Axsome Malta Ltd v. Hetero USA Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Axsome Malta Ltd. (Malta) and Axsome Therapeutics, Inc. (Delaware)
  • Defendant: Hetero USA Inc. (Delaware), Hetero Labs Limited Unit-V (India), and Hetero Labs Ltd. (India)
  • Plaintiff’s Counsel: Saul Ewing LLP
• Case Identification: 2:24-cv-03999, D.N.J., 03/19/2024
• Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey based on Defendant Hetero USA Inc.’s established physical place of business in Piscataway, NJ, and the systematic and continuous business contacts of all defendants with the state, including the marketing and distribution of pharmaceutical products.
• Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) to market generic versions of Plaintiff's Sunosi® (solriamfetol) tablets infringes nine U.S. patents directed to methods of using the drug.
• Technical Context: The technology concerns specific pharmaceutical dosing regimens for solriamfetol, a dopamine and norepinephrine reuptake inhibitor, to treat excessive daytime sleepiness associated with conditions like narcolepsy and obstructive sleep apnea.
• Key Procedural History: The action was initiated under the Hatch-Waxman Act following Plaintiff’s receipt of a Paragraph IV certification notice letter from Defendant, dated no earlier than March 11, 2024, which asserted that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by Defendant’s proposed generic product.

Case Timeline

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 11,839,598 - “Methods of Providing Solriamfetol Therapy to Subjects with Impaired Renal Function”

Issued December 12, 2023

The Invention Explained

• Problem Addressed: The patent describes that solriamfetol is primarily eliminated via renal excretion. Therefore, administration to patients with impaired renal function would be expected to result in higher drug exposure, but prior to the invention, it was not known what dosage or dose escalation scheme, if any, would be safe for this patient population (’598 Patent, col. 2:40-54).
• The Patented Solution: The invention provides specific methods for administering solriamfetol (APC-HCl) to subjects with moderate or severe renal impairment to reduce toxicity. For subjects with moderate renal impairment, the method involves a dose escalation scheme starting with an initial daily dose equivalent to 37.5 mg and increasing to a maximum of 75 mg only after at least five days (’598 Patent, col. 3:1-13). For subjects with severe renal impairment, the method specifies a maximum daily dose equivalent to 37.5 mg (’598 Patent, Abstract).
• Technical Importance: The claimed methods provide a defined safety protocol, allowing for the therapeutic use of solriamfetol in specific patient subpopulations who might otherwise be unable to use the drug or would face an unknown risk of dose-dependent adverse effects (’598 Patent, col. 2:47-54).

Key Claims at a Glance

• The complaint asserts at least independent claim 1 (Compl. ¶42).
• Claim 1 of the ’598 Patent requires:
  • A method of reducing toxicity due to [R]-2-amino-3-phenylpropylcarbamate (APC) administration in a subject having moderate or severe renal impairment, comprising:
  • (a) providing to a subject with an estimated glomerular filtration rate (eGFR) of about 30 mL/min/1.73 m² to about 59 mL/min/1.73 m² (moderate impairment): a first oral daily dose of 37.5 mg APC for n₁ days, and a second oral daily dose of 75 mg APC starting on day n₂, where n₁ is an integer ≥ 5;
  • (b) providing to a subject with an eGFR of about 15 mL/min/1.73 m² to about 29 mL/min/1.73 m² (severe impairment): an oral daily dose equivalent to 37.5 mg APC.
• The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 11,839,599 - “Methods of Providing Solriamfetol Therapy to Subjects with Impaired Renal Function”

Issued December 12, 2023

The Invention Explained

• Problem Addressed: The technical problem is identical to that described for the ’598 Patent: determining a safe and effective dosing regimen for solriamfetol in patients with impaired renal function, given the drug's reliance on renal excretion for elimination (’599 Patent, col. 2:40-54).
• The Patented Solution: The invention provides a method of treating excessive daytime sleepiness in subjects with obstructive sleep apnea (OSA) and co-morbid moderate or severe renal impairment. The solution involves specific, adjusted dosing regimens: a dose-escalation protocol (37.5 mg to a maximum of 75 mg) for moderately impaired patients and a fixed maximum dose (37.5 mg) for severely impaired patients (’599 Patent, Abstract; col. 4:41-56).
• Technical Importance: This method provides a specific therapeutic protocol for a defined patient population (OSA with renal impairment), enabling clinicians to treat excessive daytime sleepiness while managing the risks associated with reduced drug clearance (’599 Patent, col. 2:47-54).

