United States Drug Patent 10,045,991: Larotrectinib Pediatric Cancer Patent Scope and Landscape

U.S. Patent No. 10,045,991 protects specific pediatric cancer treatment methods using larotrectinib, including administration in a beta-cyclodextrin liquid formulation at defined pH and concentration. The patent is unusually narrow at the independent-claim level because infringement requires the claimed cancer indication, larotrectinib stereochemistry, and formulation parameters. Its reported U.S. patent expiration date is December 15, 2035, subject to any applicable patent-term adjustment or terminal disclaimer recorded in the patent file.[1]

What drug does U.S. Patent 10,045,991 protect?

The claimed compound is larotrectinib, also known as LOXO-101 and BAY 2751834. The claims identify the compound by its full chemical name:

(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide.

Larotrectinib is a selective tropomyosin receptor kinase, or TRK, inhibitor directed against TRKA, TRKB and TRKC, which are encoded by NTRK1, NTRK2 and NTRK3, respectively. The marketed product is Vitrakvi, approved by the FDA in capsule and oral-solution dosage forms.[2]

Item	Patent-relevant information
U.S. patent	10,045,991
Active ingredient	Larotrectinib
Development codes	LOXO-101; BAY 2751834
Product	Vitrakvi
Applicant/developer history	Loxo Oncology; later Bayer
Therapeutic area	NTRK fusion-positive solid tumors and pediatric cancers
Patent type	Treatment method with formulation and solid-form limitations
Reported expiration	December 15, 2035
FDA approval	November 26, 2018
Regulatory pathway	New molecular entity, accelerated approval
Key commercial limitation	Claims focus on pediatric Trk-associated cancers and a defined liquid formulation

The patent does not broadly claim every use of larotrectinib. Its central claim is directed to a defined treatment setting and a defined pharmaceutical presentation.

What is the scope of claim 1 of U.S. Patent 10,045,991?

Claim 1 is a highly aggregated method claim. To fall within the claim, a product or treatment must satisfy each required limitation.

Required elements of claim 1

The claimed method requires:

Treatment of a Trk-associated pediatric cancer.
A cancer selected from eight listed categories:
- 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; or
- spindle cell sarcoma.
Administration of the specified larotrectinib stereoisomer, a pharmaceutically acceptable salt, or a combination.
A liquid formulation.
A solubilizing agent comprising a beta-cyclodextrin.
A base.
Formulation pH of approximately 2.5 to 5.5.
Larotrectinib concentration of approximately 15 mg/mL to 35 mg/mL.

The claim therefore combines a method-of-treatment limitation with formulation limitations. Treatment with larotrectinib in a capsule, tablet, or liquid formulation outside the claimed concentration and pH ranges would not satisfy every express limitation of claim 1.

Claim construction issues

Several terms could affect enforcement:

"About" creates numerical boundary questions around the 2.5 to 5.5 pH range and 15 to 35 mg/mL concentration.
"Comprising" generally permits additional formulation components.
"A beta-cyclodextrin" likely covers hydroxypropyl-beta-cyclodextrin and other beta-cyclodextrin derivatives, subject to intrinsic evidence and prosecution history.
"A base" is broad enough to include citrate-based systems, but the dependent claims narrow the disclosure to citrate and sodium citrate dihydrate.
The claim requires a pediatric cancer selected from the listed categories, not merely any pediatric tumor with an NTRK alteration.

The claim’s narrow formulation requirements create a potential design-around path. A competing larotrectinib product using a different solubilizer, a non-liquid dosage form, a pH outside the claimed range, or a concentration outside the claimed range could avoid literal infringement, although other patents may apply.

What do claims 2 through 27 add?

The dependent claims add patient characteristics, biomarker criteria, salt and solid-form limitations, dosing schedules, excipients and diagnostic steps.

