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-01695, D.N.J., 03/24/2023
• Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Teva maintains its U.S. Headquarters and a principal place of business in Parsippany, New Jersey.
• Core Dispute: Plaintiffs allege that Defendant's filing of an Abbreviated New Drug Application (ANDA) for a generic version of Plaintiffs' Auvelity® drug product constitutes an act of infringement of four U.S. patents related to methods of treating major depressive disorder.
• Technical Context: The technology concerns a combination therapy using bupropion to inhibit the metabolic breakdown of dextromethorphan, thereby increasing dextromethorphan's plasma concentration and therapeutic efficacy for treating central nervous system conditions.
• Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendant's submission of ANDA No. 218147 to the FDA and its subsequent delivery of a Paragraph IV Certification notice to Plaintiffs, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product.

Case Timeline

Date	Event
2019-01-07	Priority Date for ’064, ’842, ’124, and ’942 Patents
2020-09-22	U.S. Patent No. 10,780,064 Issues
2021-02-23	U.S. Patent No. 10,925,842 Issues
2021-03-09	U.S. Patent No. 10,940,124 Issues
2021-04-06	U.S. Patent No. 10,966,942 Issues
2023-02-09	Earliest Date Defendant Sent Paragraph IV Notice Letter
2023-03-24	Complaint Filing Date

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

U.S. Patent No. 10,780,064 - Bupropion as a Modulator of Drug Activity

(Issued September 22, 2020)

The Invention Explained

• Problem Addressed: The patent describes that dextromethorphan, a compound with potential therapeutic uses for neurological disorders, is rapidly metabolized in the human liver. This rapid breakdown limits its systemic exposure and clinical utility, particularly in the majority of the population who are "extensive metabolizers" of the drug (U.S. Patent No. 10780064, col. 15:10-34).
• The Patented Solution: The invention involves co-administering bupropion (or its metabolites and prodrugs) with dextromethorphan. Bupropion is described as an inhibitor of the enzyme responsible for dextromethorphan metabolism (cytochrome P450 2D6), which increases the plasma concentration and metabolic half-life of dextromethorphan, thereby enhancing its therapeutic effects (’064 Patent, Abstract; col. 6:51-60). This approach is intended to make dextromethorphan a more effective treatment for conditions such as depression (’064 Patent, col. 17:1-14).
• Technical Importance: The claimed method provides a way to overcome the known pharmacokinetic limitations of dextromethorphan, enabling its use as an effective therapeutic for neurological disorders by ensuring therapeutically relevant plasma concentrations are achieved and maintained in patients (’064 Patent, col. 15:35-44).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶26).
• The essential elements of Claim 1 are:
  • A method of treating major depressive disorder.
  • Administering a drug combination to a human in need thereof.
  • The combination comprises bupropion (about 105 mg of hydrochloride salt or equivalent).
  • The combination also comprises dextromethorphan (about 45 mg of hydrobromide salt or equivalent).
  • Both components are administered on a specific escalating dosing schedule: once daily for the first three days, then twice daily for at least 11 days.
  • The human being is selected for being male.
  • The treatment results in a greater reduction in a MADRS score compared to administering bupropion alone.
• The complaint does not explicitly reserve the right to assert dependent claims but alleges infringement of "one or more" claims (Compl. ¶26).

U.S. Patent No. 10,925,842 - Bupropion as a Modulator of Drug Activity

(Issued February 23, 2021)

The Invention Explained

• Problem Addressed: The patent addresses the same technical problem as the ’064 Patent: the rapid hepatic metabolism of dextromethorphan limits its therapeutic effectiveness in most individuals (U.S. Patent No. 10925842, col. 15:10-34).
• The Patented Solution: The solution is identical to that described in the ’064 Patent, involving the co-administration of bupropion to inhibit dextromethorphan's metabolism, thereby increasing its plasma levels and enhancing its therapeutic properties for treating neurological disorders (’842 Patent, Abstract; col. 6:51-60).
• Technical Importance: The technical importance is the same as described for the ’064 Patent, enabling the effective therapeutic use of dextromethorphan by modifying its pharmacokinetic profile (’842 Patent, col. 15:35-44).

Key Claims at a Glance

• The complaint asserts independent claim 1 (Compl. ¶34).
• The essential elements of Claim 1 are:
  • A method of treating major depressive disorder.
  • Administering a drug combination to a human in need thereof.
  • The combination comprises bupropion (about 105 mg of hydrochloride salt or equivalent).
  • The combination also comprises dextromethorphan (about 45 mg of hydrobromide salt or equivalent).
  • Both components are administered on a specific escalating dosing schedule: once daily for the first three days, then twice daily for at least 11 days.
  • The human being is selected for having received prior first line treatment in their current major depressive episode.
  • The treatment results in a greater reduction in a MADRS score compared to administering bupropion alone.
• The complaint alleges infringement of "one or more" claims of the patent (Compl. ¶34).

