Details for Patent: 10,005,783

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Which drugs does patent 10,005,783 protect, and when does it expire?

Patent 10,005,783 protects VITRAKVI and is included in two NDAs.

This patent has one hundred and thirteen patent family members in thirty-nine countries.

Summary for Patent: 10,005,783

Title:	Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
Abstract:	Compounds useful in the synthesis of compounds for treating pain, cancer, inflammation, neurodegenerative disease or Typanosoma cruzi infection in a mammal.
Inventor(s):	Julia Haas, Steven W. Andrews, Yutong Jiang, Gan Zhang
Assignee:	Array Biopharma Inc
Application Number:	US15/399,389
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,005,783
Patent Claim Types: see list of patent claims	Use; Formulation; Dosage form;

US Patent 10,005,783: Larotrectinib Method-of-Use Claims, Scope and Patent Landscape

US Patent 10,005,783 protects methods of treating neuroblastoma, glioma, thyroid cancer, and breast cancer with a broad class of tropomyosin receptor kinase, or Trk, inhibitors that includes larotrectinib sulfate, the active pharmaceutical ingredient in Vitrakvi. The patent covers both biomarker-selected treatment and treatment without an express biomarker-selection step, together with specified salts, oral dosage forms, TrkA/B/C targets, and breast-cancer combination therapy.

The patent was granted June 26, 2018, and has an Orange Book-listed expiration date of April 27, 2035. It is a method-of-use patent rather than the primary composition-of-matter patent for larotrectinib. The principal commercial risk is therefore directed at use of larotrectinib in the claimed cancer settings, not merely manufacture or sale of the molecule.

What drug and biological target does US Patent 10,005,783 cover?

The claims cover Formula (I) Trk inhibitors and expressly identify the following compound:

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

This compound is larotrectinib. The commercial product is larotrectinib sulfate, marketed by Bayer under the Vitrakvi brand following Bayer's acquisition of Loxo Oncology.

The patent targets Trk kinase biology, including:

• TrkA, encoded by NTRK1;
• TrkB, encoded by NTRK2; and
• TrkC, encoded by NTRK3.

The claims refer to Trk overexpression, activation, amplification, and mutation. They do not expressly limit the biomarker to an NTRK gene fusion, even though FDA-approved Vitrakvi labeling is centered on solid tumors with an NTRK gene fusion without a known acquired resistance mutation.

What are the independent claims in US Patent 10,005,783?

The 140 claims form several repeated claim groups. The principal independent claims are summarized below.

Claim group	Disease	Biomarker determination required?	Principal drug limitation
Claim 1	Neuroblastoma	Yes	Formula (I) Trk inhibitor
Claim 16	Neuroblastoma	No	Formula (I) Trk inhibitor
Claim 30	Glioma	Yes	Formula (I) Trk inhibitor
Claim 45	Glioma	No	Formula (I) Trk inhibitor
Claim 59	Thyroid cancer	Yes	Formula (I) Trk inhibitor
Claim 74	Thyroid cancer	No	Formula (I) Trk inhibitor
Claim 88	Breast cancer	Yes	Formula (I) Trk inhibitor
Claim 115	Breast cancer	No	Formula (I) Trk inhibitor

Claims 103 and 129 add combination treatment limitations to the breast-cancer claim families. These claims cover administration of the Trk inhibitor together with other cancer treatments, including surgery, radiation, endocrine agents, chemotherapy, monoclonal antibodies, kinase inhibitors, aromatase inhibitors, and specified drugs such as palbociclib, abemaciclib, fulvestrant, trastuzumab, pertuzumab, topotecan, gemcitabine, cisplatin, and carboplatin.

What diseases are protected by the patent?

The patent is disease-specific. Its primary therapeutic categories are:

1. Neuroblastoma.
2. Glioma.
3. Thyroid cancer.
4. Breast cancer.

The patent does not provide a general claim to treating every solid tumor with larotrectinib. That broader tumor-agnostic commercial positioning comes from the drug's regulatory label and other patent rights, not solely from US Patent 10,005,783.

