DCT

2:19-cv-11755

Immunex Corp v. Samsung Bioepis Co Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:19-cv-11755, D.N.J., 12/23/2019
  • Venue Allegations: Venue is asserted based on the defendant being a foreign corporation, which subjects it to suit in any U.S. judicial district.
  • Core Dispute: Plaintiffs allege that Defendant’s submission of a Biologics License Application to the FDA for its biosimilar drug Eticovo, and its intended commercialization, infringes five patents covering the biologic drug Enbrel® (etanercept), its methods of manufacture, and materials used in its production.
  • Technical Context: The technology involves biologic fusion proteins designed to treat autoimmune diseases by inhibiting Tumor Necrosis Factor (TNF), a key signaling protein in inflammatory responses.
  • Key Procedural History: The action arises under the Biologics Price Competition and Innovation Act (BPCIA). The complaint alleges that the Defendant, a biosimilar applicant, failed to engage in the information exchange procedures mandated by the BPCIA, thereby triggering an act of infringement upon submission of its application to the FDA.

Case Timeline

Date Event
1990-08-31 Priority Date for U.S. Patent Nos. 8,063,182 and 8,163,522
2001-02-27 Priority Date for U.S. Patent No. 7,157,557
2001-08-23 Priority Date for U.S. Patent No. 6,924,124
2002-03-27 Priority Date for U.S. Patent No. 6,872,549
2005-03-29 U.S. Patent No. 6,872,549 Issued
2005-08-02 U.S. Patent No. 6,924,124 Issued
2007-01-02 U.S. Patent No. 7,157,557 Issued
2011-11-22 U.S. Patent No. 8,063,182 Issued
2012-04-24 U.S. Patent No. 8,163,522 Issued
2019-04-25 FDA Approves Defendant's Biologics License Application for Eticovo
2019-12-23 Complaint Filed

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

U.S. Patent No. 8,063,182 - "Human TNF Receptor Fusion Protein," Issued Nov. 22, 2011

The Invention Explained

  • Problem Addressed: The overproduction of Tumor Necrosis Factor (TNF), a cell-signaling protein, is implicated in various autoimmune and inflammatory disorders (Compl. ¶19). The biological effects of TNF are mediated through specific TNF receptors on cell membranes, which, upon binding, can trigger inflammatory responses (Compl. ¶20).
  • The Patented Solution: The invention is a fusion protein that acts as a decoy receptor for TNF. It combines a soluble, TNF-binding fragment of a human TNF receptor with a portion of a human immunoglobulin (IgG) heavy chain (’182 Patent, Abstract; Compl. ¶46). This construct is designed to bind to TNF in the body, preventing it from interacting with cell-surface TNF receptors and thereby inhibiting the inflammatory cascade (’182 Patent, col. 42:1-24; Compl. ¶24). The fusion with the IgG fragment is intended to improve the protein's stability and therapeutic properties.
  • Technical Importance: This fusion protein approach provided a therapeutic agent that could directly neutralize a key inflammatory cytokine, representing a significant advancement in the treatment of autoimmune diseases like rheumatoid arthritis (Compl. ¶25).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims of the patent (Compl. ¶61, 63). Independent claim 1 is representative.
  • Independent Claim 1 Elements:
    • A protein comprising (a) a human tumor necrosis factor (TNF)-binding soluble fragment of an insoluble human TNF receptor, wherein the insoluble human TNF receptor (i) specifically binds human TNF, (ii) has an apparent molecular weight of about 75 kilodaltons on a non-reducing SDS-polyacrylamide gel, and (iii) comprises a specific amino acid sequence; and
    • (b) all of the domains of the constant region of a human immunoglobulin IgG heavy chain other than the first domain of said constant region;
    • wherein said protein specifically binds human TNF.

U.S. Patent No. 8,163,522 - "Human TNF Receptor," Issued Apr. 24, 2012

The Invention Explained

  • Problem Addressed: To produce the therapeutic TNF receptor fusion protein at a commercially viable scale, one needs the underlying genetic material, host cells capable of expressing it, and methods for its production (’522 Patent, col. 42:5-24).
  • The Patented Solution: This patent claims the genetic blueprints for producing the fusion protein described in the ’182 Patent. It covers DNA sequences that encode the fusion protein, vectors containing these DNA sequences for delivery into host cells, and the transformed host cells themselves that are engineered to produce the protein (’522 Patent, Abstract). The invention provides the necessary tools for the recombinant DNA production of etanercept (Compl. ¶48, 73).
  • Technical Importance: This technology enabled the consistent, large-scale manufacturing of a complex biologic drug using recombinant DNA technology, a foundational requirement for its clinical development and commercialization (Compl. ¶23).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims of the patent (Compl. ¶74, 76). Independent claim 1 is representative.
  • Independent Claim 1 Elements:
    • An isolated DNA sequence comprising a DNA sequence that encodes a protein, wherein the protein comprises:
    • (a) a human tumor necrosis factor (TNF)-binding soluble fragment of an insoluble human TNF receptor, wherein the insoluble human TNF receptor has an apparent molecular weight of about 75 kilodaltons on a non-reducing SDS-polyacrylamide gel and comprises a specific amino acid sequence; and
    • (b) all of the domains of the constant region of a human immunoglobulin IgG heavy chain other than the first domain of said constant region.

