Details for Patent: 10,285,993

Which drugs does patent 10,285,993 protect, and when does it expire?

Patent 10,285,993 protects VITRAKVI and is included in one NDA.

This patent has forty-six patent family members in thirty-three countries.

Summary for Patent: 10,285,993

Title:	Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
Abstract:	A novel crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, pharmaceutical compositions containing said crystalline form and the use of said crystalline form in the treatment of pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection are disclosed. In some embodiments, the novel crystalline form comprises a stable polymorph of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate. The present invention is further directed to a process for the preparation of the novel crystalline form.
Inventor(s):	Alisha B. Arrigo, Derrick Juengst, Khalid Shah
Assignee:	Array Biopharma Inc
Application Number:	US15/706,062
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,285,993
Patent Claim Types: see list of patent claims	Use;

US Patent 10,285,993: Larotrectinib Sulfate Crystal Form I-HS Patent Scope and Competitive Landscape

US Patent 10,285,993 protects the use of a specific crystalline sulfate form of larotrectinib, the active pharmaceutical ingredient in Vitrakvi, for treating Trk-mediated cancers. The patent does not broadly claim every larotrectinib formulation or every Trk inhibitor. Its central limitation is the administration of crystalline form I-HS, identified by defined powder X-ray diffraction and thermal characteristics.

The patent is commercially relevant because it covers the solid form used to manufacture and administer larotrectinib sulfate. Its nominal patent term extends into 2037, subject to any patent-term adjustment or extension recorded by the USPTO. The patent is listed in FDA Orange Book records for Vitrakvi-related protection. [1-3]

What drug does US Patent 10,285,993 protect?

US 10,285,993 protects crystalline form I-HS of larotrectinib sulfate.

Larotrectinib is a selective tropomyosin receptor kinase inhibitor. It inhibits TrkA, TrkB and TrkC signaling caused by NTRK1, NTRK2 and NTRK3 gene fusions. The FDA-approved product is Vitrakvi, marketed as capsules and an oral solution by Bayer. [2]

Item	Patent-relevant information
Patent	US 10,285,993 B2
Patent subject	Crystalline form I-HS of larotrectinib sulfate
Patent holder / originating company	Loxo Oncology, Inc.
Current commercial product	Vitrakvi
Active ingredient	Larotrectinib sulfate
Therapeutic class	Selective Trk inhibitor
Relevant targets	TrkA, TrkB and TrkC
US filing	August 4, 2017
Priority date	August 5, 2016
Issue date	May 7, 2019
Nominal expiration	August 4, 2037, before any applicable adjustment
Dosage forms	Oral capsules and oral solution are commercially relevant
FDA pathway	Accelerated approval for an NTRK fusion-positive solid-tumor indication

The claims supplied identify the active ingredient through a chemical formula that was omitted from the text. The patent’s identity and Trk context correspond to the larotrectinib sulfate crystalline-form patent. The chemical formula, salt state and solid-form designation remain important for infringement analysis.

What is the scope of claim 1 of US 10,285,993?

Claim 1 is a method-of-treatment claim with four central requirements:

1. The subject has a cancer mediated by a Trk kinase.
2. The subject needs treatment.
3. A therapeutically effective amount is administered.
4. The administered material is crystalline form I-HS of the claimed compound, characterized by at least four specified XRPD peaks.

The minimum XRPD limitations in claim 1 are:

XRPD peak	Permitted range
18.4° 2θ	±0.2°
20.7° 2θ	±0.2°
23.1° 2θ	±0.2°
24.0° 2θ	±0.2°

A product or process that uses larotrectinib sulfate but produces a different polymorph, amorphous material, solvate or crystal form may fall outside the literal scope of claim 1 if it does not satisfy the claimed diffraction limitations.

The claim is narrower than a composition-of-matter claim. It does not cover all molecules having larotrectinib’s chemical structure. It covers treatment using a specified solid form.

How do claims 2 through 4 narrow the XRPD scope?

Claims 2 through 4 add increasingly detailed XRPD peak patterns. The claims create alternative infringement positions based on the number and identity of observed diffraction peaks.

Claim	Additional XRPD requirements
Claim 1	18.4°, 20.7°, 23.1° and 24.0°
Claim 2	Claim 1 plus 10.7°
Claim 3	10.7°, 18.4°, 19.2°, 20.2°, 20.7°, 21.5°, 23.1° and 24.0°
Claim 4	Full pattern with 20 listed peaks, including 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°

Claim 4 is the most analytically specific XRPD claim. It provides a stronger fingerprint for the claimed form but also creates more opportunities for an accused batch to dispute whether every listed peak is present within the stated tolerance.