U.S. Patent No. 10,940,124 - Bupropion as a Modulator of Drug Activity

(Issued March 9, 2021; Compl. ¶8)

Technology Synopsis

The patent describes a method for treating major depressive disorder by overcoming the rapid metabolism of dextromethorphan. The solution involves co-administering bupropion, a metabolic inhibitor, to increase plasma concentrations of dextromethorphan and thereby enhance its therapeutic effect (U.S. Patent No. 10940124, Abstract; col. 15:10-44).

Asserted Claims

At least independent claim 1 (Compl. ¶42).

Accused Features

The accused features are the composition and intended use of Teva's proposed generic drug, which combines dextromethorphan and bupropion for the treatment of major depressive disorder (Compl. ¶¶ 10, 16).

U.S. Patent No. 10,966,942 - Bupropion as a Modulator of Drug Activity

(Issued April 6, 2021; Compl. ¶9)

Technology Synopsis

The patent addresses the challenge of dextromethorphan's limited clinical utility due to its rapid metabolic breakdown. The invention solves this by co-administering bupropion, which inhibits the metabolism and increases the bioavailability of dextromethorphan, making it effective for treating neurological conditions like major depressive disorder (U.S. Patent No. 10966942, Abstract; col. 15:10-44).

Asserted Claims

At least independent claim 1 (Compl. ¶50).

Accused Features

The infringement allegations target Teva's proposed generic dextromethorphan/bupropion combination product and its intended labeled use for treating major depressive disorder (Compl. ¶¶ 10, 16).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendant Teva's proposed generic version of Plaintiffs' dextromethorphan hydrobromide and bupropion hydrochloride extended-release tablets, for which Teva filed ANDA No. 218147 (Compl. ¶1, ¶16).

Functionality and Market Context

The proposed product is a combination drug intended for the treatment of major depressive disorder (MDD) in adult patients (Compl. ¶10). As a generic version of Auvelity®, it is designed to be therapeutically equivalent to the Plaintiffs' branded product (Compl. ¶1). The complaint alleges that upon receiving FDA approval, Teva will manufacture, market, and sell this generic product throughout the United States (Compl. ¶16, ¶24).

Visual Evidence

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain a detailed element-by-element infringement analysis. The infringement allegation is based on 35 U.S.C. § 271(e)(2)(A), which defines the submission of an ANDA for a patented drug as an act of infringement. The core theory is that the product described in Teva's ANDA, if approved and used according to its proposed label, will practice the methods claimed in the patents-in-suit.

’064 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method of treating major depressive disorder...	Teva's Proposed Product is a generic version of Auvelity®, which is approved for the treatment of major depressive disorder.	¶10; ¶16	col. 17:1-14
...administering a drug combination...comprises: a bupropion...and a dextromethorphan...	Teva's Proposed Product is a combination of dextromethorphan hydrobromide and bupropion hydrochloride.	¶1; ¶16	col. 6:47-57
...bupropion...about 105 mg...dextromethorphan...about 45 mg...administered once a day for the first three days and twice a day thereafter for at least 11 days...	As a generic equivalent, Teva’s Proposed Product is expected to be prescribed and administered at the same dosage and regimen as Auvelity®.	¶1; ¶10	col. 113:54-67
...wherein the human being is selected for being male...	The complaint does not provide sufficient detail for analysis of this element.	¶26; ¶28	col. 124:8-9

’842 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method of treating major depressive disorder...	Teva's Proposed Product is indicated for the treatment of major depressive disorder.	¶10; ¶16	col. 17:1-14
...administering a drug combination...comprises: a bupropion...and a dextromethorphan...	Teva's Proposed Product is a combination of dextromethorphan hydrobromide and bupropion hydrochloride.	¶1; ¶16	col. 6:47-57
...bupropion...about 105 mg...dextromethorphan...about 45 mg...administered once a day for the first three days and twice a day thereafter for at least 11 days...	As a generic equivalent, Teva’s Proposed Product is expected to be prescribed and administered at the same dosage and regimen as Auvelity®.	¶1; ¶10	U.S. Patent No. 10,925,842, col. 128:2-13
...wherein the human being is selected for having received prior first line treatment in their current major depressive episode...	The complaint does not provide sufficient detail for analysis of this element.	¶34; ¶36	U.S. Patent No. 10,925,842, col. 128:14-16

