DCT
1:24-cv-00565
Exelixis Inc v. Cipla Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Exelixis, Inc. (Delaware)
- Defendant: Cipla, Ltd. (India) & Cipla USA, Inc. (Delaware)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:24-cv-00565, D. Del., 05/09/2024
- Venue Allegations: Venue is alleged to be proper as to Cipla, Ltd. as a foreign resident and as to Cipla USA, Inc. as a Delaware corporation. The complaint further notes that Cipla has previously availed itself of the District of Delaware for litigating patent disputes.
- Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application to manufacture and sell a generic version of the cancer drug CABOMETYX® infringes five U.S. patents related to the drug's active ingredient salt, its specific crystalline forms, and processes for its preparation.
- Technical Context: The technology concerns pharmaceutical compositions of cabozantinib, a tyrosine kinase inhibitor used in oncology, focusing on specific salt forms and polymorphs designed to ensure stability and efficacy.
- Key Procedural History: This action follows a prior lawsuit (23-287-RGA) filed by Exelixis against Cipla concerning an ANDA for a 60 mg dosage strength of the same drug. That action was stayed pending resolution of litigation between Exelixis and MSN Laboratories. The current complaint was triggered by Cipla's major amendment to its ANDA to add 20 mg and 40 mg dosage strengths.
Case Timeline
| Date | Event |
|---|---|
| 2009-01-16 | Earliest Priority Date for ’776, ’439, ’440, and ’015 Patents |
| 2011-02-10 | Earliest Priority Date for ’349 Patent |
| 2014-11-04 | U.S. Patent No. 8,877,776 Issued |
| 2016-01-01 | FDA Approval of CABOMETYX® (approximate date) |
| 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 | Cipla Notifies Exelixis of Original ANDA Submission |
| 2023-03-16 | Exelixis Files First Lawsuit Against Cipla (No. 23-287) |
| 2023-05-04 | Court Stays First Lawsuit (No. 23-287) |
| 2024-03-27 | Cipla Submits Amended ANDA for New Dosage Strengths |
| 2024-05-09 | 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: The patent background describes the general field of protein kinase inhibitors for treating cancer, where deregulation of kinase activity can lead to uncontrolled cell growth (’776 Patent, col. 2:5-11). While not explicitly stated as a problem, the development of a specific salt form of a known active pharmaceutical ingredient (API) is typically undertaken to solve physicochemical problems like poor solubility, stability, or manufacturability that can hinder the API's development into a viable drug product.
- The Patented Solution: The invention is a specific salt form of the API N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. Specifically, it claims the (L)-malate salt of the compound, which is formed by combining the API with (L)-malic acid (’776 Patent, col. 5:27-40). The patent discloses that this particular salt form has a combination of properties, including stability and suitable solubility, that make it preferable for pharmaceutical development (’776 Patent, col. 7:10-24).
- Technical Importance: Selecting an optimal salt form is a critical step in pharmaceutical development, as it can directly impact a drug's stability, shelf-life, dissolution rate, and bioavailability, thereby affecting its safety and efficacy.
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claim 2 (Compl. ¶38).
- Independent Claim 1 requires:
- (L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
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: The background section addresses the role of protein kinases like Ret, c-Met, and VEGFR2 in diseases associated with abnormal cell proliferation and angiogenesis, such as cancer (’439 Patent, col. 2:19-22). For a drug to be manufactured consistently and perform predictably, its solid-state form must be well-characterized and controlled, as different crystalline forms (polymorphs) of the same compound can have different physical properties.
- The Patented Solution: The patent discloses and claims specific crystalline forms of the malate salt of the API, identified as Form N-1 and Form N-2 (’439 Patent, col. 8:36-40; col. 9:1-4). These crystalline forms are defined by their unique physical characteristics, such as their x-ray powder diffraction (XRPD) patterns, which provide a structural fingerprint for each polymorph (’439 Patent, FIG. 1; FIG. 8).
- Technical Importance: Identifying and patenting specific, stable crystalline forms of a drug is crucial for ensuring batch-to-batch consistency in manufacturing and predictable clinical performance, including dissolution and bioavailability.
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claims 3 and 4 (Compl. ¶48).
- Independent Claim 1 requires:
- A crystalline malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,
- wherein the salt is the (L)-malate salt,
- 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, 12.8, etc.).
U.S. Patent No. 11,091,440 - "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"
- Technology Synopsis: This patent is related to the ’439 Patent and also claims specific crystalline forms of the malate salt of cabozantinib. The claims cover pharmaceutical compositions containing these specific crystalline forms.
- Asserted Claims: Claims 1 and 3 are asserted (Compl. ¶58).
- Accused Features: The Cipla ANDA Product, as a generic version of CABOMETYX®, is alleged to be a pharmaceutical composition containing a crystalline form of the claimed malate salt (Compl. ¶¶ 58-61).
U.S. Patent No. 11,098,015 - "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"
- Technology Synopsis: This patent is also related to the ’439 and ’440 patents and claims methods of treating cancer by administering specific crystalline forms of the (L)-malate or (D)-malate salt of cabozantinib.
- Asserted Claims: Claims 1 and 2 are asserted (Compl. ¶68).
- Accused Features: Cipla's submission of its ANDA and its proposed labeling are alleged to constitute infringement, as the product is intended for the treatment of cancer (Compl. ¶¶ 68-71).
U.S. Patent No. 11,298,349 - "Processes for Preparing Quinoline Compounds and Pharmaceutical Compositions Containing Such Compounds"
- Technology Synopsis: This patent claims processes for preparing quinoline compounds, including cabozantinib, and pharmaceutical compositions made by such processes. The claims focus on specific reaction steps and conditions intended to produce the compound.
