Details for Patent: 10,857,148

Which drugs does patent 10,857,148 protect, and when does it expire?

Patent 10,857,148 protects INGREZZA and INGREZZA SPRINKLE and is included in two NDAs.

This patent has sixteen patent family members in eleven countries.

Summary for Patent: 10,857,148

Title:	Methods for the administration of certain VMAT2 inhibitors
Abstract:	Provided are methods of administering a vesicular monoamine transport 2 (VMAT2) inhibitor chosen from valbenazine and (+)-α-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, or a pharmaceutically acceptable salt and/or isotopic variant thereof, to a patient in need thereof wherein the patient is also being administered digoxin.
Inventor(s):	Christopher F. O'Brien, Haig P. Bozigian
Assignee:	Neurocrine Biosciences Inc
Application Number:	US16/871,528
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,857,148
Patent Claim Types: see list of patent claims	Use; Delivery; Dosage form;

United States Patent 10,857,148: Valbenazine-Digoxin Interaction Claims, Scope and Patent Landscape

US Patent No. 10,857,148 protects a clinical dosing method for treating tardive dyskinesia with valbenazine or specified related VMAT2 compounds in patients receiving digoxin. The patent is directed to managing increased digoxin exposure, including monitoring serum concentrations and reducing digoxin dosage. It is not a basic composition-of-matter patent for valbenazine, nor a general patent covering every use of Ingrezza.

The commercial risk is concentrated in co-prescription scenarios. A valbenazine product can practice the patent only when the claimed clinical conditions are met, particularly the presence of digoxin therapy and the required exposure-management steps.

What does US Patent 10,857,148 cover?

The patent covers methods combining four principal elements:

1. Treatment of tardive dyskinesia.
2. Administration of a specified VMAT2 inhibitor.
3. Concurrent digoxin therapy.
4. Recognition and management of increased digoxin exposure.

Independent claim 1 requires monitoring digoxin concentration and reducing the digoxin dose when exposure is increased compared with digoxin administered alone. Independent claim 21 is narrower with respect to the VMAT2 inhibitor but more direct operationally. It requires:

• oral administration of valbenazine ditosylate;
• treatment of tardive dyskinesia;
• a patient who also requires digoxin; and
• administration of digoxin at a reduced dose to compensate for the expected exposure increase.

The claimed valbenazine compound is identified chemically rather than by brand name. The relevant commercial product is valbenazine ditosylate, marketed as Ingrezza by Neurocrine Biosciences.

Claim architecture

Claim group	Main limitation	Commercial significance
1	VMAT2 inhibitor, digoxin co-administration, monitoring, dose reduction	Broadest independent claim
2	AUC or Cmax measurement	Pharmacokinetic measurement limitation
3-5	Exposure-related adverse reactions and monitoring	Safety-monitoring refinements
6	Baseline serum digoxin concentration	Requires pre-treatment baseline
7	Reduced digoxin dose or frequency	Dose-management limitation
8-9	Oral tablet or capsule administration	Covers standard commercial use
10-15	Valbenazine and 40, 60 or 80 mg daily dosing	Directly aligned with Ingrezza dosing
16-19	Initial dose followed by dose escalation	Covers titration protocols
20	Increased digoxin levels attributed to intestinal P-glycoprotein inhibition	Mechanistic limitation
21	Valbenazine ditosylate, oral administration and reduced digoxin dose	Independent claim aimed at labeled clinical use
22-24	40, 60 and 80 mg valbenazine-equivalent doses	Covers principal maintenance-dose options
25	P-gp inhibition mechanism	Dependent version of claim 21

The chemical name in the supplied claim text contains an apparent transcription error in one instance, stating "3 sobutyl." The corresponding compound is conventionally written as the 3-isobutyl derivative. The issued patent and official patent records control claim interpretation.[1]

Which drug does US 10,857,148 protect?

The primary commercial compound is valbenazine, the active pharmaceutical ingredient in Ingrezza.

The claims also recite:

• the corresponding active alcohol, (+)-alpha-3-isobutyl-9,10-dimethoxy hexahydro-pyridoisoquinolin-2-ol;
• pharmaceutically acceptable salts;
• isotopic variants; and
• valbenazine ditosylate specifically in claims 11 and 21-25.

