DCT

2:24-cv-09535

Axsome Therap Inc v. Teva Pharma Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:24-cv-09535, D.N.J., 09/30/2024
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Teva Pharmaceuticals, Inc. maintains its U.S. Headquarters and a principal place of business in Parsippany, New Jersey, and will market and sell its accused product in the district.
  • 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 patent infringement under the Hatch-Waxman Act.
  • Technical Context: The technology involves a combination therapy using dextromethorphan and bupropion for the treatment of major depressive disorder (MDD), with the patents-in-suit directed to specific methods of use in patient subpopulations.
  • Key Procedural History: This action was initiated in response to a Paragraph IV Certification notice letter sent by Teva, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by its proposed generic product. The complaint notes that other patents covering Auvelity® are already the subject of existing litigation between the same parties.

Case Timeline

Date Event
2022-06-30 Earliest Priority Date ('444 and '191 Patents)
2022-07-07 Earliest Priority Date ('473 Patent)
2024-05-21 U.S. Patent No. 11,986,444 Issues
2024-07-16 U.S. Patent No. 12,036,191 Issues
2024-07-23 U.S. Patent No. 12,042,473 Issues
2024-08-30 Teva sends Fifth Paragraph IV Notice Letter (no earlier than)
2024-09-30 Complaint Filed

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

U.S. Patent No. 11,986,444 - Treatment of Poor Metabolizers of Dextromethorphan with a Combination of Bupropion and Dextromethorphan

The Invention Explained

  • Problem Addressed: The patent addresses the treatment of neurological or psychiatric conditions in patients who are "poor metabolizers" of dextromethorphan ('444 Patent, col. 1:16-24). Such patients have little or no function of the CYP2D6 enzyme, which metabolizes many drugs; standard dosing can lead to significantly higher drug exposure and an increased risk of adverse events compared to patients with normal enzyme function ('444 Patent, col. 4:3-16; col. 8:7-15).
  • The Patented Solution: The invention provides a method for safely treating major depressive disorder in this specific patient sub-population by administering a once-daily combination of bupropion and dextromethorphan ('444 Patent, col. 1:25-38). This specific dosing regimen is designed to manage the pharmacokinetic profile to achieve therapeutic benefit while mitigating the risk of side effects, such as dizziness, associated with the higher dextromethorphan exposure inherent in CYP2D6 poor metabolizers ('444 Patent, col. 2:5-15; col. 5:61-col. 6:2).
  • Technical Importance: The claimed method represents a personalized medicine approach, tailoring a therapeutic regimen to a patient's specific genetic metabolic profile to enhance the treatment's safety and efficacy.

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 18 ('444 Patent, Compl. ¶28).
  • Independent Claim 1: A method of treating major depressive disorder in a CYP2D6 poor metabolizer, comprising:
    • selecting a human patient known to be a poor CYP2D6 metabolizer;
    • administering, once daily in the morning for at least two weeks, a dosage form containing 1 mg to 105 mg of bupropion hydrochloride and 1 mg to 45 mg of dextromethorphan hydrobromide;
    • wherein the patient's resulting dextromethorphan area-under-the-curve (AUC0-12) is increased 208% to 557% compared to that of extensive or ultra-extensive CYP2D6 metabolizers.
  • Independent Claim 18: A method structurally similar to Claim 1, but requiring administration for "at least four weeks."
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 12,036,191 - Treatment of Poor Metabolizers of Dextromethorphan with a Combination of Bupropion and Dextromethorphan

The Invention Explained

  • Problem Addressed: The patent addresses the same technical challenge as the ’444 Patent: the safe and effective treatment of individuals who are poor metabolizers of dextromethorphan due to their CYP2D6 enzyme status (’191 Patent, col. 1:10-14). The risk of adverse events from high drug exposure in this population necessitates a tailored therapeutic strategy (’191 Patent, col. 5:65-col. 6:2).
  • The Patented Solution: The invention is a method of treating major depressive disorder in this patient population by administering a specific daily dose of bupropion (105 mg or less) and dextromethorphan (45 mg or less) (’191 Patent, col. 5:35-45). By defining specific dosage amounts for this genetically distinct group, the method aims to provide a predictable and safe therapeutic window, avoiding the pharmacokinetic variability and heightened side-effect risk that might otherwise occur (’191 Patent, Abstract).
  • Technical Importance: As with the ’444 Patent, this invention provides a targeted dosing strategy based on pharmacogenomics, allowing for optimized treatment of a psychiatric condition in a specific sub-population.