The disease claims are potentially valuable because they reach cancer treatment outside the central FDA indication, particularly where a product is used in a tumor type with an NTRK alteration but where the prescribing decision is not framed as treatment of an FDA-labeled tumor-agnostic indication.

How broad is the Formula (I) chemical genus?

The independent claims cover a chemical genus with several structural variables:

• R1 is hydrogen or C1-C6 alkyl.
• R2 is an amino substituent forming a five- or six-membered nitrogen-containing heterocycle.
• The heterocycle may contain a second nitrogen, oxygen, or sulfone group.
• The heterocycle may carry substituents such as hydroxyl, fluorine, amino, carboxylic acid, ester, trifluoromethyl, alkyl, or oxo groups.
• Y is optionally substituted phenyl.
• Y substituents include halogen, C1-C4 alkoxy, CF3, and CHF2.
• X is methylene.
• R3 is hydrogen or C1-C4 alkyl.
• R4 includes halogen, alkyl, hydroxyl, alkoxy, amino, alkylamino, and hydroxymethyl.
• n is 0, 1, or 2.

The dependent claims progressively narrow this genus. The most commercially important narrowing sequence is:

1. Y is halogen-substituted phenyl.
2. Y contains one or two fluorine atoms.
3. n is zero or one.
4. R3 is hydrogen.
5. R1 is hydrogen.
6. The active compound is larotrectinib.
7. The salt is a trifluoroacetate, sulfate, or hydrochloride.
8. The salt is sulfate, including hydrogen sulfate.
9. The dosage form is oral.
10. The oral preparation is a capsule, tablet, solution, dispersion, suspension, syrup, or emulsion.

The genus claims create a broader technical perimeter than larotrectinib alone. Their practical enforceability will depend on written-description support, enablement across the full genus, anticipation, obviousness, and claim construction.

What larotrectinib salt and formulation claims are included?

The claims expressly cover:

• Free-base larotrectinib;
• Pharmaceutically acceptable salts;
• Trifluoroacetate salts;
• Sulfate salts;
• Hydrochloride salts;
• Hydrogen sulfate larotrectinib;
• Oral dosage forms;
• Solid oral preparations;
• Liquid oral preparations;
• Capsules;
• Tablets;
• Solutions;
• Dispersions;
• Suspensions;
• Syrups; and
• Emulsions.

Claim 11 and its corresponding dependent claim families are commercially significant because they identify the hydrogen sulfate salt used in Vitrakvi. The formulation language is broad and does not require a particular excipient, release profile, particle-size distribution, tablet coating, dose strength, or manufacturing process.

This means the patent is stronger against a generic that uses larotrectinib sulfate in a conventional oral capsule or tablet than against a competitor that uses a different active compound within the Formula (I) genus. Separate formulation or solid-state patents would be needed to protect a specific crystalline form, polymorph, particle-size distribution, excipient system, or manufacturing process.

Does the patent require biomarker testing?

Some independent claims require a preliminary determination that the cancer exhibits one or more of:

• Trk overexpression;
• Trk activation;
• Trk amplification; or
• Trk mutation.

Claims 1, 30, 59, and 88 contain this step.

Other independent claims do not include the determination step. Claims 16, 45, 74, and 115 broadly cover administering the claimed compound to a subject with neuroblastoma, glioma, thyroid cancer, or breast cancer.

This distinction matters for infringement analysis. A product label, clinical protocol, treatment guideline, or diagnostic workflow that directs testing for an NTRK alteration may create a clearer pathway to infringement of the biomarker-selected claims. The no-testing claims present a broader literal scope, although their validity and construction may be more vulnerable because they reach treatment without requiring the claimed molecular selection.

The claims also use "comprising," which generally leaves room for additional treatment steps, concomitant drugs, and supportive care unless those additions create a separate claim issue.

Which claims cover TrkA, TrkB, and TrkC?

Claims 15, 44, 73, 102, and 140 specify that the Trk kinase is selected from TrkA, TrkB, and TrkC.