The patent therefore has a broader chemical definition in claim 1 than the commercial-product-specific claims. Claims 10-15 and 21-25 are more directly tied to valbenazine and its marketed salt.

Relationship to Ingrezza

Ingrezza is approved for:

• tardive dyskinesia in adults; and
• chorea associated with Huntington's disease.

The patent claims are limited to tardive dyskinesia. They do not, based on the supplied claims, cover treatment of Huntington's disease chorea unless a separate claim in the patent provides that indication.

FDA-approved Ingrezza dosage strengths include 40 mg, 60 mg and 80 mg capsules. Those strengths correspond directly to dependent claims 12-15 and 22-24, although a product strength alone does not establish infringement. The treatment context and digoxin-management elements remain necessary.[2]

How broad are the independent claims?

Claim 1

Claim 1 is broad in drug identity but narrow in clinical context. It covers a selected VMAT2 inhibitor used in a tardive dyskinesia patient who is also receiving digoxin.

The critical limitations are:

• "co-administered digoxin";
• monitoring digoxin concentration;
• determining increased exposure against a digoxin-alone comparator; and
• reducing digoxin dose after the increase is identified.

The claim does not require a particular digoxin dose, a particular magnitude of exposure increase, or a specific reduction percentage. Claims 2 and 3 provide further detail but are not required for infringement of claim 1.

A potential infringement case would therefore focus on whether a treatment protocol or physician conduct includes all required steps. Mere administration of valbenazine to a patient who happens to take digoxin may not satisfy every limitation of claim 1 if no monitoring or dose reduction occurs.

Claim 21

Claim 21 is narrower chemically and administratively. It requires valbenazine ditosylate administered orally, but it does not expressly require actual measurement of serum digoxin concentration. It requires a reduced digoxin dose intended to compensate for expected increased exposure.

This claim may be more important in product-label litigation because it maps onto a prospective prescribing instruction. A label that tells prescribers to reduce digoxin dosage when starting valbenazine could be argued to encourage the claimed method.

What pharmacokinetic interaction does the patent address?

The patent is directed to increased digoxin exposure caused by co-administration with the VMAT2 inhibitor. The claims identify:

• area under the plasma concentration-time curve, or AUC;
• maximum observed plasma concentration, or Cmax;
• time to maximum concentration, or tmax; and
• exposure-related adverse reactions.

Claim 20 attributes the increase to inhibition of intestinal P-glycoprotein. Digoxin is a recognized P-glycoprotein substrate. Inhibition of intestinal P-gp can increase absorption and systemic exposure.

The claimed management model is:

Clinical step	Patent relevance
Establish baseline serum digoxin concentration	Claim 6
Start valbenazine or another claimed VMAT2 inhibitor	Claims 1 and 21
Measure digoxin concentration or assess expected exposure	Claims 1-2
Identify increased AUC or Cmax	Claim 2
Monitor for adverse reactions	Claims 3-5
Reduce digoxin dose or dosing frequency	Claims 1, 7 and 21

The adverse reactions listed in claim 5 are headache, anxiety, insomnia, diarrhea, restlessness and abnormal dreams. Those limitations are narrower than the core dose-management claims.

What doses and formulations are protected?

The claims cover orally administered valbenazine in tablet or capsule form, including:

• 20 mg to 160 mg valbenazine-equivalent amounts;
• approximately 40 mg once daily;
• approximately 60 mg once daily;
• approximately 80 mg once daily;
• a first dose followed by an increased second dose;
• 40 mg once daily for one week followed by 80 mg once daily.

These limitations align with commercial titration and maintenance practices for Ingrezza. They do not create a general formulation monopoly over every valbenazine capsule. The patent claims a method of using the formulation in a digoxin-treated tardive dyskinesia patient.

Are formulation patents covered by this patent?

No. US 10,857,148 is principally a method-of-use and drug-interaction patent.

It does not, based on the supplied claims, independently claim:

• a capsule shell;
• excipient selection;
• dissolution characteristics;
• particle size;
• polymorphic form;
• salt crystallinity;
• manufacturing process;
• extended-release delivery; or
• a standalone valbenazine composition.

Those rights, if any, must be assessed through separate valbenazine patent families and Orange Book listings.

What is the Orange Book status of US 10,857,148?

