DCT
2:24-cv-06489
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: 2:24-cv-06489, D.N.J., 06/03/2024
- Venue Allegations: Venue is based on allegations that Defendant Teva maintains its U.S. Headquarters and a principal place of business in Parsippany, New Jersey, within the judicial 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 infringement of five U.S. patents directed to methods of using and formulating combinations of dextromethorphan and bupropion.
- Technical Context: The technology involves pharmaceutical compositions combining dextromethorphan, an NMDA receptor antagonist, and bupropion, a norepinephrine and dopamine reuptake inhibitor, for the treatment of major depressive disorder and other neurological conditions.
- Key Procedural History: This Hatch-Waxman litigation was triggered by Defendant Teva’s filing of ANDA No. 218147 and its subsequent sending of Paragraph IV certification notice letters to Plaintiff Axsome. These letters asserted that the patents-in-suit are invalid, unenforceable, and/or will not be infringed by Teva’s proposed generic product. The complaint also references a separate, existing lawsuit between the parties involving different patents related to the same drug product.
Case Timeline
| Date | Event |
|---|---|
| 2020-12-01 | ’563 Patent Priority Date |
| 2022-06-30 | ’636 Patent Priority Date |
| 2022-07-07 | ’612, ’797, ’373 Patent Priority Date |
| 2023-12-12 | U.S. Patent No. 11,839,612 Issued |
| 2023-12-19 | U.S. Patent No. 11,844,797 Issued |
| 2024-01-30 | U.S. Patent No. 11,883,373 Issued |
| 2024-02-13 | U.S. Patent No. 11,896,563 Issued |
| 2024-03-12 | U.S. Patent No. 11,925,636 Issued |
| 2024-04-10 | Teva sends Paragraph IV Notice Letter for ’612 and ’373 patents |
| 2024-05-01 | Teva sends Paragraph IV Notice Letter for ’797, ’563, and ’636 patents |
| 2024-06-03 | Amended Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 11,839,612 - "Compounds and Combinations Thereof For Treating Neurological and Psychiatric Conditions"
- Patent Identification: U.S. Patent No. 11,839,612, "Compounds and Combinations Thereof For Treating Neurological and Psychiatric Conditions," issued December 12, 2023.
The Invention Explained
- Problem Addressed: The patent addresses the need for specific dosing regimens of a dextromethorphan and bupropion combination for "certain patient populations," including those with moderate renal impairment, who may experience different pharmacokinetic profiles or side effects compared to the general population. (’612 Patent, col. 1:15-18, col. 6:43-52).
- The Patented Solution: The invention describes methods for treating conditions like major depressive disorder by administering a specific once-daily dosage of about 45 mg of dextromethorphan and 105 mg of bupropion. This once-daily regimen is disclosed to reduce the risk of adverse events such as somnolence and dizziness for patients with moderate renal impairment when compared to a twice-daily regimen. (’612 Patent, col. 2:1-12, col. 2:13-24).
- Technical Importance: This approach provides a tailored dosing strategy for a specific patient sub-population to improve the drug's safety profile and therapeutic window. (’612 Patent, col. 1:44-51).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 1. (Compl. ¶29).
- Claim 1 recites the following essential elements:
- A method of treating major depressive disorder in a human patient who requires concomitant treatment with paroxetine,
- comprising administering, once daily to the human patient, a combination of about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide,
- wherein the combination is present in a solid dosage form, administered in the morning,
- wherein the dextromethorphan is in an immediate-release formulation and the bupropion is in an extended-release formulation, and
- wherein the solid dosage form further contains L-cysteine hydrochloride monohydrate.
- The complaint alleges infringement of "one or more" claims of the patent. (Compl. ¶29).
U.S. Patent No. 11,844,797 - "Combination of Dextromethorphan and Bupropion for Treating Depression"
- Patent Identification: U.S. Patent No. 11,844,797, "Combination of Dextromethorphan and Bupropion for Treating Depression," issued December 19, 2023.
The Invention Explained
- Problem Addressed: This patent addresses the need to define a proper dosing regimen for patients with mild or moderate hepatic impairment. (’797 Patent, col. 1:15-24). The invention is based on the finding that dose adjustment may not be necessary for this patient population. (’797 Patent, col. 3:12-16).
- The Patented Solution: The invention claims a method of treating major depressive disorder in patients with moderate hepatic impairment (defined as Child-Pugh B) by administering a twice-daily tablet containing about 45 mg of dextromethorphan and 105 mg of bupropion. This dosage is the same as what would be administered to a patient with normal hepatic function. (’797 Patent, col. 1:25-34, col. 11:1-11).
- Technical Importance: The claimed method simplifies prescribing by establishing that a standard dose can be used safely and effectively in patients with mild to moderate hepatic impairment, avoiding the need for complex dose adjustments in this common co-morbidity. (’797 Patent, col. 3:12-16).
Key Claims at a Glance
- The complaint asserts infringement of at least independent claim 1. (Compl. ¶38).
