Details for Patent: 10,519,142

Which drugs does patent 10,519,142 protect, and when does it expire?

Patent 10,519,142 protects FRUZAQLA and is included in one NDA.

This patent has fifty patent family members in thirty-seven countries.

Summary for Patent: 10,519,142

Title:	Crystalline forms of 6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide
Abstract:	The present invention relates to the pharmaceutical field, provides novel crystalline forms, solvates and the crystalline forms thereof of compound 6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide, pharmaceutical compositions, as well as the methods of preparation and the use thereof.
Inventor(s):	Zhenping Wu, Wenji Li, Yuping CHU
Assignee:	Hutchmed Ltd
Application Number:	US15/510,631
Patent Claim Types: see list of patent claims	Use; Composition; Formulation;

US Patent 10,519,142: Fruquintinib Form I Claims, Scope, Expiration and Patent Landscape

US Patent No. 10,519,142 protects Form I of fruquintinib, the active ingredient in Fruzaqla, with additional claims covering its XRPD-defined crystalline structure, pharmaceutical compositions, colorectal-cancer treatment, and manufacturing processes. The strongest product coverage is claim 1, while claims 2 through 11 provide crystallographic limitations and claims 12 and 13 cover alternative polymorph-conversion processes. The patent is commercially relevant because fruquintinib received FDA approval for previously treated metastatic colorectal cancer and is marketed in the United States by Takeda.[1][2]

What compound and drug does US Patent 10,519,142 cover?

The claimed compound is fruquintinib, chemically identified as:

6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide.

Fruquintinib is a small-molecule vascular endothelial growth factor receptor inhibitor. The marketed US product is Fruzaqla, supplied as 1 mg and 5 mg capsules and approved for adults with metastatic colorectal cancer previously treated with specified chemotherapy and anti-VEGF, anti-EGFR, or anti-BRAF therapies, as applicable.[2]

Item	Description
Active ingredient	Fruquintinib
Patent subject	Form I crystalline fruquintinib
Drug product	Fruzaqla
US sponsor	Takeda Pharmaceuticals USA, Inc.
FDA approval	November 8, 2023
Therapeutic area	Previously treated metastatic colorectal cancer
Dosage form	Oral capsule
Patent	US 10,519,142
Patent type	Polymorph, composition, method-of-use, and manufacturing-process patent
Patent assignee identified in patent record	Hutchison Medipharma Limited

The patent is directed primarily to solid-state protection rather than a new molecular entity. Its central legal distinction is Form I, not merely fruquintinib as a chemical substance.

What patents protect fruquintinib and Form I?

US 10,519,142 contains 20 claims divided into five practical categories:

1. An unconstrained Form I product claim.
2. XRPD-defined Form I claims.
3. Composition claims.
4. Colorectal-cancer method-of-treatment claims.
5. Manufacturing and polymorph-conversion claims.

Claim-category analysis

Claims	Subject matter	Principal limitation	Commercial significance
1	Form I product	Form I of fruquintinib	Broadest claim in the patent
2	Form I product	Peaks at 5.3, 10.7, 13.9 and 14.6° 2θ	Structural identification by XRPD
3	Composition	Form I, four XRPD peaks, carrier, effective amount for colorectal cancer	Covers drug-product compositions
4	Treatment method	Administering Form I for colorectal cancer	Method-of-use coverage
5-6	Preparation process	Reflux, selected solvents, cooling, isolation and drying; claim 6 specifies acetone	Process coverage
7-11	Form I product	Increasingly detailed XRPD peak sets or Figure 1	Narrower evidentiary subclaims
12	Preparation process	Dissolution solvent, anti-dissolution solvent, cooling, isolation and drying	Anti-solvent crystallization route
13	Preparation process	Suspension conversion in a solvent system	Solid-state conversion route
14-19	Composition	Crystalline Formula A, four XRPD peaks, impurity-form thresholds	Product-quality and formulation coverage
20	Treatment method	Administration of composition in claim 14	Use of controlled-polymorph composition

Claim 1 is the most important claim for product-level enforcement. It does not recite the four XRPD peaks, a particular solvent, a purity threshold, or a therapeutic use. If a competing product contains Form I, claim 1 could potentially be implicated even if the competitor uses a different manufacturing process or markets a different dosage regimen.

