DCT
1:19-cv-02017
Exelixis Inc v. MSN Laboratories Pvt Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Exelixis, Inc. (Delaware)
- Defendant: MSN Laboratories Private Limited (India) and MSN Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:19-cv-02017, D. Del., 10/29/2019
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant MSN Pharmaceuticals, Inc. is a Delaware corporation and thus resides in the district, and Defendant MSN Laboratories Private Limited is not a resident of the United States and may be sued in any judicial district.
- Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the cancer drug CABOMETYX® constitutes an act of infringement of a patent covering a specific crystalline salt form of the drug's active ingredient.
- Technical Context: The technology concerns pharmaceutical formulation, specifically the creation of a particular crystalline polymorph of an active pharmaceutical ingredient to achieve desirable properties for drug development, such as improved stability and solubility.
- Key Procedural History: This action was commenced under the Hatch-Waxman Act following Defendants' submission of an ANDA containing a Paragraph IV certification, which asserted that U.S. Patent No. 8,877,776 is invalid, unenforceable, and/or would not be infringed by the proposed generic product.
Case Timeline
| Date | Event |
|---|---|
| 2009-01-16 | '776 Patent Priority Date |
| 2014-11-04 | '776 Patent Issue Date |
| 2016 | FDA approval for Plaintiff's CABOMETYX® |
| 2019-09-24 | Date of Defendants' notice letter regarding ANDA submission |
| 2019-10-29 | 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,” Issued November 4, 2014
The Invention Explained
- Problem Addressed: The patent addresses the general need in drug development to find a form of a therapeutic agent with suitable properties for "processing, manufacturing, storage stability, and/or usefulness as a drug" ('776 Patent, col. 3:3-8). While the base compound, a known kinase inhibitor, had therapeutic efficacy, creating a commercially viable drug product required identifying a form with optimal physical and chemical characteristics ('776 Patent, col. 1:49-52, col. 3:3-8).
- The Patented Solution: The invention is a specific salt of the active compound: the (L)-malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, also known as cabozantinib ('776 Patent, Abstract). The patent further identifies and claims specific crystalline forms (polymorphs) of this salt, designated N-1 and N-2, which are described as having a "preferred combination of pharmaceutical properties for development" ('776 Patent, col. 6:55-61). Table 1 of the patent presents data suggesting the (L)-malate salt is crystalline, non-hygroscopic, and possesses suitable solubility compared to other tested salts ('776 Patent, col. 7-8, Table 1).
- Technical Importance: Identifying a stable, consistently manufacturable crystalline form (polymorph) of a drug is often critical for ensuring product quality, consistent bioavailability, and a stable shelf life, which are fundamental requirements for regulatory approval and commercial success ('776 Patent, col. 3:3-8).
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claim 2 (Compl. ¶29).
- Independent Claim 1 requires:
- N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (L)-malate salt,
- wherein said salt is in crystalline Form N-2,
- and said Form N-2 is characterized by at least one of three specified analytical criteria: (i) a solid state ¹³C NMR spectrum with certain peaks, (ii) an X-ray powder diffraction (XRPD) pattern with certain 2θ values, or (iii) an XRPD pattern "substantially in accordance with the pattern shown in FIG. 8." ('776 Patent, col. 31:1-14).
- The complaint reserves the right to assert additional claims, though only claims 1-2 are specifically identified in the infringement count and prayer for relief (Compl. ¶29, Prayer for Relief ¶(a)).
III. The Accused Instrumentality
Product Identification
- Defendants' proposed generic "Cabozantinib S-Malate Tablets, 20 mg, 40 mg, and 60 mg," as described in Abbreviated New Drug Application (ANDA) No. 213878 (Compl. ¶21).
