DCT
0:18-cv-61828
Amgen Inc v. Accord Biopharma
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Amgen Inc. (Delaware) and Amgen Manufacturing Limited (Bermuda)
- Defendant: Apotex Inc. (Canada) and Apotex Corp. (Delaware)
- Plaintiff’s Counsel: Hogan Lovells
- Case Identification: 0:18-cv-61828, S.D. Fla., 08/07/2018
- Venue Allegations: Venue is alleged based on Defendant Apotex Corp. having its principal place of business in Weston, Florida, within the district, as well as both defendants' alleged business activities in Florida and prior submission to the court's jurisdiction in related litigation.
- Core Dispute: Plaintiff alleges that Defendant’s manufacturing processes for its filgrastim and pegfilgrastim biosimilar drug products infringe a patent related to methods for refolding complex proteins.
- Technical Context: The technology concerns the industrial-scale manufacturing of biologic drugs, specifically addressing the challenge of correctly folding complex proteins produced in non-mammalian expression systems to ensure therapeutic activity.
- Key Procedural History: The complaint notes prior litigation between the parties in the same court (No. 0:15-cv-61631-JIC), which concluded with a finding of non-infringement for a different patent. The patent-in-suit in the current action was issued after the Federal Circuit mandate in the prior case, forming the basis for this new infringement action under the Biologics Price Competition and Innovation Act (BPCIA).
Case Timeline
| Date | Event |
|---|---|
| 2009-06-22 | ’287 Patent Priority Date |
| 2014-12-16 | FDA accepted Apotex Pegfilgrastim aBLA |
| 2015-02-13 | FDA accepted Apotex Filgrastim aBLA |
| 2016-07-01 | Bench trial held in prior litigation |
| 2016-09-06 | Final judgment issued in prior litigation |
| 2017-12-12 | Federal Circuit mandate issued in prior litigation |
| 2018-01-02 | ’287 Patent Issued |
| 2018-01-31 | Amgen supplemented its patent list to Apotex to include the ’287 Patent |
| 2018-03-02 | Apotex provided Amgen with its non-infringement statement for the ’287 Patent |
| 2018-08-07 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,856,287 - "Refolding Proteins Using a Chemically Controlled Redox State"
- Patent Identification: U.S. Patent No. 9,856,287, "Refolding Proteins Using a Chemically Controlled Redox State", issued January 2, 2018.
The Invention Explained
- Problem Addressed: When complex recombinant proteins are produced in non-mammalian systems like bacteria, they frequently misfold and aggregate into insoluble, non-functional "inclusion bodies" (’287 Patent, col. 1:24-34). Existing methods to renature these proteins were inefficient, particularly at the high concentrations required for commercially viable, industrial-scale production (’287 Patent, col. 2:8-24).
- The Patented Solution: The invention claims to solve this problem with a method that enables efficient protein refolding at high concentrations (≥ 2.0 g/L) by precisely managing a "chemically controlled redox state" (’287 Patent, Abstract). This is achieved by systematically controlling and optimizing two key parameters: 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), which together create an environment that facilitates correct disulfide bond formation (’287 Patent, col. 4:51-67).
- Technical Importance: The described method addresses a significant bottleneck in biopharmaceutical manufacturing by providing a predictable and scalable process for producing active, complex biologic drugs from more efficient bacterial expression systems (’287 Patent, col. 2:35-41).
Key Claims at a Glance
- The complaint asserts infringement of the ’287 Patent, citing independent claim 16 as an example (Compl. ¶33).
- The essential elements of independent claim 16 are:
- A method of refolding proteins expressed in a nonmammalian expression system.
- 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.
- 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.
- The complaint reserves the right to assert additional claims (Compl. ¶46).
III. The Accused Instrumentality
Product Identification
The accused instrumentalities are Apotex's manufacturing processes used to produce its "Apotex Pegfilgrastim Product" and "Apotex Filgrastim Product" (Compl. ¶¶ 35-37).
Functionality and Market Context
- The complaint alleges that Apotex uses the same underlying process to produce the filgrastim that serves as the active drug substance for both of its biosimilar products (Compl. ¶35). This process allegedly involves expressing the protein in E. coli bacteria and then using a specific refolding solution to achieve the correct protein structure (Compl. ¶¶ 36-37).
- The complaint provides "Table S.2.2-33: Refolding – Solution Composition," which lists the specific components Apotex allegedly uses in its refolding buffer, including arginine, sorbitol, cystine, and cysteine (Compl. ¶37). This table, sourced from prior litigation documents, outlines the chemical composition of the accused process.
- The accused products are biosimilars intended to compete with Amgen’s Neulasta® and Neupogen® products, which are commercially significant therapies for neutropenia, a common side effect of chemotherapy (Compl. ¶¶ 9, 13, 19-20).