How broad is claim 1 of US 10,519,142?

Claim 1 is broad within the patent’s subject matter because it claims “Form I” of fruquintinib without expressly listing analytical peak positions. The scope depends on how Form I is defined by the specification, prosecution history, and expert evidence.

The claim raises four central enforcement questions:

• Whether Form I is a distinct crystalline form identifiable by the patent’s disclosure.
• Whether a commercial batch contains Form I as the claimed solid form.
• Whether mixtures containing Form I fall within the claim.
• Whether the accused material is another polymorph, an amorphous solid, a solvate, or a hydrate.

The claim does not require:

• A pharmaceutical carrier.
• A colorectal-cancer indication.
• A particular dosage strength.
• A specific XRPD instrument.
• The complete peak list in claims 7 through 10.
• A specified manufacturing method.

That structure gives claim 1 substantially greater practical reach than the process claims. A generic or alternative manufacturer would generally need solid-state characterization, not only chemical identity testing, to assess infringement.

What XRPD peaks define Form I?

Claims 2 through 11 use powder X-ray diffraction to identify Form I. The recurring mandatory peaks are:

• 5.3° 2θ ± 0.2°
• 10.7° 2θ ± 0.2°
• 13.9° 2θ ± 0.2°
• 14.6° 2θ ± 0.2°

The dependent claims add progressively more peaks:

Claim	Required XRPD peak set
2	5.3, 10.7, 13.9, 14.6
7	Claim 2 peaks plus 7.3 and 19.9
8	Claim 7 peaks plus 16.3
9	Claim 8 peaks plus 21.1, 21.3 and 25.8
10	Claim 9 peaks plus 15.2, 23.1 and 23.3
11	XRPD pattern shown in Figure 1

The ±0.2° tolerance is important. A competing batch does not avoid the claims merely because its measured peaks differ slightly from the listed positions. Instrument calibration, sample preparation, preferred orientation, particle size, and data-processing conditions can shift or affect observed peak positions.

At the same time, peak matching should not be treated as sufficient by itself. A reliable comparison would normally evaluate the complete diffractogram, relative intensities, sample preparation, crystallinity, and the presence of other forms. Claims 2 through 10 are structured as partial peak recitations, while claim 11 refers to the Figure 1 pattern.

What pharmaceutical compositions are protected?

Claims 3 and 14 through 19 protect pharmaceutical compositions containing the claimed crystalline material.

Claim 3 requires:

• Form I fruquintinib.
• The four specified XRPD peaks.
• An effective amount for treating colorectal cancer.
• At least one pharmaceutically acceptable carrier.

Claims 14 through 19 use a different formulation concept. They require a crystalline form of “Formula A” with the same four characteristic peaks and set a maximum amount of other crystalline forms:

Claim	Maximum content of other crystalline forms
14	Less than 40% by weight
15	Less than 30%
16	Less than 20%
17	Less than 10%
18	Less than 5%
19	Less than 1%

These claims create a descending impurity ladder. Claim 14 is the broadest composition claim in this group. Claim 19 is the narrowest and requires a highly controlled solid-state composition.

The term “Formula A” should be analyzed against the specification and prosecution record because the supplied claim text does not reproduce the formula definition. If Formula A is fruquintinib, claims 14 through 19 likely function as alternative composition claims directed to Form I or an equivalent crystalline form. If the patent defines Formula A more broadly, the claims could extend beyond the exact nomenclature used in claims 1 through 13.

What manufacturing methods does US 10,519,142 protect?

Claims 5, 12 and 13 cover three process families.

Reflux and cooling process

Claim 5 requires:

1. Mixing fruquintinib with a dissolution solvent or solvent mixture.
2. Heating to reflux to form a solution.
3. Cooling to ambient temperature.
4. Isolating Form I.
5. Drying the solid.