Functionality and Market Context
- The complaint alleges that by filing the ANDA, Defendants have represented to the FDA that their product has the same active ingredient, dosage forms, and strengths as Plaintiff's branded drug, CABOMETYX®, and is bioequivalent to it (Compl. ¶22). CABOMETYX® is a tyrosine kinase inhibitor approved for treating certain types of advanced kidney and liver cancer (Compl. ¶19). The complaint alleges that Defendants seek FDA approval to market this generic product before the expiration of the ’776 Patent (Compl. ¶23).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
'776 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 (L)-malate salt... | The complaint alleges that Defendants' ANDA product contains the same active ingredient as CABOMETYX®, which is alleged to be the claimed (L)-malate salt of cabozantinib. | ¶22 | col. 5:6-15 |
| ...wherein said salt is in crystalline Form N-2... | Infringement is alleged based on the ANDA filing for a product asserted to be bioequivalent to CABOMETYX®, which is listed in the FDA's Orange Book as being covered by the claims of the '776 Patent, including claims to Form N-2. | ¶20, ¶29 | col. 8:46-48 |
| ...and said Form N-2 is characterized by... an x-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 8. | The allegation is based on the statutory act of filing the ANDA. The complaint notes that the confidential data required to prove the product meets this characterization has been requested from Defendants but not yet provided. | ¶24, ¶29 | col. 8:57-61 |
- Identified Points of Contention:
- Technical Questions: A primary factual dispute will be whether the active pharmaceutical ingredient in Defendants' ANDA product actually exhibits the specific analytical characteristics (e.g., the XRPD pattern) required to meet the definition of "crystalline Form N-2" in claim 1. The complaint indicates Plaintiff has not yet been provided with the confidential Drug Master File containing this technical information (Compl. ¶24).
- Scope Questions: The case may raise the question of what degree of analytical similarity is required by the phrase "substantially in accordance with the pattern shown in FIG. 8." The resolution will determine how much the XRPD pattern of Defendants' product can deviate from the patent's reference figure while still falling within the claim's scope.
V. Key Claim Terms for Construction
The Term: "crystalline Form N-2"
Context and Importance: This term is the central limitation of the asserted claims. The infringement analysis will hinge entirely on whether Defendants' product is properly classified as this specific polymorph. Practitioners may focus on this term because the patent defines it not by chemical structure alone, but by specific, instrument-based analytical data ('776 Patent, col. 8:46-61).
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language states Form N-2 is "characterized by at least one of the following" analytical criteria ('776 Patent, col. 31:4-5). This structure may support an interpretation that a product need only meet one of the three listed characterizations (NMR, specific XRPD peaks, or the overall XRPD pattern) to be considered "Form N-2."
- Evidence for a Narrower Interpretation: The patent provides extensive characterization data for Form N-2, including not only XRPD (Fig. 8) and NMR (Figs. 9-11) data but also thermal analysis (Figs. 12-13) and moisture sorption data (Fig. 14). A party could argue that for a product to truly be "Form N-2," it must be consistent with the full set of characteristics disclosed in the specification for that polymorph, not just the minimum required by the claim language.
The Term: "substantially in accordance with"
Context and Importance: This phrase, used in claim 1(iii) to relate an accused product's XRPD pattern to the patent's Figure 8, introduces a degree of ambiguity that is common in patent litigation over polymorphs. Its construction will define the boundaries of infringement.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification does not provide an explicit definition for "substantially." This may support relying on the understanding of a person of ordinary skill in the art, who would expect minor variations in peak position and intensity in XRPD patterns due to differences in sample preparation and instrumentation.
- Evidence for a Narrower Interpretation: The patent distinguishes Form N-1 from Form N-2 using unique reflection peaks in their respective XRPD patterns ('776 Patent, Table 2, col. 10:21-37). This emphasis on specific distinguishing peaks could support a narrower interpretation where "substantially in accordance with" requires a very high degree of correlation with Figure 8, including the presence and relative intensity of all major peaks.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that upon approval of the ANDA, Defendants' commercial manufacture, use, and sale of the product would induce and/or contribute to infringement by others (Compl. ¶30).
- Willful Infringement: The complaint alleges that Defendants acted "without a reasonable basis for believing that they would not be liable" for infringement, which forms the basis for a willfulness claim (Compl. ¶34). This allegation is based on Defendants having knowledge of the ’776 Patent, as evidenced by their Paragraph IV certification, and proceeding with actions to market a generic equivalent (Compl. ¶23, ¶25).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central evidentiary question will be one of polymorphic identity: does the crystalline form of the active ingredient in Defendants' ANDA product, as evidenced by their confidential characterization data, meet the specific analytical criteria defining "crystalline Form N-2" as required by claim 1 of the '776 patent?
- A core legal question will be one of definitional scope: how much variance is permitted by the claim term "substantially in accordance with"? The court's construction of this term will determine the degree of similarity required between the accused product's X-ray diffraction pattern and the patent's reference Figure 8 to prove infringement.