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 26 (’191 Patent, Compl. ¶37).
  • Independent Claim 1: A method of treating major depressive disorder in a CYP2D6 poor metabolizer, comprising:
    • selecting a human patient known to be a poor CYP2D6 metabolizer;
    • administering, once daily for at least two weeks, a dosage form containing 105 mg or less of bupropion hydrochloride and 45 mg or less of dextromethorphan hydrobromide.
  • Independent Claim 26: A method identical to Claim 1, but requiring administration for "at least four weeks."
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 12,042,473 - Compounds and Combinations Thereof for Treating Neurological and Psychiatric Conditions

Technology Synopsis

This patent discloses methods of administering a combination of dextromethorphan and bupropion to treat major depressive disorder in specific patient populations who may have altered drug metabolism or heightened risk profiles ('473 Patent, Abstract). The invention provides specific dosing regimens for patients with moderate renal impairment, patients who are known CYP2D6 poor metabolizers, or patients at risk of QT prolongation, aiming to ensure safety and efficacy in these vulnerable groups ('473 Patent, col. 1:30-col. 2:5).

Asserted Claims

Claims 1-9 (Compl. ¶46).

Accused Features

The complaint alleges that Teva's proposed generic product, a combination of dextromethorphan and bupropion, will be used according to a label that instructs physicians and patients to practice the patented methods of treatment (Compl. ¶¶ 1, 9, 46).

III. The Accused Instrumentality

Product Identification

Teva's proposed generic version of Auvelity® (dextromethorphan hydrobromide and bupropion hydrochloride extended-release tablets), for which Teva submitted ANDA No. 218147 to the FDA (Compl. ¶¶ 1, 9).

Functionality and Market Context

Auvelity® is an FDA-approved treatment for major depressive disorder (MDD) in adults (Compl. ¶9). It combines dextromethorphan, an NMDA receptor antagonist, with bupropion, which functions as a CYP450 2D6 enzyme inhibitor (Compl. ¶9). The inhibition of the CYP2D6 enzyme by bupropion increases the plasma concentration and prolongs the half-life of dextromethorphan, allowing it to exert its therapeutic effect (See, e.g., '444 Patent, col. 8:44-56). The infringement action is based on Teva's filing of an ANDA, which is a statutory act of infringement under 35 U.S.C. § 271(e)(2) if the proposed generic product, once marketed, would infringe the patents-in-suit (Compl. ¶1).

IV. Analysis of Infringement Allegations

The complaint does not provide sufficient detail for a claim-chart analysis. The infringement theory is predicated on 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 (Compl. ¶¶ 28, 37, 46). The central allegation is that the label for Teva's Proposed Product will instruct or encourage physicians and patients to administer the drug in a manner that directly infringes the asserted method claims of the patents-in-suit.

The '444 Patent includes a figure plotting the pharmacokinetic effects of the drug combination, which shows a greater than 3-fold increase in dextromethorphan exposure (AUC and Cmax) for CYP2D6 Poor Metabolizers relative to a reference population (’444 Patent, FIG. 1). This visual evidence directly supports the quantitative pharmacokinetic limitation recited in asserted claims 1 and 18 of the '444 patent and may be central to arguments regarding infringement and validity.

Identified Points of Contention

  • Scope Questions: A potential dispute may arise over the construction of "a human patient known to be a poor CYP2D6 metabolizer." The question will be whether this requires a specific genetic test or can be satisfied by a clinical diagnosis of a patient's metabolic phenotype, and whether Teva’s proposed label will instruct use in a manner that meets the court's construction.
  • Technical Questions: For the ’444 Patent, a key factual question will be whether administration of Teva's proposed generic product according to its proposed label will necessarily result in the specific pharmacokinetic profile (an AUC increase of 208% to 557%) recited in the claims. This will likely involve analysis of the bioequivalence data submitted in Teva’s ANDA. For the ’191 Patent, the question will be whether the proposed label instructs the administration of the claimed dosages to the claimed patient population.