- Claim 1 recites the following essential elements:
- A method of treating major depressive disorder in a human patient who has moderate hepatic impairment, defined as Child-Pugh B,
- comprising administering twice daily, by mouth, one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide,
- wherein the dextromethorphan hydrobromide is in an immediate-release formulation,
- wherein the bupropion hydrochloride is in an extended-release formulation, and
- wherein the tablet is a bilayer tablet.
- The complaint alleges infringement of "one or more" claims of the patent. (Compl. ¶38).
U.S. Patent No. 11,883,373 - "Treatment of Depression in Certain Patient Populations"
- Patent Identification: U.S. Patent No. 11,883,373, "Treatment of Depression in Certain Patient Populations," issued January 30, 2024.
- Technology Synopsis: The patent claims methods of treating major depressive disorder in specific patient populations, such as those with moderate renal impairment or who are known CYP2D6 poor metabolizers. The claimed methods involve administering a once-daily dose of a dextromethorphan and bupropion combination. (’373 Patent, col. 1:30-45).
- Asserted Claims: At least claims 1 and 10. (Compl. ¶47).
- Accused Features: Teva's proposed generic product, when used as directed by its label, is alleged to meet the limitations of the claimed methods of treatment. (Compl. ¶47, ¶49-51).
U.S. Patent No. 11,896,563 - "Bupropion and Dextromethorphan for Reduction of Suicide Risk in Depression Patients"
- Patent Identification: U.S. Patent No. 11,896,563, "Bupropion and Dextromethorphan for Reduction of Suicide Risk in Depression Patients," issued February 13, 2024.
- Technology Synopsis: The patent claims a method of treating depression and reducing the risk of suicide. The method involves administering a combination of bupropion and dextromethorphan to a human patient suffering from major depressive disorder and having a score of 3 or greater on the Suicidality Item of the Montgomery-Åsberg Depression Rating Scale (MADRS-SI). (’563 Patent, col. 1:20-31).
- Asserted Claims: At least claim 1. (Compl. ¶56).
- Accused Features: The intended use of Teva's proposed generic product is alleged to infringe the claimed method for reducing suicide risk in the specified patient population. (Compl. ¶56, ¶58-60).
U.S. Patent No. 11,925,636 - "Bupropion Dosage Forms with Reduced Food and Alcohol Dosing Effects"
- Patent Identification: U.S. Patent No. 11,925,636, "Bupropion Dosage Forms with Reduced Food and Alcohol Dosing Effects," issued March 12, 2024.
- Technology Synopsis: The patent is directed to dosage forms containing bupropion and dextromethorphan that include a polymer and are formulated to have no significant dose dumping in the presence of alcohol or a food effect when taken with a high-fat meal. (’636 Patent, col. 2:45-51).
- Asserted Claims: At least claims 1, 6, and 11. (Compl. ¶65).
- Accused Features: Teva's proposed product itself is alleged to be a dosage form that infringes the patent's composition claims. (Compl. ¶65, ¶67-69).
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), which is the subject of ANDA No. 218147. (Compl. ¶1, ¶17).
- Functionality and Market Context: The Proposed Product is a combination drug intended for the treatment of major depressive disorder (MDD) in adults. (Compl. ¶11). As a generic equivalent to Auvelity®, it is expected to contain the same active ingredients and be prescribed for the same indications. (Compl. ¶1, ¶11). The complaint alleges that upon FDA approval, Teva will manufacture, market, and sell this product in the United States. (Compl. ¶17, ¶27).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
11,839,612 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 requires concomitant treatment with paroxetine, | The complaint alleges that Teva's Proposed Product will be prescribed and used for treating major depressive disorder, including in patients taking paroxetine. | ¶29 | col. 17:23-25 |
| comprising administering, once daily to the human patient, a combination of about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide, | The complaint alleges that Teva's proposed label will instruct or encourage physicians and patients to administer the Proposed Product on a once-daily basis at these dosages. | ¶29 | col. 17:25-29 |
| wherein the combination is present in a solid dosage form, wherein the solid dosage form is orally administered in the morning, | Teva's Proposed Product is a solid oral tablet, and the complaint alleges its labeling will instruct administration in a manner that meets this limitation. | ¶29 | col. 17:30-32 |
| wherein the dextromethorphan is in an immediate-release formulation, wherein the bupropion is in an extended-release formulation, | Teva's Proposed Product is an extended-release tablet that, as a generic of Auvelity®, is alleged to have the same release profile. | ¶29 | col. 17:32-35 |
| and wherein the solid dosage form further contains L-cysteine hydrochloride monohydrate. | Teva's Proposed Product, as a generic equivalent, is alleged to contain the same excipients as the branded drug. | ¶29 | col. 17:35-37 |
11,844,797 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 hepatic impairment, defined as Child-Pugh B, | The complaint alleges that Teva's Proposed Product will be prescribed for treating MDD in patients including those with moderate hepatic impairment. | ¶38 | col. 11:1-3 |
| comprising administering twice daily, by mouth, one tablet containing about 105 mg of bupropion hydrochloride and about 45 mg of dextromethorphan hydrobromide to the human patient... | The complaint alleges Teva's proposed label will instruct or encourage twice-daily administration of its tablet containing these dosages. | ¶38 | col. 11:3-7 |
| wherein the dextromethorphan hydrobromide is in an immediate-release formulation, wherein the bupropion hydrochloride is in an extended-release formulation, | As a generic of Auvelity®, Teva's Proposed Product is alleged to have the same immediate-release and extended-release characteristics. | ¶38 | col. 11:8-10 |
| and wherein the tablet is a bilayer tablet. | Teva's Proposed Product is alleged to be a bilayer tablet, consistent with the formulation of the branded drug. | ¶38 | col. 11:10-11 |
- Identified Points of Contention:
- Scope Questions: A primary question for the method claims (’612, ’797, ’373, ’563 Patents) will be one of induced infringement: does the specific language in Teva's proposed product label instruct, encourage, or recommend that physicians and patients perform the patented methods? For example, for the ’612 Patent, does the label direct a once-daily regimen specifically for patients with moderate renal impairment taking paroxetine? For the composition-focused ’636 Patent, the question will be one of direct infringement: does Teva's formulation fall within the scope of the claims related to reduced food and alcohol effects?
