DCT
1:24-cv-01208
Exelixis Inc v. Sun Pharmaceutical Industries Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Exelixis, Inc. (Delaware)
- Defendant: Sun Pharmaceutical Industries Ltd. (India); Sun Pharmaceutical Industries, Inc. (Delaware)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP; Wilmer Cutler Pickering Hale and Dorr LLP
- Case Identification: 1:24-cv-01208, D. Del., 10/30/2024
- Venue Allegations: Plaintiff alleges venue is proper in Delaware because Defendant Sun Pharmaceutical Industries, Inc. is a Delaware corporation, and Defendant Sun Pharmaceutical Industries 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 a generic version of Plaintiff's cancer drug CABOMETYX® constitutes an act of patent infringement.
- Technical Context: The technology concerns specific salt forms and crystalline structures of cabozantinib, a tyrosine kinase inhibitor compound used in oncology, which are designed to improve the compound's suitability for pharmaceutical development and administration.
- Key Procedural History: The litigation was triggered by Defendants notifying Plaintiff of their ANDA filing, which included a "Paragraph IV certification" alleging that the patents-in-suit are invalid and/or would not be infringed by the proposed generic product. The patents are listed in the FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations," commonly known as the "Orange Book."
Case Timeline
| Date | Event |
|---|---|
| 2009-01-16 | Earliest Patent Priority Date ('’776, '’439, '’440, '’015 Patents) |
| 2014-11-04 | U.S. Patent No. 8,877,776 Issued |
| 2016-01-01 | Plaintiff's CABOMETYX® Product Approved by FDA |
| 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 |
| 2024-09-17 | Plaintiff Receives Defendants' ANDA Notice Letter |
| 2024-10-30 | Complaint Filing Date |
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 the base compound cabozantinib was known to have therapeutic activity, developing it into a viable drug product requires a form with suitable physicochemical properties for large-scale manufacturing, formulation stability, and consistent bioavailability ('439 Patent, col. 3:21-25).
- The Patented Solution: The invention is a specific salt of the active drug compound, combining it with (L)-malic acid ('776 Patent, Abstract). This salt form was found to possess a combination of desirable properties, including stability and solubility, making it suitable for development into a pharmaceutical product ('439 Patent, col. 7:10-25).
- Technical Importance: The selection of an optimal salt form is a critical step in pharmaceutical development that can determine whether a promising compound can become a successful medicine.
Key Claims at a Glance
- Independent claim 1 is asserted (Compl. ¶33).
- The claim recites a single composition of matter:
- The (L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
- The complaint also asserts dependent claims 2, 3, and 5 (Compl. ¶33).
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: Beyond selecting a salt, ensuring consistency in a solid dosage form requires controlling the solid-state structure of the drug substance. Different crystalline arrangements, or polymorphs, can have different properties affecting stability and dissolution ('439 Patent, col. 7:31-44).
- The Patented Solution: This patent claims specific crystalline forms of the cabozantinib malate salt ('439 Patent, Abstract). These forms are defined by unique physical characteristics, such as their X-ray powder diffraction (XRPD) patterns, which provide a structural "fingerprint" ensuring lot-to-lot consistency in the manufactured drug substance ('439 Patent, col. 8:46-64; Fig. 1).
- Technical Importance: Controlling polymorphism is crucial for ensuring the safety, efficacy, and quality of a solid oral drug, as different forms can have different bioavailabilities.
Key Claims at a Glance
- Independent claim 1 is asserted (Compl. ¶41).
- Claim 1 recites a composition of matter with a structural requirement:
- N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt,
- wherein said salt is crystalline.
- The complaint also asserts dependent claims 3 and 4 (Compl. ¶41).
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 claims pharmaceutical compositions that contain the crystalline malate salt of cabozantinib along with a pharmaceutically acceptable excipient ('440 Patent, col. 32:5-11). The invention moves from the drug substance itself to the formulated drug product intended for administration to patients.
Asserted Claims
Claims 1 and 3 are asserted (Compl. ¶49).
Accused Features
The Sun ANDA Product is alleged to be a pharmaceutical composition containing the claimed crystalline active ingredient (Compl. ¶¶ 26-27, 49).
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 claims methods of treating specific cancers, such as kidney or liver cancer, by administering the crystalline (L)-malate or (D)-malate salt of cabozantinib ('015 Patent, col. 32:5-20). The invention covers the therapeutic application of the specific crystalline salt form.
Asserted Claims
Claims 1, 2, and 3 are asserted (Compl. ¶57).
Accused Features
The complaint alleges that the label for the Sun ANDA Product will instruct users to administer the drug for the claimed indications, which would induce infringement of these method claims (Compl. ¶¶ 24, 26, 57-58).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Defendants' proposed generic version of CABOMETYX®, identified as the "Sun ANDA Product" associated with ANDA No. 214385 (Compl. ¶¶ 1, 26). The product is specified as Cabozantinib (S)-Malate Tablets in 20 mg, 40 mg, and 60 mg strengths (Compl. ¶26).