V. Key Claim Terms for Construction

The Term: "a human patient known to be a poor CYP2D6 metabolizer" (from '444 Patent, Claim 1; '191 Patent, Claim 1)

Context and Importance

This term defines the specific patient population to which the patented methods apply. The construction of "known" will be critical; it raises the question of what level of diagnostic certainty or what type of diagnostic method (e.g., genetic testing, phenotypic analysis) is required to practice the invention. The outcome will directly impact the scope of infringement, particularly for inducement.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The specification states that individuals with a poor metabolizer genotype "may be identified by obtaining a biological sample... and performing a genotyping assay," but also notes that a poor metabolizer phenotype "may be obtained by comparing the plasma levels of dextromethorphan" or by measuring metabolic ratios ('444 Patent, col. 4:20-38). This language suggests the term is not limited to a specific diagnostic test.
  • Evidence for a Narrower Interpretation: The specification provides a detailed list of specific CYP2D6 alleles and polymorphisms associated with poor metabolism ('444 Patent, col. 10:18-col. 11:22). A party could argue that "known to be a poor... metabolizer" should be construed to mean a patient confirmed to have one of these specific genetic markers, narrowing the claim's scope.

The Term: "wherein the dextromethorphan AUC0-12 of the human patient is increased 208% to 557% compared to extensive or ultra-extensive CYP2D6 metabolizers" (from '444 Patent, Claim 1)

Context and Importance

This is a result-oriented functional limitation that defines the invention by a specific pharmacokinetic outcome. Practitioners may focus on this term because infringement hinges on proving that the accused method necessarily achieves this quantitative result. Its construction will also be relevant to validity challenges, such as written description and enablement.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: A party may argue that this is a straightforward numerical range that must be met, and any method that produces a result within this range infringes, regardless of the precise mechanism. The claim language itself is the strongest evidence for this interpretation.
  • Evidence for a Narrower Interpretation: The specification includes a figure showing that in a study, poor metabolizers exhibited a 3.40-fold increase in dextromethorphan AUC, with a 90% confidence interval corresponding to a 108% to 457% increase ('444 Patent, FIG. 1; col. 16:60-64). A defendant might argue that the claimed range of "208% to 557%" is not fully supported by this disclosure, potentially raising questions of written description or suggesting the range should be interpreted in light of the specific results disclosed.

VI. Other Allegations

Indirect Infringement

The complaint alleges induced and contributory infringement for all three patents. It asserts that upon FDA approval, Teva will intentionally encourage infringement by physicians and patients through its product labeling and instructions, and that Teva's product lacks substantial non-infringing uses (e.g., Compl. ¶¶ 31, 32, 40, 41, 49, 50).

Willful Infringement

The complaint does not use the term "willful," but it alleges that Teva had knowledge of the patents-in-suit, at the latest, upon receipt of the Paragraph IV notice letter (Compl. ¶¶ 24, 31). These allegations could form the basis for a claim of post-suit willful infringement and a request for enhanced damages.

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

  • A core issue will be one of definitional scope and induced infringement: can the term "known to be a poor CYP2D6 metabolizer" be met without a specific genetic test, and will Teva’s proposed product label be found to actively encourage or instruct physicians to prescribe the drug to this specific patient population, thereby inducing infringement of the method claims?
  • A key evidentiary question for the ’444 patent will be one of functional performance: does the bioequivalence data for Teva’s proposed generic product demonstrate that its use, as instructed, will necessarily result in the specific 208%-557% increase in dextromethorphan AUC required by the claims, or is there a material difference in the pharmacokinetic profile?
  • A central theme of the defense will likely be patent validity: can Teva demonstrate by clear and convincing evidence that claiming a specific dosing regimen and pharmacokinetic outcome for a known drug combination in a genetically-defined sub-population was obvious over the prior art or lacks adequate written description in the patent specification?