U.S. Patent No. 6,872,549 - "Methods for Increasing Polypeptide Production," Issued Mar. 29, 2005

  • Technology Synopsis: The patent is directed to methods for improving the production yield of a polypeptide like etanercept from cultured mammalian cells (Compl. ¶50, 87). The method involves culturing the cells at a temperature below 37°C and adding a xanthine derivative or a hybrid polar compound to the culture medium during the production phase (Compl. ¶50, 87).
  • Asserted Claims: One or more claims (Compl. ¶88, 90).
  • Accused Features: Defendant’s process for manufacturing its biosimilar etanercept product is alleged to infringe these method claims (Compl. ¶88).

U.S. Patent No. 6,924,124 - "Feeding Strategies for Cell Culture," Issued Aug. 2, 2005

  • Technology Synopsis: The patent describes methods for increasing the production of a recombinant protein, such as etanercept, by culturing Chinese Hamster Ovary (CHO) cells (Compl. ¶51, 94). The method involves adding a specific feed solution containing a phosphate compound to the cell culture medium to achieve a certain phosphate concentration (Compl. ¶51, 94).
  • Asserted Claims: One or more claims (Compl. ¶95, 97).
  • Accused Features: Defendant’s process for manufacturing its biosimilar etanercept product is alleged to infringe these method claims (Compl. ¶95).

U.S. Patent No. 7,157,557 - "Increased Recovery of Active Proteins," Issued Jan. 2, 2007

  • Technology Synopsis: The patent is directed to methods for increasing the yield of a desired, active conformation of the p75 TNF-receptor (etanercept) (Compl. ¶52, 101). The method involves treating a preparation of the recombinant protein with a reduction/oxidation coupling reagent to convert undesired conformations into the desired conformation, which has a higher binding affinity for its target (Compl. ¶52, 101).
  • Asserted Claims: One or more claims (Compl. ¶102, 104).
  • Accused Features: Defendant’s process for manufacturing and purifying its biosimilar etanercept product is alleged to infringe these method claims (Compl. ¶102).

III. The Accused Instrumentality

  • Product Identification: The accused product is Defendant’s etanercept biosimilar product, marketed as Eticovo (etanercept-ykro) (Compl. ¶10). The act of infringement is Defendant's submission of its abbreviated Biologics License Application (aBLA) to the FDA for approval (Compl. ¶12, 61, 74).
  • Functionality and Market Context:
    • The complaint alleges that Eticovo is a biosimilar version of Plaintiffs' Enbrel® product (Compl. ¶10). According to its FDA-approved label, it is described as a "dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1" (Compl. ¶34).
    • The complaint states that the Defendant's product has the "identical primary amino acid sequence" as Enbrel® and is "highly similar to US-licensed Enbrel, notwithstanding minor differences in clinically inactive components" (Compl. ¶32, 35). It is produced using recombinant DNA technology in a Chinese hamster ovary (CHO) cell expression system (Compl. ¶34).
    • The product is approved for the same therapeutic indications as Enbrel®, including rheumatoid arthritis and psoriasis, and functions by binding to and inhibiting human TNF (Compl. ¶24, 37). Defendant allegedly seeks to market this product as a lower-cost alternative to Enbrel® (Compl. ¶30). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’182 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A protein comprising (a) a human tumor necrosis factor (TNF)-binding soluble fragment of an insoluble human TNF receptor... Defendant's Eticovo product is alleged to be a fusion protein containing the extracellular ligand-binding portion of the human p75 TNFR. ¶34 col. 42:5-24
...wherein the insoluble human TNF receptor (i) specifically binds human TNF, (ii) has an apparent molecular weight of about 75 kilodaltons... The complaint alleges Eticovo is a biosimilar of Enbrel® and specifically binds human TNF, and that its label describes it as a fusion protein of the human 75 kilodalton (p75) TNFR. ¶34 col. 42:5-24
...and (b) all of the domains of the constant region of a human immunoglobulin IgG heavy chain other than the first domain of said constant region... The complaint alleges that the Fc component of Eticovo contains the CH2, CH3, and hinge regions, but not the CH1 domain, of human IgG1. ¶34 col. 42:12-20
...wherein said protein specifically binds human TNF. The product's alleged function is to bind to and inhibit human TNF, thereby reducing inflammatory responses. ¶24 col. 42:21-24