XRPD testing would normally be performed on the active pharmaceutical ingredient, an intermediate or the finished dosage form, depending on sample preparation and the relevant claim-construction question. Excipient interference, preferred orientation, particle size and instrument calibration can affect peak intensity and detectability. The claim language focuses on peak position rather than peak intensity.

What do claims 5 and 6 protect?

Claim 5 adds a differential scanning calorimetry limitation. The claimed crystalline form has an onset-to-maximum event of approximately 193°C to 205°C.

Claim 6 adds a thermal measurement of approximately 2.415 mW. The claim text describes this value as a heat of melting, although mW is a power unit normally associated with a DSC signal or heat-flow measurement. That drafting issue could affect claim construction and the evidentiary value of a DSC comparison.

Claim	Analytical characterization
Claim 5	DSC onset-to-maximum of about 193°C to about 205°C
Claim 6	DSC-related value of about 2.415 mW
Claims 5 and 6	Depend from claim 1 and retain all claim 1 requirements

A generic developer could challenge claims 5 and 6 by arguing that the DSC parameter is method-dependent, insufficiently reproducible or inconsistent with the stated unit. Those arguments would not necessarily defeat claims 1 through 4, which rely principally on XRPD data.

What cancers are covered by claims 7 through 9?

Claims 7 through 9 specify Trk kinase-mediated cancers.

Claim	Target limitation
Claim 7	Cancer mediated by TrkA
Claim 8	Cancer mediated by TrkB
Claim 9	Cancer mediated by both TrkA and TrkB

These claims do not expressly recite TrkC, although claim 1 uses the broader phrase “a Trk kinase.” The prosecution history and specification would be relevant to determine whether claim 1 encompasses TrkC-mediated disease and how the term “mediated” should be construed.

The claims are not limited to a particular tumor type, stage, biomarker assay, dosing schedule or line of therapy. Their breadth is counterbalanced by the requirement that the administered compound be crystalline form I-HS.

What patents protect Vitrakvi and larotrectinib?

The Vitrakvi estate has at least two principal protection categories:

1. Foundational larotrectinib compound and therapeutic-use patents.
2. Solid-form patents covering crystalline larotrectinib sulfate.

US 10,285,993 belongs to the second category. It is distinct from a patent that claims larotrectinib’s chemical structure irrespective of physical form.

Protection category	Typical scope	Commercial significance
Composition of matter	Larotrectinib chemical structure and salts	Blocks manufacture and sale of the molecule generally
Crystalline form	Form I-HS larotrectinib sulfate	Blocks use of the protected polymorph
Method of treatment	Treatment of Trk or NTRK-driven cancers	Relevant to induced or direct infringement
Formulation	Capsules, oral solution, excipient systems or dosage forms	May restrict product-specific design-arounds
Manufacturing	Crystallization, salt formation or isolation process	May create process and supply-chain barriers

US 10,285,993 is most important where the commercial product uses form I-HS. A generic applicant could attempt to use a non-infringing polymorph, but that approach would require demonstrating equivalent stability, dissolution, bioavailability and manufacturing performance.

What is the Orange Book status of US 10,285,993?

FDA Orange Book listings identify patents submitted by the NDA holder as potentially relevant to approved drug products. The listing of US 10,285,993 for Vitrakvi-related protection gives it direct significance in an ANDA challenge.

An Orange Book listing does not establish validity or infringement. It does affect the regulatory pathway for a generic applicant that files an ANDA with a Paragraph IV certification.

The relevant consequences are:

• The applicant must address the listed patent.
• A Paragraph IV certification may trigger patent litigation.
• A timely infringement action can produce a 30-month stay of ANDA approval under the Hatch-Waxman framework.
• The patent’s listed expiration date, not merely its grant date, controls the ordinary ANDA approval barrier.
• A generic applicant may also certify that it will wait for patent expiration or that the patent is not infringed, invalid or unenforceable.

The FDA Orange Book should be checked for the current listing, expiration date and any pediatric exclusivity attached to the listed patent. [1]

When does larotrectinib lose exclusivity?

The patent term for US 10,285,993 is nominally scheduled to end in 2037, based on its 2016 priority date and 2017 US filing. The actual terminal date may reflect USPTO patent-term adjustment.