The claim identifies methanol, C3-C6 alkanols, acetic acid and aprotic solvents. It also covers selected solvent mixtures, including water-miscible organic solvent and water where the organic solvent is less than approximately 50% by volume.

Claim 6 narrows the process to acetone.

Anti-solvent crystallization process

Claim 12 requires:

• A dissolution solvent selected from ethanol, isopropanol, acetone, dichloromethane, dimethyl sulfoxide or dimethylformamide.
• Heating to reflux.
• Addition of at least one anti-dissolution solvent.
• Cooling.
• Isolation and drying of Form I.

This claim is relevant to processes using controlled supersaturation and anti-solvent precipitation rather than simple cooling crystallization.

Suspension conversion process

Claim 13 starts with a solid form of fruquintinib and suspends it in a solvent system. The suspension is stirred, isolated and dried to obtain Form I. The solvent system may include a dissolution solvent or a water-miscible organic solvent and water containing less than approximately 80% organic solvent by volume.

This claim can reach solid-state conversion processes even where the starting material is not Form I. It may therefore matter to manufacturers attempting to convert an existing polymorph into the protected form during final processing.

When does US Patent 10,519,142 lose exclusivity?

The patent issued on December 31, 2019. Its reported priority date is in November 2016. On a standard 20-year patent-term calculation, the base expiration is expected in November 2037, subject to any patent-term adjustment or extension recorded by the USPTO.[1]

Milestone	Date
Earliest reported priority	November 2016
Patent grant	December 31, 2019
Expected base expiration	November 2037
FDA approval of Fruzaqla	November 8, 2023
Potential pediatric extension	Not established from the supplied record

The patent term should be checked against the USPTO patent-term calculation and the FDA Orange Book listing before relying on an exact launch date. FDA approval does not itself eliminate the patent. Any ANDA applicant seeking an earlier launch would need to address the listed patent through certification, litigation, or a negotiated settlement.

What is the Orange Book status of fruquintinib?

Fruzaqla is an FDA-approved small-molecule product. Its regulatory pathway is an NDA, not a biologics license application. Biosimilar provisions do not apply.

The relevant regulatory issues are:

• Whether US 10,519,142 is listed against the current Fruzaqla NDA.
• Whether the listing covers the drug substance, drug product, method of use, or formulation.
• Whether the FDA has identified a use code that limits the listed patent’s scope.
• Whether additional fruquintinib patents are listed for the approved product.
• Whether any pediatric exclusivity or other statutory exclusivity modifies the commercial date.

The FDA Orange Book is the controlling public source for listed patents and use codes, while the patent itself controls the technical claim language.[3] A patent can be enforceable without appearing in the Orange Book, but an unlisted patent generally does not create the same ANDA certification mechanism as an Orange Book-listed patent.

Which companies are challenging fruquintinib patents?

No Paragraph IV challenger, ANDA applicant, federal patent case, or settlement agreement is identified in the patent claims or bibliographic material supplied for US 10,519,142.

A Paragraph IV challenge would require an ANDA applicant to certify that the listed patent is invalid, unenforceable, or not infringed. If the patent holder sued within the statutory period, FDA approval could be subject to a 30-month stay, subject to the Hatch-Waxman framework and applicable court outcomes.[4]

The principal litigation theories would likely include:

• Non-infringement because the product contains a different polymorph.
• Invalidity for anticipation or obviousness based on earlier fruquintinib crystalline-form disclosures.
• Lack of written description or enablement for broad Form I language.
• Indefiniteness concerning “Form I,” “Formula A,” or XRPD identification.
• Non-infringement of process claims because the accused process uses different solvents, temperatures or isolation conditions.
• Lack of infringement of treatment claims where the proposed label omits the patented indication or falls outside the claim language.

A process patent may be difficult to evaluate from a finished dosage form alone. Product testing can identify Form I, but it may not establish whether the manufacturer used the specific reflux, anti-solvent, or suspension-conversion steps recited in claims 5, 12 and 13.

How strong is the patent estate for fruquintinib?

US 10,519,142 has meaningful but form-specific strength.

