US Patent 11,191,766: Scope, Claim Construction, Exclusivity and Competitive Patent Landscape for Larotrectinib Liquid Formulations

US Patent 11,191,766 protects specific liquid formulations of larotrectinib, marketed as Vitrakvi, when used to treat Trk-associated pediatric cancers. Its commercial value is narrower than a compound patent: infringement generally requires the accused product to contain the claimed formulation components, concentration, pH and pediatric cancer treatment indication.

The patent has two independent method-of-treatment claims. Claim 1 covers a formulation using a multi-component sweetener system containing sucrose, glycerin, sorbitol and flavoring. Claim 12 covers a separate formulation using sucralose and a defined flavoring concentration. Both claims require hydroxypropyl-beta-cyclodextrin, sodium citrate, a pH of approximately 2.5 to 5.5, and an active-ingredient concentration of approximately 20 to 30 mg/mL.

What drug does US Patent 11,191,766 protect?

US 11,191,766 protects pediatric liquid formulations of larotrectinib, specifically larotrectinib or a pharmaceutically acceptable salt or combination identified as compound formula (I) in the patent specification. Larotrectinib is a selective tropomyosin receptor kinase, or Trk, inhibitor targeting NTRK1, NTRK2 and NTRK3 gene fusions.

Vitrakvi is approved in the United States for adult and pediatric patients with solid tumors that:

Have an NTRK gene fusion;
Are metastatic or likely to cause severe morbidity from surgical resection; and
Have no satisfactory alternative treatments or have progressed after treatment.

The FDA approved Vitrakvi in capsule and oral-solution dosage forms in November 2018. The oral solution contains larotrectinib sulfate at 20 mg/mL, matching the concentration range recited in the patent claims. [1]

Patent identity and commercial relationship

Item	Data
Patent	US 11,191,766 B2
Patent subject	Liquid formulations and methods of treating Trk-associated pediatric cancers
Active ingredient	Larotrectinib, administered as a pharmaceutically acceptable salt
Commercial product	Vitrakvi oral solution
Commercial partners	Loxo Oncology and Bayer; Loxo is now part of Eli Lilly
FDA dosage form	20 mg/mL oral solution
Therapeutic class	TRK inhibitor
Relevant pathway	FDA approval for NTRK fusion-positive solid tumors
Claim type	Method-of-treatment claims incorporating formulation limitations

The claims supplied by the requester omit the chemical identity of formula (I). That identity must be read from the patent specification and prosecution record. The claimed concentration and the Vitrakvi oral-solution presentation identify larotrectinib as the relevant commercial product.

What are the independent claims of US 11,191,766?

The patent has two principal independent claims.

Claim 1: sucrose, glycerin and sorbitol formulation

Claim 1 requires all of the following:

Limitation	Claimed requirement
Therapeutic use	Treatment of a Trk-associated pediatric cancer
Active ingredient	Compound of formula (I), salt or combination
Cyclodextrin	Hydroxypropyl-beta-cyclodextrin at about 13 wt.% to about 17 wt.%
Buffer	Sodium citrate at about 0.7 wt.% to about 1.5 wt.%
Sweetener system	Sucrose, glycerin, sorbitol and flavoring
Sweetener concentration	About 45 wt.% to about 55 wt.%
Sweetener buffer	Citric acid and sodium phosphate
Preservatives	Methylparaben and potassium sorbate
Bitterness masking agent	About 0.2 wt.% to about 0.5 wt.%
pH	About 2.5 to about 5.5
Drug concentration	About 20 mg/mL to about 30 mg/mL

This claim is highly formulation-specific. A competing oral solution could avoid literal infringement by changing one or more required parameters, such as the sweetener composition, preservative system, cyclodextrin level or bitterness-masking concentration.

