT

3:19-cv-01374

Amgen Inc v. Tanvex Biopharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:19-cv-01374, S.D. Cal., 07/23/2019
  • Venue Allegations: Plaintiff alleges venue is proper because Defendants are subject to personal jurisdiction in the district, have operations and facilities in the district, and following FDA approval, will sell the accused product in the district.
  • Core Dispute: Plaintiff alleges that the manufacturing process for Defendants' proposed biosimilar drug (Tanvex Filgrastim) infringes a patent covering methods for efficiently refolding recombinant proteins at high concentrations.
  • Technical Context: The lawsuit concerns the complex and costly process of manufacturing biologic drugs, where proteins produced in non-mammalian cells must be correctly folded to become biologically active.
  • Key Procedural History: The complaint details the pre-suit information exchange between the parties as mandated by the Biologics Price Competition and Innovation Act (BPCIA). This exchange included Defendants providing their abbreviated Biologics License Application (aBLA) and Plaintiffs identifying the patent-in-suit. The parties subsequently agreed that the '287 Patent would be the subject of this infringement action.

Case Timeline

Date Event
2009-06-22 '287 Patent Priority Date
1991-01-01 Amgen receives FDA approval for reference product NEUPOGEN® (approximate)
2018-01-02 U.S. Patent No. 9,856,287 issues
2018-06-24 Amgen and Tanvex engage in negotiation (as stated in complaint)
2018-09-30 Tanvex submits its aBLA to the FDA (approximate)
2018-11-27 FDA accepts Tanvex aBLA for review (approximate)
2018-12-10 Tanvex notifies Amgen of aBLA acceptance
2018-12-17 Tanvex provides Amgen with a copy of its aBLA
2019-02-01 Tanvex produces additional batch records to Amgen
2019-02-15 Amgen provides Tanvex its list of patents, including the '287 Patent
2019-04-01 Tanvex provides Amgen with notice of intent for commercial marketing
2019-04-12 Tanvex provides Amgen with its detailed non-infringement/invalidity statement
2019-06-11 Amgen provides Tanvex with its detailed infringement statement
2019-07-23 Complaint filed

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

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

The Invention Explained

  • Problem Addressed: The patent describes the difficulty of manufacturing complex recombinant proteins in non-mammalian systems like bacteria. At high expression levels, these proteins often misfold and precipitate into insoluble "inclusion bodies." Prior methods for refolding these proteins into their active forms were inefficient, particularly at the high concentrations and large volumes required for industrial-scale production ('287 Patent, col. 1:25-40, 1:57-65).
  • The Patented Solution: The invention provides a method to refold proteins at high concentrations (2.0 g/L or greater) by creating a "chemically controlled redox state." This is achieved by precisely defining and controlling two key parameters of the refolding buffer: the "thiol-pair ratio" (the ratio of a reducing agent to an oxidizing agent) and the "thiol-pair buffer strength" (the total concentration of these redox agents). This control allows for efficient, reproducible, and scalable refolding of complex proteins that was not previously achievable at an industrial scale ('287 Patent, Abstract; col. 3:37-54).
  • Technical Importance: This method allows for a significant increase in protein concentration during the refolding step, which can translate into "higher efficiencies and cost savings to a protein production process" by reducing volumes and the need for additional equipment ('287 Patent, col. 2:32-40).

Key Claims at a Glance

  • The complaint asserts claims 16-18 and 26-28, noting it may assert others later (Compl. ¶86).
  • Independent Claim 16, quoted as representative, includes the following essential elements:
    • A method of refolding proteins expressed in a nonmammalian system.
    • Preparing a solution comprising the proteins, a denaturant/suppressor/stabilizer, an oxidant, and a reductant.
    • The amounts of oxidant and reductant are related through a "thiol-pair ratio" and a "thiol-pair buffer strength."
    • The thiol-pair ratio is in the range of 0.001-100.
    • The thiol-pair buffer strength maintains the solubility of the solution.
    • Incubating the solution so that at least about 25% of the proteins are properly refolded.

III. The Accused Instrumentality

Product Identification

The "Tanvex Filgrastim Product" (also known as TX01), a proposed biosimilar to Amgen's NEUPOGEN® (filgrastim) (Compl. ¶¶9, 56). The accused instrumentality is the process by which this product is manufactured.

Functionality and Market Context

  • The infringement allegations focus on the Defendants' manufacturing process, specifically the method used to refold the filgrastim protein after it is expressed in a nonmammalian system (Compl. ¶¶85-86). The complaint alleges, based on confidential information exchanged under the BPCIA, that this process uses specific chemical conditions that fall within the scope of the asserted patent claims (Compl. ¶86).
  • The Tanvex Filgrastim Product is designed to be a biosimilar version of, and to compete directly with, Amgen's NEUPOGEN®, a biologic drug used to decrease the incidence of infection in patients receiving certain anti-cancer drugs (Compl. ¶¶48, 58).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 9,856,287 Infringement Allegations