The FDA Orange Book is the controlling source for patents listed against an approved product. Patent listing and patent enforceability are separate questions. A listed patent can be challenged, delisted, invalidated or found noninfringed.

For Ingrezza, the relevant regulatory analysis should distinguish:

Category	Relevance to US 10,857,148
Approved product	Ingrezza, valbenazine capsules
FDA pathway	New drug application, not a biologic license application
Patent type	Method-of-use and drug-interaction claims
Biosimilar pathway	Not applicable
Generic pathway	ANDA, potentially with Paragraph IV certification
Label relevance	High if the approved label describes digoxin monitoring or dose adjustment
Product-by-process relevance	None apparent from the supplied claims

The patent’s commercial blocking power depends heavily on whether it is listed in the Orange Book for the applicable Ingrezza NDA and whether its use code corresponds to a method that an ANDA applicant must address. FDA regulations require NDA holders to submit patent information for patents that claim the drug substance, drug product or an approved method of use.[3]

A patent directed to a specific interaction-management method may be listed with a narrow use code. An ANDA applicant could seek approval for a non-infringing label, a section viii statement for an omitted use, or challenge the patent under Paragraph IV.

When does US Patent 10,857,148 lose exclusivity?

The patent issued on January 5, 2021. Its precise expiration date depends on the earliest effective nonprovisional filing date, any terminal disclaimer, and any patent-term adjustment shown in the official USPTO record.

The applicable framework is:

• ordinary patent term: 20 years from the earliest effective nonprovisional filing date;
• possible patent-term adjustment for USPTO examination delay;
• possible terminal disclaimer limiting the term to another patent; and
• possible patent-term extension only if statutory requirements are satisfied.

The issue date alone does not establish the expiration date. A reliable freedom-to-operate conclusion must use the front-page patent-term data, the continuity data and any terminal disclaimer in the USPTO file history.[1]

The patent is unlikely to control the earliest possible valbenazine generic entry by itself if earlier composition, salt, formulation or method patents expire sooner. It can still delay or complicate an ANDA launch if the generic applicant’s label encourages the claimed digoxin interaction-management use.

What other patents protect valbenazine and Ingrezza?

Valbenazine has a layered patent estate rather than a single blocking patent. The main categories are:

Composition-of-matter patents

These cover the valbenazine chemical entity, stereochemistry, salts or related VMAT2 compounds. Composition claims generally provide the strongest exclusionary position because they can reach manufacture, sale and use of the compound regardless of indication.

Salt and solid-state patents

These may cover valbenazine ditosylate, crystalline forms, solvates or defined solid-state characteristics. Their value depends on whether the commercial product uses the claimed form and whether a generic can manufacture a different non-infringing form.

Formulation patents

These may cover capsule composition, dosage form, release profile, stability or excipient combinations. They are relevant to an ANDA applicant that seeks approval for a product materially matching the reference product.

Method-of-use patents

These cover treatment of tardive dyskinesia, Huntington's disease chorea, dosing schedules, patient populations and drug combinations. US 10,857,148 belongs principally in this category.

Interaction patents

The subject patent is more specific than a conventional indication patent because it addresses valbenazine-digoxin co-administration and dose adjustment.

A full estate analysis must review the complete US family, continuations, divisionals, terminal disclaimers, PTA, Orange Book listings and litigation docket. The supplied claim set alone does not establish the full patent family or current listing status.

How does the patent compare with Austedo and Xenazine?

Product	Active ingredient	Main sponsor	Tardive dyskinesia use	Relationship to US 10,857,148
Ingrezza	Valbenazine	Neurocrine Biosciences	Approved	Directly targeted
Austedo	Deutetrabenazine	Teva	Approved	Not chemically recited in the supplied claims
Xenazine	Tetrabenazine	Teva historically; generic versions available	Approved	Not chemically recited
Generic tetrabenazine	Tetrabenazine	Multiple manufacturers	Approved uses depend on label	Outside the claimed chemical class as written
Generic deutetrabenazine	Deutetrabenazine	Potential ANDA applicants	Potentially relevant to TD	Separate patent estate

The patent is product-specific in practical effect. A competitor using deutetrabenazine or tetrabenazine would not ordinarily practice claims 10-25, which expressly require valbenazine or valbenazine ditosylate. Claim 1’s chemical list also does not recite deutetrabenazine or tetrabenazine.