Claim 12: sucralose formulation

Claim 12 covers a different formulation architecture:

Limitation	Claimed requirement
Therapeutic use	Treatment of a Trk-associated pediatric cancer
Active ingredient	Compound of formula (I), salt or combination
Cyclodextrin	Hydroxypropyl-beta-cyclodextrin at about 13 wt.% to about 17 wt.%
Buffer	Sodium citrate dihydrate at about 0.7 wt.% to about 1.5 wt.%
Sweetener	Includes sucralose
Flavoring agent	About 0.01 wt.% to about 0.1 wt.%
pH	About 2.5 to about 5.5
Drug concentration	About 20 mg/mL to about 30 mg/mL

Claim 12 does not repeat the detailed sucrose/glycerin/sorbitol, preservative and bitterness-masking requirements of claim 1. It therefore appears designed to capture a distinct liquid formulation using sucralose.

How do the dependent claims narrow the patent scope?

Claims 2 and 3 narrow claim 1 by specifying the sodium citrate form. Claim 3 is the narrowest version because it requires sodium citrate dihydrate.

Claims 13 and 14 perform the same function for claim 12. Claim 14 expressly requires sodium citrate dihydrate.

Claims 4 and 15 restrict the subject to an infant, child or adolescent. The independent claims already require a pediatric cancer, but these claims provide a more explicit age-based limitation.

Claims 5 and 16 list the covered pediatric cancers:

Congenital mesoblastic nephroma;
Ph-like acute lymphoblastic leukemia;
Infantile fibrosarcoma;
Pediatric high-grade glioma;
Diffuse intrinsic pontine glioma;
Pediatric papillary thyroid carcinoma;
Soft-tissue sarcoma; and
Spindle-cell sarcoma.

Claims 6 and 17 require cancer associated with dysregulation of an NTRK gene, Trk protein, or related expression, activity or level.

Claims 7 through 9 and 18 through 20 address chromosome translocations and Trk fusion proteins. Claim 9 and claim 20 specifically identify the ETV6-NTRK3 fusion, one of the best-characterized NTRK oncogenic drivers.

Claims 10 and 11, and claims 21 and 22, cover specified NTRK point mutations. These claims are directed to tumors driven by altered Trk proteins rather than only gene fusions.

How strong is the patent estate for Vitrakvi oral solution?

The patent is strongest against a product that replicates the marketed oral solution and is labeled for pediatric NTRK fusion-positive cancer. The risk decreases when a competitor uses a materially different excipient system or markets a product without the patented pediatric method-of-use labeling.

Strengths

The claims combine composition and treatment limitations. A competitor must address both the formulation and the therapeutic use.
The concentration range of 20 to 30 mg/mL closely tracks the FDA-approved 20 mg/mL oral solution.
The claims cover two distinct sweetener strategies.
The claims include pediatric disease and molecular-biomarker limitations, which align with the targeted nature of larotrectinib therapy.
The formulation limitations may be difficult to design around while preserving palatability, solubility and dose uniformity.

Vulnerabilities

The claims are narrow and require multiple excipient and quantitative limitations.
The use of “about” creates potential claim-construction disputes around the numerical ranges.
Prior-art liquid formulations containing cyclodextrins, citrate buffers, sweeteners and preservatives could support an obviousness challenge if they disclose larotrectinib or a predictable formulation path.
The method claims may face written-description and enablement challenges if the specification does not adequately support the full combination of formulation ranges and the extensive list of cancers, fusions and mutations.
The claims may be difficult to enforce against a generic product whose formulation is not publicly disclosed before launch.

The patent does not appear to claim larotrectinib as a chemical compound in the broad sense. Its practical value depends on whether the commercial product and any follow-on product fall within the exact formulation and indication limitations.

What formulations are protected by US 11,191,766?

The patent protects two formulation families.

Formulation family 1: compound sweetener system

The first family uses a high-concentration sweetener system containing sucrose, glycerin and sorbitol, together with flavoring. It also requires citric acid and sodium phosphate as sweetener buffers, methylparaben and potassium sorbate as preservatives, and a bitterness-masking agent.

This architecture appears directed to the palatability and stability problems associated with an orally administered kinase inhibitor for young children. The claim does not merely require a sweetened solution. It specifies the identity and concentration of the sweetener system and associated preservation and masking components.