Claims	Added subject matter
2	Infant patient
3	Cancer mediated by TRKA, TRKB, TRKC or combinations
4-6	Infantile fibrosarcoma; failed surgery or chemotherapy
7	Morphological diagnosis or molecular testing before treatment
8	Hydrogen sulfate salt
9	Crystalline form
10	Narrower pH range of about 3 to 4
11	Hydroxypropyl-beta-cyclodextrin
12-13	Citrate base, including sodium citrate dihydrate
14	Sweetener, bitterness masking agent and flavoring agent
15-19	Liquid formulation prepared from a specified crystalline hydrogen sulfate form with XRPD limitations
20	Administration in 28-day cycles
21	Pediatric dose calculated to match adult exposure at 100 mg twice daily
22-24	NTRK dysregulation and specified TRK fusion proteins, including ETV6-NTRK3
25-26	NTRK point mutations in TRKA, TRKB or TRKC
27	Approximately 20 mg/mL concentration

Claims 15 through 19 are particularly important for solid-form analysis. They link the liquid formulation to a crystalline hydrogen sulfate starting material and define the solid form using powder X-ray diffraction peaks.

What formulation is protected by U.S. Patent 10,045,991?

The formulation protection centers on an oral liquid containing larotrectinib and beta-cyclodextrin in an acidic medium.

The most commercially relevant dependent-claim combination is:

larotrectinib hydrogen sulfate;
crystalline starting material;
hydroxypropyl-beta-cyclodextrin;
sodium citrate dihydrate or another citrate base;
pH of about 3 to 4;
larotrectinib concentration of about 20 mg/mL;
taste-masking excipients, including sweetener, bitterness masking agent and flavoring agent.

The patent’s formulation architecture addresses solubility and palatability. Those attributes are commercially relevant for infants and young children who may have difficulty swallowing capsules.

XRPD limitations in claims 16 through 19

Claims 16 through 19 define the crystalline material through XRPD peak sets. The broadest listed peak set includes peaks at:

10.7, 15.3, 16.5, 18.4, 19.2, 19.9, 20.2, 20.7, 21.5, 22.1, 23.1, 24.0, 24.4, 25.6, 26.5, 27.6, 28.2, 28.7, 30.8 and 38.5 degrees 2-theta, each with a tolerance of plus or minus 0.2 degrees.

These claims may create an evidentiary issue in litigation because infringement would require reliable characterization of the accused solid material. XRPD peak positions can vary with instrument calibration, sample preparation, crystallinity and polymorphic composition. The patent’s claim language nevertheless provides defined analytical markers that can be tested in a generic or alternative-product investigation.

How do the pediatric cancer and biomarker claims operate?

The cancer claims are divided into disease-based and molecularly defined coverage.

Disease-based coverage

The independent claim lists pediatric diseases associated with TRK signaling. Claims 4 through 6 focus on infantile fibrosarcoma and treatment after unsuccessful surgery or chemotherapy.

This creates commercially meaningful coverage for a rare pediatric indication, but it also limits enforcement to patients and treatment contexts meeting the claim language. A treatment for an adult NTRK fusion-positive tumor would generally fall outside claim 1 unless covered by another patent.

Fusion-based coverage

Claims 22 through 24 cover cancers associated with NTRK dysregulation caused by chromosomal translocation and resulting TRK fusion proteins. The listed fusions include:

ETV6-NTRK3;
RET/NTRK1;
TPM3-NTRK1;
BTBD1-NTRK3;
VCL-NTRK2;
AGBL4-NTRK2;
LMNA-NTRK1;
TFG-NTRK1;
QKI-NTRK2;
NACC2-NTRK2;
TPR-NTRK1;
RABGAP1L-NTRK1;
MPRIP-NTRK1;
SQSTM1-NTRK1;
EML4-NTRK3; and
AFAP1-NTRK2.

Claim 24 singles out ETV6-NTRK3, a fusion strongly associated with infantile fibrosarcoma and congenital mesoblastic nephroma.

Point-mutation coverage

Claims 25 and 26 extend coverage to specified activating or otherwise relevant point mutations in TRKA, TRKB and TRKC. The claim lists mutations across the extracellular, kinase and other functional regions of the receptors.