IV. Analysis of Infringement Allegations
Claim Chart Summary
| Claim Element (from Independent Claim 16) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of refolding proteins expressed in a nonmammalian expression system, | Apotex expresses its filgrastim protein, a recombinant protein, in Escherichia coli (E. coli) bacterial cells. | ¶36 | col. 1:21-28 |
| 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; | Apotex prepares a refolding solution containing the filgrastim protein, as well as arginine and sorbitol, which are alleged to function as aggregation suppressors or protein stabilizers. | ¶¶ 37-38 | col. 3:41-50 |
| an amount of oxidant; and an amount of reductant, | Apotex's refolding solution allegedly contains cysteine (reductant) and cystine (oxidant). | ¶¶ 37-38 | col. 3:51-54 |
| wherein the amounts of the oxidant and the reductant are related through a thiol-pair ratio and a thiol-pair buffer strength, | The complaint alleges that in Apotex's process, the amounts of cysteine and cystine are related through a thiol-pair ratio and buffer strength. | ¶39 | col. 6:50-64 |
| wherein the thiol-pair ratio is in the range of 0.001-100, and | The complaint alleges that the thiol-pair ratio of Apotex's process falls within the claimed range. | ¶39 | col. 6:50-54 |
| wherein the thiol-pair buffer strength maintains the solubility of the solution; and | The complaint alleges that the thiol-pair buffer strength used by Apotex maintains the solution's solubility. | ¶39 | col. 6:58-64 |
| incubating the solution so that at least about 25% of the proteins are properly refolded. | Apotex's process allegedly achieves a refolding step yield with an expected range of "≥ 60%," which exceeds the claimed 25% threshold. | ¶40 | col. 7:45-49 |
Identified Points of Contention
- Scope Questions: A potential dispute may arise over whether Apotex's specific formulation, including arginine and sorbitol, meets the claim limitation of "at least one ingredient selected from the group consisting of a denaturant, an aggregation suppressor and a protein stabilizer." The interpretation of these functional categories will be relevant.
- Technical Questions: A central technical question will be whether the specific concentrations of cysteine and cystine in Apotex's process actually result in a "thiol-pair ratio" and "thiol-pair buffer strength" that fall within the claimed numerical ranges. The complaint's allegations for these elements rely on a non-public appendix from prior litigation, suggesting the factual basis for these calculations will be a primary focus of discovery and expert analysis. Further, the functional limitation that the buffer strength "maintains the solubility of the solution" raises an evidentiary question of how this function is demonstrated or disproven for the accused process.
V. Key Claim Terms for Construction
"thiol-pair buffer strength"
- Context and Importance: This term appears to be defined by the patentee and is central to the invention's purported novelty. Its precise construction, including both its mathematical calculation (provided in Equation 2 of the patent) and its functional requirement, will be critical for determining infringement of the numerical limitations. Practitioners may focus on this term because it is a primary technical point of differentiation claimed by the patent.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification provides a direct mathematical formula: "Thiol-Pair Buffer Strength=2[oxidant]+[reductant]" (’287 Patent, col. 6:58-64). A party could argue the term should be construed simply as this objective calculation based on the molar concentrations of the redox couple.
- Evidence for a Narrower Interpretation: The claim itself links the term to a functional outcome: "wherein the thiol-pair buffer strength maintains the solubility of the solution" (’287 Patent, Claim 16). A party could argue that a calculated value is insufficient to meet the limitation unless that functional result is also achieved in the accused process.
"properly refolded"
- Context and Importance: The claim requires that "at least about 25% of the proteins are properly refolded." The definition of this term is critical for assessing whether Apotex's alleged "≥ 60%" yield meets this limitation. The dispute may center on whether achieving a certain analytical result (e.g., a peak on an HPLC chart) is sufficient, or if proof of biological activity is required.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent's examples measure refolding success and product quality using analytical chemistry techniques like RP-HPLC and SE-HPLC (’287 Patent, col. 13:51-55). A party might argue that "properly refolded" should be construed in line with these analytical measurements, which aligns with the complaint's allegation regarding "Refolding Step Yield" (Compl. ¶40).
- Evidence for a Narrower Interpretation: The ultimate goal of refolding is to restore function. The patent specification discusses renaturation to a "biologically active form" (’287 Patent, col. 7:45-49). A party could argue that "properly refolded" requires not just a correct analytical signature but also a demonstration of the protein's intended biological activity.
VI. Other Allegations
Indirect Infringement
The complaint alleges that Apotex Corp.'s role in the aBLA submissions constitutes contributory and induced infringement under 35 U.S.C. § 271(e)(2)(C)(i), which defines the submission of a biosimilar application as an artificial act of infringement (Compl. ¶¶ 72, 87). The primary allegation is for direct infringement of the process claims by the entity performing the manufacturing.
Willful Infringement
The complaint does not use the word "willful." However, it alleges that Amgen provided Apotex with notice of the ’287 Patent on January 31, 2018 (Compl. ¶43). This allegation may form the basis for a claim of willful infringement for any infringing acts (e.g., commercial manufacture and sale) that occur after Apotex became aware of the patent.
VII. Analyst’s Conclusion: Key Questions for the Case
- A key evidentiary question will be one of numerical compliance: does the precise chemical composition of Apotex's refolding process result in a "thiol-pair ratio" and "thiol-pair buffer strength" that fall within the ranges mandated by Claim 16? The resolution will depend on confidential manufacturing and regulatory data.
- A central legal issue will be one of claim scope: can the term "thiol-pair buffer strength," which is defined by both a mathematical formula and a functional outcome ("maintains the solubility"), be met by Apotex's process? The court's construction of this and other terms will likely dictate the infringement outcome.
- The case exists in the shadow of prior litigation where Amgen failed to prove infringement of a related process patent. A determinative question will be whether Amgen can now demonstrate that the novel limitations of the ’287 Patent, particularly the "thiol-pair buffer strength" concept, are different enough to capture Apotex's process where the earlier asserted patent did not.