DCT
1:25-cv-00639
AVEO Pharma Inc v. Hetero USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: AVEO Pharmaceuticals, Inc. (Delaware)
- Defendant: Hetero USA Inc. (Delaware), Hetero Labs Limited Unit-V (India), and Hetero Labs Limited (India)
- Plaintiff’s Counsel: Farnan LLP (with Dechert LLP as Of Counsel)
- Case Identification: 1:25-cv-00639, D. Del., 05/23/2025
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Hetero USA is incorporated in Delaware, and the other foreign-based Defendant entities may be sued in any judicial district.
- Core Dispute: Plaintiff alleges that Defendants' Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's FOTIVDA® (tivozanib) cancer treatment product infringes a patent covering a specific method of using the drug.
- Technical Context: The technology relates to a method-of-use for tivozanib, a tyrosine kinase inhibitor, for treating adult patients with relapsed or refractory advanced renal cell carcinoma (RCC) who have undergone prior therapies.
- Key Procedural History: This action was filed under the Hatch-Waxman Act following Plaintiff's receipt of a Paragraph IV Notice Letter from Defendants. The letter asserted that the patent-in-suit is invalid and not infringed by Defendants' proposed generic product. The complaint was filed within the 45-day statutory window, which triggers an automatic 30-month stay on the FDA’s approval of the Defendants' ANDA.
Case Timeline
| Date | Event |
|---|---|
| 2018-11-05 | U.S. Patent No. 11,504,365 Priority Date |
| 2020-03-31 | AVEO submits New Drug Application (NDA) for FOTIVDA® |
| 2021-03-10 | FDA approves AVEO's NDA for FOTIVDA® |
| 2022-11-22 | U.S. Patent No. 11,504,365 Issues |
| 2025-04-22 | Hetero submits ANDA No. 220437 for generic tivozanib |
| 2025-04-23 | AVEO receives Hetero's Paragraph IV Notice Letter |
| 2025-05-23 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 11,504,365 - Use of Tivozanib to Treat Subjects with Refractory Cancer
- Patent Identification: 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 failed first and second-line therapies, including other tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors (’365 Patent, col. 2:5-12). This patient population is considered to have "refractory" cancer.
- The Patented Solution: The patent discloses a specific method of treating this refractory patient population with tivozanib, a potent and selective vascular endothelial growth factor (VEGF) receptor inhibitor. The method involves a specific dosing regimen (1.5 mg daily for 21 days followed by 7 days off) that is reduced upon evidence of moderate hepatic impairment, with the goal of achieving a clinically significant progression-free survival period (’365 Patent, Abstract; col. 2:15-24; col. 4:25-35).
- Technical Importance: The claimed method provides a third-line therapeutic option that demonstrated a statistically significant improvement in progression-free survival in a difficult-to-treat patient population compared to another established therapy (’365 Patent, col. 5:20-34).
Key Claims at a Glance
- The complaint asserts independent claims 1 and 7 (Compl. ¶52).
- Essential elements of Independent Claim 1:
- A method of treating a human subject with refractory advanced RCC who has previously received at least two anti-cancer therapies, one of which was a TKI.
- The method comprises administering treatment cycles "consisting essentially of" orally administering a 1.5 mg dose of tivozanib hydrochloride daily for 21 days, followed by 7 days off.
- This cycle continues until the subject experiences moderate hepatic impairment.
- Upon impairment, the dose is reduced from 1.5 mg to 1.0 mg.
- The method thereby achieves a progression-free survival of at least 5 months.
- Essential elements of Independent Claim 7:
- A method of treating a human subject with refractory advanced RCC who has previously received at least two anti-cancer therapies (one a TKI) and is currently experiencing moderate hepatic impairment.
- The method comprises administering one or more treatment cycles "consisting essentially of" orally administering a 1.0 mg dose of tivozanib hydrochloride daily for 21 days, followed by 7 days off.
- The method is "thereby to treat RCC."
- The complaint does not explicitly reserve the right to assert dependent claims.
III. The Accused Instrumentality
Product Identification
- Defendants' proposed generic tivozanib hydrochloride products, equivalent to 1.34 mg and 0.89 mg base strengths, as described in ANDA No. 220437 (the "Proposed ANDA Product") (Compl. ¶42).