This coverage is narrower than a general claim to all NTRK mutations. An accused treatment would need to involve one or more of the listed mutations, and the remaining limitations of claim 1 would still apply.

When does larotrectinib lose U.S. patent exclusivity?

The reported expiration date for U.S. Patent 10,045,991 is December 15, 2035.[1] The relevant exclusivity timeline is:

Date	Event
December 15, 2015	Earliest priority date associated with the patent family, based on published patent-family information
November 26, 2018	FDA approval of Vitrakvi
November 26, 2023	Five-year new molecular entity exclusivity generally expired
November 26, 2025	Seven-year orphan-drug exclusivity generally expires, subject to the scope of the orphan designation
December 15, 2035	Reported expiration of U.S. Patent 10,045,991

FDA regulatory exclusivity and patent exclusivity are separate. Expiration of NME or orphan exclusivity does not remove a patent. Conversely, a patent expiry does not necessarily eliminate other listed patents, pediatric exclusivity, regulatory exclusivity, or litigation-based stays.

The exact patent-term calculation should be read with the issued patent, certificate history, terminal-disclaimer record and USPTO Patent Center documents. The effective blocking date can also be affected by other patents in the larotrectinib estate.

What is the Orange Book status of larotrectinib and Vitrakvi?

Vitrakvi is an FDA-approved small-molecule drug, so its patents can be listed in the Orange Book. Patent 10,045,991 has been associated with Vitrakvi’s U.S. patent protection and is directed to treatment use and formulation subject matter.[3]

The Orange Book assessment should distinguish:

product patents;
formulation patents;
method-of-use patents;
patents covering crystalline or salt forms; and
patents that may have been removed, expired or superseded.

A method-of-use listing can support a Paragraph IV certification against a generic applicant seeking approval for a use covered by the listed patent. It does not necessarily block an ANDA applicant that excludes the patented use through a section viii statement, provided the remaining label and product design do not induce infringement.

Because claim 1 is a method claim tied to pediatric cancers and a specific liquid formulation, its practical Orange Book leverage depends on the listed use code and on the proposed generic label.

Which companies could challenge larotrectinib patents?

The principal potential challengers are generic pharmaceutical companies pursuing an ANDA for larotrectinib capsules or oral solution. A challenger could use one or more of the following strategies:

File a Paragraph IV certification asserting invalidity, unenforceability or noninfringement.
File a section viii statement carving out a patented pediatric use.
Develop a formulation outside the claimed beta-cyclodextrin, pH or concentration limitations.
Use a different salt or crystalline form.
Seek approval for a dosage form not covered by the formulation limitations.
Challenge related compound, salt, polymorph or formulation patents rather than Patent 10,045,991 alone.

No biosimilar pathway applies because larotrectinib is a chemically synthesized small molecule, not a biologic. The relevant competitive pathway is an ANDA under the Hatch-Waxman Act.

A generic seeking approval for a 20 mg/mL oral solution designed for pediatric NTRK-positive cancers would face materially greater exposure than a generic seeking only capsules for adult solid tumors. The product label, formulation composition and proposed indications would determine the risk profile.

What Paragraph IV and patent litigation risks affect Vitrakvi?

A Paragraph IV filing normally triggers patent litigation if the NDA holder or patent owner files suit within the statutory period. The resulting 30-month stay can delay ANDA approval, subject to court decisions and regulatory exceptions.[4]

For Patent 10,045,991, the most important litigation questions would be:

whether the accused product contains a beta-cyclodextrin;
whether its pH and concentration fall within the claimed ranges;
whether the proposed indication includes one of the listed pediatric cancers;
whether a hydrogen sulfate crystalline form is used in manufacture;
whether the XRPD profile meets claims 16 through 19;
whether the asserted claim is valid over prior art concerning larotrectinib, TRK inhibitors, pediatric oncology and oral liquid formulations;
whether the patent adequately supports the full disease and mutation lists; and
whether prosecution history limits the scope of "about," "beta-cyclodextrin" or the claimed formulation.