Formulation family 2: sucralose system

The second family uses sucralose and a flavoring agent. It expressly requires sodium citrate dihydrate in the claimed range but does not include all of the formulation details required by claim 1.

A product using sucralose may fall within claim 12 even if it does not contain the claim 1 combination of sucrose, glycerin, sorbitol, methylparaben, potassium sorbate and the specified bitterness-masking agent.

What is the likely infringement analysis for a generic Vitrakvi oral solution?

A generic applicant seeking approval of larotrectinib oral solution would likely use an ANDA under section 505(j) of the Federal Food, Drug, and Cosmetic Act. The applicant would need to address listed patents through a certification under paragraph I, II, III or IV, depending on patent status and expiration.

Literal infringement

Literal infringement would require the generic formulation to satisfy every limitation of at least one asserted claim. For claim 1, this includes:

Hydroxypropyl-beta-cyclodextrin in the 13 to 17 wt.% range;
Sodium citrate in the 0.7 to 1.5 wt.% range;
The four-part sweetener description;
The specified buffering and preservation system;
The bitterness-masking range;
pH of 2.5 to 5.5; and
Active concentration of 20 to 30 mg/mL.

For claim 12, the central formulation issues are hydroxypropyl-beta-cyclodextrin, sodium citrate dihydrate, sucralose, flavoring concentration, pH and drug concentration.

Doctrine of equivalents

A patentee could argue that a formulation outside a numerical range or using a chemically similar excipient is equivalent. That argument would be limited by prosecution-history estoppel, the specificity of the claimed ranges and the possibility that the patent applicant made narrowing amendments or distinctions over prior art.

Label-based infringement

The pediatric method limitation creates a separate risk. A generic label that includes the patented pediatric NTRK indication could create a direct method-of-use infringement theory. A section viii “skinny label” may reduce risk if the FDA-approved labeling can omit the patented use, but that strategy depends on the scope of the remaining Vitrakvi indication and the FDA’s labeling requirements.

Because larotrectinib’s principal indication is biomarker-defined rather than age-defined, removing the pediatric use may be commercially difficult if pediatric treatment is an important portion of the reference product’s market.

When does US 11,191,766 lose exclusivity?

US 11,191,766 is expected to have a nominal patent term extending into approximately 2037 or 2038, subject to the patent’s recorded priority date, patent-term adjustment, terminal disclaimers and any applicable patent-term extension.

The patent’s exact enforceable expiration date should be taken from the USPTO patent record and the FDA Orange Book listing rather than inferred solely from the grant date. The grant date does not establish the expiration date.

Exclusivity timeline for Vitrakvi

Event	Date
FDA approval of Vitrakvi	November 2018
FDA approval type	Accelerated approval
Reference product	Vitrakvi capsules and oral solution
Pediatric approval relevance	Pediatric patients with qualifying NTRK fusion-positive solid tumors
Small-molecule generic pathway	ANDA under section 505(j)
Principal formulation patent discussed here	US 11,191,766
Expected patent-term horizon	Approximately 2037-2038, subject to USPTO term adjustments
Regulatory exclusivity	Separate from patent exclusivity and dependent on the FDA product record

Vitrakvi also has other relevant compound, formulation and method-of-use patents. The last blocking patent may determine generic entry even if US 11,191,766 expires earlier.

What is the Orange Book status of US 11,191,766?

The Orange Book determines whether a patent is formally listed for the reference drug and whether an ANDA applicant must address it. Patent listing is separate from validity and enforceability.

For Vitrakvi, the relevant FDA listing analysis should distinguish among:

Compound patents;
Formulation patents;
Method-of-use patents;
Patents covering oral solution dosage forms; and
Patents that have expired, been delisted or remain active.

US 11,191,766 is commercially relevant because its claims are directed to a formulation and pediatric treatment method corresponding to the FDA-approved oral solution. Whether the patent is currently listed, and for which product number, must be confirmed in the current FDA Orange Book patent-use-code data. The patent number alone does not establish current listing status.

Which companies are challenging Vitrakvi exclusivity?

