Axsome Therap Inc v. Teva Pharma Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Axsome Therapeutics, Inc. (Delaware) and Antecip Bioventures II LLC (Delaware)
  • Defendant: Teva Pharmaceuticals, Inc. (Delaware)
  • Plaintiff’s Counsel: Saul Ewing LLP
• Case Identification: 2:23-cv-23142, D.N.J., 12/15/2023
• Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Teva maintains a principal place of business in Parsippany, New Jersey.
• Core Dispute: Plaintiffs allege that Defendant's filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiffs' Auvelity® product constitutes an act of infringement of three U.S. patents covering drug formulations and methods of treating major depressive disorder.
• Technical Context: The technology involves a combination drug product containing dextromethorphan and bupropion, approved for treating major depressive disorder, a prevalent central nervous system condition.
• Key Procedural History: This action was triggered by Defendant's November 2, 2023 Paragraph IV certification notice, which asserted that the patents-in-suit are invalid, unenforceable, or would not be infringed by its proposed generic product. The complaint also notes a related case involving the same parties and product, suggesting prior litigation context.

Case Timeline

Date	Event
2022-06-30	Earliest Priority Date for '518 Patent
2022-07-07	Earliest Priority Date for '706 and '144 Patents
2023-02-09	Teva's First Notice Letter sent (regarding other patents)
2023-08-08	'518 Patent Issued
2023-08-22	'706 Patent Issued
2023-09-12	'144 Patent Issued
2023-11-02	Teva's Second Notice Letter sent (regarding patents-in-suit)
2023-12-15	Complaint Filed

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

U.S. Patent No. 11,717,518 - "Bupropion Dosage Forms with Reduced Food and Alcohol Dosing Effects," issued August 8, 2023

The Invention Explained

• Problem Addressed: The patent addresses the safety risks associated with controlled-release bupropion formulations, specifically the phenomenon of "dose dumping"—a rapid, unintended release of the active ingredient—when taken with alcohol ('518 Patent, col. 5:4-9). This can lead to potentially toxic drug levels in a patient's system.
• The Patented Solution: The invention is a specific dosage form combining bupropion and dextromethorphan with a polymer that prevents significant dose dumping when exposed to ethanol ('518 Patent, col. 1:29-35). This formulation allows for methods of treating major depressive disorder (MDD) in patients who consume alcohol, without requiring complete abstinence, thereby addressing a real-world clinical scenario ('518 Patent, col. 11:24-36).
• Technical Importance: Developing a formulation of a widely used antidepressant that is more stable and safer for patients who consume alcohol represents a meaningful improvement in drug safety and patient management.

Key Claims at a Glance

• The complaint asserts independent claim 1 and dependent claim 4 (Compl. ¶25).
• Independent Claim 1 includes the following essential elements:
  • A method of treating major depressive disorder.
  • Comprising administering, twice a day, a dosage form to a human patient in need thereof.
  • The dosage form comprises 105 mg of bupropion hydrochloride, 45 mg of dextromethorphan hydrobromide, and a polymer.
  • The human patient consumes alcohol on a day that the dosage form is administered.
• The complaint reserves the right to assert additional claims.

U.S. Patent No. 11,730,706 - "Treatment of Depression in Certain Patient Populations," issued August 22, 2023

The Invention Explained

• Problem Addressed: The co-administration of bupropion and dextromethorphan presents a pharmacokinetic challenge. Bupropion inhibits the CYP2D6 enzyme, which is responsible for metabolizing dextromethorphan ('706 Patent, col. 2:44-48). This interaction leads to significantly higher dextromethorphan exposure. The problem is exacerbated in specific patient populations, such as those with moderate renal impairment, who have a reduced ability to clear the drug, creating a risk of adverse effects from overexposure ('706 Patent, col. 1:29-36).
• The Patented Solution: The patent claims a specific, adjusted dosing regimen to manage this risk. For patients with moderate renal impairment, the invention prescribes administering the combination tablet (105 mg bupropion / 45 mg dextromethorphan) only once daily, rather than the standard twice-daily dose ('706 Patent, Claim 1). This reduced frequency is intended to achieve a therapeutic effect while avoiding the potentially harmful drug accumulation observed in this patient group.
• Technical Importance: This invention provides a method for personalized medicine, enabling the safe and effective use of the drug combination in a vulnerable patient subgroup that might otherwise experience adverse events or be unable to use the therapy.