The patent is strongest against a directly substitutive pediatric oral solution that copies the Vitrakvi formulation architecture. It is weaker against a non-liquid product, an adult-only label, or a formulation using a different solubilization system.

No settlement agreement should be treated as established without a reported court filing, FTC disclosure, SEC filing, or other primary record. Patent settlements in this area can include licensed entry dates, authorized generic provisions, supply arrangements and label restrictions, but those terms are not inferable from the patent claims.

How strong is the patent estate for larotrectinib?

Patent 10,045,991 is important but should be evaluated as one layer of a broader estate.

Estate layer	Likely commercial role
Core compound patents	Protect larotrectinib chemistry and stereochemistry
Salt and crystalline-form patents	Protect hydrogen sulfate and polymorphic material
Formulation patents	Protect oral liquid composition, solubility and taste-masking systems
Method-of-use patents	Protect NTRK fusion-positive tumors and specific pediatric cancers
Dosing patents	Protect exposure-based pediatric dosing and administration schedules
Manufacturing patents	May protect preparation, crystallization or purification processes

The asserted patent’s claim 1 is narrower than a core compound claim. A competitor that avoids the claim’s formulation and pediatric-use limitations may still need to address other patents covering the active ingredient, salt, polymorph or broader oncology uses.

Patent-strength assessment

The patent has four principal strengths:

It covers a commercially relevant pediatric liquid formulation.
It ties larotrectinib to NTRK-driven pediatric cancers, including infantile fibrosarcoma.
It includes specific salt and crystalline-form claims.
It contains molecularly defined fusion and mutation subclaims.

Its principal weaknesses are:

claim 1 contains many cumulative limitations;
the disease list is limited;
the liquid formulation requirement excludes capsules and other dosage forms;
the numerical ranges may permit formulation design-arounds;
claims 16 through 19 depend on potentially contestable XRPD characterization; and
some disease and mutation combinations may face written-description, enablement or obviousness challenges depending on the cited prior art.

What generic launch scenarios exist for larotrectinib?

Scenario 1: Capsule-only generic

A capsule product would likely avoid the liquid-formulation limitations of claim 1. It could still face separate compound, method-of-use, salt or polymorph patents.

Scenario 2: Pediatric oral-solution generic with a different formulation

A solution using a non-beta-cyclodextrin solubilizer, a different pH, or a concentration outside 15 to 35 mg/mL could reduce literal infringement risk under claim 1. The formulation would remain exposed to other formulation patents and the doctrine of equivalents.

Scenario 3: Same formulation with a carved-out label

A generic may seek approval without pediatric indications covered by the method-of-use listing. This strategy depends on the final label, prescribing information, promotional conduct and whether the remaining indications still create induced-infringement risk.

Scenario 4: Paragraph IV challenge

A challenger could attack validity or noninfringement before the reported 2035 patent expiration. The commercial value of that strategy depends on the strength of the core compound and formulation patents, not Patent 10,045,991 alone.

Scenario 5: Authorized or licensed entry

The patent owner could permit entry before expiry through a settlement or license. Any such entry date would depend on the agreement and cannot be inferred from the statutory exclusivity dates.

What manufacturing and geographic barriers exist?

The patent is a U.S. right. It does not directly prevent manufacture, sale or use outside the United States. Parallel foreign rights must be evaluated separately in Europe, Japan, Canada, China and other relevant markets.

Manufacturing risk is highest where the process uses:

larotrectinib hydrogen sulfate;
the claimed crystalline form;
hydroxypropyl-beta-cyclodextrin;
sodium citrate dihydrate;
acidic pH near 3 to 4; and
approximately 20 mg/mL larotrectinib.

A manufacturer can face infringement risk even if the finished product is not sold in the United States when the relevant patented method is practiced domestically or when manufacturing steps implicate separate process patents. The XRPD claims may also create supply-chain risk if the active pharmaceutical ingredient is sourced in the claimed crystalline form.

How does Patent 10,045,991 compare with broader larotrectinib protection?

