Details for Patent: 11,298,352

Which drugs does patent 11,298,352 protect, and when does it expire?

Patent 11,298,352 protects AUVELITY and is included in one NDA.

This patent has two hundred and twenty-one patent family members in thirty-three countries.

Summary for Patent: 11,298,352

Title:	Bupropion as a modulator of drug activity
Abstract:	Dosage forms, drug delivery systems, and methods related to sustained release of dextromethorphan or improved therapeutic effects are disclosed. Typically, bupropion or a related compound is orally administered to a human being to be treated with, or being treated with, dextromethorphan.
Inventor(s):	Herriot Tabuteau
Assignee:	Antecip Bioventures II LLC
Application Number:	US17/201,820
Patent Claim Types: see list of patent claims	Use;

United States Drug Patent 11,298,352: Claim Scope, Exclusivity, Orange Book Status, and Competitive Patent Landscape

U.S. Patent No. 11,298,352 protects a pharmacokinetic method for administering dextromethorphan with bupropion to an extensive metabolizer. The patent is directed to sustained CYP2D6 inhibition that raises dextromethorphan exposure by at least approximately 20-fold after repeated dosing. Its narrowest commercial overlap is with Auvelity, Axsome Therapeutics' extended-release dextromethorphan hydrobromide/bupropion hydrochloride product.

The commercial dose most closely aligned with the claims is 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride per tablet, administered twice daily after initial titration. The patent does not broadly claim every dextromethorphan-bupropion product. It requires a defined patient phenotype, repeated administration, dose ranges, pharmacokinetic results, and, in dependent claims, specific therapeutic uses and exposure thresholds.

What patent is U.S. Patent 11,298,352?

U.S. Patent 11,298,352 B2 is an Axsome-associated patent covering methods of increasing dextromethorphan plasma exposure through co-administration with bupropion. The patent issued on April 12, 2022. Its independent claim requires all of the following:

Required limitation	Scope
Patient	Human being who is an extensive metabolizer of dextromethorphan
Active agents	Bupropion and dextromethorphan are the only therapeutically active agents co-administered
Dosing frequency	Once daily or twice daily
Duration	At least eight consecutive days
Bupropion dose	About 90 mg to about 220 mg bupropion hydrochloride, or molar equivalent
Dextromethorphan dose	Dextromethorphan hydrobromide, free base, or another salt form
Pharmacokinetic result	Day-eight dextromethorphan AUC0-24 is at least approximately 20 times the comparator AUC
Comparator	Same daily dextromethorphan dose administered without bupropion for eight consecutive days

The claim is a method-of-treatment and pharmacokinetic-result claim. It is not simply a composition claim covering a tablet containing the two active ingredients.

What does claim 1 of U.S. Patent 11,298,352 cover?

Claim 1 covers a regimen that uses bupropion to inhibit dextromethorphan metabolism in a dextromethorphan extensive metabolizer. The claim compares exposure under combination therapy with exposure from dextromethorphan alone.

The comparator is internally defined by the claim. The relevant question is not whether dextromethorphan has a high absolute plasma concentration, but whether the combination produces a day-eight AUC0-24 at least about 20 times higher than the AUC0-24 produced by the same daily dextromethorphan dose without bupropion.

This structure creates several infringement-sensitive elements:

1. The patient must be an extensive metabolizer of dextromethorphan.
2. The regimen must continue for at least eight consecutive days.
3. Bupropion must fall within the stated dose range.
4. The combination must produce the claimed exposure ratio.
5. The two drugs must be the only therapeutically active agents co-administered.

A product label that recommends the claimed regimen can create method-of-use exposure even if the product itself is physically identical to an unclaimed formulation.

How do claims 2 through 20 narrow the patent?

The dependent claims progressively limit exposure, dose, treatment duration, pharmacokinetic parameters, and indication.

