DCT

2:16-cv-01118

Immunex Corp v. Sandoz Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:16-cv-01118, D.N.J., 02/26/2016
  • Venue Allegations: Venue is alleged to be proper based on Defendants' business activities in the District of New Jersey, including manufacturing, seeking regulatory approval, and selling pharmaceutical products.
  • Core Dispute: Plaintiffs allege that Defendants’ submission of an Abbreviated Biologics License Application (aBLA) to the FDA for a biosimilar version of Plaintiffs' ENBREL® (etanercept) product constitutes an act of infringement of five patents covering the etanercept fusion protein, its methods of manufacture, and its therapeutic uses for treating psoriasis and psoriatic arthritis.
  • Technical Context: The dispute concerns etanercept, a biologic drug known as a TNF inhibitor, which is a highly successful therapy for autoimmune diseases like rheumatoid arthritis and psoriasis.
  • Key Procedural History: The complaint alleges this action arises under the Biologics Price Competition and Innovation Act (BPCIA), which governs the approval of biosimilar drugs. Plaintiffs allege that Defendants engaged in but then refused to complete the BPCIA’s pre-litigation information exchange and negotiation process, known as the "patent dance." The complaint also notes that U.S. Patent No. 8,163,522 is the subject of a pending inter partes review (IPR) proceeding before the Patent Trial and Appeal Board.

Case Timeline

Date Event
1990-08-31 Priority Date for ’182 and ’522 Patents
1999-08-11 Priority Date for ’225, ’605, and ’631 Patents
2011-03-29 U.S. Patent No. 7,915,225 issues
2011-11-22 U.S. Patent No. 8,063,182 issues
2012-02-21 U.S. Patent No. 8,119,605 issues
2012-04-24 U.S. Patent No. 8,163,522 issues
2014-05-13 U.S. Patent No. 8,722,631 issues
2015-07-01 Defendants allegedly file aBLA with the FDA (approximate date)
2015-09-29 FDA accepts Defendants' aBLA for review
2015-10-02 Novartis (Sandoz parent) issues press release on FDA acceptance
2015-10-19 Sandoz provides Immunex with initial remote access to its aBLA
2015-12-18 Immunex provides Sandoz its list of patents for potential assertion
2016-01-27 Sandoz responds to patent list, allegedly waiving BPCIA negotiations
2016-02-26 Complaint for Patent Infringement filed

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

U.S. Patent No. 8,063,182 - Human TNF Receptor Fusion Protein

The Invention Explained

  • Problem Addressed: The complaint describes Tumor Necrosis Factor ("TNF") as a cell-signaling protein that, when overproduced, is implicated in autoimmune diseases and inflammatory disorders (Compl. ¶40). The biological effects of TNF are mediated through specific receptors on cell surfaces (Compl. ¶41). The unstated problem is how to inhibit the activity of excess TNF.
  • The Patented Solution: The invention is a genetically engineered fusion protein that combines the extracellular, TNF-binding portion of a human p75 TNF receptor with a portion of a human immunoglobulin (antibody) heavy chain (Compl. ¶¶43-44). This fusion protein, known as etanercept, binds to TNF in the body, preventing it from interacting with cell-surface receptors and thereby reducing inflammatory responses (Compl. ¶45; ’182 Patent, Abstract). The patent describes fusing the TNF receptor portion to "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, Abstract; col. 2:5-10).
  • Technical Importance: This approach created a stable, soluble version of a TNF receptor that could act as a therapeutic "decoy" to neutralize excess TNF, representing a major advance in treating autoimmune disorders (Compl. ¶46).

Key Claims at a Glance

  • The complaint does not identify specific asserted claims but alleges infringement of "one or more claims" (Compl. ¶85). Independent claim 1 is representative of the core invention.
  • Essential elements of Independent Claim 1:
    • A fusion 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 (LPAQVAFXPYAPEPGSTC); 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.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 8,163,522 - Human TNF Receptor

The Invention Explained

  • Problem Addressed: The technical challenge addressed is the production of the therapeutic TNF receptor fusion protein described in the '182 Patent. This requires creating the genetic instructions (nucleic acids) and cellular machinery (host cells) to manufacture the non-naturally occurring protein (Compl. ¶70).
  • The Patented Solution: The patent claims the methods and materials for producing the etanercept fusion protein. This includes methods of culturing a host cell that contains the polynucleotide (DNA) encoding the fusion protein and purifying the resulting protein product from the cell mass or culture medium (’522 Patent, Abstract; col. 45:46-63). The patent describes the use of various host cell lines and expression vectors to accomplish this production (’522 Patent, col. 8:37-67).
  • Technical Importance: This patent covers the fundamental tools for manufacturing the biologic drug etanercept at a commercial scale, a critical step in making the therapy available to patients.