The principal future challenge would come from generic drug manufacturers filing ANDAs for larotrectinib capsules or oral solution. Public information supplied with the request does not identify a particular ANDA filer, paragraph IV notice or federal patent action directed to US 11,191,766.

A paragraph IV certification would create potential litigation under 35 U.S.C. section 271(e)(2). The statutory litigation window generally begins when the NDA holder and patent owner receive notice of the paragraph IV certification. A timely action can trigger an automatic 30-month stay of FDA approval, subject to statutory exceptions.

No biosimilar pathway applies. Larotrectinib is a chemically synthesized small molecule, not a biologic. A competitor would pursue an ANDA, not a biosimilar application under the Public Health Service Act.

What patent litigation affects larotrectinib?

The relevant litigation questions are:

Whether US 11,191,766 is listed for Vitrakvi;
Whether an ANDA applicant certifies paragraph IV;
Whether the patent owner files a section 271(e)(2) action;
Whether the patent is asserted against an oral solution, capsule or both;
Whether the case involves claim construction of “about,” wt.% ranges or “Trk-associated pediatric cancer”; and
Whether a settlement provides a licensed generic entry date.

A patent dispute would likely focus on formulation testing and the applicant’s confidential composition. The formulation may not be fully apparent from public labeling. Discovery could therefore become important in determining whether a generic product falls within the excipient and concentration limitations.

How does US 11,191,766 compare with larotrectinib compound patents?

Patent category	Typical scope	Commercial effect
Compound patent	Larotrectinib molecule or salt	Broadest product protection
Formulation patent	Oral solution composition and excipient ranges	Protects a specific dosage form
Method-of-use patent	NTRK fusion-positive or pediatric cancer treatment	Can support indication-based enforcement
Manufacturing patent	Processes, intermediates or solid-state forms	May create supply-chain barriers
US 11,191,766	Liquid formulation combined with pediatric cancer treatment	Narrower but closely aligned with pediatric oral-solution use

A compound patent usually presents the largest barrier to an ANDA. US 11,191,766 is more vulnerable to formulation design-around strategies, but its commercial relevance is high because pediatric patients may need a liquid dosage form.

What generic launch scenarios exist for Vitrakvi?

Scenario 1: No early generic challenge

If no paragraph IV challenge is filed, the generic applicant may wait until the relevant patents expire or until FDA exclusivity barriers end. The commercial entry date would be controlled by the latest blocking patent and any regulatory exclusivity.

Scenario 2: Paragraph IV challenge and litigation

A generic applicant may certify that US 11,191,766 is invalid, unenforceable or not infringed. Litigation could delay approval through the 30-month stay. The patent owner could seek preliminary relief, although the statutory framework and case-specific facts would control.

Scenario 3: Formulation design-around

A competitor could attempt to use:

A different cyclodextrin or cyclodextrin concentration;
A pH outside the claimed range;
A concentration below 20 mg/mL or above 30 mg/mL;
A different sweetener system;
A different preservative;
No claimed bitterness-masking agent; or
A formulation using a different buffer.

The regulatory challenge is that a formulation change must still provide acceptable stability, palatability, dose accuracy and bioequivalence.

Scenario 4: Capsule-first entry

A generic company could target capsules rather than oral solution. That approach may avoid US 11,191,766 if the patent is not asserted against the capsule dosage form, but compound or method-of-use patents could remain barriers.

What manufacturing and geographic barriers exist?

US 11,191,766 is a United States patent. It does not directly block manufacturing or sales outside the United States unless corresponding foreign patents exist.

The international landscape may include counterpart applications in Europe, Japan, Canada and other jurisdictions. Each counterpart requires separate analysis because claim scope, prosecution amendments, term dates and litigation outcomes vary by country.

Manufacturing barriers may arise from:

Control of larotrectinib active pharmaceutical ingredient;
Access to validated oral-solution manufacturing processes;
Excipient compatibility;
Long-term stability at acidic pH;
Preservation performance;
Palatability testing in pediatric populations; and
Regulatory requirements for a 505(j) product.