Claims	Added limitation
2	Day-eight AUC0-24 is about 20-fold to about 80-fold the dextromethorphan-only comparator
3	90-150 mg bupropion hydrochloride with 40-60 mg dextromethorphan hydrobromide, once or twice daily
4	Day-eight dextromethorphan AUC0-24 is about 1,900 ng·hr/mL
5	Day-eight AUC0-24 is about 1,300-2,975 ng·hr/mL
6	Approximately 105 mg bupropion hydrochloride with 42-48 mg dextromethorphan hydrobromide
7-9	Treatment of depression, nicotine addiction, or agitation associated with Alzheimer's disease
10	Day-eight dextromethorphan Cmax is about 69-154 ng/mL
11-13	The claim 10 regimen is used for the same three indications
14	Day-eight bupropion AUC0-12 is at least 600 ng·hr/mL
15-17	The claim 14 regimen is used for the same three indications
18	Treatment continues for at least 14 consecutive days
19	Treatment continues for at least 30 consecutive days
20	The patient is converted to poor-metabolizer status by day eight

Claims 6, 10, and 14 are particularly relevant to Auvelity because the commercial product contains 105 mg bupropion hydrochloride and 45 mg dextromethorphan hydrobromide per tablet. Two tablets per day provide 210 mg bupropion hydrochloride and 90 mg dextromethorphan hydrobromide.

Does U.S. Patent 11,298,352 cover Auvelity?

The claims materially overlap with the labeled Auvelity regimen, but claim coverage must be analyzed limitation by limitation.

Auvelity is approved for major depressive disorder in adults. The FDA-approved label describes an extended-release tablet containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride. The recommended schedule is one tablet once daily for the first three days, followed by one tablet twice daily, with a maximum of two tablets per day (FDA, 2022).

The overlap is strongest for:

• 105 mg bupropion hydrochloride per tablet;
• 45 mg dextromethorphan hydrobromide per tablet;
• once-daily or twice-daily administration;
• repeated administration beyond eight days;
• depression treatment;
• pharmacokinetic exposure consistent with CYP2D6 inhibition.

The first claim requires the bupropion and dextromethorphan to be the only therapeutically active agents co-administered. A patient taking an antidepressant, stimulant, opioid, antipsychotic, or other active therapy could fall outside that specific limitation, depending on how “therapeutically active agents” is construed and applied.

The claims also require an extensive metabolizer. The FDA label does not generally require prescribers to genotype patients before prescribing Auvelity. That fact does not necessarily eliminate claim exposure. A patient can be an extensive metabolizer without being tested, and infringement theories may focus on the prescribed regimen, induced phenotype, or clinical population.

What pharmacokinetic mechanism does the patent protect?

Dextromethorphan is substantially metabolized by CYP2D6. Bupropion and its metabolites inhibit CYP2D6, reducing conversion of dextromethorphan to dextrorphan. Repeated dosing produces a pharmacokinetic interaction that increases dextromethorphan exposure and changes metabolizer status.

Claim 20 captures the induced phenotype directly. It requires that the patient be converted to poor-metabolizer status by day eight. That limitation is narrower than the claims based only on AUC or Cmax.

The patent therefore protects a pharmacokinetic treatment platform rather than only a fixed-dose product. The protected value lies in using bupropion as a metabolic inhibitor to create sustained dextromethorphan exposure at clinically useful doses.

What patents protect Auvelity and the dextromethorphan-bupropion combination?

The Auvelity patent estate includes patents directed to the combination, dosing regimen, pharmacokinetic effects, therapeutic uses, and formulation. U.S. Patent 11,298,352 is one component of that estate.

Patent category	Relevant subject matter	Commercial significance
Combination therapy	Co-administration of dextromethorphan and bupropion	Protects the therapeutic pairing
Pharmacokinetics	Increased AUC, Cmax, and altered CYP2D6 phenotype	Creates method-of-use barriers tied to exposure
Dose regimen	Approximately 45 mg dextromethorphan and 105 mg bupropion per tablet	Aligns with the marketed strength
Indications	Depression and other neuropsychiatric uses	Supports indication-specific enforcement
Extended-release formulation	Controlled release of the active ingredients	Raises formulation and development barriers
Manufacturing and dosage form	Tablet composition, release profile, and production	Can create separate formulation infringement risk

The exact scope of each related patent depends on its issued claims and current Orange Book listing. U.S. Patent 11,298,352 should not be treated as a complete substitute for a claim-by-claim review of the entire Axsome family.

