DCT

1:16-cv-00988

Onyx Therap Inc v. Cipla Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:16-cv-00988, D. Del., 10/24/2016
  • Venue Allegations: Venue is alleged to be proper as Defendant CIPLA USA, Inc. is a Delaware corporation, and Defendant CIPLA Limited is alleged to have systematic and continuous contacts with Delaware, to have previously submitted to the jurisdiction of the court, and to be acting in concert with its U.S. agent.
  • Core Dispute: Plaintiff alleges that Defendants’ filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff’s multiple myeloma drug KYPROLIS® (carfilzomib) constitutes an act of infringement of nine U.S. patents.
  • Technical Context: The patents relate to peptide-based epoxyketone compounds that function as proteasome inhibitors, a class of drugs used in oncology to induce apoptosis in cancer cells.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff’s receipt of a notice letter from CIPLA Limited on September 12, 2016, which included a Paragraph IV Certification against the patents-in-suit. This certification asserts that the patents are invalid, unenforceable, and/or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2004-04-15 Earliest Priority Date for ’818, ’704, ’346, ’125, ’126, ’127, ’297 Patents
2004-08-06 Earliest Priority Date for ’042 Patent
2004-12-07 Earliest Priority Date for ’112 Patent
2007-06-19 U.S. Patent No. 7,232,818 Issues
2008-08-26 U.S. Patent No. 7,417,042 Issues
2009-02-17 U.S. Patent No. 7,491,704 Issues
2010-06-15 U.S. Patent No. 7,737,112 Issues
2012-03-06 U.S. Patent No. 8,129,346 Issues
2012-06-26 U.S. Patent Nos. 8,207,125, 8,207,126, 8,207,127, and 8,207,297 Issue
2012-07-20 FDA grants approval for Onyx’s KYPROLIS® (carfilzomib)
2016-09-09 CIPLA Limited sends Paragraph IV notice letter to Onyx
2016-10-24 Complaint for Patent Infringement Filed

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

U.S. Patent No. 7,417,042 - Compounds For Enzyme Inhibition

  • Issued: August 26, 2008 (Compl. ¶15)

The Invention Explained

  • Problem Addressed: The background of the related ’818 Patent notes a need for small-molecule inhibitors of the proteasome—a key component in cellular protein degradation—that possess improved specificity, stability, and potency for use as therapeutic agents and research tools (’818 Patent, col. 2:11-21).
  • The Patented Solution: The invention provides peptide-based compounds, specifically tetrapeptide epoxyketones, which are designed to inhibit enzymes known as N-terminal nucleophile (Ntn) hydrolases (’818 Patent, col. 3:25-31). The core of the solution is a terminal epoxide functional group that forms an irreversible covalent bond with a nucleophile (e.g., a threonine residue) in the active site of the target enzyme, such as the 20S proteasome, thereby inactivating it (’818 Patent, col. 4:5-14).
  • Technical Importance: This chemical approach provides for potent and selective inhibition of the chymotrypsin-like activity of the proteasome, which can trigger apoptosis (programmed cell death) in tumor cells, making such compounds effective as anti-cancer agents (Compl. ¶28; ’818 Patent, col. 2:22-24).

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 15 (Compl. ¶43).
  • Claim 1 of the ’042 Patent recites a peptide of a specific chemical structure comprising four amino acid residues with a terminal epoxyketone moiety, and includes a morpholino group at the N-terminus.
  • Claim 15 of the ’042 Patent recites a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the structure recited in claim 1.
  • The complaint also asserts dependent claims 2-6, 16-24, and 37 (Compl. ¶43).

U.S. Patent No. 7,232,818 - Compounds For Enzyme Inhibition

  • Issued: June 19, 2007 (Compl. ¶16)

The Invention Explained

  • Problem Addressed: As described in Section II above for the related ’042 Patent, the patent addresses the need for potent and selective small-molecule inhibitors of the proteasome for therapeutic and research purposes (’818 Patent, col. 2:11-21).
  • The Patented Solution: The ’818 Patent discloses a class of peptide α',β'-epoxy ketones that irreversibly bind to and inhibit Ntn hydrolases like the proteasome (’818 Patent, Abstract; col. 3:25-31). The invention specifies a peptide backbone, typically with two to eight units, and functionalization at the N-terminus, which allows for differential inhibition of the proteasome's multiple catalytic activities (’818 Patent, col. 3:30-44, Abstract).
  • Technical Importance: As with the ’042 Patent, this class of compounds provides a mechanism for selectively inhibiting proteasome activity, which is a key pathway for regulating cell growth and inducing apoptosis, particularly in tumor cells (Compl. ¶28; ’818 Patent, col. 2:22-24).