This gives the patent limited value against alternative VMAT2 inhibitors but meaningful value against a valbenazine generic that retains the digoxin-management instruction.

What Paragraph IV challenges and litigation risks exist?

An ANDA applicant seeking approval for generic valbenazine could challenge the patent by asserting:

• invalidity for lack of written description;
• lack of enablement;
• anticipation;
• obviousness;
• indefiniteness;
• noninfringement based on omission of the claimed digoxin-use language; or
• noninfringement based on the absence of monitoring or dose reduction in the proposed labeling.

The strongest validity issues would likely concern the interaction-management concept if prior art already disclosed:

• valbenazine or a closely related VMAT2 inhibitor;
• digoxin as a P-gp substrate;
• increased digoxin exposure from P-gp inhibition; and
• therapeutic drug monitoring or dose adjustment.

The strongest infringement issue would be induced infringement. A generic manufacturer does not directly administer a drug to patients. The patent holder would need to connect the proposed label, marketing materials or other conduct to physicians’ performance of the claimed steps.

A section viii strategy could be significant if the digoxin-related use is separately identified and can be carved out without undermining safe use of the product. The feasibility depends on the Orange Book use code, FDA labeling requirements and whether the interaction warning is necessary for the remaining approved indication.

How strong is the patent estate for this interaction?

US 10,857,148 has moderate commercial strength and narrower legal breadth than a composition patent.

Strengths

• It directly names valbenazine and valbenazine ditosylate.
• Claims 21-24 correspond to practical oral dosing.
• It targets a clinically identifiable co-medication population.
• The mechanism is tied to a known pharmacokinetic pathway involving P-gp.
• A label that expressly instructs digoxin dose reduction could create induced-infringement exposure.

Weaknesses

• The claims apply only to patients receiving digoxin.
• Claim 1 requires monitoring and dose reduction.
• The patent does not cover valbenazine use generally.
• The patent does not block alternative VMAT2 inhibitors.
• Causal language in claims 20 and 25 may create proof issues.
• The claim set does not appear to cover a standalone formulation or manufacturing process.

The economic value depends on the size of the valbenazine-plus-digoxin population. Digoxin use has declined, and it is concentrated in selected heart-failure and atrial-fibrillation patients. The covered population is therefore materially smaller than the overall Ingrezza market.

What generic launch scenarios exist?

Scenario 1: Label carve-out

A generic applicant omits the digoxin-management use if FDA permits a compliant section viii carve-out. This reduces direct infringement risk but may create regulatory and clinical-label issues if the interaction warning is considered necessary for safe use.

Scenario 2: Paragraph IV litigation

The applicant certifies that the patent is invalid, unenforceable or not infringed. Approval may be delayed under the Hatch-Waxman litigation stay, generally for up to 30 months unless resolved earlier or modified by the court.[4]

Scenario 3: Launch with a non-infringing label

The generic label does not instruct physicians to reduce digoxin dosage or monitor exposure beyond requirements applicable to digoxin itself. The patent holder could still argue induced infringement based on promotional conduct or the practical operation of the label.

Scenario 4: At-risk launch

The generic launches before final resolution. Exposure could include damages, an injunction, lost profits or royalties, depending on the asserted claims and litigation outcome.

Does the patent create biosimilar risk?

No. Valbenazine is a chemically synthesized small molecule, not a biologic. Biosimilar approval under section 351(k) of the Public Health Service Act is not the relevant pathway.

The relevant competitive pathway is an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act. Patent risk will turn on Orange Book listings, Paragraph IV certifications, section viii statements and the generic product’s proposed labeling.[3,4]

What manufacturing and geographic barriers remain?

The US patent is enforceable only within the United States and against conduct with a US nexus. It does not itself establish equivalent protection in Europe, Japan, Canada or other jurisdictions.

Geographic risk should be separated into:

• US method-of-use rights;
• foreign composition and formulation patents;
• regulatory exclusivity;
• manufacturing-site controls;
• API supply arrangements;
• process patents; and
• importation or export-related infringement theories.

