DCT

1:23-cv-00287

Exelixis Inc v. Cipla Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-00287, D. Del., 03/16/2023
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Cipla USA, Inc. is a Delaware corporation, and Defendant Cipla Ltd. is not a resident of the United States and may be sued in any judicial district.
  • Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for approval to market a generic version of the cancer drug CABOMETYX® constitutes an act of infringement of five U.S. patents.
  • Technical Context: The technology concerns pharmaceutical chemistry, specifically relating to cabozantinib, a tyrosine kinase inhibitor used for treating certain cancers, and its specific salt forms, crystalline structures, and manufacturing processes.
  • Key Procedural History: The dispute was triggered by a Notice Letter, dated February 2, 2023, in which Cipla informed Exelixis of its ANDA filing and its Paragraph IV certification asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed. The patents are listed in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the "Orange Book") in connection with CABOMETYX®.

Case Timeline

Date Event
2009-01-16 Priority Date for ’776, ’439, ’440, and ’015 Patents
2011-02-10 Priority Date for ’349 Patent
2014-11-04 U.S. Patent No. 8,877,776 Issued
2016-01-01 FDA Approved Plaintiff's CABOMETYX® Product
2021-08-17 U.S. Patent No. 11,091,439 Issued
2021-08-17 U.S. Patent No. 11,091,440 Issued
2021-08-24 U.S. Patent No. 11,098,015 Issued
2022-04-12 U.S. Patent No. 11,298,349 Issued
2023-02-02 Defendant Cipla Sent Notice Letter to Plaintiff
2023-03-16 Complaint Filed

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

U.S. Patent No. 8,877,776 - “(L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide”

The Invention Explained

  • Problem Addressed: While a specific chemical compound, N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, was known to have therapeutic potential as a kinase inhibitor for cancer treatment, a drug developer must find a form of that compound with suitable properties for processing, manufacturing, storage, and stability to be useful as a medicine (U.S. Patent No. 11,091,439, col. 3:20-25).
  • The Patented Solution: The invention is a specific salt form of the therapeutic compound: the (L)-malate salt. This salt form was selected for having a desirable combination of pharmaceutical properties, including suitable solubility and chemical/physical stability, which are critical for developing a chemical compound into a viable drug product (’776 Patent, Abstract; ’439 Patent, col. 7:10-25, Table 1).
  • Technical Importance: The selection of an optimal salt form is a critical step in pharmaceutical development that can determine whether a promising active ingredient can be successfully manufactured into a safe, stable, and effective drug.

Key Claims at a Glance

  • The complaint asserts infringement of at least claims 1 and 2 (Compl. ¶33). Claim 1 is independent.
  • The essential element of independent claim 1 is:
    • The (L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (’776 Patent, col. 32:38-42).

U.S. Patent No. 11,091,439 - “Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and Crystalline Forms Therof for the Treatment of Cancer”

The Invention Explained

  • Problem Addressed: As described for the ’776 Patent, the development of a therapeutically active compound requires identifying a form with optimal physicochemical properties for drug manufacturing and performance (’439 Patent, col. 3:20-25). Even within a chosen salt, different solid-state forms (polymorphs) can exist with vastly different properties.
  • The Patented Solution: This invention discloses and claims specific crystalline forms of the (L)-malate salt from the ’776 Patent, designated as Form N-1 and Form N-2. These crystalline forms are defined by their unique X-ray powder diffraction (XRPD) patterns, which provide a structural fingerprint ensuring consistent physical properties like dissolution rate and stability, which are essential for a reliable drug product (’439 Patent, Abstract, col. 7:31-40). The XRPD pattern for Form N-1 is depicted in Figure 1 of the patent (’439 Patent, Fig. 1).
  • Technical Importance: Identifying and characterizing a specific, stable crystalline polymorph of a drug substance is crucial to avoid manufacturing inconsistencies and ensure predictable clinical performance of the final pharmaceutical product.