These dependent claims narrow the relevant target but do not require a particular NTRK gene fusion, mutation, amino-acid substitution, tumor stage, or line of therapy. The claims therefore reach treatment of a tumor involving any of the three Trk family members, subject to the disease and compound limitations of the parent claim.

The broad biology creates commercial value but also creates validity exposure. A challenger could examine whether the specification demonstrates that the full range of claimed Trk alterations and cancer subtypes can be treated with the entire Formula (I) genus.

What breast-cancer combination treatments are protected?

Claims 103 through 114 and 129 through 140 cover breast-cancer treatment in combination with additional therapies. The listed combinations include:

• Aromatase inhibitors such as anastrozole, letrozole, exemestane, and formestane;
• CDK4/6 inhibitors such as palbociclib and abemaciclib;
• Fulvestrant;
• HER2-directed agents such as trastuzumab, pertuzumab, ado-trastuzumab emtansine, and lapatinib;
• Platinum agents;
• Taxanes;
• Anthracyclines;
• Topotecan;
• Gemcitabine;
• Cyclophosphamide;
• Vinca alkaloids;
• Tamoxifen;
• Irinotecan;
• Surgery; and
• Radiotherapy.

These claims are narrower than the standalone breast-cancer claims but may be useful against a label or clinical protocol that specifically recommends larotrectinib with endocrine therapy, chemotherapy, HER2 therapy, or another listed agent.

The combination claims have a practical limitation: many of the listed therapies are not standard components of the FDA-approved Vitrakvi label. Enforcement may therefore depend on actual clinical use, promotional materials, trial protocols, or prescribing instructions rather than the drug's core label.

What is the FDA and Orange Book status?

Vitrakvi received FDA approval on November 26, 2018, for adult and pediatric patients with solid tumors that:

• Have an NTRK gene fusion;
• Are metastatic or would likely cause severe morbidity with surgical resection; and
• Have no satisfactory alternative treatments or have progressed following treatment.

The approval was tumor-agnostic and based on the presence of an NTRK fusion rather than a particular organ of origin. FDA's approval materials identify larotrectinib as an oral selective Trk inhibitor. [2]

The FDA Orange Book lists US Patent 10,005,783 among the patents associated with Vitrakvi. The listed patent term extends to April 27, 2035. The product also has separate composition-of-matter and related patent protection, including US Patent 9,944,907. [3]

Exclusivity timeline

Event	Date
FDA approval of Vitrakvi	November 26, 2018
New chemical entity exclusivity	November 26, 2023
Pediatric exclusivity, if applied to the NCE term	May 26, 2024
US Patent 10,005,783 listed expiration	April 27, 2035

Regulatory exclusivity and patent exclusivity are separate. The end of NCE exclusivity did not remove the patent barrier. Generic applicants may seek approval before patent expiration through a Paragraph IV certification, but launch risk depends on litigation, settlement terms, patent validity, and any applicable pediatric or other regulatory exclusivity.

Are there Paragraph IV challenges or patent litigation?

The principal Paragraph IV risk would involve an ANDA applicant certifying that US Patent 10,005,783 is invalid, unenforceable, or not infringed. Because the patent is a method-of-use patent, the scope of a challenge would depend heavily on:

• The applicant's proposed label;
• Whether the label includes the patented cancer uses;
• Whether a section viii statement can carve out the patented methods;
• Whether the applicant's product is larotrectinib sulfate;
• Whether the Orange Book-listed use code is sufficiently specific; and
• Whether induced-infringement allegations can be supported.

A section viii carve-out may reduce risk for a generic that omits the patented neuroblastoma, glioma, thyroid-cancer, and breast-cancer uses. It may not eliminate risk if the generic label retains tumor-agnostic NTRK-fusion language that reads on a patented method or if physicians are expected to use the product for the patented diseases.

No settlement terms or final court judgment are established by the claim text supplied. Patent litigation status must be separated from patent scope: the existence of an issued patent does not establish that every claim would survive validity review.

How does US Patent 10,005,783 compare with the larotrectinib composition patent?