’522 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An isolated DNA sequence comprising a DNA sequence that encodes a protein, wherein the protein comprises: (a) a human tumor necrosis factor (TNF)-binding soluble fragment of an insoluble human TNF receptor... Defendant is alleged to manufacture Eticovo using recombinant DNA technology in a CHO mammalian cell expression system. This process necessarily requires a DNA sequence that encodes the fusion protein. ¶34 col. 43:30-47
...and (b) all of the domains of the constant region of a human immunoglobulin IgG heavy chain other than the first domain of said constant region. The complaint alleges that Defendant's manufacturing process produces the specific fusion protein structure, which requires an underlying DNA sequence encoding that structure. ¶34, 73 col. 43:40-47
  • Identified Points of Contention:
    • Scope Questions: A central question for the product patent (’182) will be whether the definition of the claimed fusion protein, including limitations such as "about 75 kilodaltons" and the specific structure of the Fc region, reads directly on the molecular structure of Defendant's Eticovo product. The complaint's allegation that Eticovo is "highly similar" and has an identical amino acid sequence suggests this may not be a primary point of contention unless there are subtle structural differences arising from manufacturing.
    • Technical Questions: For the manufacturing patents (’522, ’549, ’124, ’557), the key technical question will be evidentiary: what specific processes does the Defendant actually use to manufacture, feed, and purify Eticovo? Since the Defendant did not provide its aBLA to the Plaintiffs, the infringement allegations are based on "information and belief," which will require discovery to substantiate the claims that Defendant's proprietary manufacturing methods fall within the scope of the patented methods.

V. Key Claim Terms for Construction

  • The Term: "a human tumor necrosis factor (TNF)-binding soluble fragment of an insoluble human TNF receptor" (’182 Patent, Claim 1)

  • Context and Importance: This term defines the active, target-binding portion of the therapeutic molecule. The construction of "soluble fragment" and the characteristics of the "insoluble human TNF receptor" from which it is derived will be critical. Practitioners may focus on this term because any structural or functional deviation in the Defendant's protein from the claimed fragment could form the basis of a non-infringement argument.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification describes obtaining the binding proteins from various sources, including membrane extracts of different cell lines and human placenta, suggesting the term is not limited to a single, specific sequence but rather to a functional class of proteins (’182 Patent, col. 42:2-11).
    • Evidence for a Narrower Interpretation: The patent provides specific amino acid and nucleotide sequences in figures (e.g., ’182 Patent, FIG. 1, FIG. 4). A defendant might argue that the term should be limited to the specific embodiments and sequences disclosed, particularly the p75 TNFR referenced throughout the complaint (Compl. ¶23, 34).

  • The Term: "all of the domains of the constant region of a human immunoglobulin IgG heavy chain other than the first domain of said constant region" (’182 Patent, Claim 1)

  • Context and Importance: This term defines the structural "backbone" of the fusion protein, which provides stability and other therapeutic properties. The precise composition of this Fc portion is a key structural limitation. A dispute could arise if the defendant's Fc portion lacks a claimed domain or includes a portion of the "first domain," which could allow for a non-infringement defense.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The specification refers generally to "human immunoglobulin IgG, IgA, IgM, or IgE," suggesting some flexibility in the choice of immunoglobulin backbone, although the claim is specific to IgG (’182 Patent, col. 42:30-34).
    • Evidence for a Narrower Interpretation: The complaint itself, in describing the accused product, specifies that the Fc component "contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1" (Compl. ¶34). This aligns with the claim language requiring exclusion of the "first domain" (CH1) and could be used to argue for a very specific structural requirement.

VI. Other Allegations

  • Indirect Infringement: The complaint does not contain specific counts for indirect infringement.
  • Willful Infringement: The complaint alleges that Defendant knew of or was willfully blind to the existence of the patents-in-suit (Compl. ¶62, 75, 89, 96, 103). The basis for this allegation is the assertion that each patent issued years before Defendant's formation and that a company entering the lucrative biosimilar market for Enbrel® would have investigated the patent landscape protecting the innovative drug (Compl. ¶29, 30, 31).

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

  • A core issue will be one of procedural compliance and its consequences: did the Defendant's failure to participate in the BPCIA's pre-suit "patent dance" constitute an act of infringement for all asserted patents, and does this failure expand the scope of patents that Plaintiffs can assert beyond what might have been permissible had the statutory exchange occurred?
  • A key evidentiary question will be one of manufacturing equivalence: for the four asserted method patents, what evidence will discovery reveal about the Defendant's proprietary cell culturing, feeding, and protein recovery processes, and will those processes be found to practice the specific temperature, feeding, and purification steps required by the claims?
  • A central question of molecular identity will determine infringement of the product patent: despite allegations of being "highly similar," are there any structural or functional differences between the accused biosimilar product, Eticovo, and the specific fusion protein structure defined in claim 1 of the '182 patent that are sufficient to place it outside the claim's scope?