Claim Element (from Independent Claim 16) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of refolding proteins expressed in a nonmammalian expression system, the method comprising: Defendants practice a method of refolding proteins expressed in a nonmammalian expression system. ¶86 col. 1:25-35
preparing a solution comprising: the proteins; at least one ingredient selected from the group consisting of a denaturant, an aggregation suppressor and a protein stabilizer; an amount of oxidant; and an amount of reductant, Defendants prepare a solution comprising the proteins; at least one ingredient selected from a denaturant, an aggregation suppressor and a protein stabilizer; an amount of oxidant; and an amount of reductant. ¶86 col. 3:1-4
wherein the amounts of the oxidant and the reductant are related through a thiol-pair ratio and a thiol-pair buffer strength, The amounts of the oxidant and the reductant in Defendants’ solution are related through a thiol-pair ratio and a thiol-pair buffer strength. ¶86 col. 3:37-40
wherein the thiol-pair ratio is in the range of 0.001-100, In Defendants’ process, the thiol-pair ratio is in the range of 0.001-100. ¶86 col. 3:8-9
and wherein the thiol-pair buffer strength maintains the solubility of the solution; The thiol-pair buffer strength maintains the solubility of the solution. ¶86 col. 19:18-19
and incubating the solution so that at least about 25% of the proteins are properly refolded. Defendants incubate the solution so that at least about 25% of the proteins are properly refolded. ¶86 col. 16:41-42

Identified Points of Contention

  • Evidentiary Questions: The complaint's infringement allegations are conclusory and directly track the claim language, asserting that they are based on confidential information from the aBLA (Compl. ¶86). A central point of contention will be whether the underlying, confidential manufacturing data actually substantiates these claims. The dispute over Defendants' alleged failure to provide "all data on protein concentration measurements" suggests that the sufficiency of the evidence for infringement may be a key issue (Compl. ¶¶67-70).
  • Functional Limitation Questions: The infringement analysis may focus on functional limitations, such as whether the accused process achieves an outcome where "at least about 25% of the proteins are properly refolded" and whether its "thiol-pair buffer strength maintains the solubility of the solution." The parties may dispute the factual evidence and the technical standard required to meet these claimed functions.

V. Key Claim Terms for Construction

"thiol-pair buffer strength"

  • Context and Importance: This is a central, inventor-defined term that, along with "thiol-pair ratio," defines the core of the patented method. Infringement hinges on whether Defendants’ process uses a "strength" that falls within the scope of this term. Practitioners may focus on this term because its definition is tied to both a specific formula in the patent and a functional outcome.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent provides an explicit formula: "Thiol-Pair Buffer Strength=2[oxidant]+[reductant]" ('287 Patent, col. 6:56-65, Equation 2). A party may argue that any process meeting this mathematical definition satisfies the limitation, regardless of other process conditions or efficiencies.
    • Evidence for a Narrower Interpretation: The patent repeatedly frames the invention as a solution for refolding complex proteins at high concentrations (≥ 2.0 g/L) ('287 Patent, col. 2:25-31). A party could argue that the term should be construed in light of this stated purpose, and is therefore limited to conditions that are effective for such applications, not just any condition that meets the bare formula.

"maintains the solubility of the solution"

  • Context and Importance: This functional language qualifies the "thiol-pair buffer strength" and is critical for distinguishing the claimed invention from prior art processes that may have failed. The parties will likely dispute what technical standard is required to satisfy "maintains."
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: A party may argue this simply means the process avoids large-scale precipitation of the protein, a necessary condition for any successful refolding that would be inherent if the other claim limitations are met. The complaint itself glosses the term as the concentrations being "at which the solubility of solutes...is maintained," suggesting it is an inherent property of the buffer (Compl. ¶86).
    • Evidence for a Narrower Interpretation: A party could argue that "maintains the solubility" must be interpreted in the context of the problem the patent solves: the tendency of proteins to become insoluble and form aggregates at high concentrations ('287 Patent, col. 1:28-35). This could support a construction requiring a specific, measurable degree of solubility preservation, particularly at the high protein concentrations that are a focus of the patent.

VI. Other Allegations

Indirect Infringement

The complaint alleges that the foreign parent entities, Tanvex BioPharma, Inc. (Cayman Islands) and Tanvex Biologics Corp. (Taiwan), induced infringement by directing and controlling their U.S. subsidiary, Tanvex BioPharma USA, Inc., to prepare and file the aBLA, which is the statutory act of infringement (Compl. ¶¶34, 43, 82). The allegations detail a unitary corporate structure where the parent entities control development, manufacturing, and regulatory strategy (Compl. ¶¶18, 30-33, 40-42).

Willful Infringement

The complaint does not contain a formal count for willful infringement, but it lays the factual groundwork for such a claim. It alleges that Defendants had pre-suit knowledge of the '287 Patent, at the latest by February 15, 2019, when Amgen formally identified it in the BPCIA patent exchange (Compl. ¶64). It further alleges that Amgen provided a detailed basis for its infringement allegations on June 11, 2019, well before the suit was filed (Compl. ¶71). The prayer for relief requests a finding that the case is "exceptional" and an award of attorneys' fees (Compl. p. 22, ¶E).

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

  • A central issue will be one of evidentiary proof: As the infringement allegations are based on confidential manufacturing information, the case will depend on whether the evidence contained within Defendants' aBLA and related process documentation factually demonstrates that their method meets the specific quantitative limitations of the asserted claims, particularly the "thiol-pair ratio" and "thiol-pair buffer strength".
  • A key legal question will be one of claim scope: The dispute will likely focus on the proper construction of the term "thiol-pair buffer strength". The court will need to decide if this term is defined purely by the mathematical formula in the patent's specification, or if its scope is implicitly narrowed by the patent's stated purpose of enabling the efficient, high-concentration refolding of complex proteins.
  • A final question will be one of functional performance: The court will likely have to determine the meaning of the functional requirement that the buffer strength "maintains the solubility of the solution." The issue is whether this is an inherent result of meeting the other chemical parameters or if it imposes a separate, heightened standard of performance that Defendants' process must be proven to meet.