Identified Points of Contention

• Scope Questions: The infringement analysis for the method claims may turn on whether Teva's proposed label instructs physicians to select patients according to specific claim limitations. For the ’064 Patent, a key question is whether a label for general use in adults with MDD can be read to induce infringement of a claim limited to a patient "selected for being male." Similarly, for the ’842 Patent, the analysis will question whether the proposed label instructs use specifically in patients "having received prior first line treatment."
• Technical Questions: While the complaint is filed on the premise of bioequivalence, a potential issue for the court could be whether Teva's proposed extended-release formulation for bupropion achieves the same pharmacokinetic profile and metabolic inhibition as the formulation used to support the patent claims.

V. Key Claim Terms for Construction

The Term: "wherein the human being is selected for being male" (’064 Patent, Claim 1)

Context and Importance

This limitation defines a specific patient sub-population. The viability of Plaintiffs' infringement claim against Teva for the ’064 patent may depend entirely on the construction of this phrase, as Teva’s proposed generic product is likely intended for a general adult population. Practitioners may focus on this term because it appears to significantly narrow the claim scope in a way that a generic drug label may not directly address.

Intrinsic Evidence for Interpretation

• Evidence for a Broader Interpretation: The specification generally describes the invention as applicable to "a human being" without a gender-specific focus, suggesting the core inventive concept is not limited to males (e.g., ’064 Patent, Abstract; col. 6:51-57). Plaintiffs may argue that "selected for" does not require an express instruction but is satisfied by prescribing the drug to a patient who happens to be male.
• Evidence for a Narrower Interpretation: The plain language of the claim requires an affirmative act of "selecting" a patient for "being male." Defendants may argue this requires the label to instruct, or at least encourage, physicians to choose male patients for the treatment, an instruction unlikely to be present for a general antidepressant.

The Term: "a method of treating ... comprising administering" (e.g., ’064 Patent, Claim 1)

Context and Importance

In this Hatch-Waxman context, the defendant (Teva) is not the party "administering" the drug to a patient. Therefore, liability must be based on indirect infringement. The construction of this term, in conjunction with the law on inducement, will be critical to determine whether Teva’s act of seeking FDA approval with a proposed label that instructs the claimed administration method is sufficient to establish infringement.

Intrinsic Evidence for Interpretation

• Evidence for a Broader Interpretation: The specification describes the invention as a "method of treating" various disorders by "administering" the drug combination, which is standard language for method-of-treatment claims (’064 Patent, col. 6:47-50). Plaintiffs will argue that by filing an ANDA for this indication with a label that will inevitably be used by doctors, Teva has the specific intent to cause the "administering" step to be performed.
• Evidence for a Narrower Interpretation: Defendants may argue that "administering" requires the direct performance of the step and that merely making a drug available for a general population does not meet the legal standard for inducing every specific limitation of a claimed method, particularly patient-selection criteria.

VI. Other Allegations

Indirect Infringement

The complaint alleges both induced and contributory infringement for all four patents-in-suit. The basis for inducement is the allegation that Teva’s proposed product labeling will instruct physicians and patients to use the generic drug in a manner that directly infringes the claimed methods, and that Teva has knowledge of the patents (e.g., Compl. ¶29, ¶37). The basis for contributory infringement is that Teva's product is designed for an infringing use and lacks substantial non-infringing uses (e.g., Compl. ¶30, ¶38).

Willful Infringement

The complaint does not contain an explicit allegation of willful infringement or a request for enhanced damages. It does, however, request a finding of an "exceptional case" warranting an award of attorneys' fees pursuant to 35 U.S.C. § 285 (Prayer for Relief ¶J).

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

• A core issue will be one of induced infringement: Can Plaintiffs demonstrate that Teva's proposed product label will encourage or instruct physicians to perform every step of the asserted method claims, including the specific patient selection criteria such as "selected for being male" ('064 Patent) or having "received prior first line treatment" ('842 Patent)?
• A second central question will be the validity of the asserted claims: Although not detailed in the complaint, Teva’s Paragraph IV notice asserts invalidity. The case will likely involve a significant dispute over whether the claimed dosage regimens and patient populations are obvious in light of prior knowledge regarding the metabolic interaction between bupropion and dextromethorphan.
• A final question will be one of claim differentiation: The patents-in-suit appear to be directed to similar methods with claims distinguished by different patient populations. The court will need to determine whether these distinctions are patentably significant and how they affect the infringement analysis for a drug proposed for a broad patient population.