Key Claims at a Glance

  • The complaint asserts infringement of at least claims 1, 3, and 4 (Compl. ¶43). Claim 1 is independent.
  • The essential elements of independent claim 1 are:
    • A crystalline N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, (L)-malate salt,
    • which is characterized by an x-ray powder diffraction pattern comprising four or more peaks selected from a specific list of 2θ values (e.g., 6.4, 9.0, 12.0, etc.) (’439 Patent, col. 32:41-53).

Multi-Patent Capsule: U.S. Patent No. 11,091,440

  • Patent Identification: 11091440, titled “Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)- N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and Crystalline Forms Thereof for the Treatment of Cancer,” issued August 17, 2021.
  • Technology Synopsis: This patent claims pharmaceutical compositions that contain the specific crystalline forms of the cabozantinib (L)-malate salt described in the ’439 Patent. The invention addresses the technical challenge of formulating the stable crystalline active ingredient into a finished dosage form with suitable excipients for administration to patients (’440 Patent, col. 11:54-12:2).
  • Asserted Claims: Claims 1 and 3 are asserted (Compl. ¶53).
  • Accused Features: The Cipla ANDA Product is accused of being a pharmaceutical composition that contains the claimed crystalline salt form (Compl. ¶53-55).

Multi-Patent Capsule: U.S. Patent No. 11,098,015

  • Patent Identification: 11098015, titled “Malate Salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and Crystalline Forms Thereof for the Treatment of Cancer,” issued August 24, 2021.
  • Technology Synopsis: This patent claims methods of treating specific cancers, such as kidney and liver cancer, by administering the crystalline (L)-malate or (D)-malate salt of cabozantinib. The invention addresses the need for effective cancer treatments by claiming the use of this specific, stable form of the drug to treat indicated diseases (’015 Patent, Abstract, col. 12:35-41).
  • Asserted Claims: Claims 1 and 2 are asserted (Compl. ¶63).
  • Accused Features: The future use of the Cipla ANDA Product, as will be instructed by its FDA-approved labeling, for treating cancer is the accused act (Compl. ¶66).

Multi-Patent Capsule: U.S. Patent No. 11,298,349

  • Patent Identification: 11298349, titled “Processes for Preparing Quinoline Compounds and Pharmaceutical Compositions Containing Such Compounds,” issued April 12, 2022.
  • Technology Synopsis: This patent claims pharmaceutical compositions of cabozantinib that are "essentially free" of a specific process impurity, 6,7-dimethoxy-quinoline-4-ol. The invention addresses the technical challenge of producing a highly pure and safe final drug product by defining compositions with minimal levels of this potential byproduct (’349 Patent, col. 8:15-20).
  • Asserted Claims: Claims 1-3 are asserted (Compl. ¶73).
  • Accused Features: The Cipla ANDA Product itself is accused of infringing, which suggests an allegation that the product meets the claimed purity profile (Compl. ¶73-75).

III. The Accused Instrumentality

Product Identification

  • The "Cipla ANDA Product," which is Cipla Ltd. and Cipla USA, Inc.'s proposed generic version of CABOMETYX® tablets, identified as "Cabozantinib S-Malate Tablets, 60 mg" (Compl. ¶1, ¶27).

Functionality and Market Context

  • The Cipla ANDA Product contains cabozantinib, a tyrosine kinase inhibitor for oral administration approved for treating advanced kidney cancer and certain types of liver cancer (Compl. ¶25). By filing an ANDA, Cipla has represented to the FDA that its product contains the same active ingredient, has the same dosage form and strength, and is bioequivalent to Exelixis's branded CABOMETYX® product (Compl. ¶28). The complaint alleges that Cipla seeks to manufacture and sell this generic product in the United States prior to the expiration of the patents-in-suit (Compl. ¶29, ¶31).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 8,877,776 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. The Cipla ANDA Product is identified as "Cabozantinib S-Malate Tablets," where S-malate is synonymous with (L)-malate. The complaint alleges the product contains the same active ingredient as CABOMETYX®, which is covered by the patent. ¶27, ¶28, ¶33 col. 5:25-35