Key Claims at a Glance

• The complaint asserts independent claims 1 and 9 (Compl. ¶33).
• Independent Claim 1 includes the following essential elements:
  • A method of treating major depressive disorder in a human patient who has moderate renal impairment.
  • Comprising administering once daily, by mouth, one bilayer tablet.
  • The tablet contains about 105 mg of bupropion hydrochloride in an extended-release formulation and about 45 mg of dextromethorphan hydrobromide in an immediate-release formulation.
• The complaint reserves the right to assert additional claims.

Multi-Patent Capsule

• Patent Identification: U.S. Patent No. 11,752,144, "Compounds and Combinations Thereof for Treating Neurological and Psychiatric Conditions," issued September 12, 2023.
• Technology Synopsis: This patent addresses the use of the bupropion/dextromethorphan combination to treat MDD in patient populations that may be at higher risk for drug abuse. The invention claims a method of using an NMDA receptor antagonist (dextromethorphan) to treat MDD without causing dissociation, a psychoactive side effect associated with other NMDA antagonists like esketamine, and without requiring the clinical monitoring that those other drugs necessitate ('144 Patent, col. 5:20-6:8).
• Asserted Claims: Independent claim 1 is asserted (Compl. ¶41).
• Accused Features: Teva's proposed generic product is accused of infringing because its future marketing and sale for the treatment of MDD would constitute a method of using a non-competitive NMDA receptor antagonist in a patient with a history of drug abuse without causing dissociation, as claimed (Compl. ¶¶ 41-45).

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is "Teva's Proposed Product," a generic version of Auvelity® (dextromethorphan hydrobromide and bupropion hydrochloride extended-release tablets), for which Teva filed ANDA No. 218147 with the FDA (Compl. ¶¶ 1, 9, 19).

Functionality and Market Context

• The complaint alleges that Teva's Proposed Product is a generic drug that will have the same active ingredients, dosage form, and strength as Plaintiffs' FDA-approved Auvelity® product (Compl. ¶¶ 1, 9). The basis of the infringement action is that Teva is seeking approval to market this product for the treatment of MDD, and that its proposed label will instruct physicians and patients to use it in a manner that directly infringes the methods claimed in the patents-in-suit (Compl. ¶¶ 27, 35, 43).

IV. Analysis of Infringement Allegations

The complaint does not provide detailed claim charts. The following tables summarize the infringement theories for the lead patents as alleged under 35 U.S.C. § 271(e)(2), where the filing of the ANDA is the statutory act of infringement.

'518 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method of treating major depressive disorder comprising administering, twice a day, a dosage form to a human patient in need thereof...	Teva seeks approval to market its Proposed Product for treating MDD, and its label will instruct twice-daily administration, mirroring the dosage for Plaintiffs' Auvelity® product.	¶27	col. 11:59-62
...wherein the dosage form comprises 105 mg of bupropion hydrochloride ... 45 mg of dextromethorphan hydrobromide ... and a polymer...	Teva’s ANDA is for a product containing the specified amounts of the same active ingredients in a formulation that, to be bioequivalent, must contain a polymer for extended release.	¶¶9, 19, 27	col. 12:62-col. 13:1
...and wherein the human patient consumes alcohol on a day that the dosage form is administered.	Teva's proposed label will not prohibit alcohol use, making it inevitable that patients who consume alcohol will be treated with the product, thereby directly infringing the claimed method. Teva's label will induce this infringement.	¶¶27, 28	col. 13:1-3

'706 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method of treating major depressive disorder in a human patient who has moderate renal impairment...	Teva's proposed product label, by mirroring the Auvelity® label, will provide specific instructions for treating patients with moderate renal impairment, thereby inducing physicians to prescribe the drug for this claimed patient population.	¶¶35, 36	col. 11:15-18
...comprising administering once daily, by mouth, one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide...	The proposed label will instruct a once-daily administration of a tablet with the specified formulation for this specific patient group, directly mapping onto the claimed method steps.	¶¶9, 35	col. 11:18-24
...wherein the tablet is a bilayer tablet.	Teva's Proposed Product is alleged to be a generic equivalent of Auvelity®, which the patent describes as a bilayer tablet.	¶¶9, 35	col. 11:24-25

The '706 Patent includes a chart showing pharmacokinetic data that underpins the rationale for the claimed dosing regimen ('706 Patent, FIG. 1). This figure visually depicts the approximately two-fold increase in drug exposure for both dextromethorphan and bupropion in patients with moderate renal impairment compared to a reference population, providing the technical basis for the patent's claimed solution of a reduced, once-daily dosage.