Key Claims at a Glance

  • The complaint asserts independent claim 1 (Compl. ¶54).
  • Claim 1 of the ’818 Patent recites a compound having a specific chemical structure defined by Formula (I), which includes:
    • A peptide backbone of at least three peptide units.
    • An epoxide or aziridine functional group.
    • Functionalization at the N-terminus.
  • The complaint also asserts dependent claims 2-4, 23-25, 38, and 49-50 (Compl. ¶54).

U.S. Patent No. 7,491,704 - Compounds For Enzyme Inhibition

  • Patent Identification: U.S. Patent No. 7,491,704, issued February 17, 2009 (Compl. ¶17).
  • Technology Synopsis: This patent, related to the ’818 Patent, discloses peptide-based compounds with a terminal epoxyketone moiety designed to selectively and irreversibly inhibit the chymotrypsin-like activity of the proteasome for therapeutic purposes, such as treating cancer.
  • Asserted Claims: Independent claim 1 is asserted (Compl. ¶65).
  • Accused Features: The complaint alleges infringement because the Proposed ANDA Product contains carfilzomib as its active ingredient, and its proposed label will instruct for its use in treating multiple myeloma (Compl. ¶65).

U.S. Patent No. 7,737,112 - Compounds For Enzyme Inhibition

  • Patent Identification: U.S. Patent No. 7,737,112, issued June 15, 2010 (Compl. ¶18).
  • Technology Synopsis: This patent claims pharmaceutical compositions comprising a specific peptide epoxyketone (carfilzomib), a cyclodextrin such as sulfobutyl ether beta-cyclodextrin (SBECD), and a buffer such as citric acid. This formulation is designed to improve the solubility and stability of the active drug substance.
  • Asserted Claims: Independent claims 1 and 18 are asserted (Compl. ¶75).
  • Accused Features: The Proposed ANDA Product is alleged to infringe because it is a composition containing carfilzomib, SBECD, and citric acid (Compl. ¶75).

U.S. Patent No. 8,129,346 - Compounds For Enzyme Inhibition

  • Patent Identification: U.S. Patent No. 8,129,346, issued March 6, 2012 (Compl. ¶19).
  • Technology Synopsis: This patent, related to the ’818 Patent, claims methods of treating cancer by administering a therapeutically effective amount of a specific peptide epoxyketone compound, carfilzomib, which inhibits an N-terminal nucleophile hydrolase.
  • Asserted Claims: Independent claim 1 is asserted (Compl. ¶86).
  • Accused Features: The use of the Proposed ANDA Product is alleged to infringe because its label will instruct for the administration of carfilzomib to inhibit the 20S proteasome to treat cancer (Compl. ¶86).

Seven additional patents are asserted in the complaint. Due to their number and the similarity of the allegations, they are summarized collectively. U.S. Patent Nos. 8,207,125; 8,207,126; 8,207,127; and 8,207,297 are all related to the ’818 Patent and generally claim specific compositions comprising carfilzomib, methods of its manufacture, and/or its use to treat hematopoietic cancers like multiple myeloma. The infringement allegations are based on the Proposed ANDA Product being a composition containing carfilzomib and its label instructing for these uses (Compl. ¶¶96, 107, 118, 128).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is the "Proposed ANDA Product," identified as a generic version of Onyx’s KYPROLIS® (carfilzomib) for injection, which is the subject of ANDA No. 209479 filed by CIPLA (Compl. ¶¶4, 8).