U.S. Patent No. 11,091,439 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, (L)-malate salt, The Cipla ANDA product is a solid oral tablet formulation alleged to contain the (L)-malate salt of cabozantinib. Infringement is premised on the ANDA representing that the generic product is the same as the branded product, which is covered by this patent. ¶26, ¶28, ¶43 col. 8:30-41
characterized by an x-ray powder diffraction pattern (CuKα λ=1.5418 Å) comprising four or more peaks selected from: 6.4, 9.0, 12.0, 12.8, 13.5, 16.9, 19.4, 21.5, 22.8, 25.1, and 27.6°2θ±0.2°2θ. The complaint does not present direct evidence of the accused product's XRPD pattern. The allegation of infringement is based on Cipla's representation to the FDA that its product is the same as CABOMETYX®, which Exelixis alleges is characterized by this specific crystalline form. ¶26, ¶28, ¶43 col. 8:42-53

Identified Points of Contention

  • Technical Questions: The central infringement question for the ’439, ’440, and ’015 patents is evidentiary: does the cabozantinib salt in Cipla’s ANDA product exist in the specific crystalline form (Form N-1) defined by the characteristic XRPD peaks recited in the claims? The complaint does not provide direct evidence of the accused product's solid-state structure, and this point will likely require discovery into Cipla's confidential ANDA data.
  • Scope Questions: For the ’349 patent, a potential dispute may arise over whether Cipla’s manufacturing process is covered by the claims or if its final product, while potentially pure, is produced by a materially different and non-infringing method. Proving infringement of process claims can raise significant evidentiary challenges regarding the activities within a defendant's manufacturing facilities.

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail for a deep analysis of claim construction disputes. However, based on the technology, certain terms are central to the infringement case.

  • The Term: "crystalline...characterized by an x-ray powder diffraction pattern...comprising four or more peaks selected from..." (from Claim 1 of the ’439 Patent)
  • Context and Importance: This limitation defines the patented invention, Form N-1, by its structural fingerprint. The entire infringement analysis for the crystalline form patents will depend on whether the accused product possesses a crystal structure that meets this definition. Practitioners may focus on this term because any slight variation in Cipla's crystal structure, leading to a different set of XRPD peaks, could form the basis of a non-infringement defense.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The claim language "four or more peaks selected from" provides some flexibility, as it does not require the presence of every listed peak, potentially capturing materials that are substantially similar but not identical.
    • Evidence for a Narrower Interpretation: The patent provides highly specific characterization data for Form N-1, including the full experimental XRPD pattern in Figure 1 and a corresponding list of peaks in Table 2 (’439 Patent, Fig. 1, Table 2). A defendant may argue that this detailed disclosure limits the claim scope to crystalline forms that closely match the exemplified Form N-1, particularly with respect to the relative intensity and position of the most prominent peaks.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement for all asserted patents. The basis for this allegation is that Cipla's proposed product labeling will instruct healthcare providers and patients to administer the Cipla ANDA Product for the treatment of cancer, thereby encouraging infringement of the asserted method-of-use claims (e.g., Compl. ¶36, ¶46, ¶66).
  • Willful Infringement: The complaint does not use the term "willful infringement," but alleges for each patent count that Cipla acted "without a reasonable basis for believing that they would not be liable for directly and/or indirectly infringing" and that "This is an exceptional case" (e.g., Compl. ¶40, ¶50, ¶60). These allegations lay the groundwork for potential claims for enhanced damages and attorneys' fees. The alleged basis is Cipla’s knowledge of the patents, which were listed in the FDA's Orange Book and identified in Cipla’s own Paragraph IV certification letter to Exelixis before the suit was filed (Compl. ¶26, ¶27, ¶30).

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

  • A core issue will be one of polymorphic identity: What is the specific solid-state crystal structure of the cabozantinib S-malate in Cipla’s ANDA product? A key evidentiary question for the court will be whether the product's X-ray powder diffraction data shows a pattern that meets the specific peak requirements of the asserted crystalline form claims.
  • The case will also present a question of process versus product: For the ’349 patent, which claims a composition that is "essentially free" of a certain impurity, the central issue will be whether infringement can be proven from the final product's characteristics alone, or if Exelixis will need to show through discovery that Cipla uses an infringing manufacturing process.