DCT
1:25-cv-00735
Aveo Pharma Inc v. Glenmark Pharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: AVEO Pharmaceuticals, Inc. (Delaware) and Kyowa Kirin Co., Ltd. (Japan)
- Defendant: Glenmark Pharmaceuticals Limited (India) and Glenmark Pharmaceuticals Inc., USA (Delaware)
- Plaintiff’s Counsel: Farnan LLP
- Case Identification: 1:25-cv-00735, D. Del., 06/13/2025
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Glenmark USA is a Delaware corporation, and Defendant Glenmark Pharmaceuticals is a foreign corporation subject to suit in any judicial district.
- Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' FOTIVDA® (tivozanib) product constitutes an act of infringement of two U.S. patents.
- Technical Context: The technology is in the field of oncology therapeutics, specifically concerning the small-molecule drug tivozanib, a tyrosine kinase inhibitor used for treating advanced renal cell carcinoma (RCC).
- Key Procedural History: This action was filed under the Hatch-Waxman Act following Plaintiffs' receipt of a Paragraph IV Notice Letter from Defendants. Plaintiffs' drug, FOTIVDA®, was approved by the FDA on March 10, 2021, and was awarded New Chemical Entity (NCE) exclusivity, which expires on March 10, 2026. Both patents-in-suit are listed in the FDA's Orange Book for FOTIVDA®.
Case Timeline
| Date | Event |
|---|---|
| 2002-10-21 | ’722 Patent Priority Date |
| 2007-01-23 | ’722 Patent Issue Date |
| 2018-11-05 | ’365 Patent Priority Date |
| 2020-03-31 | FOTIVDA® New Drug Application (NDA) Submitted |
| 2021-03-10 | FOTIVDA® FDA Approval Date |
| 2022-11-22 | ’365 Patent Issue Date |
| 2025-05-02 | Glenmark sent Paragraph IV Notice Letter (on or before) |
| 2025-05-05 | Plaintiffs received Paragraph IV Notice Letter |
| 2025-06-13 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 11,504,365 - Use of Tivozanib to Treat Subjects with Refractory Cancer
Issued November 22, 2022
The Invention Explained
- Problem Addressed: The patent describes a need for effective treatments for patients with advanced renal cell carcinoma (RCC) who have already been treated with and failed multiple prior lines of therapy, including modern targeted and immune-oncology therapies (’365 Patent, col. 2:5-12).
- The Patented Solution: The invention is a method of treating these "refractory" cancer patients by administering a specific regimen of tivozanib, a VEGF receptor tyrosine kinase inhibitor. The patent discloses that this method can improve patient outcomes, such as progression-free survival, in this heavily pre-treated population (’365 Patent, col. 2:15-28, Fig. 1).
- Technical Importance: The method provides a therapeutic option for a patient population with advanced, difficult-to-treat cancer for whom other therapies, including other kinase inhibitors, are no longer effective (’365 Patent, col. 2:5-12).
Key Claims at a Glance
- The complaint asserts independent claims 1 and 7 (Compl. ¶51).
- Independent Claim 1 recites a method of treating a human subject with refractory advanced RCC who has received at least two prior anti-cancer therapies (including a TKI), which comprises:
- Administering treatment cycles consisting essentially of 1.5 mg of tivozanib hydrochloride daily for 21 days, followed by 7 days off.
- Continuing this cycle until the subject experiences moderate hepatic impairment.
- Reducing the dose to 1.0 mg upon moderate hepatic impairment.
- Thereby achieving a progression-free survival of at least 5 months.
- Independent Claim 7 recites a method of treating a human subject with refractory advanced RCC who has received at least two prior anti-cancer therapies (including a TKI) and is experiencing moderate hepatic impairment, which comprises:
- Administering treatment cycles consisting essentially of 1.0 mg tivozanib hydrochloride daily for 21 days, followed by 7 days off.
- Thereby to treat RCC.
- The complaint reserves the right to assert additional claims (Compl. ¶51).
U.S. Patent No. 7,166,722 - N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea salt in crystalline form
Issued January 23, 2007
The Invention Explained
- Problem Addressed: The patent addresses the need for active pharmaceutical ingredients to have specific physicochemical properties, such as thermal stability and low hygroscopicity, that make them suitable for formulation into reliable and mass-producible oral medications (’722 Patent, col. 1:21-34).
