DCT

0:15-cv-61631

Amgen Inc v. Apotex Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 0:15-cv-61631, S.D. Fla., 08/06/2015
  • Venue Allegations: Venue is alleged to be proper based on Defendant Apotex Corp.’s principal place of business being located in the district, and Defendant Apotex Inc.’s alleged substantial and continuous business contacts within Florida. The complaint also notes that Apotex has previously submitted to the court's jurisdiction in other matters.
  • Core Dispute: Plaintiff alleges that Defendant’s submission of a Biologic License Application (BLA) to the FDA for a proposed biosimilar version of pegfilgrastim constitutes an act of infringement of two patents related to methods of refolding proteins and compositions of N-terminally modified proteins.
  • Technical Context: The technology concerns the complex manufacturing processes for biologic drugs, specifically methods for correctly folding proteins produced via recombinant DNA technology and chemically modifying them to enhance their therapeutic properties, such as stability and circulation time in the body.
  • Key Procedural History: The litigation arises from the patent dispute resolution procedures of the Biologics Price Competition and Innovation Act (BPCIA). The complaint states the parties engaged in the statutory information exchange, or "patent dance," which resulted in an agreement to litigate the two patents-in-suit. A significant portion of the complaint is also dedicated to a dispute over the legal effectiveness of Apotex’s pre-FDA-approval Notice of Commercial Marketing. Subsequent to the filing of this complaint, U.S. Patent No. 8,952,138 was subject to an Inter Partes Review (IPR2016-01542), which concluded with a certificate issued on November 7, 2022, confirming all challenged claims (1-24) as patentable.

Case Timeline

Date Event
1994-10-12 ’784 Patent Priority Date
1998-10-20 ’784 Patent Issue Date
2009-06-22 ’138 Patent Priority Date
2014-12-16 Amgen notified that Apotex BLA accepted for FDA review
2015-02-10 ’138 Patent Issue Date
2015-04-17 Apotex sends purported Notice of Commercial Marketing
2015-08-06 Complaint Filing Date
2016-08-05 Inter Partes Review filed against the ’138 Patent
2022-11-07 IPR Certificate issued confirming patentability of ’138 Patent claims

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

U.S. Patent No. 8,952,138 - "Refolding Proteins Using a Chemically Controlled Redox State," issued February 10, 2015

The Invention Explained

  • Problem Addressed: The patent addresses the difficulty of efficiently refolding complex recombinant proteins that are expressed in non-mammalian systems (like bacteria) at high concentrations. At concentrations suitable for industrial-scale manufacturing (e.g., above 2.0 g/L), proteins tend to misfold and aggregate, which significantly limits production efficiency. (’138 Patent, col. 1:12-2:32).
  • The Patented Solution: The invention provides a method to refold proteins at high concentrations by precisely controlling the chemical redox environment of the refolding buffer. This involves identifying and applying an optimal "thiol-pair ratio" and "redox buffer strength" to maximize the rate of correct disulfide bond formation while minimizing aggregation and misfolding, thereby enabling efficient, large-scale production. (’138 Patent, Abstract; col. 4:20-56).
  • Technical Importance: This method provides a scalable and predictable process for manufacturing complex biologics, overcoming a significant bottleneck in the industry and potentially reducing the cost and complexity of producing these therapeutic proteins. (’138 Patent, col. 2:25-32).

Key Claims at a Glance

  • The complaint alleges infringement of one or more unspecified claims. Independent claim 1 is representative:
  • A method of refolding a protein expressed in a non-mammalian expression system and present in a volume at a concentration of 2.0 g/L or greater comprising:
    • (a) contacting the protein with a refold buffer comprising a redox component with a specific final thiol-pair ratio (0.001 to 100) and redox buffer strength (≥2 mM), plus a denaturant, aggregation suppressor, and protein stabilizer;
    • (b) incubating the mixture; and
    • (c) isolating the refolded protein.

U.S. Patent No. 5,824,784 - "N-Terminally Chemically Modified Protein Compositions and Methods," issued October 20, 1998

The Invention Explained

  • Problem Addressed: The patent identifies a problem with then-existing methods of attaching water-soluble polymers like polyethylene glycol (PEG) to proteins. These methods were non-selective, attaching polymers to various reactive sites on the protein, which created a heterogeneous mixture of molecules with inconsistent structures, unpredictable biological activity, and reduced stability. (’784 Patent, col. 3:1-24).
  • The Patented Solution: The invention describes a method using reductive alkylation at a specific pH to selectively attach a polymer to the protein's N-terminus. This exploits the different chemical reactivity (pK) of the N-terminal α-amino group compared to other amino groups (e.g., on lysine residues). The result is a "substantially homogenous" preparation of protein conjugates where the polymer is attached at a single, defined location, leading to a more uniform and stable product. (’784 Patent, Abstract; col. 7:8-28).
  • Technical Importance: By enabling the creation of a uniform drug substance with predictable properties, this invention was a key step in developing more effective and reliable long-acting protein therapeutics like pegfilgrastim. The patent itself demonstrates that the N-terminally modified G-CSF is more stable than other forms. (’784 Patent, col. 4:5-7; col. 18:1-4).

Key Claims at a Glance

  • The complaint alleges infringement of one or more unspecified claims. Independent claim 1 is a representative composition claim:
  • A substantially homogenous preparation of N-terminally PEGylated G-CSF or analog thereof,
  • optionally in a pharmaceutically acceptable diluent, carrier or adjuvant,
  • said preparation being essentially free of G-CSF or analog thereof PEGylated at sites other than the N-terminus.