Functionality and Market Context

  • The product is described as a 60 mg lyophilized powder containing the active pharmaceutical ingredient carfilzomib, intended for reconstitution and intravenous use (Compl. ¶6). Carfilzomib is a tetrapeptide epoxyketone that functions as a proteasome inhibitor (Compl. ¶28). The complaint alleges that the proposed product’s label will substantially copy the instructions for KYPROLIS®, directing healthcare providers to administer it for the treatment of multiple myeloma (Compl. ¶¶38, 39). This mechanism of action involves irreversibly binding to the 20S proteasome, causing an accumulation of protein in myeloma cells and triggering apoptosis (Compl. ¶28, ¶40).
  • The filing of ANDA No. 209479 represents a commercial effort by CIPLA to market and sell a generic equivalent to KYPROLIS® in the United States prior to the expiration of the patents-in-suit (Compl. ¶7).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’042 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A peptide having the structure: [Chemical structure depicted in claim 1] The Proposed ANDA Product contains carfilzomib as its active ingredient, which the complaint alleges is a peptide having the structure recited in claim 1. ¶43 col. 52:37-67

’818 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound having a structure of formula (I) ... The Proposed ANDA Product contains carfilzomib as its active ingredient, which the complaint alleges is a compound having the structure of formula (I). ¶54 col. 65:25-67
  • Identified Points of Contention:
    • Scope Questions: In ANDA litigation, the act of infringement is the filing of the ANDA itself. The primary dispute is typically not whether the proposed generic product literally meets the claim limitations, but whether the patent claims are valid and enforceable. The central question for the court, prompted by CIPLA's Paragraph IV certification, will be whether the asserted claims are invalid for reasons such as obviousness or lack of written description.
    • Technical Questions: The complaint does not provide sufficient detail for analysis of specific technical disputes. However, potential issues could arise concerning the specific crystalline form (polymorph) of carfilzomib in the Proposed ANDA Product or the presence and effect of any excipients, and whether these details might support a non-infringement argument under a particular claim construction.

V. Key Claim Terms for Construction

  • The Term: The complete chemical structure recited in Claim 1 of the ’042 Patent.
  • Context and Importance: The infringement analysis for the composition claims hinges entirely on whether the carfilzomib in CIPLA's Proposed ANDA Product is the same molecule as the one defined by this structure. Practitioners may focus on this "term" because any structural or stereochemical ambiguity could provide a basis for a non-infringement defense.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification of the related ’818 Patent discloses a broad genus of peptide epoxy ketones in Formula (I), suggesting the inventors conceived of a class of related compounds, which may support a broader understanding of equivalents (’818 Patent, col. 5:40-67).
    • Evidence for a Narrower Interpretation: The claim recites a single, precise chemical structure with specific stereochemistry indicated. The patent's examples detail the synthesis of specific compounds, which could be used to argue that the claims should be limited to the exact structures disclosed and produced by those methods (’818 Patent, cols. 45-66).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement, stating that CIPLA's proposed product labeling will instruct healthcare providers to reconstitute and administer the carfilzomib product to treat multiple myeloma in a manner that directly infringes method-of-use claims (Compl. ¶¶38-40, 47). The complaint also alleges contributory infringement on the basis that the Proposed ANDA Product will have no substantial non-infringing use (Compl. ¶41, ¶47).
  • Willful Infringement: The complaint alleges that Defendants had knowledge of the patents-in-suit when they filed the ANDA with a Paragraph IV certification (Compl. ¶35, ¶50). It further alleges that Defendants lacked a good faith basis for their allegations of invalidity and non-infringement, asserting that the case is exceptional under 35 U.S.C. § 285 (Compl. ¶52).

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

  • A core issue will be one of patent validity: As is typical in Hatch-Waxman litigation, the central dispute will likely focus on CIPLA's assertions, made in its Paragraph IV certification, that the asserted claims are invalid (e.g., as obvious over the prior art) or unenforceable. The case will depend on whether CIPLA can meet its burden of proving invalidity by clear and convincing evidence.
  • A key legal question will be one of claim scope and infringement: Does the specific carfilzomib formulated in CIPLA's Proposed ANDA Product—including its particular solid-state form, purity profile, and excipients—fall within the scope of all asserted claims? While the complaint asserts direct structural identity, the litigation will likely explore subtle differences to support arguments for non-infringement under the court's claim construction.