Strengths

• Claim 1 does not require the detailed XRPD peak list.
• Claims cover the active solid form, compositions, treatment and manufacturing.
• Claims 7 through 11 provide fallback positions if broader XRPD language is challenged.
• Claims 14 through 19 address mixtures of crystalline forms and solid-state purity.
• The patent may remain commercially relevant beyond any earlier compound patent if the active ingredient itself is otherwise available.

Vulnerabilities

• Polymorph claims depend on reproducible analytical identification.
• The claim set contains apparent drafting inconsistencies, including the “benzofuran--carboxamide” wording in claim 5 and the separate “Formula A” terminology in claim 14.
• Broad product claims may face prior-art and written-description scrutiny.
• Process claims can be avoided through alternative crystallization routes.
• Composition claims with quantitative limits require validated measurement of the proportion of other crystalline forms.
• Treatment claims may have narrower practical value if the approved label or generic label does not track the exact claim language.

The estate is stronger against a manufacturer that intentionally produces Form I for the US market than against one that develops a validated alternative polymorph or amorphous form.

What generic launch risks exist for fruquintinib?

A generic launch strategy would likely fall into one of four categories:

Strategy	Main patent exposure	Practical assessment
Copy Form I	Claims 1-4, 7-11, 14-20	Highest infringement risk
Use a different polymorph	Claim 1 if Form I is present; possible process claims	Requires rigorous solid-state control
Use amorphous fruquintinib	Usually lower Form I risk	Must establish stability, bioequivalence and manufacturability
Use a different crystallization process but still produce Form I	Claim 1 and potentially composition claims	Process redesign may not avoid product claims

The largest risk is accidental formation or persistence of Form I during drug-substance manufacture, milling, granulation, drying or capsule production. Polymorphic conversion can occur during thermal processing, solvent exposure, humidity changes and mechanical stress.

Because fruquintinib is a small molecule, the principal entry barrier is Hatch-Waxman patent and regulatory risk, not biosimilar interchangeability or biologic manufacturing complexity.

How does US 10,519,142 compare with compound and method patents?

A compound patent generally claims fruquintinib irrespective of polymorphic state. A polymorph patent claims a particular solid-state arrangement. A method-of-use patent claims administration for a specified disease or patient population. US 10,519,142 combines the latter two categories with manufacturing protection.

Patent type	What it protects	Relevance to US 10,519,142
Compound patent	Molecular structure	Broader chemical coverage, usually earlier expiration
Polymorph patent	Specific crystalline form	Core focus of claims 1-19
Formulation patent	Dosage form, excipients or release profile	Claims 3 and 14-19 provide limited composition coverage
Method-of-use patent	Treatment indication	Claims 4 and 20
Process patent	Crystallization or conversion method	Claims 5, 6, 12 and 13

The patent should therefore be assessed as one layer in the fruquintinib estate. A complete freedom-to-operate opinion requires review of the underlying compound patents, formulation patents, use patents, Orange Book entries, terminal disclaimers, prosecution history and any continuation or divisional applications.

What geographic coverage does the patent provide?

US 10,519,142 provides rights only in the United States. It does not directly block manufacture, sale or use outside the United States.

The same invention may have corresponding patent-family members in China, Europe, Japan, India and other jurisdictions. Family members can differ materially in:

• Claim scope.
• Grant status.
• Priority entitlement.
• Patent-term dates.
• Opposition history.
• National-phase prosecution.
• Validity outcomes.
• Use and formulation coverage.

A US launch using active pharmaceutical ingredient manufactured overseas may still infringe US claims if the protected Form I is imported, sold, offered for sale or used in the United States. US process claims can also raise importation issues under 35 U.S.C. § 271(g) if a patented process is practiced abroad and the resulting product is imported, subject to statutory exceptions.[5]