Patent 10,045,991 should be classified as a pediatric treatment and formulation patent rather than the primary molecule patent.

Feature	Patent 10,045,991	Core compound patent
Claim category	Method of treatment	Chemical compound
Patient focus	Pediatric cancers	Usually broader
Dosage form	Liquid formulation required in claim 1	Usually not required
Biomarker focus	NTRK fusions and mutations	May be absent or broader
Design-around potential	Relatively high at claim 1	Usually lower
Relevance to pediatric oral solution	High	Variable
Relevance to adult capsules	Limited	Potentially high
Litigation value	Strong for copied pediatric formulation	Stronger for broad product blocking

The principal commercial question is not whether Patent 10,045,991 alone blocks all larotrectinib competition. It does not. The question is whether a proposed generic or alternative manufacturer can avoid the cumulative claim limitations while also clearing the rest of the larotrectinib patent estate.

Key Takeaways

U.S. Patent 10,045,991 covers larotrectinib treatment of specified pediatric Trk-associated cancers using a beta-cyclodextrin liquid formulation.
Claim 1 requires all major limitations, including the listed pediatric cancer, larotrectinib, liquid dosage form, beta-cyclodextrin, acidic pH and 15 to 35 mg/mL concentration.
Claims 8 through 19 add hydrogen sulfate, crystalline-form and XRPD restrictions.
Claims 22 through 26 extend the method to selected NTRK fusions and point mutations.
The reported patent expiration date is December 15, 2035.
FDA NME exclusivity expired in 2023, and orphan-drug exclusivity generally runs through 2025 for the applicable designation.
Biosimilar risk does not apply. Generic risk proceeds through the ANDA and Paragraph IV framework.
A capsule-only generic or a pediatric liquid using a different solubilizer, pH or concentration may have a stronger design-around position.
The commercial blocking strength depends on the broader larotrectinib estate, including compound, salt, polymorph, formulation and method-of-use patents.

Frequently Asked Questions

Is Patent 10,045,991 a compound patent for larotrectinib?

No. It is principally a method-of-treatment patent with liquid-formulation, pediatric-cancer, salt and crystalline-form limitations.

Does the patent cover Vitrakvi capsules?

Claim 1 requires a liquid formulation, so it does not read directly on capsules. Separate larotrectinib patents may cover the active ingredient, salt, crystalline form or methods of use.

Can a generic sell larotrectinib after orphan exclusivity expires?

Potentially, but orphan exclusivity is only one barrier. Listed patents and any associated Paragraph IV litigation can delay approval or launch.

Does the patent cover all NTRK fusion-positive cancers?

No. The asserted claim is limited to specified pediatric cancers. Other larotrectinib patents or regulatory protections may have broader oncology coverage.

What is the highest-risk generic product under this patent?

A pediatric oral solution containing larotrectinib hydrogen sulfate, hydroxypropyl-beta-cyclodextrin, citrate buffer and approximately 20 mg/mL active ingredient at pH 3 to 4 presents the greatest direct infringement exposure.

References

United States Patent and Trademark Office. (2018). U.S. Patent No. 10,045,991, methods of treating pediatric cancers using TRK inhibitors. U.S. Department of Commerce.
U.S. Food and Drug Administration. (2024). Vitrakvi (larotrectinib) prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). ANDA submissions: Amendments and FDA-related submissions.
National Library of Medicine. (2024). DailyMed: Vitrakvi, larotrectinib oral solution and capsules. National Institutes of Health.

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	10,045,991	⤷ Start Trial				METHOD OF TREATING CMN, IFS, HGG, DIPGS, PTC, SOFT TISSUE SARCOMA, AND SPINDLE CELL SARCOMA SOLID TUMORS EXHIBITING AN NTRK GENE FUSION IN A PEDIATRIC PATIENT WITH AN ORAL SOLUTION	⤷ 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
Brazil	112018070017	⤷ Start Trial
Brazil	112018070304	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,045,991

Which drugs does patent 10,045,991 protect, and when does it expire?

Summary for Patent: 10,045,991