When does U.S. Patent 11,298,352 lose exclusivity?

The patent's ordinary term is expected to run to approximately June 14, 2037, based on the publicly reported family priority timeline and the 20-year patent-term framework. The operative expiration date can be affected by patent-term adjustment, terminal disclaimers, patent-term extension, or later legal events. The patent is not a Hatch-Waxman five-year new chemical entity patent by itself because the active ingredients, dextromethorphan and bupropion, were previously known drugs.

The relevant exclusivity periods are separate:

Exclusivity type	Relevance
Patent exclusivity	Primarily extends into the 2030s for the combination and related methods
FDA new-drug exclusivity	Auvelity received regulatory exclusivity associated with its approval, but that period is shorter than the patent term
Orphan exclusivity	Not the principal basis for Auvelity's depression exclusivity
Pediatric exclusivity	Any applicable six-month extension depends on an FDA-issued pediatric determination
Data exclusivity	Does not by itself prevent an ANDA applicant from challenging patents after the applicable period

The patent term, not FDA marketing exclusivity, is the principal long-term barrier for a generic Auvelity-style product.

What is the Orange Book status of U.S. Patent 11,298,352?

Auvelity is approved under NDA 212278 and is listed in FDA drug-product records. Axsome has reported Orange Book-listed patents covering Auvelity and its approved use. The Orange Book analysis must distinguish between:

• patents listed against the NDA;
• patents directed to the approved drug product;
• patents directed to an approved method of use;
• patents that remain enforceable after expiration, disclaimer, or litigation;
• patents for which a generic applicant must make a Paragraph IV certification.

U.S. Patent 11,298,352 is relevant to an Orange Book strategy because its claims cover the labeled combination regimen and depression treatment. A patent's listing does not establish validity or infringement. It determines the regulatory certification and litigation framework available to the NDA holder.

Which companies are challenging Auvelity patent rights?

The principal competitive risk comes from generic-drug companies seeking to market a dextromethorphan-bupropion product after filing an ANDA. A generic applicant could challenge listed patents through a Paragraph IV certification asserting that a patent is invalid, unenforceable, or not infringed.

A Paragraph IV certification can trigger a patent-infringement action under 35 U.S.C. §271(e)(2). If the NDA holder files suit within the statutory period, FDA approval may be stayed for up to 30 months, subject to court and regulatory events.

Publicly available patent records and company disclosures should be reviewed for current ANDA notices, district-court complaints, settlements, and appellate decisions. The supplied claim set alone does not establish that a particular generic company has filed a Paragraph IV challenge or that a settlement exists.

What generic entry risks exist for Auvelity?

A generic applicant has several possible design strategies:

Separate-component strategy

A company could seek approval for dextromethorphan and bupropion as separate products or as a co-packaged regimen. That approach may avoid some composition claims but can remain exposed to method-of-use claims if the labeling directs the patented regimen.

Different strength strategy

A product using a materially different dose could avoid claims requiring approximately 105 mg bupropion and 42-48 mg dextromethorphan. It may still face broader claims requiring 90-220 mg bupropion and at least a 20-fold AUC increase.

Different dosing frequency

A regimen outside once-daily or twice-daily administration could avoid the asserted claims. Such a design may not be therapeutically or commercially equivalent.

Pharmacokinetic design-around

A generic could attempt to avoid the claimed exposure range, metabolizer conversion, or day-eight threshold. This is difficult if the product is intended to reproduce the reference product's clinical effect and labeling.

Label carve-out

If patents are limited to specific indications, a generic could seek a skinny label excluding patented uses. That strategy is less effective where the product's dosing instructions themselves induce use of the claimed regimen.

How strong is the patent estate for dextromethorphan and bupropion?

The estate is stronger against a direct Auvelity copy than against all conceivable dextromethorphan-bupropion regimens.

Strengths

• The claims align with the marketed dose.
• The claims use objective pharmacokinetic thresholds.
• The combination addresses a defined CYP2D6 interaction.
• The claims include both broad regimen limitations and narrower commercial-dose embodiments.
• The product has an FDA-approved indication that overlaps with dependent claims 7, 11, and 15.