The commercial exclusivity timeline is separate from patent expiration:

Event	Date or period
US patent priority	August 5, 2016
US filing	August 4, 2017
Patent grant	May 7, 2019
FDA approval of Vitrakvi	November 26, 2018
Orphan-drug exclusivity	Seven years from approval, subject to FDA records
Nominal US patent expiration	August 4, 2037, before adjustment
Earliest ordinary patent-based generic entry	After relevant listed patents expire or are successfully defeated

Larotrectinib’s orphan designation provides market exclusivity for the approved indication. Orphan exclusivity does not prevent approval of a clinically superior product or a product that does not rely on the same orphan indication. It also does not replace patent protection.

The practical generic-entry date will depend on the full Orange Book estate, pediatric exclusivity, patent-term adjustment, Paragraph IV litigation and any settlement agreement.

Which companies are challenging the Vitrakvi patent estate?

The supplied claim set does not identify an ANDA filer, Paragraph IV notice letter or patent litigation defendant. Public identification of a challenger requires review of FDA ANDA litigation records, district-court dockets and applicable settlement disclosures.

No conclusion about a specific generic challenger follows from US 10,285,993 alone. The patent can be challenged through:

• Paragraph IV invalidity allegations;
• Non-infringement of the claimed crystalline form;
• Lack of enablement or written description;
• Obviousness based on known larotrectinib salts and polymorph-screening methods;
• Indefiniteness or ambiguity in the DSC limitation;
• Failure to show that the marketed product contains form I-HS.

A Paragraph IV challenge directed only to the solid-form patent would not automatically invalidate separate composition-of-matter or method-of-use patents.

How strong is the patent estate for larotrectinib?

The estate has meaningful blocking value because the patented form is tied to the commercial active ingredient and because polymorph substitution can create regulatory and manufacturing risk.

Strengths

• The claims identify multiple XRPD peaks with defined tolerances.
• Claim 4 provides a detailed form fingerprint.
• The patent covers therapeutic administration, not merely laboratory preparation.
• Claims 7 through 9 connect the form to TrkA and TrkB-driven cancers.
• A generic using the same API and crystal form would face a direct infringement risk if the product is imported, sold or administered in the United States.

Weaknesses

• The claims are narrower than composition-of-matter claims.
• XRPD results depend on sample handling and analytical conditions.
• DSC limitations may create construction and reproducibility disputes.
• A non-infringing polymorph or amorphous form could provide a design-around route.
• Method claims may require proof that the accused product is used for the claimed cancer treatment.
• The “Trk-mediated” limitation may create questions about biomarker testing and clinical use.

The highest-value claim set is likely claims 1 through 4. Claims 5 and 6 provide additional characterization-based coverage but may be more vulnerable to analytical disputes.

What generic launch scenarios exist for Vitrakvi?

Scenario 1: Paragraph IV challenge to the solid-form patent

A generic applicant argues that its larotrectinib product does not contain form I-HS or that the patent claims are invalid. Litigation could delay approval for up to the statutory stay period if the patent holder brings a timely infringement action.

Scenario 2: Polymorph design-around

The applicant develops a different crystalline form, hydrate, solvate or amorphous form. This strategy would require independent control of dissolution, stability, manufacturability and bioequivalence.

Scenario 3: Waiting for patent expiry

The applicant files with a Paragraph III certification and launches after the relevant patents expire. This reduces litigation risk but delays market entry.

Scenario 4: Settlement and licensed entry

The patent holder and generic applicant enter a settlement that specifies an authorized or agreed entry date. Any antitrust assessment would depend on payment terms, entry timing and scope.

Does US 10,285,993 create biosimilar risk?

No. Larotrectinib is a small-molecule drug, not a biologic. The relevant competitive pathway is an ANDA for a generic drug, not a biosimilar application under the Public Health Service Act.

The key regulatory issues are pharmaceutical equivalence, bioequivalence, formulation differences and patent certifications. A biosimilar-style interchangeability analysis does not apply.

What licensing deals affect larotrectinib?

Loxo Oncology entered into a global collaboration with Bayer for larotrectinib and related development rights. Publicly reported deal terms included a $400 million upfront payment and potential milestone payments of approximately $1.5 billion. Eli Lilly later acquired Loxo Oncology, while Bayer retained its commercial relationship for Vitrakvi under the collaboration structure. [4-5]

The deal is commercially relevant because patent ownership, NDA sponsorship, manufacturing rights and commercialization rights may be divided among different entities. Those contractual allocations do not change the statutory scope of US 10,285,993 but affect enforcement, licensing and authorized-generic possibilities.

What manufacturing and IP barriers does the patent create?

The patent creates a potential barrier at the crystallization and final API-release stages. A manufacturer must determine whether its larotrectinib sulfate is form I-HS or another solid form.