- Asserted Claims: Claims 1-3 are asserted (Compl. ¶78).
- Accused Features: The Cipla ANDA Product is alleged to be made by a process that infringes the claimed methods, or is a pharmaceutical composition containing a compound made by such a process (Compl. ¶¶ 78-81).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is the generic drug product described in Cipla's Abbreviated New Drug Application (ANDA) No. 217870, including amendments to add 20 mg and 40 mg dosage strengths of Cabozantinib (S)-Malate tablets (Compl. ¶¶ 1, 31).
Functionality and Market Context
The Cipla ANDA Product is a generic version of Exelixis’s CABOMETYX® (cabozantinib), a tyrosine kinase inhibitor for oral administration (Compl. ¶25, 27). The complaint alleges that by filing its ANDA, Cipla has represented to the FDA that its product has the same active ingredient, dosage form, and strengths as CABOMETYX®, and is bioequivalent to it (Compl. ¶33). CABOMETYX® is approved by the FDA for treating patients with advanced kidney cancer and certain types of liver cancer (Compl. ¶25).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
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 complaint alleges that Cipla's ANDA Product contains the same active ingredient as CABOMETYX®, which is the claimed (L)-malate salt. | ¶33, ¶38 | col. 5:27-40 |
- Identified Points of Contention:
- Scope Questions: In the context of ANDA litigation, a defendant’s Paragraph IV certification typically asserts non-infringement and/or invalidity (Compl. ¶34). A potential non-infringement argument could question whether the salt formed by Cipla's process is identical to the claimed "(L)-malate salt," for instance, regarding stoichiometry, purity, or other physicochemical characteristics not explicitly recited in the claim.
- Technical Questions: A key question for the court may be whether the ANDA specification defines a product that, if manufactured and sold, would necessarily contain the specific (L)-malate salt as claimed.
U.S. Patent No. 11,091,439 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A crystalline malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, wherein said salt is the (L)-malate salt. | The complaint alleges that the Cipla ANDA Product contains the same active ingredient in the same dosage form as CABOMETYX®, which is alleged to be the claimed crystalline (L)-malate salt. | ¶33, ¶48 | col. 8:36-40 |
| and which is characterized by an x-ray powder diffraction pattern 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 alleges that the Cipla ANDA Product is a generic equivalent of CABOMETYX®, which is covered by this patent, suggesting the product will exhibit the claimed crystalline structure. | ¶26, ¶48 | col. 8:46-54; FIG. 1 |
- Identified Points of Contention:
- Scope Questions: Does the term "comprising four or more peaks" require only the presence of those peaks, or does it imply a substantial match to the overall diffraction pattern of the exemplified Form N-1 polymorph? Cipla may argue for a narrower construction limited to the specific polymorph disclosed in the patent specification.
- Technical Questions: What evidence does the complaint provide that the product Cipla intends to manufacture will possess the specific crystalline structure defined by the recited XRPD peaks? The central technical dispute will likely revolve around comparing the characterization data of Cipla's product with the claim limitations.
V. Key Claim Terms for Construction
- The Term: "crystalline malate salt... characterized by an x-ray powder diffraction pattern comprising four or more peaks selected from..." (from '439 Patent, Claim 1)
- Context and Importance: The definition of this term is central to the infringement analysis for the patents covering crystalline forms. The case may turn on whether the specific polymorph manufactured by Cipla for its generic product falls within the scope of this definition. Practitioners may focus on this term because polymorphism is a common area of dispute in pharmaceutical patent litigation, where even minor variations in crystal structure can differentiate a patented form from a non-infringing one.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The use of the open-ended term "comprising" could support an interpretation that the accused product need only exhibit four or more of the listed peaks, even if other peaks are present or some are absent.
- Evidence for a Narrower Interpretation: The specification provides detailed characterization of a specific crystalline form, "Form N-1," including a full XRPD pattern in Figure 1 (’439 Patent, FIG. 1). A party might argue that the claim should be construed to cover only crystalline forms that are substantially identical to Form N-1 as depicted and described, not any form that happens to have a subset of the listed peaks.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that upon FDA approval, Cipla will induce infringement by encouraging healthcare providers and patients to use the ANDA Product in accordance with its proposed labeling, which will track the approved uses for CABOMETYX® (Compl. ¶¶ 41, 51, 61, 71, 81). Contributory infringement is also alleged on the basis that the product is not a staple article of commerce suitable for substantial non-infringing use (Compl. ¶¶ 42, 52, 62, 72, 82).
- Willful Infringement: The complaint does not use the word "willful," but alleges that Cipla acted "without a reasonable basis for believing that they would not be liable for directly and/or indirectly infringing" the patents-in-suit, and states that "This is an exceptional case" (Compl. ¶¶ 45, 55, 65, 75, 85). These allegations are based on Cipla's knowledge of the patents, as evidenced by its Paragraph IV certifications submitted with its ANDA (Compl. ¶¶ 34, 35).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of validity: as this is a Hatch-Waxman action triggered by a Paragraph IV certification, a central question will be whether Cipla can demonstrate by clear and convincing evidence that the asserted claims—directed to a specific salt and its crystalline forms—are invalid as anticipated or obvious in light of prior art disclosing the underlying active compound.
- A key evidentiary question will be one of structural identity: assuming the patents are valid, does the crystalline form of cabozantinib malate produced by Cipla's manufacturing process meet the specific structural limitations defined by the XRPD and other characterization data in the asserted claims, or does it represent a distinct, non-infringing polymorph?
- For the process patent (’349 Patent), a central issue will be one of process comparison: will Exelixis be able to demonstrate that the manufacturing process Cipla intends to use to synthesize its active ingredient is the same as, or equivalent to, the process claimed in the ’349 Patent?