Identified Points of Contention

• Scope Questions: For the '518 Patent, a question will be whether the term "consumes alcohol" requires a specific quantity or timing of consumption to fall within the claim, or if any alcohol use on a dosing day suffices. For the '144 Patent, a key question is how the scope of the negative limitation "does not experience dissociation" will be determined and proven.
• Technical Questions: A primary question for the '706 Patent will be whether the claimed once-daily dosing adjustment for patients with moderate renal impairment would have been obvious to a person of ordinary skill in the art, given the general practice of adjusting drug doses for renally impaired patients, even without the specific pharmacokinetic data presented in the patent.

V. Key Claim Terms for Construction

Term 1 ('518 Patent): "consumes alcohol on a day that the dosage form is administered"

• Context and Importance: This phrase defines a key condition of the asserted method claim. The breadth of its construction will determine the extent to which the ordinary, foreseeable behavior of patients taking an antidepressant creates an act of infringement. Practitioners may focus on this term because Teva could argue for a narrow construction (e.g., requiring simultaneous ingestion) to limit the scope of infringement, while Plaintiffs will likely advocate for a broader, plain-meaning interpretation.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The plain language "on a day" suggests any alcohol consumption within the same 24-hour period as a drug dose would meet the limitation ('518 Patent, col. 13:1-3). The specification's discussion of "limiting" but not "discontinuing" alcohol consumption may support this broader view ('518 Patent, col. 2:19-23).
  • Evidence for a Narrower Interpretation: The specification provides data for in vitro dissolution testing in the "presence of ethanol" ('518 Patent, col. 5:4-24). A defendant could argue this focus on simultaneous presence implies the invention is directed at co-ingestion, not merely consumption at any point during the day.

Term 2 ('706 Patent): "moderate renal impairment"

• Context and Importance: This term defines the specific patient population for the asserted claims. Its precise definition is critical for determining infringement, as only prescriptions for this group would infringe. Practitioners may focus on this term because, while seemingly technical, any ambiguity could provide grounds for a non-infringement defense.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: Independent claim 1 uses the general term "moderate renal impairment" without a specific quantitative definition, potentially allowing for a range of clinical assessments to fall within its scope ('706 Patent, col. 11:16).
  • Evidence for a Narrower Interpretation: Dependent claim 9 explicitly defines the term by reference to a specific range: "an estimated glomerular filtration rate that is between about 30 mL/min/1.72 m² and 59 mL/min/1.72 m²" ('706 Patent, col. 12:12-15). This provides a strong basis for a court to import this specific definition into the parent claim, significantly narrowing the scope for debate.

VI. Other Allegations

• Indirect Infringement: The complaint alleges both induced and contributory infringement for all three patents. Inducement is premised on allegations that Teva, with knowledge of the patents, will create a product label that intentionally encourages and instructs physicians and patients to perform the claimed methods (Compl. ¶¶ 28, 36, 44). Contributory infringement is based on allegations that Teva's product is specifically designed for an infringing use and lacks a substantial non-infringing use (Compl. ¶¶ 29, 37, 45).
• Willful Infringement: The complaint does not use the word "willful" but requests a judgment that the case is "exceptional" pursuant to 35 U.S.C. § 285, seeking attorneys' fees (Compl., Prayer for Relief ¶(J)). The factual basis for this is Teva's alleged knowledge of the patents, established by its own Paragraph IV notice letter sent to Plaintiffs on November 2, 2023, prior to the filing of the lawsuit (Compl. ¶21).

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

• A core issue will be one of obviousness: For the '706 patent, was it an obvious step for a skilled artisan to adjust the standard twice-daily dose of the Auvelity® combination to once-daily for patients with moderate renal impairment, based on general knowledge of pharmacokinetics, or does the patent’s specific disclosure of the resulting drug exposure levels confer non-obviousness?
• A second key question will involve infringement and claim scope: For the '518 patent, does a method claim that includes a common patient behavior (consuming alcohol) as a limitation create an enforceable patent right against a generic manufacturer whose product is simply not contraindicated for that behavior?
• A final dispositive question may be one of patentable subject matter: For the '144 patent, can a valid and enforceable method claim be based on a "negative" limitation—the absence of a particular side effect (dissociation)—especially when asserted against a generic product whose label will primarily describe what the drug does, not what it fails to do?