- The Patented Solution: The invention provides a specific crystalline form of a tivozanib salt—a monohydrochloric acid salt monohydrate—that possesses these desirable properties (’722 Patent, Abstract; col. 4:35-43). The patent characterizes this crystalline form using techniques like X-ray powder diffraction and differential scanning calorimetry (’722 Patent, col. 4:35-43, Fig. 1).
- Technical Importance: Developing a stable, well-characterized crystalline form of a drug is a critical and non-obvious step in creating a safe, effective, and commercially viable oral drug product.
Key Claims at a Glance
- The complaint asserts independent claims 1 and 13 (Compl. ¶82).
- Independent Claim 1 claims the composition of matter itself:
- Crystalline N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea monohydrochloric acid salt monohydrate.
- Independent Claim 13 claims a process for producing the crystal of claim 1, comprising the steps of:
- Adding hydrochloric acid to a solution of the tivozanib compound in an aprotic polar solvent (N,N-dimethylformamide or N,N-dimethylacetamide).
- Adding ethanol and water to the solution to precipitate the crystals.
- The complaint reserves the right to assert additional claims (Compl. ¶82).
III. The Accused Instrumentality
Product Identification
Defendants' proposed generic tivozanib hydrochloride products, which are the subject of ANDA No. 220307 (the "Proposed ANDA Product") (Compl. ¶1, ¶41).
Functionality and Market Context
The Proposed ANDA Product is a generic version of Plaintiffs' FOTIVDA® and seeks approval for the same strengths, EQ 0.89 mg base and EQ 1.34 mg base (Compl. ¶28-29, ¶41). As a generic drug, it is designed to be bioequivalent to FOTIVDA® (Compl. ¶18). The complaint alleges that the label for the Proposed ANDA Product will substantively copy the FOTIVDA® label and will therefore be indicated for the treatment of adult patients with relapsed or refractory advanced RCC following two or more prior systemic therapies (Compl. ¶52-53). The product is a tyrosine kinase inhibitor targeting VEGFR-1, -2, and -3 to inhibit angiogenesis (Compl. ¶35).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
'365 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating a human subject with refractory advanced renal cell carcinoma (RCC) having previously received at least two anti-cancer therapies, at least one of which included a tyrosine kinase inhibitor (TKI)... | The label for Glenmark’s Proposed ANDA Product will be indicated for treating adult patients with relapsed or refractory advanced RCC following two or more prior systemic therapies. The label will also describe the TIVO-3 study, where all patients had received a prior TKI. | ¶53, ¶56 | col. 2:15-28 |
| ...administering...treatment cycles consisting essentially of: orally administering a pharmaceutical composition comprising an active agent consisting essentially of 1.5 mg tivozanib hydrochloride daily for 21 days followed by 7 days... | The label for Glenmark's Proposed ANDA Product will instruct a recommended dosage of 1.34 mg tivozanib base (equivalent to 1.5 mg tivozanib hydrochloride) taken once daily for 21 days on treatment followed by 7 days off treatment. | ¶57 | col. 2:35-41 |
| ...until the subject experiences moderate hepatic impairment, upon which the amount of tivozanib hydrochloride in each treatment cycle is reduced from 1.5 mg to 1.0 mg, | Glenmark’s proposed label will include instructions to reduce the dose for patients with moderate hepatic impairment from 1.5 mg to 1.0 mg of tivozanib hydrochloride. This corresponds to the 0.89 mg tivozanib base dosage form. | ¶59, ¶60 | col. 31:1-6 |
| ...thereby to achieve a progression free survival in the subject of at least 5 months. | The label for Glenmark's Proposed ANDA Product will report efficacy results from clinical trials where the median duration of progression-free survival in patients receiving tivozanib was 5.6 months. | ¶62 | col. 31:7-9 |
Identified Points of Contention
- Scope Questions: The infringement analysis for the '365 Patent will turn on whether the instructions in the proposed label for Glenmark's product induce physicians to perform every step of the claimed method. A central question may be the interpretation of the "thereby to achieve" clause. Does reporting a median clinical trial result of 5.6 months on a label satisfy a claim limitation requiring the achievement of "at least 5 months" of progression-free survival?
- Technical Questions: Infringement is based on the contents of a proposed label that will allegedly mirror the FOTIVDA® label. The dispute will be whether following these label instructions necessarily results in direct infringement by physicians and patients.