Key Claims at a Glance

  • The complaint does not identify specific asserted claims but alleges infringement of "one or more claims" (Compl. ¶102). Independent claim 1 is representative.
  • Essential elements of Independent Claim 1:
    • A method comprising the steps of:
    • (a) culturing a host cell comprising a polynucleotide, wherein the polynucleotide encodes a protein consisting of: (i) the extracellular region of an insoluble human TNF receptor, and (ii) all of the domains of the constant region of a human IgG immunoglobulin heavy chain other than the first domain of said constant region; and
    • (b) purifying an expression product of the polynucleotide from the cell mass or the culture medium.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 7,915,225 - Soluble Tumor Necrosis Factor Receptor Treatment of Medical Disorders

  • Technology Synopsis: The patent addresses the need for effective treatments for psoriasis and psoriatic arthritis, noting that in the late 1990s there were no approved biologic therapies (Compl. ¶¶72-74). The claimed solution is a method of treating these conditions by administering etanercept (TNFR:Fc), often in specific dosage regimens (’225 Patent, col. 22:11-20).
  • Asserted Claims: The complaint asserts "one or more claims" (Compl. ¶121). Independent claims 1 and 12 are directed to methods of treating psoriasis and psoriatic arthritis.
  • Accused Features: The accused feature is Defendants' intent to market their biosimilar product for the treatment of psoriasis and psoriatic arthritis, allegedly by copying ENBREL's labeling, which instructs physicians and patients on the patented methods of use (Compl. ¶118).

U.S. Patent No. 8,119,605 - Soluble Tumor Necrosis Factor Receptor Treatment of Medical Disorders

  • Technology Synopsis: This patent is part of the same family as the ’225 Patent and addresses the same technical problem. It claims methods for treating psoriasis by administering etanercept (’605 Patent, col. 22:1-4).
  • Asserted Claims: The complaint asserts "one or more claims" (Compl. ¶139). Independent claim 1 is directed to a method of treating ordinary psoriasis.
  • Accused Features: The accused feature is Defendants' intent to market their biosimilar for treating psoriasis, allegedly by copying ENBREL's labeling that instructs physicians on the patented dosages and administration methods (Compl. ¶136).

U.S. Patent No. 8,722,631 - Soluble Tumor Necrosis Factor Receptor Treatment of Medical Disorders

  • Technology Synopsis: This patent is part of the same family as the ’225 and ’605 Patents and addresses the same technical problem. It claims methods for treating psoriatic arthritis and/or plaque psoriasis by administering etanercept (’631 Patent, Abstract).
  • Asserted Claims: The complaint asserts "one or more claims" (Compl. ¶157). Independent claim 1 is directed to a method of treatment for psoriatic arthritis and/or plaque psoriasis.
  • Accused Features: The accused feature is Defendants' intent to market their biosimilar for treating psoriasis and psoriatic arthritis, allegedly by copying ENBREL's labeling that instructs administration of specific dosages covered by the patent (Compl. ¶154).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendants' etanercept biosimilar product, for which Sandoz Inc. submitted an aBLA to the FDA seeking approval to market it as a biosimilar version of Immunex's ENBREL® (Compl. ¶¶14, 50).

Functionality and Market Context

  • The complaint alleges that Defendants' product is a biosimilar to ENBREL® and that the amino acid sequence of the etanercept fusion protein is the same in both products (Compl. ¶¶54-55).
  • Functionally, the accused product is alleged to utilize the same mechanism of action as ENBREL®: binding to and inhibiting TNF to reduce inflammatory responses (Compl. ¶55).
  • The complaint alleges that Defendants are seeking approval for all indications on the ENBREL® label, including rheumatoid arthritis and psoriasis, thereby leveraging the clinical data generated by Plaintiffs (Compl. ¶51).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 8,063,182 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A fusion 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... Defendants' product is alleged to be an etanercept fusion protein that is a biosimilar version of ENBREL®, which is known to be a TNF-binding fusion protein (Compl. ¶¶43, 55). ¶¶54-55, 81-82 col. 1:16-19
and (iii) comprises the amino acid sequence LPAQVAFXPYAPEPGSTC... The complaint alleges that the amino acid sequence of Defendants' etanercept fusion protein is the same as the amino acid sequence of the etanercept fusion protein in ENBREL® (Compl. ¶54). The patent identifies this sequence as part of the claimed TNF receptor (’182 Patent, col. 16:45-53). ¶54 col. 16:45-53
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 Defendants' product is a biosimilar to ENBREL®, which is a fusion protein constructed with a portion of a human immunoglobulin heavy chain (Compl. ¶44). The patent specification describes this specific immunoglobulin structure as a key feature of the invention (’182 Patent, col. 2:5-10). ¶44, 54 col. 2:5-10
wherein said protein specifically binds human TNF. The complaint alleges that Defendants' product utilizes the same mechanism of action as ENBREL®, which functions by binding to and inhibiting TNF (Compl. ¶¶45, 55). ¶55 col. 3:3-4