Functionality and Market Context
- The complaint alleges that the "instrumentality" is the use of the Proposed ANDA Product in accordance with its proposed labeling, which is expected to substantively copy the label of AVEO's FOTIVDA® (Compl. ¶53). The allegations state this proposed label will instruct healthcare providers and patients to administer the drug for the treatment of adult patients with relapsed or refractory advanced RCC following two or more prior systemic therapies (Compl. ¶54). The label will allegedly recommend a dosage equivalent to 1.5 mg of tivozanib hydrochloride and instruct a dose reduction to the equivalent of 1.0 mg for patients with moderate hepatic impairment (Compl. ¶¶58, 60, 61). The complaint also alleges the label will report clinical trial efficacy results, including a median progression-free survival of 5.6 months (Compl. ¶63).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
- Claim Chart Summary:
11,504,365 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 proposed label for Hetero's product will indicate it for the treatment of adult patients with relapsed or refractory advanced RCC following two or more prior systemic therapies, a population that would have received at least one prior TKI. | ¶54, ¶56-57 | col. 2:15-24 |
| administering to the subject 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 without administration... | The proposed label will recommend a dosage of 1.34 mg tivozanib (equivalent to 1.5 mg tivozanib hydrochloride) once daily for 21 days on treatment followed by 7 days off treatment. | ¶58 | col. 2:35-40 |
| ...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, | The proposed label will include instructions to reduce the dose for patients with moderate hepatic impairment from the 1.5 mg hydrochloride equivalent dose to a 1.0 mg hydrochloride equivalent dose. | ¶59-61 | col. 5:6-12 |
| thereby to achieve a progression free survival in the subject of at least 5 months. | The proposed label will report clinical trial efficacy results showing a median progression-free survival of 5.6 months, thereby promoting the administration of the drug to achieve this result. | ¶63 | col. 24:47-52 |
11,504,365 Patent Infringement Allegations
| Claim Element (from Independent Claim 7) | 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), and experiencing moderate hepatic impairment... | The proposed label will instruct use in patients with refractory RCC after prior therapies, including TKIs, and contains specific instructions for patients who will have or develop moderate hepatic impairment. | ¶54, ¶56-57, ¶59 | col. 3:36-50 |
| ...the method comprising: administering to the subject one or more treatment cycles consisting essentially of: orally administering a pharmaceutical composition comprising an active agent consisting essentially of 1.0 mg tivozanib hydrochloride daily for 21 days followed by 7 days without administration... | The proposed label will instruct a dose reduction to the 0.89 mg tivozanib dosage form (equivalent to 1.0 mg tivozanib hydrochloride) for patients with moderate hepatic impairment, to be taken daily for a 21-day on, 7-day off cycle. | ¶60-61 | col. 18:8-13 |
| thereby to treat RCC. | The overall indication for the proposed product is the treatment of RCC. | ¶54 | col. 2:15-24 |
- Identified Points of Contention:
- Scope Questions: Do the terms "consisting essentially of," as applied to the dosing regimen, permit the presence of different excipients in Hetero's formulation without avoiding infringement? The analysis will question whether any such differences would materially affect the basic and novel properties of the claimed method, namely its efficacy and safety profile.
- Technical Questions: Does the reporting of a median progression-free survival of 5.6 months on the proposed label satisfy the claim limitation "thereby to achieve a progression free survival... of at least 5 months"? The court will need to determine if this functional language is met by the statistical outcome taught and promoted by the label, or if it requires a different standard of proof.
V. Key Claim Terms for Construction
The Term: "consisting essentially of"
- Context and Importance: This transitional phrase appears in both asserted independent claims and defines the scope of the treatment cycles. Its construction is critical because it determines whether any unlisted steps or components in Defendants' proposed method of use would fall outside the claim scope. Practitioners may focus on this term to argue that differences in formulation or permitted concomitant medications materially alter the invention's properties (e.g., safety profile or efficacy), thereby avoiding infringement.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent does not appear to explicitly define the phrase, which could support giving it its ordinary meaning in patent law, allowing for unlisted elements that do not materially affect the "basic and novel properties" of the invention.
- Evidence for a Narrower Interpretation: The "basic and novel properties" could be narrowly defined by the patent's emphasis on tivozanib's specific safety profile (e.g., lower incidence of certain adverse events compared to sorafenib) and its efficacy (achieving a specific PFS) (’365 Patent, col. 1:40-49; col. 26:39-44). Any additional element that alters this specific safety/efficacy balance could be argued to be a material alteration.
The Term: "moderate hepatic impairment"
- Context and Importance: This term is a crucial functional limitation in Claim 1, as it triggers the mandatory dose reduction. It is also a required patient characteristic at the start of treatment in Claim 7. A precise definition is essential to define the boundaries of the claimed method.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The term itself, without further definition, might be open to any clinically reasonable definition of "moderate" impairment.
- Evidence for a Narrower Interpretation: The specification explicitly links the term to a standard clinical scale, stating the dose of tivozanib is reduced for a subject experiencing "moderate hepatic impairment (Child-Pugh class B)" (’365 Patent, col. 5:8-10). This provides strong intrinsic evidence to limit the term's meaning to a specific, measurable clinical state.
VI. Other Allegations
- Indirect Infringement: The core of the complaint is inducement of infringement. It is alleged that Defendants, by creating and seeking approval for a product with a label that will substantively copy the FOTIVDA® label, specifically intend for physicians and patients to perform the patented methods (Compl. ¶¶ 51, 53, 65, 67). The complaint also alleges the proposed product is not a staple article of commerce and has no substantial non-infringing uses, supporting a claim for contributory infringement (Compl. ¶69).
- Willful Infringement: The complaint alleges willful infringement based on Defendants having full knowledge of the ’365 Patent, as evidenced by their Paragraph IV Notice Letter, yet proceeding with actions to market the Proposed ANDA Product (Compl. ¶¶ 66, 72, 78).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of induced infringement: Will the instructions on Defendants' proposed product label, assuming it copies the innovator's label as alleged, be sufficient to prove Defendants' specific intent for doctors to directly infringe the method claims, which include both treating a specific patient population and achieving a particular clinical outcome?
- A key question for claim construction and infringement will be the scope of "consisting essentially of": Can Defendants establish that differences in their generic formulation or its instructions for use with other medications introduce elements that "materially affect" the claimed invention's properties, particularly its unique efficacy and safety profile as detailed in the patent, thereby placing their product outside the scope of the claims?
- An underlying question, central to any validity defense, will be obviousness: Was it obvious to a person of ordinary skill in the art to treat this specific, heavily pre-treated refractory RCC population with this particular tivozanib dosing regimen, including the dose reduction for hepatic impairment, with a reasonable expectation of achieving at least five months of progression-free survival?