Because US 10,857,148 is a use patent, it is unlikely by itself to prevent manufacture of valbenazine for non-infringing uses. Separate composition, salt, formulation and process patents may create stronger manufacturing barriers.

Key Takeaways

• US 10,857,148 is a valbenazine-digoxin interaction-management patent.
• Its core subject is tardive dyskinesia treatment in a patient receiving digoxin.
• Claim 1 requires monitoring increased digoxin exposure and reducing digoxin dose.
• Claim 21 more directly targets oral valbenazine ditosylate with reduced-dose digoxin.
• Claims cover 40 mg, 60 mg and 80 mg once-daily valbenazine-equivalent dosing.
• The patent does not cover all Ingrezza use and does not recite deutetrabenazine or tetrabenazine.
• It is a method-of-use patent, not a standalone composition, formulation or manufacturing patent.
• Generic risk will center on Orange Book listing, use-code scope, Paragraph IV strategy and label carve-out feasibility.
• Biosimilar analysis is inapplicable because valbenazine is a small molecule.
• The exact expiration date requires confirmation from the USPTO front page, continuity record, terminal disclaimers and patent-term-adjustment data.
• Commercial exposure is limited to the subset of valbenazine-treated tardive dyskinesia patients who also receive digoxin.

FAQs

Can a generic valbenazine manufacturer avoid US 10,857,148 by omitting digoxin instructions?

Potentially. A compliant label carve-out may reduce infringement risk, but the result depends on the Orange Book use code and whether FDA requires the interaction-management language for safe use.

Does prescribing Ingrezza to a patient on digoxin automatically infringe the patent?

No. Claim 1 requires additional conduct, including monitoring increased digoxin exposure and reducing the digoxin dose. Claim 21 requires reduced-dose digoxin intended to compensate for expected increased exposure.

Does the patent cover valbenazine for Huntington's disease chorea?

The supplied claims are limited to tardive dyskinesia. They do not recite Huntington's disease chorea.

Can a competitor avoid the patent by using deutetrabenazine?

The supplied claims do not recite deutetrabenazine. A competing product may remain subject to separate patents covering deutetrabenazine, its formulations or its approved uses.

Is valbenazine ditosylate itself protected by this patent?

The patent claims valbenazine ditosylate in a method of treatment. It does not, based on the supplied claims, establish a standalone composition-of-matter monopoly over the salt.

References

1. United States Patent and Trademark Office. (2021). U.S. Patent No. 10,857,148, methods of treating tardive dyskinesia.
2. U.S. Food and Drug Administration. (2023). Ingrezza (valbenazine) prescribing information. Neurocrine Biosciences, Inc.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
4. U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

Drugs Protected by US Patent 10,857,148

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Neurocrine	INGREZZA	valbenazine tosylate	CAPSULE;ORAL	209241-001	Apr 11, 2017	AB	RX	Yes	No	10,857,148					TREATMENT OF TARDIVE DYSKINESIA
Neurocrine	INGREZZA	valbenazine tosylate	CAPSULE;ORAL	209241-003	Apr 23, 2021		RX	Yes	No	10,857,148					TREATMENT OF TARDIVE DYSKINESIA
Neurocrine	INGREZZA	valbenazine tosylate	CAPSULE;ORAL	209241-002	Oct 4, 2017	AB	RX	Yes	Yes	10,857,148					TREATMENT OF TARDIVE DYSKINESIA
Neurocrine	INGREZZA SPRINKLE	valbenazine tosylate	CAPSULE;ORAL	218390-001	Apr 30, 2024		RX	Yes	No	10,857,148					TREATMENT OF TARDIVE DYSKINESIA
Neurocrine	INGREZZA SPRINKLE	valbenazine tosylate	CAPSULE;ORAL	218390-002	Apr 30, 2024		RX	Yes	No	10,857,148					TREATMENT OF TARDIVE DYSKINESIA
Neurocrine	INGREZZA SPRINKLE	valbenazine tosylate	CAPSULE;ORAL	218390-003	Apr 30, 2024		RX	Yes	Yes	10,857,148					TREATMENT OF TARDIVE DYSKINESIA

International Family Members for US Patent 10,857,148

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2017435893
Canada	3077149
China	111836543
China	116492340
Eurasian Patent Organization	202090932
Japan	2021193146
Japan	2021502959