Key Claims at a Glance

• The complaint asserts at least independent claim 1 (Compl. ¶51).
• Claim 1 of the ’599 Patent requires:
  • A method of treating excessive daytime sleepiness in a subject with obstructive sleep apnea (OSA) and having moderate or severe renal impairment, comprising:
  • (a) providing a specific dose escalation regimen (from 37.5 mg to 75 mg over ≥ 5 days) to a subject with moderate renal impairment;
  • (b) providing a daily dose equivalent to 37.5 mg to a subject with severe renal impairment.
• The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 11,850,226 - “Methods of Providing Solriamfetol Therapy to Subjects with Impaired Renal Function”

Issued December 26, 2023

• Technology Synopsis: This patent addresses the same technical problem as the ’598 and ’599 patents: determining a safe dosing regimen for solriamfetol in renally impaired patients (’226 Patent, col. 2:40-54). It claims a method of treating excessive daytime sleepiness specifically in subjects with narcolepsy and co-morbid moderate or severe renal impairment by administering specific dose-adjusted regimens (’226 Patent, Abstract).
• Asserted Claims: At least independent claim 1 (Compl. ¶60).
• Accused Features: The administration of Hetero's proposed generic solriamfetol product according to its proposed label is alleged to infringe (Compl. ¶60).

U.S. Patent No. 11,850,227 - “Methods of Providing Solriamfetol Therapy to Subjects with Impaired Renal Function”

Issued December 26, 2023

• Technology Synopsis: This patent covers a method of guiding solriamfetol therapy for a subject with narcolepsy and renal impairment (’227 Patent, col. 4:60-63). The method involves determining the subject's level of renal impairment (mild, moderate, severe, or end-stage) and then administering a corresponding recommended dosing regimen, which includes dose escalation for moderate impairment and a fixed maximum dose for severe impairment (’227 Patent, Abstract).
• Asserted Claims: At least independent claim 1 (Compl. ¶69).
• Accused Features: The instructions in the proposed product label for Hetero's generic solriamfetol are alleged to guide healthcare providers to perform the claimed infringing method (Compl. ¶69).

U.S. Patent No. 11,850,228 - “Methods of Providing Solriamfetol Therapy to Subjects with Impaired Renal Function”

Issued December 26, 2023

• Technology Synopsis: This patent claims a method of guiding solriamfetol therapy in a subject with obstructive sleep apnea and renal impairment (’228 Patent, col. 4:16-19). The method requires determining the subject's degree of renal impairment and then administering a specific, corresponding dosing regimen, which is adjusted for moderate and severe impairment levels to ensure safety and efficacy (’228 Patent, Abstract).
• Asserted Claims: At least independent claim 1 (Compl. ¶78).
• Accused Features: The proposed labeling for Hetero's generic solriamfetol product, which would guide its administration, is alleged to infringe (Compl. ¶78).

U.S. Patent No. 11,857,528 - “Methods of Providing Solriamfetol Therapy to Subjects with Impaired Renal Function”

Issued January 2, 2024

• Technology Synopsis: This patent claims a method for treating excessive daytime sleepiness in a subject with moderate or severe renal impairment by administering solriamfetol according to specific dosing regimens (’528 Patent, Abstract). The patent specifies dose adjustments and escalation protocols to manage drug exposure and minimize adverse effects in this patient population (’528 Patent, col. 1:19-31).
• Asserted Claims: At least independent claim 1 (Compl. ¶87).
• Accused Features: The use of Hetero's proposed generic solriamfetol product as instructed by its label is alleged to constitute infringement (Compl. ¶87).