- Technical Questions: Since the complaint is filed at the pre-discovery stage of an ANDA case, it does not contain technical evidence comparing Teva's product to the claims. A key evidentiary question for the court will be how Teva's specific formulation, once disclosed, compares to the claim limitations. For the ’636 Patent, this will involve technical analysis of Teva's formulation and its dissolution profiles in the presence of alcohol. For the method patents, this will involve a close analysis of the proposed label and other instructional materials.
V. Key Claim Terms for Construction
The Term: "administering, once daily" (’612 Patent, Claim 1)
Context and Importance: This term is critical because the patent’s specification distinguishes this once-daily regimen for patients with moderate renal impairment from a twice-daily regimen for other patients, tying the specific frequency to a reduction in side effects. (Compl. ¶29; ’612 Patent, col. 2:13-24). Practitioners may focus on this term because the infringement case will depend on whether Teva’s label is found to induce this specific dosing frequency for this specific patient group.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim phrase itself is straightforward. A party could argue it means simply one administration per 24-hour period, without further limitation.
- Evidence for a Narrower Interpretation: The specification repeatedly contrasts the "once a day" administration for patients with moderate renal impairment with a "twice a day" administration for patients without such impairment, framing the once-daily schedule as the solution to a technical problem (risk of somnolence). (’612 Patent, col. 2:13-24). This context suggests the "once daily" limitation is a specific, inventive selection for this population, potentially narrowing its interpretation.
The Term: "a human patient who has moderate hepatic impairment, defined as Child-Pugh B" (’797 Patent, Claim 1)
Context and Importance: The claim scope is explicitly limited to a specific, clinically defined patient population. Infringement will require evidence that Teva’s proposed label induces use in this particular group. (Compl. ¶38; ’797 Patent, col. 1:25-27). Practitioners may focus on how Teva's label addresses dosing in hepatically impaired patients and whether those instructions meet the legal standard for inducement.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The term itself is a standard clinical definition and offers little room for a "broader" reading.
- Evidence for a Narrower Interpretation: The specification provides context by stating that "No dose adjustment is recommended in patients with mild (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B)". (’797 Patent, col. 3:12-16). This ties the claim directly to the technical finding that a standard dose is appropriate for this group, reinforcing the term's specific clinical meaning.
VI. Other Allegations
- Indirect Infringement: The complaint alleges both induced infringement under 35 U.S.C. § 271(b) and contributory infringement under § 271(c) for all asserted patents. (Compl. ¶¶ 32-33, 41-42, 50-51, 59-60, 68-69). The inducement allegations are based on the assertion that Teva's proposed product labeling and marketing will instruct and encourage medical professionals and patients to use the generic product in an infringing manner. (Compl. ¶¶ 32, 41, 50, 59, 68). The contributory infringement allegations are based on the assertion that Teva's product is designed for an infringing use and lacks a substantial non-infringing use. (Compl. ¶¶ 33, 42, 51, 60, 69).
- Willful Infringement: The complaint does not use the word "willful" but does allege that Teva knew of the patents-in-suit based on its sending of Paragraph IV Notice Letters. (Compl. ¶¶ 24-25). For each count, Plaintiffs request a finding that the case is "exceptional" and an award of attorneys' fees under 35 U.S.C. § 285, which is often associated with findings of willful infringement or other litigation misconduct. (Compl. ¶¶ 36, 45, 54, 63, 72).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of induced infringement: will the specific language of Teva's proposed product label be found to actively encourage or instruct physicians to prescribe, and patients to use, the generic product in the precise manner claimed by the patents, particularly concerning the specific patient subpopulations (e.g., moderate renal or hepatic impairment) and dosing regimens required?
- A second key question will be one of validity and non-obviousness: can patent claims directed to specific dosing regimens for known compounds in particular patient populations withstand challenges that they are obvious modifications of prior art, representing routine clinical practice or predictable outcomes for those skilled in pharmacology and medicine?
- A third question will be direct infringement of the composition patent: for U.S. Patent No. 11,925,636, the case will turn on technical evidence of whether Teva's specific formulation, particularly its choice of polymers and excipients, falls within the scope of claims directed to reduced food and alcohol dosing effects.