United States Patent 10,105,361: Scope, Claims, Exclusivity and Patent Landscape for Dextromethorphan-Bupropion
U.S. Patent No. 10,105,361 protects a pharmacokinetic method for administering dextromethorphan with bupropion to reduce the initial “trough effect” associated with rapid dextromethorphan metabolism. The independent claim is directed to a staged regimen: once-daily co-administration for one to seven days, followed by twice-daily co-administration for at least eight consecutive days.
The patent is important to Axsome Therapeutics’ Auvelity product, an extended-release combination of dextromethorphan hydrobromide and bupropion hydrochloride approved by the FDA for major depressive disorder. The core claim does not merely require the presence of both active ingredients. It requires a specified loading sequence, an extensive-metabolizer patient population, dose ranges, and pharmacokinetic outcomes measured through minimum plasma concentration, or Cmin.
What does U.S. Patent 10,105,361 protect?
The patent protects a method of reducing a dextromethorphan trough effect by using bupropion to inhibit dextromethorphan metabolism and increase systemic exposure.
The principal claim limitations are:
| Claim element |
Requirement |
| Patient |
Human subject who is an extensive metabolizer of dextromethorphan |
| Clinical need |
Patient needs treatment with dextromethorphan |
| Combination |
Bupropion plus dextromethorphan |
| Initial regimen |
Once daily for 1 to 7 days |
| Maintenance regimen |
Twice daily for at least 8 consecutive days |
| Bupropion dose |
About 50 mg to about 500 mg |
| Pharmacokinetic result |
First dextromethorphan Cmin of at least about 20 ng/mL |
| Comparator |
First Cmin at least about 20 times higher than Cmin from dextromethorphan alone |
| Administration |
Oral administration is covered by dependent claims |
The claim is a method-of-treatment claim rather than a simple composition claim. A product containing dextromethorphan and bupropion does not automatically infringe claim 1. Infringement would generally require performance of the claimed dosing sequence and satisfaction of the specified pharmacokinetic conditions.
How should claim 1 of Patent 10,105,361 be construed?
Claim 1 has four principal enforcement components.
Staged dosing sequence
The first phase requires once-daily dosing for one through seven days. The second phase requires twice-daily dosing for at least eight consecutive days.
This limitation distinguishes the claim from a product administered twice daily from the first dose. It also creates potential design-around space for a competing product that uses a different loading period, a different dosing frequency, or no staged initiation.
The phrase “for 1, 2, 3, 4, 5, 6, or 7 days” is unusually specific. It covers each integer duration individually. A regimen lasting eight days before twice-daily dosing would fall outside the express initial-period limitation unless another claim or doctrine supplied coverage.
Extensive-metabolizer limitation
The patient must be an extensive metabolizer of dextromethorphan. The claim therefore focuses on a pharmacogenetic or phenotypic subgroup with comparatively rapid CYP2D6-mediated metabolism.
This limitation narrows the claim but also creates factual complexity. An accused infringer would likely examine:
- CYP2D6 genotype;
- measured dextromethorphan or dextrorphan exposure;
- the assay or classification method used to identify the metabolizer status;
- whether the patient was known to be an extensive metabolizer before treatment; and
- whether the claim requires actual status or only treatment of a subject who falls within that category.
A product label that does not identify extensive metabolizers may reduce direct infringement evidence, but it would not necessarily eliminate risk if clinical protocols, prescribing records, pharmacokinetic studies, or product instructions support the limitation.
Cmin threshold
Claim 1 requires a first dextromethorphan Cmin of at least approximately 20 ng/mL on the eighth day of twice-daily administration.
The claim therefore contains an outcome limitation. It is not enough to administer the claimed doses. The resulting exposure must meet the threshold. The patent’s dependent claims add higher Cmin thresholds and narrower ranges.
The “about” language creates a potential claim-construction issue. The practical scope may depend on accepted analytical variability, assay precision, and the specification’s disclosed examples. A measured value near 20 ng/mL would likely require technical evidence concerning the assay and the meaning of “about.”
Twenty-fold comparator
The first Cmin must be at least approximately 20 times higher than the second Cmin that would result from administering dextromethorphan without bupropion for eight days of twice-daily administration.
This is a relative pharmacokinetic limitation. It requires a comparator based on dextromethorphan monotherapy in the same human subject, or an appropriately established subject-specific comparison.
The limitation may create evidentiary disputes because the comparator is a counterfactual result: what would have occurred without bupropion. Clinical trials, historical controls, modeling, and genotype-based pharmacokinetic data may be relevant. The claim is narrower than a claim requiring only a fixed Cmin or a fixed dose ratio.
What do dependent claims 2 through 30 add?
The dependent claims expand the technical coverage across stereochemistry, exposure, dose, formulation, duration and patient history.
Stereochemical coverage
Claims 2 and 3 cover bupropion with an enantiomeric excess of either R-bupropion or S-bupropion. Together, they are drafted to cover stereochemically enriched bupropion compositions rather than only racemic bupropion.