Vulnerabilities

• The active ingredients are individually old and generic.
• The claims depend on patient phenotype and pharmacokinetic results.
• “About” ranges can create claim-construction disputes.
• The comparator AUC may require a defined study design and reproducible baseline.
• Extensive-metabolizer status and conversion to poor-metabolizer status may require clinical evidence.
• A generic may contest enablement, written description, obviousness, or indefiniteness for exposure-result limitations.

The estate is therefore commercially meaningful but more fact-dependent than a simple composition patent covering a novel chemical entity.

Is there biosimilar risk for Auvelity?

No conventional biosimilar pathway applies. Auvelity is a small-molecule drug, not a biologic. The principal regulatory route for a competing product is an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act, or potentially a 505(b)(2) application for a materially different formulation, dosage form, or clinical reliance strategy.

The competitive issue is generic substitution, not biosimilar interchangeability.

What manufacturing and formulation barriers exist?

A direct competitor must reproduce more than the nominal active-ingredient amounts. It may need to match:

• extended-release characteristics;
• dissolution profile;
• tablet architecture;
• stability of dextromethorphan and bupropion;
• impurity controls;
• dose uniformity;
• food-effect behavior;
• pharmacokinetic exposure over the dosing interval.

Formulation patents can be more commercially important than a pharmacokinetic method claim because they may cover the tablet sold to every patient. A generic can challenge or design around formulation claims, but a successful design must still satisfy ANDA pharmaceutical-equivalence and bioequivalence requirements.

How does the patent landscape compare with generic bupropion and dextromethorphan?

Issue	Generic bupropion	Generic dextromethorphan	Auvelity combination
Active ingredient status	Long-established generic	Long-established generic	Combination product
Principal barrier	Formulation and indication patents	Formulation and indication patents	Combination, PK, formulation, and use patents
Biosimilar pathway	No	No	No
ANDA risk	Usually lower	Usually lower	Higher due to listed combination patents
Pharmacokinetic interaction	Not central	Not central	Central to the patented technology
Commercial substitution	Broad availability	Broad availability	Requires combination-specific approval

A competitor can freely market the individual active ingredients subject to their own applicable patents and approvals. That does not necessarily authorize the patented co-administration regimen.

What litigation and settlement issues should investors monitor?

The principal indicators are:

1. FDA Orange Book changes for NDA 212278.
2. Paragraph IV notices involving listed Auvelity patents.
3. District-court complaints under 35 U.S.C. §271(e)(2).
4. 30-month-stay orders and abbreviated new drug application timing.
5. Patent-terminal-disclaimer or continuation activity.
6. Settlement agreements that set an authorized-generic date.
7. Federal Circuit decisions affecting pharmacokinetic-result claims.
8. Axsome disclosures concerning patent litigation, revenue forecasts, or generic entry assumptions.

A settlement can materially change the effective market-exclusivity date even when the patent's nominal expiration remains unchanged. No settlement date or authorized-generic launch date is established by the claim text supplied.

What is the revenue exposure from U.S. Patent 11,298,352?

The patent has direct relevance to Auvelity revenue because its claims overlap the commercial dose and depression indication. Auvelity is Axsome's principal marketed product and the combination's value depends on maintaining branded pricing before generic entry.

Revenue exposure has three layers:

Exposure layer	Business impact
Direct generic entry	Price erosion and unit conversion from Auvelity
Label-induced method risk	Potential infringement disputes even where the formulation differs
Formulation substitution	Delayed or partial erosion if a competitor cannot match release characteristics

The financial effect depends on the number of surviving listed patents, the timing of ANDA approval, any settlement, and the ability of a competitor to obtain a label covering the commercially important use.