Key Takeaways

• US 10,519,142 is a fruquintinib Form I patent covering product, XRPD profile, compositions, colorectal-cancer treatment and manufacturing processes.
• Claim 1 is the broadest and most commercially important claim because it does not recite the four XRPD peaks.
• Claims 2 through 11 create analytical fallback positions based on characteristic diffraction peaks.
• Claims 5, 6, 12 and 13 target cooling crystallization, anti-solvent crystallization and suspension conversion.
• Claims 14 through 19 regulate the amount of other crystalline forms in a pharmaceutical composition.
• Fruquintinib is an FDA-approved small molecule marketed as Fruzaqla, so ANDA and Paragraph IV risk is more relevant than biosimilar risk.
• The reported base patent expiration is in November 2037, subject to the official USPTO term calculation and any applicable adjustment.
• A generic using Form I faces the greatest risk under claim 1, even if it uses a different manufacturing process.
• A different polymorph or amorphous form may reduce risk, but it requires proof that Form I is absent or below any applicable claim threshold.
• The patent is US-only; foreign family rights must be analyzed separately.

FAQs About US Patent 10,519,142 and Fruquintinib

Does US 10,519,142 cover all forms of fruquintinib?

No. Its central subject is Form I and crystalline compositions having the specified XRPD characteristics. Other polymorphs, hydrates, solvates or amorphous material may fall outside the claims unless they contain or convert to the claimed Form I.

Is Fruzaqla protected by a biologic patent or biosimilar exclusivity?

No. Fruzaqla contains fruquintinib, a small molecule. Generic entry proceeds through the ANDA pathway, not the biosimilar pathway.

Can a company avoid US 10,519,142 by using a different solvent?

Possibly for the process claims, but not necessarily for claim 1. If the alternative process still produces Form I, the product claim may remain relevant regardless of solvent choice.

Do the XRPD peaks alone prove infringement?

No. The peaks are important claim limitations, but infringement analysis should compare the complete solid-state profile and account for measurement conditions, relative intensities, mixtures and polymorphic content.

Does an Orange Book listing guarantee that US 10,519,142 is valid?

No. Listing supports the Hatch-Waxman certification framework but does not establish validity, enforceability or infringement. Those issues remain subject to litigation and judicial determination.

References

1. United States Patent and Trademark Office. (2019). U.S. Patent No. 10,519,142, crystalline form of fruquintinib and preparation method thereof.
2. U.S. Food and Drug Administration. (2023, November 8). FDA approves fruquintinib for metastatic colorectal cancer.
3. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. 21 U.S.C. § 355(j). Abbreviated new drug applications and patent certifications.
5. 35 U.S.C. § 271(g). Infringement of process patents involving imported products.

Drugs Protected by US Patent 10,519,142

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Takeda Pharms Usa	FRUZAQLA	fruquintinib	CAPSULE;ORAL	217564-001	Nov 8, 2023		RX	Yes	No			Y	Y		TREATMENT OF PATIENTS WITH METASTATIC COLORECTAL CANCER WHO HAVE BEEN PREVIOUSLY TREATED WITH FLUOROPYRIMIDINE-, OXALIPLATIN-, AND IRINOTECAN-BASED CHEMOTHERAPY, ANTI-VEGF THERAPY, AND, IF RAS WILD-TYPE AND MEDICALLY APPROPRIATE, ANTI-EGFR THERAPY
Takeda Pharms Usa	FRUZAQLA	fruquintinib	CAPSULE;ORAL	217564-002	Nov 8, 2023		RX	Yes	Yes			Y	Y		TREATMENT OF PATIENTS WITH METASTATIC COLORECTAL CANCER WHO HAVE BEEN PREVIOUSLY TREATED WITH FLUOROPYRIMIDINE-, OXALIPLATIN-, AND IRINOTECAN-BASED CHEMOTHERAPY, ANTI-VEGF THERAPY, AND, IF RAS WILD-TYPE AND MEDICALLY APPROPRIATE, ANTI-EGFR THERAPY

International Family Members for US Patent 10,519,142

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	3191475		CA 2024 00052	Denmark
European Patent Office	3191475		PA2024541	Lithuania
European Patent Office	3191475		301307	Netherlands
European Patent Office	3191475		LUC00372	Luxembourg
European Patent Office	3191475		CR 2024 00052	Denmark
European Patent Office	3191475		122024000069	Germany
European Patent Office	3191475		47/2024	Austria