The claims do not appear limited to one particular enantiomer. This may complicate attempts to avoid the patent through use of an enriched bupropion stereoisomer.
Dextromethorphan Cmin ranges
Claims 4 through 9 cover the following exposure parameters:
| Claim |
Cmin limitation |
| 4 |
At least about 40 ng/mL |
| 5 |
At least about 65 ng/mL |
| 6 |
About 30 ng/mL to about 40 ng/mL |
| 7 |
About 40 ng/mL to about 50 ng/mL |
| 8 |
About 60 ng/mL to about 65 ng/mL |
| 9 |
About 65 ng/mL to about 70 ng/mL |
Claims 6 through 9 create overlapping or adjacent ranges. Claim 7 overlaps the endpoint of claim 6, while claim 9 overlaps the threshold in claim 5. These claims provide fallback positions if the broad “at least 20 ng/mL” limitation is challenged.
Dosing and product architecture
The dependent claims cover:
- oral co-administration;
- deuterium-modified dextromethorphan;
- deuterium-modified bupropion;
- treatment for at least 60 days;
- bupropion doses of approximately 90 mg to 105 mg;
- bupropion doses of approximately 105 mg to 110 mg;
- dextromethorphan doses of approximately 42 mg to 46 mg;
- dextromethorphan doses of approximately 44 mg to 48 mg;
- daily bupropion doses of approximately 150 mg to 300 mg or 200 mg to 250 mg; and
- daily dextromethorphan doses of approximately 55 mg to 120 mg or 60 mg to 100 mg.
The dose ranges closely surround the Auvelity commercial strength of 45 mg dextromethorphan and 105 mg bupropion per extended-release tablet, administered twice daily. The product’s total daily dose is therefore 90 mg dextromethorphan and 210 mg bupropion.
Formulation claims
Claims 27 through 29 identify tablets, troches, capsules, elixirs, suspensions, syrups and wafers. They also cover excipients, binders, disintegrants, lubricants, sweeteners and flavoring agents.
Claim 29 specifically requires a dosage form that provides sustained release of bupropion. This is relevant to extended-release products because the claim is not limited to an immediate-release bupropion profile.
The patent does not appear to require a particular tablet architecture, coating, dissolution profile or release-control polymer in the claims provided. Those limitations may be addressed in related patents or patent applications.
When does Patent 10,105,361 expire?
The patent has a priority date of April 22, 2013. Its nominal 20-year patent term, calculated from the earliest applicable nonprovisional filing date, is expected to extend to approximately April 22, 2035, before any patent-term adjustment or patent-term extension.
| Milestone |
Date |
| Earliest reported priority date |
April 22, 2013 |
| Patent issued |
October 23, 2018 |
| Expected nominal expiration |
April 22, 2035 |
| FDA approval of Auvelity |
August 18, 2022 |
| Three-year regulatory exclusivity period |
Expected to end August 18, 2025 |
The exact expiration date should be determined from the USPTO patent-term calculation, including any patent-term adjustment. Patent-term extension under 35 U.S.C. § 156 is a separate issue and generally depends on the regulatory history and statutory eligibility of the approved product.
What is the Orange Book status of Patent 10,105,361?
Patent 10,105,361 is associated with the dextromethorphan-bupropion product Auvelity and is relevant to Orange Book patent protection for the approved product.
The Orange Book separates:
- patents claiming the drug substance;
- patents claiming the drug product or formulation; and
- patents claiming an approved method of use.
Patent 10,105,361 is principally a method-of-use patent. Its relevance depends on whether the listed use corresponds to the FDA-approved labeling and whether the product label directs or encourages performance of the patented regimen.
For a generic applicant filing an ANDA, a Paragraph IV certification could challenge the patent’s validity, enforceability or infringement. A Paragraph IV notice would expose the applicant to patent litigation under the Hatch-Waxman framework and could trigger a 30-month stay of approval if the statutory conditions are met.
What generic entry risks exist for Auvelity?
Generic risk depends on both formulation substitution and method-of-use exposure.
A generic applicant could pursue several strategies:
- Market a product with a different dextromethorphan-bupropion dose.
- Avoid the claimed one-to-seven-day once-daily initiation sequence.
- Use a label that does not instruct treatment of extensive metabolizers.
- Challenge the pharmacokinetic limitations as indefinite, unsupported or not enabled.
- Argue that the product does not produce the claimed Cmin or twenty-fold comparator result.
- Pursue a skinny label excluding the patented method, where legally and commercially feasible.
- Develop a different release profile or separate administration schedule.
The strongest infringement risk arises where a generic product reproduces the 45 mg/105 mg twice-daily commercial regimen, is used after an initial loading period, and is supported by labeling or clinical instructions that correspond to the patented pharmacokinetic method.
How strong is the patent estate for the dextromethorphan-bupropion combination?
Patent 10,105,361 is technically focused but commercially relevant. Its strengths are:
- direct relationship to the pharmacology of the combination;
- coverage of the commercial dose neighborhood;
- coverage of both initial and maintenance treatment;
- inclusion of Cmin thresholds that can be tied to clinical pharmacology;
- dependent claims covering oral and sustained-release dosage forms; and
- a projected expiration in 2035.