U.S. Patent No. 11,865,098 - “Methods and Compositions for Treating Excessive Sleepiness”

Issued January 9, 2024

• Technology Synopsis: This patent is directed to methods of treating excessive sleepiness by administering solriamfetol to achieve "normal" levels of wakefulness as measured by standard objective (Maintenance of Wakefulness Test) and subjective (Epworth Sleepiness Scale) tests (’098 Patent, Abstract). The invention claims that administration of the drug results in a specific, quantifiable improvement in these standard clinical measures of sleepiness (’098 Patent, col. 2:1-17).
• Asserted Claims: At least independent claim 1 (Compl. ¶96).
• Accused Features: The use of Hetero's generic solriamfetol product to treat excessive sleepiness is alleged to infringe the claimed method (Compl. ¶96).

U.S. Patent No. 11,872,203 - “Methods of Administering Solriamfetol to Lactating Women”

Issued January 16, 2024

• Technology Synopsis: This patent discloses a method for reducing the potential for adverse events in an infant fed breast milk from a subject being treated with solriamfetol (’203 Patent, Abstract). The method comprises administering a daily dose of solriamfetol to the lactating subject and then feeding the infant breast milk at least 5 hours after administration, thereby decreasing the infant's exposure to the drug (’203 Patent, col. 2:1-11).
• Asserted Claims: At least independent claim 1 (Compl. ¶105).
• Accused Features: The instructions in the proposed product label for Hetero's generic solriamfetol are alleged to guide lactating women to perform the claimed infringing method (Compl. ¶105).

U.S. Patent No. 11,872,204 - “Methods of Administering Solriamfetol to Lactating Women”

Issued January 16, 2024

• Technology Synopsis: Similar to the ’203 patent, this patent claims a method for decreasing the potential for adverse events in a breastfed infant by managing the timing of feeding relative to the maternal dose of solriamfetol (’204 Patent, Abstract). The claimed method involves administering a specific daily dose (e.g., 37.5 mg to 300 mg) and feeding the infant at least 5 hours later to reduce the infant's drug exposure and risk of adverse events like agitation or insomnia (’204 Patent, col. 2:1-11).
• Asserted Claims: At least independent claim 1 (Compl. ¶114).
• Accused Features: The administration of Hetero's proposed generic solriamfetol product according to labeling that would instruct its use in lactating women is alleged to infringe (Compl. ¶114).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is "Hetero's Proposed Product," a generic version of solriamfetol oral tablets for which Defendant submitted Abbreviated New Drug Application (ANDA) No. 218654 to the FDA (Compl. ¶1, 35).

Functionality and Market Context

• The proposed product is a generic equivalent to Plaintiff's Sunosi® tablets, which function as a dopamine and norepinephrine reuptake inhibitor (DNRI) (Compl. ¶2, 18). It is indicated to improve wakefulness in adult patients who experience excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (Compl. ¶2).
• The complaint alleges that Hetero seeks FDA approval to commercially manufacture, use, market, and sell this generic product in the United States prior to the expiration of the patents-in-suit (Compl. ¶1, 35). The infringement allegations are based on this planned future conduct, triggered by the submission of the ANDA itself (Compl. ¶42).
• No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for a claim-chart analysis. The allegations are framed under 35 U.S.C. § 271(e)(2)(A), which defines the submission of an ANDA seeking approval to market a drug claimed in a patent before its expiration as an act of infringement. The complaint makes general allegations that the commercial manufacture, use, sale, or importation of Hetero's Proposed Product will infringe at least claim 1 of each asserted patent (Compl. ¶¶ 42, 44, 51, 53, 60, 62, 69, 71, 78, 80, 87, 89, 96, 98, 105, 107, 114, 116). In ANDA litigation involving method-of-use claims, the infringement analysis typically focuses on whether the proposed product's labeling will instruct or encourage medical professionals and patients to use the drug in a manner that practices the steps of the claimed methods.