A formulation patent is most commercially effective when it coincides with manufacturing know-how and a difficult-to-replicate excipient system. The patent alone does not prevent a non-infringing liquid formulation.

What is the revenue exposure from this patent?

Vitrakvi revenue is exposed to generic entry across the entire larotrectinib market, but US 11,191,766 is most relevant to pediatric oral-solution sales. Its direct revenue protection is therefore narrower than a compound patent.

The principal value drivers are:

The share of Vitrakvi patients requiring oral solution;
Pediatric use as a percentage of US sales;
Whether a generic entrant launches capsules, oral solution or both;
Whether the generic can design around the formulation claims;
Whether other patents extend the effective exclusivity period; and
Whether a settlement permits authorized or licensed generic entry.

A public revenue estimate should not be attributed specifically to US 11,191,766 without product-level sales by dosage form and patient age. Company reporting generally aggregates Vitrakvi revenue rather than isolating the patented oral-solution formulation.

Key Takeaways

US 11,191,766 is a formulation-plus-method patent for larotrectinib liquid treatment of Trk-associated pediatric cancers.
Claims 1 and 12 protect two different formulation systems.
The patent requires hydroxypropyl-beta-cyclodextrin, sodium citrate, acidic pH and a 20 to 30 mg/mL drug concentration.
Claim 1 focuses on sucrose, glycerin, sorbitol, preservatives and bitterness masking.
Claim 12 focuses on sucralose and a defined flavoring concentration.
The patent does not provide broad chemical-molecule protection comparable to a larotrectinib compound patent.
A generic oral solution would face the greatest risk if it replicates Vitrakvi’s excipient system and includes pediatric NTRK treatment in its labeling.
Larotrectinib is a small molecule, so biosimilar competition is irrelevant. The applicable pathway is an ANDA.
The nominal patent-term horizon appears to be approximately 2037-2038, subject to the USPTO’s recorded term calculations.
The latest blocking compound, formulation or method-of-use patent, rather than US 11,191,766 alone, will determine practical US generic entry.
No specific paragraph IV filer, settlement or litigation involving this patent is established by the supplied record.

FAQs About US Patent 11,191,766 and Vitrakvi

Does US 11,191,766 cover Vitrakvi oral solution?

It appears directed to the 20 mg/mL Vitrakvi oral-solution formulation, but infringement depends on the complete formulation and the claimed pediatric treatment method.

Can a generic avoid US 11,191,766 by using a different sweetener?

Potentially. A materially different sweetener system could avoid claim 1, but claim 12 may still apply if the product uses sucralose and satisfies the remaining limitations.

Does the patent cover all NTRK inhibitors?

No. The claims are directed to the compound of formula (I), its salt or combination. They do not broadly cover every NTRK or Trk inhibitor.

Is a biosimilar possible for larotrectinib?

No biosimilar pathway is applicable because larotrectinib is a small-molecule drug. Competition would proceed through the ANDA pathway.

What is the main invalidity risk for this patent?

The main risks are obviousness based on prior liquid formulations, written-description and enablement challenges for the broad cancer and mutation lists, and disputes over the scope of “about” in the formulation ranges.

References

U.S. Food and Drug Administration. (2018). FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA.
U.S. Food and Drug Administration. (2024). Vitrakvi (larotrectinib) prescribing information. FDA.
U.S. Patent and Trademark Office. (2021). U.S. Patent No. 11,191,766, liquid formulations and methods of use. USPTO Patent Center.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products and patent and exclusivity information. FDA.
Eli Lilly and Company. (2024). Annual report. Eli Lilly and Company.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Bayer Healthcare	VITRAKVI	larotrectinib sulfate	SOLUTION;ORAL	211710-001	Nov 26, 2018		RX	Yes	Yes	11,191,766	⤷ Start Trial				METHOD OF TREATING SOLID TUMORS THAT EXHIBIT AN NTRK FUSION GENE IN A PEDIATRIC PATIENT	⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	108090	⤷ Start Trial
Australia	2017246547	⤷ Start Trial
Australia	2017246554	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 11,191,766