U.S. Patent No. 8,163,522 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method comprising the steps of: (a) culturing a host cell comprising a polynucleotide, wherein the polynucleotide encodes a protein consisting of: The complaint alleges that Defendants' aBLA seeks approval to manufacture their etanercept product and that this product was manufactured by the methods of the '522 patent (Compl. ¶¶99, 101). This implies the use of host cells containing the necessary genetic material. ¶¶99, 101 col. 8:37-45
(i) the extracellular region of an insoluble human TNF receptor, and (ii) all of the domains of the constant region of a human IgG immunoglobulin heavy chain other than the first domain of said constant region... The complaint alleges that Defendants' product has the same amino acid sequence as ENBREL® (Compl. ¶54), which is the fusion protein described in the patent. Manufacturing this protein necessarily requires a polynucleotide that encodes it. ¶54, 98 col. 5:1-12
and (b) purifying an expression product of the polynucleotide from the cell mass or the culture medium. The complaint alleges that Defendants seek approval to commercially manufacture their etanercept product (Compl. ¶99). Commercial manufacturing of a biologic drug inherently requires purification steps to isolate the final product. The complaint does not provide sufficient detail for analysis of the specific purification methods used by Defendants. ¶99 col. 4:51-54

Identified Points of Contention

  • Scope Questions: A potential issue for the '182 Patent may be whether minor variations in Defendants' protein, such as post-translational modifications (e.g., glycosylation), could place it outside the literal scope of the claims, even if the primary amino acid sequence is identical as alleged.
  • Technical Questions: For the ’522 Patent, a central question will be evidentiary: what proof can be adduced that the specific cell culturing and purification processes described in Defendants' confidential aBLA fall within the scope of the patent's method claims? The complaint's allegations on this point are based on "information and belief" (Compl. ¶105) and will require discovery to substantiate.

V. Key Claim Terms for Construction

"all of the domains of the constant region of a human immunoglobulin IgG heavy chain other than the first domain of said constant region" (from '182 Patent, Claim 1)

  • Context and Importance: This term defines the precise structure of the non-receptor portion of the fusion protein. Its construction is critical because any deviation by Defendants in the immunoglobulin domains used could be a basis for a non-infringement argument. Practitioners may focus on this term because the specific selection of immunoglobulin domains is central to the protein's stability and function.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claims themselves use the general term "human immunoglobulin IgG heavy chain," which could suggest that any human IgG isotype (e.g., IgG1, IgG2, etc.) that meets the structural requirement would be covered (’182 Patent, col. 40:11-14).
    • Evidence for a Narrower Interpretation: The specification repeatedly discusses the use of human IgG1 as the preferred embodiment for constructing the fusion protein (’182 Patent, col. 5:60-61). A defendant might argue that the claims, when read in light of the specification, should be limited to fusion proteins constructed using domains from the IgG1 isotype only.

"culturing a host cell" (from '522 Patent, Claim 1)

  • Context and Importance: This term defines the first step of the claimed manufacturing method. Its scope will determine what types of cell production processes are covered. The infringement analysis for the method claims will depend on whether Defendants' specific manufacturing process, as detailed in their aBLA, involves "culturing" as understood in the patent.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification describes a wide variety of host cells that can be used, including both prokaryotic and eukaryotic cells, such as CHO cells, COS cells, and yeast (’522 Patent, col. 8:37-67). This may support a broad construction covering many different cell-based manufacturing platforms.
    • Evidence for a Narrower Interpretation: The detailed examples in the specification focus heavily on specific expression systems and culture conditions, such as the use of particular vectors in COS or CHO cells (’522 Patent, col. 17:51-67; col. 20:11-34). A defendant might argue that "culturing" should be construed as being limited to the specific types of systems and conditions disclosed as enabling the invention.

VI. Other Allegations

Indirect Infringement

The complaint alleges Defendants will induce infringement of the method-of-use patents (’225, ’605, and ’631) upon FDA approval of their product (Compl. ¶¶127, 145, 163). The basis for this allegation is that Defendants intend to market their biosimilar product for the treatment of psoriasis and psoriatic arthritis and have copied ENBREL's labeling, which instructs physicians and patients to administer the drug in a manner that allegedly infringes the method claims (Compl. ¶¶118, 136, 154).

Willful Infringement

While not pleaded as a separate count, the complaint lays the groundwork for a willfulness claim by alleging pre-suit knowledge. It states that Defendants have known of the '182 and '522 patents since at least June 2013 and knew of the '225, '605, and '631 patents before filing their aBLA in July 2015, yet proceeded with their application with the intent to market the product before patent expiration (Compl. ¶¶84, 101, 119, 137, 155).

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

  • A core issue will be one of procedural conduct and its consequences: did Defendants' alleged refusal to complete the BPCIA's statutory negotiation process constitute a failure to comply with the Act, and if so, what impact will that have on the structure and timing of the litigation?
  • A key technical question will be one of structural and process identity: can discovery confirm Plaintiffs' allegations that Defendants' biosimilar product is structurally identical to the fusion protein claimed in the ’182 Patent and is manufactured using a process that falls within the scope of the method claims of the ’522 Patent?
  • A central legal question will be one of induced infringement: assuming the method-of-use patents ('225, '605, '631) are valid, will Defendants' proposed product label, which allegedly mirrors that of ENBREL®, be sufficient evidence of the specific intent required to prove that Defendants will induce physicians and patients to infringe those patents?