Key Takeaways

• U.S. Patent 11,298,352 is a pharmacokinetic method patent associated with Axsome's dextromethorphan-bupropion program.
• Claim 1 requires an extensive metabolizer, at least eight consecutive days of dosing, specified bupropion exposure, and at least a 20-fold increase in day-eight dextromethorphan AUC.
• Claims 6, 10, and 14 closely track the marketed 105 mg bupropion/45 mg dextromethorphan strength and its pharmacokinetic profile.
• The patent is materially relevant to Auvelity but does not independently define the entire Auvelity patent estate.
• The expected ordinary expiration is approximately June 14, 2037, subject to patent-term adjustments and other statutory events.
• Generic competition would proceed through an ANDA and potentially a Paragraph IV certification, not a biosimilar application.
• The strongest generic vulnerabilities are the old status of the active ingredients, pharmacokinetic-result limitations, patient-metabolizer requirements, and claim-construction disputes over “about” ranges.
• The strongest patent-estate attributes are alignment with the commercial dose, objective exposure thresholds, and overlap with the FDA-approved depression regimen.

FAQs

Can a generic copy the 45 mg dextromethorphan and 105 mg bupropion dose?

It can seek approval for that strength, but approval and commercial launch depend on the full Orange Book patent set, certification strategy, litigation, and any settlement.

Does claim 1 require genetic testing for CYP2D6 status?

The claim requires the patient to be an extensive metabolizer, but its text does not expressly require genetic testing. Whether testing is necessary to establish infringement depends on claim construction and proof in a particular case.

Can a product avoid the patent by using dextromethorphan free base instead of hydrobromide?

Not necessarily. The claims expressly cover dextromethorphan hydrobromide, the free base, and other salt forms, subject to molar-equivalence and all other claim limitations.

Does the patent cover treatment with bupropion and dextromethorphan for depression only?

No. The independent claim is not limited to depression. Dependent claims add depression, nicotine addiction, and agitation associated with Alzheimer's disease as specific treatment uses.

Is an extended-release formulation required by the patent claims?

The supplied claims do not expressly require an extended-release dosage form. A formulation may still be protected by separate patents or may be necessary to satisfy the reference product's FDA bioequivalence requirements.

References

1. Axsome Therapeutics, Inc. (2024). Annual report on Form 10-K. U.S. Securities and Exchange Commission.

2. Food and Drug Administration. (2022). Auvelity (dextromethorphan hydrobromide and bupropion hydrochloride) extended-release tablets: Prescribing information. U.S. Department of Health and Human Services.

3. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.

4. U.S. Patent and Trademark Office. (2022). U.S. Patent No. 11,298,352 B2: Methods of increasing dextromethorphan plasma levels. U.S. Department of Commerce.

5. U.S. Food and Drug Administration. (2024). Drugs@FDA: FDA-approved drugs, NDA 212278. U.S. Department of Health and Human Services.

6. U.S. Code. (2024). 35 U.S.C. §§ 154, 271(e)(2), and 271(e)(4). United States Code.

Drugs Protected by US Patent 11,298,352

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Axsome	AUVELITY	bupropion hydrochloride; dextromethorphan hydrobromide	TABLET, EXTENDED RELEASE;ORAL	215430-002	Apr 30, 2026		RX	Yes	No						THE TREATMENT OF AGITATION ASSOCIATED WITH DEMENTIA DUE TO ALZHEIMER’S DISEASE BY INCREASING DEXTROMETHORPHAN PLASMA LEVELS IN EXTENSIVE METABOLIZERS OF DEXTROMETHORPHAN
Axsome	AUVELITY	bupropion hydrochloride; dextromethorphan hydrobromide	TABLET, EXTENDED RELEASE;ORAL	215430-001	Aug 18, 2022		RX	Yes	Yes						DEXTROMETHORPHAN AND BUPROPION IN COMBINATION TO TREAT MAJOR DEPRESSIVE DISORDER
Axsome	AUVELITY	bupropion hydrochloride; dextromethorphan hydrobromide	TABLET, EXTENDED RELEASE;ORAL	215430-001	Aug 18, 2022		RX	Yes	Yes						THE TREATMENT OF AGITATION ASSOCIATED WITH DEMENTIA DUE TO ALZHEIMER’S DISEASE BY INCREASING DEXTROMETHORPHAN PLASMA LEVELS IN EXTENSIVE METABOLIZERS OF DEXTROMETHORPHAN

International Family Members for US Patent 11,298,352

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2014346807
Australia	2015350559
Australia	2018203638
Australia	2019201548
Australia	2019223187
Australia	2019236614
Australia	2019275593