'722 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| Crystalline N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-methyl-3-isoxazolyl)urea monohydrochloric acid salt monohydrate. | Glenmark’s Proposed ANDA Product will, upon manufacture and during its shelf life, contain the same active ingredient as FOTIVDA®, which is alleged to be the claimed crystalline tivozanib hydrochloride monohydrate. | ¶84 | col. 4:35-43 |
Identified Points of Contention
- Scope Questions: For claim 13 (the process claim), the complaint alleges infringement on "information and belief" (Compl. ¶85). The central question will be what evidence, if any, Plaintiffs can obtain in discovery to show that Glenmark’s manufacturing process uses the specific solvents and steps required by the claim.
- Technical Questions: The primary dispute for claim 1 will be factual: does the generic product in Glenmark’s ANDA actually comprise the specific crystalline polymorph claimed in the ’722 Patent? Defendants in such cases often argue that their product is made of a different, non-infringing polymorph or an amorphous form.
V. Key Claim Terms for Construction
Term from '365 Patent: "thereby to achieve a progression free survival in the subject of at least 5 months"
- Context and Importance: This result-oriented "thereby" clause is a likely focus of claim construction. Its interpretation is critical because it dictates what must be proven for infringement. The dispute will center on whether this clause imposes a condition that must be met for infringement to occur or is merely a statement of the intended outcome of practicing the method.
- Intrinsic Evidence for a Broader Interpretation: A party could argue the clause merely states the purpose or benefit of the claimed dosing regimen, pointing to language in the summary of the invention that frames the methods as providing "improved methods of treating subjects" (’365 Patent, col. 2:15-18).
- Intrinsic Evidence for a Narrower Interpretation: A party could argue the clause is a material limitation, requiring proof that the method is capable of achieving this outcome. They might cite the patent's heavy reliance on the TIVO-3 clinical trial data, where the median PFS was 5.6 months, as evidence that this specific outcome is a defining, essential feature of the invention (’365 Patent, Fig. 1; col. 6:35-41).
Term from '722 Patent: "Crystalline ... monohydrochloric acid salt monohydrate"
- Context and Importance: The definition of this term is central to the infringement analysis for the ’722 Patent's composition claim. The case will depend on whether Glenmark's product falls within the scope of this term.
- Intrinsic Evidence for a Broader Interpretation: A party could argue that the term should be given its plain meaning, covering any crystalline form that is chemically a monohydrochloric acid salt and a monohydrate of the tivozanib molecule, regardless of minor variations in crystal lattice structure.
- Intrinsic Evidence for a Narrower Interpretation: A party could argue the term is implicitly defined by the specific characterization data in the patent. This would limit the claim's scope to a crystalline form that exhibits the specific powder X-ray diffraction peaks listed in Table 1 and the endothermic peaks shown in the differential scanning calorimetry chart in Figure 1 (’722 Patent, col. 4:35-43; col. 25:12-20).
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced and contributory infringement of the method claims of the ’365 Patent. The inducement allegation is based on the assertion that Glenmark's proposed product label will instruct and encourage physicians and patients to administer the drug in an infringing manner (Compl. ¶50, ¶52, ¶64). The contributory infringement allegation is based on the assertion that the product has no substantial non-infringing uses (Compl. ¶68). Similar allegations are made for the ’722 Patent (Compl. ¶86, ¶90).
- Willful Infringement: Willfulness is alleged for both patents. The complaint asserts that Defendants had knowledge of the patents, as evidenced by their filing of a Paragraph IV certification, and nonetheless proceeded with their intent to market an infringing product (Compl. ¶65-67, ¶87-89).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central evidentiary issue will be one of polymorphic identity: Will discovery reveal that Glenmark's proposed generic drug product is, in fact, the specific "crystalline...monohydrochloric acid salt monohydrate" claimed in the ’722 Patent, or will Glenmark be able to demonstrate that it utilizes a different, non-infringing crystal form?
- A key legal and factual issue will be one of induced infringement: Will Glenmark’s proposed product label, which is expected to mirror the FOTIVDA® label, be found to actively encourage or instruct physicians to perform all the steps of the methods claimed in the ’365 Patent, thereby satisfying the requirements for induced infringement?
- The dispute may also hinge on a question of claim scope: How will the court construe the result-oriented clause "thereby to achieve a progression free survival...of at least 5 months" in claim 1 of the ’365 Patent? Whether this is interpreted as a required outcome for infringement or a statement of intended purpose will significantly impact the infringement analysis.