III. The Accused Instrumentality

Product Identification

The "Apotex Pegfilgrastim Product," a proposed biosimilar to Amgen’s Neulasta® product, for which Apotex submitted Biologic License Application (BLA) No. 761026 to the FDA (Compl. ¶11).

Functionality and Market Context

The accused product is a pegylated form of granulocyte-colony stimulating factor (G-CSF) (Compl. ¶41). Its active ingredient, pegfilgrastim, is a protein that stimulates the production of neutrophils to reduce the risk of infection in patients undergoing myelosuppressive anti-cancer therapy (Compl. ¶38-39). The complaint alleges that Apotex has represented to the FDA that its product is biosimilar to Neulasta®, with the same mechanism of action, dosage form, and strength (Compl. ¶43). The act of infringement alleged is the submission of the BLA for FDA approval, a statutory act of infringement under 35 U.S.C. § 271(e)(2)(C) (Compl. ¶13-14).

IV. Analysis of Infringement Allegations

The complaint does not provide detailed infringement contentions or claim charts, as the specific details of Apotex’s manufacturing process and product composition are contained within its confidential BLA filing. The infringement allegations are therefore made on "information and belief" based on Amgen's review of that confidential information.

No probative visual evidence provided in complaint.

’138 Patent Infringement Allegations (Summary)

Amgen alleges that the manufacturing process Apotex intends to use for its Pegfilgrastim Product, as described in its BLA, will infringe one or more claims of the ’138 Patent (Compl. ¶64). The core of this allegation is that Apotex’s process involves refolding its recombinant G-CSF protein under conditions that meet the limitations of the asserted claims. A central point of contention will be whether Apotex’s process refolds the protein at a concentration of 2.0 g/L or greater while using a refold buffer with a "thiol-pair ratio" and "redox buffer strength" that fall within the ranges claimed by the patent.

’784 Patent Infringement Allegations (Summary)

Amgen alleges that the Apotex Pegfilgrastim Product itself, as a composition of matter, will infringe one or more claims of the ’784 Patent (Compl. ¶71). The core of this allegation is that Apotex's final product is a "substantially homogenous preparation of N-terminally PEGylated G-CSF" that is "essentially free" of other pegylated forms, as claimed in the patent. A key dispute will likely focus on analytical data from the BLA demonstrating the purity of the Apotex product and the precise location of the PEG moiety, and whether this data satisfies the patent's definition of "substantially homogenous."

V. Key Claim Terms for Construction

Term from ’138 Patent: "a concentration of 2.0 g/L or greater"

  • Context and Importance: This limitation in independent claim 1 defines the threshold for "high concentration" refolding that is the central purpose of the invention. Whether Apotex's process meets this numerical threshold is a potentially dispositive fact in the infringement analysis.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim provides a clear numerical floor. The specification consistently frames the invention in the context of improving upon prior art methods that were limited to concentrations below 2.0 g/L (’138 Patent, col. 2:1-12).
    • Evidence for a Narrower Interpretation: A party might argue that the term must be read in the context of the specific types of complex proteins and buffer chemistries disclosed in the patent's examples, potentially limiting its application to processes that are highly similar to those explicitly described. (’138 Patent, col. 16:40-45; col. 17:30-40).

Term from ’784 Patent: "substantially homogenous preparation"

  • Context and Importance: This is the critical purity limitation in independent claim 1. Infringement depends on whether the accused product meets this standard of uniformity. Practitioners may focus on this term because its definition will determine the scope of the patent's coverage over biosimilar products.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term "substantially" itself implies a degree of tolerance and does not require absolute 100% purity, allowing for minor amounts of other species.
    • Evidence for a Narrower Interpretation: The specification provides an explicit definition: a preparation that is "at least 90% monopolymer/protein conjugate, and at most 10% unreacted protein," with preferred embodiments being at least 95% or 99% pure (’784 Patent, col. 5:24-30). This specific quantitative language may be used to argue for a strict, narrow construction of the term.

VI. Other Allegations

Indirect Infringement

The complaint alleges that Apotex Corp. participated in, contributed to, induced, or aided and abetted the submission of the Apotex BLA, thereby constituting contributory or induced infringement under 35 U.S.C. § 271(e)(2)(C)(i) (Compl. ¶63, 70).

Willful Infringement

The complaint does not use the word "willful." However, it alleges that Amgen provided Apotex with a list of patents, including the patents-in-suit, that it believed would be infringed by the Apotex product, establishing pre-suit knowledge (Compl. ¶48). The prayer for relief requests a declaration that the case is "exceptional" and seeks attorneys' fees under 35 U.S.C. § 285, which is typically predicated on findings of willful infringement or other litigation misconduct (Compl., Prayer for Relief ¶K).

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

The resolution of this dispute will likely depend on the answers to three central questions, which are heavily reliant on confidential information contained within Apotex's BLA.

  • A key question of process equivalence: Does the confidential data describing Apotex’s manufacturing process show that it refolds its G-CSF protein at a concentration of 2.0 g/L or higher and under the specific redox buffer conditions claimed in the ’138 patent, or does it employ a distinct, non-infringing methodology?
  • A key question of compositional identity: Does analytical evidence of the Apotex Pegfilgrastim Product demonstrate that it meets the ’784 patent’s definition of a "substantially homogenous preparation"—specifically, being at least 90-95% N-terminally pegylated—or does its composition fall outside the scope of the claims?
  • A key procedural question under the BPCIA: Did Apotex's notice of commercial marketing, sent prior to receiving FDA licensure for its product, constitute an effective notice under 42 U.S.C. § 262(l)(8)(A), or was it legally premature, thus potentially delaying its market entry?