Issue	US 10,005,783	US 9,944,907
Principal protection	Methods of treatment	Composition of matter and related chemical subject matter
Disease limitation	Yes	Generally less disease-specific
Biomarker limitation	Present in some claims	Not the core limitation
Larotrectinib expressly identified	Yes	Yes, as chemical subject matter
Oral dosage-form limitation	Yes, in dependent claims	Not the primary commercial limitation
Combination therapy	Yes, breast cancer	Not the primary focus
Listed expiration	April 27, 2035	April 27, 2035
Generic exposure	Use claims and label liability	Product manufacture, sale, and use

The composition patent is generally the more fundamental barrier to an unrestricted larotrectinib generic. US 10,005,783 adds use-specific protection and can remain relevant even where a generic attempts to narrow its label.

What is the geographic coverage?

US Patent 10,005,783 is enforceable only in the United States. Parallel protection may exist through national-stage counterparts derived from the same international patent family, but foreign claim scope, prosecution history, term, opposition status, and validity are jurisdiction-specific.

Commercial diligence should distinguish:

• US patent term;
• European Patent Office and national European rights;
• Canadian rights;
• Japanese rights;
• Australian rights;
• Chinese rights;
• Patent-term adjustments or extensions;
• Supplementary protection certificates; and
• Local litigation or opposition proceedings.

The US patent does not itself block manufacture or sale outside the United States.

Are manufacturing processes protected by this patent?

No process limitation appears in the supplied claims. The claims require administration of a dosage form containing Formula (I) or a salt, not a particular synthetic route, crystallization process, impurity profile, or tablet-manufacturing method.

A generic could therefore face separate risks from:

• Composition-of-matter claims;
• Salt or polymorph claims;
• Intermediate claims;
• Process patents;
• Formulation patents;
• Regulatory exclusivity; and
• Trade-secret or know-how protection.

US Patent 10,005,783 should not be treated as a complete manufacturing freedom-to-operate clearance.

How strong is the patent estate?

The estate is commercially meaningful but uneven in strength.

Stronger features

• Larotrectinib is expressly named.
• The sulfate and hydrogen sulfate forms are expressly identified.
• The claims cover four clinically relevant cancer categories.
• Several independent claims omit the biomarker-testing requirement.
• Oral dosage forms are expressly included.
• TrkA, TrkB, and TrkC are identified.
• Breast-cancer combination claims extend the use perimeter.

Vulnerable features

• The Formula (I) genus is broad relative to the expressly identified larotrectinib species.
• The disease claims cover heterogeneous cancers with different biology.
• The biomarker language includes overexpression, activation, amplification, and mutation without requiring a specific molecular alteration.
• The claims do not recite dose, schedule, duration, response threshold, or treatment line.
• The specification would need to support treatment across the full chemical and disease breadth.
• Some claim dependencies in the supplied text appear internally inconsistent.

The most important drafting issue is the apparent dependency problem in claims 60, 65, and 66, which refer to claim 44 even though they appear within the thyroid-cancer claim sequence. Claims 78 and 79 also refer to claims 75 and 76 rather than following the immediately preceding dependency pattern. These may reflect transcription errors, issued-claim correction history, or prosecution amendments. The certified patent document and USPTO file history control the legal effect.

What generic launch scenarios exist?

Scenario	Commercial effect
No challenge until patent expiry	Launch after April 27, 2035, subject to other patents
Paragraph IV challenge to composition and method patents	Potential litigation and a 30-month stay if statutory requirements are met
Section viii carve-out of patented cancer uses	Possible earlier launch with narrower labeling
Settlement with a licensed or agreed launch date	Entry date depends on confidential or public settlement terms
At-risk launch after unsuccessful challenge	Exposure to damages, injunction risk, and induced-infringement claims
Product launch after patent invalidation	Earlier entry, subject to remaining patents and exclusivity
Alternative Trk inhibitor launch	No direct larotrectinib infringement if the product does not practice the claimed Formula (I) compound

The most credible generic strategy is likely a label carve-out combined with a Paragraph IV challenge to the composition and method-of-use estate. A fully labeled larotrectinib generic would face greater exposure because it would likely practice both product and method claims.