Functionality and Market Context
The Sun ANDA Product is a tyrosine kinase inhibitor intended for oral administration for the treatment of various cancers, including renal cell carcinoma and hepatocellular carcinoma (Compl. ¶24). The complaint alleges that by filing its ANDA, Defendants have represented to the FDA that their product contains the same active ingredient as CABOMETYX®, has the same dosage forms and strengths, and is bioequivalent (Compl. ¶27). No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint does not contain detailed infringement allegations or claim charts. The theory of infringement under 35 U.S.C. § 271(e)(2)(A) is based on the act of submitting the ANDA itself. The core factual allegation is that the Sun ANDA Product will contain the claimed salt and crystalline forms of cabozantinib.
’776 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| The (L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. | The Sun ANDA Product is for "Cabozantinib (S)-Malate Tablets," which the complaint alleges is the same active ingredient as CABOMETYX® and thus is the claimed (L)-malate salt. | ¶¶ 26, 27, 33 | col. 4:35-47 |
’439 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, malate salt, | The Sun ANDA Product is alleged to contain the malate salt of cabozantinib. | ¶¶ 26, 27, 41 | col. 4:35-47 |
| wherein said salt is crystalline. | The Sun ANDA Product is a solid tablet dosage form alleged to contain the active ingredient in a crystalline state. | ¶¶ 26, 27, 41 | col. 8:26-64 |
Identified Points of Contention
- Factual Questions: The central dispute will be factual: what is the precise chemical and physical form of the active pharmaceutical ingredient (API) in the Sun ANDA Product? As Defendants certified non-infringement (Compl. ¶28), they may argue their product uses an amorphous form, a different salt, or a crystalline polymorph not covered by the asserted claims. The case will likely depend on the results of analytical characterization of Defendants' product.
- Scope Questions: A potential question for the court is whether any differences between the API in the Sun ANDA Product and the claimed forms are sufficient to avoid infringement. This may involve interpreting the scope of terms like "crystalline" and determining whether infringement exists literally or under the doctrine of equivalents.
V. Key Claim Terms for Construction
The complaint does not provide sufficient detail for analysis of specific claim construction disputes. However, based on the technology, certain terms are likely to be central.
- The Term: "crystalline" (’439 Patent, Claim 1)
- Context and Importance: The distinction between "crystalline" and "amorphous" forms of a drug substance is fundamental in pharmaceutical patenting. The outcome of the case for the '439, '440, and '015 patents hinges on whether the Sun ANDA Product contains a "crystalline" salt. Practitioners may focus on this term because a generic manufacturer could attempt to design around the patents by developing a stable amorphous formulation.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification does not provide an explicit definition of "crystalline." A party could argue for the term’s plain and ordinary meaning, which generally refers to any solid material whose constituent atoms, molecules, or ions are arranged in an ordered pattern extending in all three spatial dimensions.
- Evidence for a Narrower Interpretation: A party might argue that "crystalline" should be construed to be limited to the specific crystalline forms disclosed in the patent, such as "Form N-1" or "Form N-2," which are defined by specific XRPD peaks and other physical data ('439 Patent, col. 8:46-64; col. 9:1-20). Opponents of this view would likely argue this constitutes improper importation of limitations from the specification into the claims.
VI. Other Allegations
- Indirect Infringement: The complaint alleges inducement of infringement for all asserted patents (e.g., ’776 Patent, Compl. ¶34). This allegation is particularly relevant for the method-of-use claims of the ’015 Patent. The basis is the allegation that Defendants' product label will instruct physicians and patients to administer the drug for the patented indications, thereby encouraging infringing acts.
- Willful Infringement: The complaint asserts that Defendants acted without a reasonable basis for believing they would not be liable for infringement, and that the case is "exceptional" (e.g., ’776 Patent, Compl. ¶38). This allegation is based on Defendants' knowledge of the patents, evidenced by their Paragraph IV certification, prior to engaging in the allegedly infringing act of filing the ANDA (Compl. ¶29).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of evidentiary proof: What is the actual solid-state form of the cabozantinib malate in Sun's proposed generic product? The dispute will likely center on competing analytical data (e.g., XRPD, DSC, NMR) to determine if the product contains the specific (L)-malate salt and crystalline forms protected by Exelixis's patents.
- A key legal question will be one of validity: As Defendants certified invalidity, the case will also turn on whether the claimed salt and crystalline forms were non-obvious inventions over the known cabozantinib compound. The court will likely have to consider whether selecting the (L)-malate salt and discovering its specific crystalline forms would have been a matter of routine experimentation for a person of ordinary skill in the art.