Relevant technical controls include:

• Solvent and antisolvent selection;
• Water activity and humidity control;
• Seeding conditions;
• Cooling and aging profiles;
• Drying temperature;
• Milling and particle-size reduction;
• XRPD release testing;
• DSC confirmation;
• Conversion during granulation, encapsulation or storage.

A process that begins with a different polymorph may still produce form I-HS during downstream processing. Solid-form conversion therefore requires testing on the final API and, where relevant, the finished dosage form.

How does US 10,285,993 compare with a composition patent?

Issue	US 10,285,993	Composition-of-matter patent
Protected subject	Specific crystalline form	Chemical structure
Primary test	XRPD and possibly DSC	Chemical identity
Design-around potential	Relatively higher	Lower
Relevance to API manufacturing	High	High
Relevance to finished product	High if form persists	High
Typical validity issues	Polymorphism, obviousness, analytical scope	Novelty, obviousness, enablement
Generic strategy	Alternative polymorph or Paragraph IV	Different molecule or litigation

US 10,285,993 is a product-linked solid-form patent with method-of-treatment claim language. It is narrower than a compound patent but can remain commercially effective if form I-HS is the only form with the required manufacturing and clinical profile.

Key Takeaways

• US 10,285,993 protects crystalline form I-HS of larotrectinib sulfate, the active ingredient in Vitrakvi.
• Claim 1 requires treatment of Trk-mediated cancer with the specified crystal form and four defined XRPD peaks.
• Claims 2 through 4 add progressively more detailed XRPD signatures.
• Claims 5 and 6 add DSC characteristics; claim 6’s mW terminology may create a construction issue.
• Claims 7 through 9 separately identify TrkA, TrkB and combined TrkA/TrkB cancers.
• The patent is a solid-form patent, not a broad larotrectinib composition patent.
• The nominal expiration is in 2037, subject to patent-term adjustment and any applicable exclusivity.
• Generic competition would most likely proceed through Paragraph IV litigation, a polymorph design-around or post-expiration entry.
• Larotrectinib is a small molecule, so biosimilar rules do not apply.
• The patent’s commercial strength depends on whether the marketed Vitrakvi API and finished product contain form I-HS and whether a stable alternative form can be developed.

FAQs About US Patent 10,285,993

Is US 10,285,993 a method-of-use patent or a crystal-form patent?

It is both in claim format, but its defining technical limitation is the crystalline form I-HS of larotrectinib sulfate. The asserted legal category is a method of treating cancer using that form.

Does the patent cover all larotrectinib sulfate?

No. The claims require the specified crystalline form and its analytical characteristics. A different polymorph, hydrate, solvate or amorphous form may fall outside the literal claims.

Does the patent cover TrkC-mediated cancer?

Claim 1 refers broadly to cancer mediated by a Trk kinase, while claims 7 through 9 specify TrkA and TrkB. The scope as to TrkC would depend on claim construction, specification language and prosecution history.

Can a generic use a different crystal form of larotrectinib?

Potentially, but the alternative form must satisfy FDA requirements for pharmaceutical quality, stability, dissolution and bioequivalence. The alternative must also avoid infringement of other larotrectinib patents.

Is US 10,285,993 relevant to a larotrectinib oral solution?

It may be relevant if the oral solution is manufactured from or contains crystalline form I-HS. The infringement analysis would depend on the product composition, conversion of the solid form during manufacture and the applicable claim construction.

References

1. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
2. U.S. Food and Drug Administration. (2024). Vitrakvi (larotrectinib) prescribing information. Bayer HealthCare Pharmaceuticals Inc.
3. United States Patent and Trademark Office. (2019). U.S. Patent No. 10,285,993, crystalline forms of larotrectinib sulfate. https://patents.google.com/patent/US10285993B2/en
4. Bayer AG. (2017). Bayer and Loxo Oncology enter global collaboration to develop and commercialize larotrectinib and LOXO-195. Bayer investor and corporate releases.
5. Eli Lilly and Company. (2019). Lilly completes acquisition of Loxo Oncology. Lilly corporate release.

Drugs Protected by US Patent 10,285,993

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	10,285,993					METHOD OF TREATING SOLID TUMORS THAT EXHIBIT AN NTRK GENE FUSION
Bayer Hlthcare	VITRAKVI	larotrectinib sulfate	CAPSULE;ORAL	210861-002	Nov 26, 2018		RX	Yes	Yes	10,285,993					METHOD OF TREATING SOLID TUMORS THAT EXHIBIT AN NTRK GENE FUSION

International Family Members for US Patent 10,285,993

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2015346046
Brazil	112017010141
Canada	2967951
Chile	2017001249