Key Takeaways

• US Patent 10,005,783 is a method-of-use patent for larotrectinib and related Trk inhibitors.
• It covers neuroblastoma, glioma, thyroid cancer, and breast cancer.
• Some claims require determination of Trk overexpression, activation, amplification, or mutation; others do not.
• The patent expressly covers larotrectinib, its sulfate and hydrogen sulfate salts, and oral dosage forms.
• Breast-cancer claims include extensive combination-treatment limitations.
• The Orange Book-listed expiration date is April 27, 2035.
• FDA approval of Vitrakvi occurred November 26, 2018; NCE exclusivity ended November 26, 2023, subject to any pediatric extension.
• The patent is commercially important but does not replace the composition-of-matter patent or any separate salt, polymorph, formulation, or process patents.
• Potential generic entry routes include Paragraph IV litigation, section viii label carving, settlement, or post-expiration launch.
• The apparent claim-dependency errors in the supplied text require review against the certified issued patent and prosecution history.

FAQs

What is the active ingredient protected by US Patent 10,005,783?

The principal identified active ingredient is larotrectinib, specifically the sulfate or hydrogen sulfate salt used in Vitrakvi.

Does US Patent 10,005,783 cover NTRK gene-fusion testing?

The claims recite determining Trk overexpression, activation, amplification, or mutation. They do not expressly require an NTRK gene fusion in the supplied claim language.

Can a generic launch larotrectinib with a section viii carve-out?

Potentially, if the proposed label omits the patented uses and the remaining label does not induce infringement. The feasibility depends on FDA use codes, the final label, and the scope of other listed patents.

Does the patent protect every Trk inhibitor?

No. It protects the claimed Formula (I) genus and specifically identified larotrectinib. A structurally unrelated Trk inhibitor, such as entrectinib or repotrectinib, would not automatically fall within these claims.

What is the difference between Vitrakvi's FDA indication and this patent?

Vitrakvi is FDA-approved for solid tumors with NTRK gene fusions under defined clinical conditions. US Patent 10,005,783 claims specific cancer types and Trk-related biological features, including uses that are broader or different from the approved label.

References

1. United States Patent and Trademark Office. (2018). US Patent No. 10,005,783, Methods of treating cancer using TRK inhibitors.
2. U.S. Food and Drug Administration. (2018, November 26). FDA approves larotrectinib for solid tumors with NTRK gene fusions.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book, Vitrakvi patent listings.
4. United States Patent and Trademark Office. (2018). US Patent No. 9,944,907, TRK inhibitors.

Drugs Protected by US Patent 10,005,783

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 Hlthcare	VITRAKVI	larotrectinib sulfate	CAPSULE;ORAL	210861-001	Nov 26, 2018		RX	Yes	No	10,005,783					METHOD OF TREATING NEUROBLASTOMA, GLIOMA, THYROID, AND BREAST CANCER SOLID TUMORS THAT EXHIBIT AN NTRK GENE FUSION
Bayer Hlthcare	VITRAKVI	larotrectinib sulfate	CAPSULE;ORAL	210861-002	Nov 26, 2018		RX	Yes	Yes	10,005,783					METHOD OF TREATING NEUROBLASTOMA, GLIOMA, THYROID, AND BREAST CANCER SOLID TUMORS THAT EXHIBIT AN NTRK GENE FUSION
Bayer Healthcare	VITRAKVI	larotrectinib sulfate	SOLUTION;ORAL	211710-001	Nov 26, 2018		RX	Yes	Yes	10,005,783					METHOD OF TREATING NEUROBLASTOMA, GLIOMA, THYROID, AND BREAST CANCER SOLID TUMORS THAT EXHIBIT AN NTRK GENE FUSION

International Family Members for US Patent 10,005,783

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3106463		301033	Netherlands
European Patent Office	3106463		PA2020504	Lithuania
European Patent Office	3106463		CA 2020 00013	Denmark