• Identified Points of Contention:
  • Scope Questions: The case may raise questions regarding whether the instructions on Hetero’s proposed product label will meet every limitation of the asserted method claims. For the renal impairment patents (e.g., the ’598 and ’599 Patents), a central question may be whether Hetero’s label instructs the specific dose escalation timeframes (e.g., "n₁ is an integer equal to or greater than 5") required by the claims.
  • Technical Questions: A key evidentiary question will be how the instructions in Hetero's proposed label are to be interpreted by a person of ordinary skill in the art, such as a prescribing physician. The dispute may focus on whether following the label's guidance for specific patient populations (e.g., those with moderate renal impairment or lactating women) would necessarily result in performance of the patented methods.

V. Key Claim Terms for Construction

• The Term: "reducing toxicity" (’598 Patent, Claim 1)

  • Context and Importance: This term appears in the preamble of claim 1 of the ’598 Patent. Its construction will be critical to determine whether the preamble is a limitation on the claim's scope. If it is limiting, Axsome would need to prove not only that Hetero's proposed label induces the claimed dosing steps, but also that performing those steps achieves the functional result of "reducing toxicity."
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The body of the claim recites specific, concrete steps (administering certain doses based on eGFR). Parties arguing for a non-limiting preamble may contend that these steps are the full extent of the invention and the preamble merely states an intended purpose.
    • Evidence for a Narrower Interpretation: The specification repeatedly links the specific dosing regimens to minimizing adverse effects and dose-dependent toxicity, suggesting the purpose is integral to the invention (’598 Patent, col. 2:31-39, col. 3:1-13). Practitioners may focus on this term because if it is limiting, it could provide a non-infringement defense if the accused infringer can argue its proposed product does not achieve this functional result.

• The Term: "a subject having an estimated glomerular filtration rate (eGFR) of about 30 mL/min/1.73 m² to about 59 mL/min/1.73 m²" (i.e., moderate renal impairment) (’598 Patent, Claim 1)

  • Context and Importance: This term defines the specific patient subpopulation for the dose-escalation portion of the claim. The definition of this group, and how a physician would identify such a patient based on Hetero's proposed label, will be central to the infringement analysis.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of "about" may support a construction that includes patients whose eGFR falls slightly outside the specified numerical range but who would be clinically considered to have moderate renal impairment.
    • Evidence for a Narrower Interpretation: The patent explicitly ties the eGFR ranges to FDA guidance, suggesting the numbers are intended to be precise definitions (’598 Patent, col. 13:3-13). Parties could argue that the term requires a specific clinical diagnosis based on these exact numerical thresholds.

VI. Other Allegations

• Indirect Infringement: The complaint alleges both induced and contributory infringement for all asserted patents. The inducement allegation is based on the assertion that Hetero, upon FDA approval, will "intentionally encourage acts of direct infringement with knowledge of the [asserted] patent" (e.g., Compl. ¶45, 54). The contributory infringement allegation is based on the assertion that Hetero's product is "designed for a use that infringes" and "lacks a substantial non-infringing use" (e.g., Compl. ¶46, 55). In this context, the primary evidence for intent and encouragement would be the instructions and indications on the proposed product label.
• Willful Infringement: The complaint does not use the term "willful infringement" but alleges that the case is "exceptional" and seeks attorneys' fees under 35 U.S.C. § 285 (e.g., Compl. ¶49). The basis for knowledge of the patents is Hetero's Paragraph IV certification notice letters, sent after the patents issued (Compl. ¶40).

VII. Analyst’s Conclusion: Key Questions for the Case

• A core issue will be one of induced infringement: Will Hetero’s proposed product label be interpreted by a court as actively encouraging or instructing physicians to prescribe solriamfetol in a manner that directly practices the specific, multi-step dosing regimens claimed in Axsome’s patents for distinct patient subpopulations, such as those with moderate renal impairment or those who are lactating?
• A central question of claim scope will be whether Hetero can design a product label that successfully “carves out” the patented methods of use—thereby avoiding inducement—while still providing sufficient information for safe and effective use, and whether such a label would be commercially viable and approved by the FDA.
• A key legal and factual question will be one of defining the patient population: The dispute may turn on how the patient populations defined in the claims (e.g., "moderate renal impairment," "lactating women") are described in Hetero's proposed label and whether a physician following the label's instructions would inevitably or necessarily prescribe the drug in an infringing manner for those patients.