Its vulnerabilities are equally defined:
- the extensive-metabolizer limitation narrows the patient population;
- the once-daily-to-twice-daily transition may not match every commercial regimen;
- Cmin and twenty-fold increase limitations require technical proof;
- the comparator may be difficult to establish in an individual patient;
- “about” ranges may generate indefiniteness and claim-construction disputes; and
- method-of-use claims are more dependent on labeling and actual treatment behavior than composition claims.
The patent is therefore stronger against a product that follows the claimed regimen and weaker against a product using a materially different initiation protocol or release design.
What patent litigation and Paragraph IV challenges affect the product?
The claims provided do not identify a filed Paragraph IV challenge, ANDA applicant or settlement agreement. No specific challenger or settlement should be treated as established solely from Patent 10,105,361.
A complete litigation assessment requires review of:
- current Orange Book listings;
- FDA Paragraph IV notice disclosures;
- federal district court dockets;
- the Patent Trial and Appeal Board docket;
- ANDA litigation complaints under 21 U.S.C. § 355(j)(5)(C); and
- any license or settlement agreements disclosed by Axsome or a generic applicant.
The patent’s method-of-use character means that litigation would likely focus on induced infringement, label content, actual use, claim construction and the reliability of pharmacokinetic evidence.
How does Patent 10,105,361 compare with formulation and composition protection?
| Protection type |
Typical subject matter |
Relevance to Auvelity |
| Method of use |
Dosing sequence and pharmacokinetic result |
Core subject of Patent 10,105,361 |
| Composition |
Combination of dextromethorphan and bupropion |
May provide broader product protection if separately patented |
| Formulation |
Extended-release profile, tablet structure and excipients |
Can restrict formulation substitution |
| Manufacturing |
Granulation, coating, release control and scale-up processes |
May create manufacturing barriers |
| Regulatory exclusivity |
FDA market protection independent of patent validity |
Applied from approval date under the applicable exclusivity category |
Patent 10,105,361 should not be treated as the entire Auvelity patent estate. Commercial protection may also depend on related continuation patents, formulation patents, manufacturing patents and later-issued patents covering the approved product.
Key Takeaways
- Patent 10,105,361 claims a staged dextromethorphan-bupropion treatment method.
- The independent claim requires once-daily dosing for one to seven days, followed by twice-daily dosing for at least eight days.
- The patient must be an extensive metabolizer of dextromethorphan.
- The claim requires a dextromethorphan Cmin of at least approximately 20 ng/mL and a twenty-fold increase over dextromethorphan monotherapy.
- The dependent claims cover commercial-dose ranges, oral administration, sustained-release bupropion, stereochemically enriched bupropion and treatment for at least 60 days.
- The expected nominal patent expiration is approximately April 22, 2035, subject to USPTO patent-term adjustment.
- FDA approved Auvelity on August 18, 2022.
- The principal generic vulnerabilities are the staged dosing limitation, extensive-metabolizer requirement, Cmin measurement and counterfactual twenty-fold comparison.
- The patent is commercially significant but should be analyzed together with related formulation, composition, manufacturing and continuation patents.
FAQs
Does Patent 10,105,361 cover every dextromethorphan-bupropion product?
No. The independent claim requires a specific treatment sequence, extensive-metabolizer patient, dose range and pharmacokinetic outcome.
Can a generic avoid Patent 10,105,361 by using immediate-release bupropion?
Potentially, depending on whether the resulting regimen satisfies the claimed sustained-release or pharmacokinetic limitations. The claims provided do not make sustained-release bupropion a requirement of claim 1, but claim 29 adds that limitation.
Does the patent cover Auvelity’s 45 mg dextromethorphan and 105 mg bupropion strength?
The dependent dose claims cover ranges surrounding those strengths. Auvelity’s twice-daily regimen also falls within the claimed daily-dose ranges.
Is a Cmin test required to prove infringement?
The claim includes Cmin limitations. In litigation, pharmacokinetic testing, clinical data, modeling or other technical evidence may be required to establish whether those limitations are met.
Can the patent be challenged through inter partes review?
A party may evaluate inter partes review for eligible patent claims based on patents or printed publications. However, method-of-treatment claims may present prior-art, claim-construction and evidentiary issues that determine whether an IPR is commercially useful.
References
- United States Patent and Trademark Office. (2018). U.S. Patent No. 10,105,361, methods of reducing a trough effect of dextromethorphan.
- U.S. Food and Drug Administration. (2022). Auvelity: Prescribing information.
- U.S. Food and Drug Administration. (2022, August 18). FDA approves new oral treatment for major depressive disorder.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, commonly known as the Orange Book.
- Drug Price Competition and Patent Term Restoration Act of 1984, 21 U.S.C. § 355(j).
- Patent Act, 35 U.S.C. §§ 154, 156 and 271.
