US Patent 11,091,440: Cabozantinib Malate Crystalline-Form Patent Scope and Patent Landscape
US Patent 11,091,440 protects pharmaceutical compositions containing crystalline cabozantinib malate, including the racemic DL-malate salt and the individual L-malate and D-malate salts. The patent is directed to solid-state form and composition claims, not to the underlying cabozantinib molecule generally. Its most commercially important application is Cabometyx, whose active ingredient is cabozantinib (S)-malate, also called cabozantinib L-malate.[1,2]
The claims can create a direct infringement risk for an ANDA product that contains crystalline cabozantinib L-malate, even if the generic manufacturer uses a different excipient system, tablet process, strength, or packaging.
What drug and active ingredient does US Patent 11,091,440 cover?
The claimed compound is cabozantinib, chemically identified as:
N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
Cabozantinib is a small-molecule tyrosine kinase inhibitor. The approved products are:
| Product |
Active ingredient |
Dosage form |
Sponsor or commercial rights holder |
FDA status |
| Cometriq |
Cabozantinib (S)-malate |
Capsules |
Exelixis |
FDA-approved for medullary thyroid cancer |
| Cabometyx |
Cabozantinib (S)-malate |
Tablets |
Exelixis |
FDA-approved for renal cell carcinoma and hepatocellular carcinoma |
Cabozantinib inhibits MET, VEGFR, AXL, RET and other kinases. The patent at issue does not claim those kinase targets or the therapeutic mechanism. It claims compositions containing a specified crystalline salt form.
What are the claims of US Patent 11,091,440?
The three claims establish a nested scope.
| Claim |
Claimed subject matter |
Relative scope |
| Claim 1 |
A pharmaceutical composition containing crystalline cabozantinib malate and a pharmaceutically acceptable excipient |
Broadest |
| Claim 2 |
A composition containing crystalline cabozantinib DL-malate and an excipient |
Narrower than claim 1 |
| Claim 3 |
A composition containing crystalline cabozantinib L-malate or D-malate and an excipient |
Narrower than claim 1; alternative stereochemical forms |
Claim 1 is the principal genus claim. It covers crystalline malate salt without limiting the claim to DL-, L-, or D-malate.
Claim 2 is limited to the racemic malate salt, in which the malic acid component is the DL mixture.
Claim 3 covers either enantiopure L-malate or enantiopure D-malate. Cabozantinib (S)-malate corresponds commercially to the L-malate form and is the most relevant product configuration for Cabometyx and Cometriq.
How broad is the crystalline cabozantinib malate claim?
Claim 1 is broad with respect to the solid-state form, but it remains limited in four material respects:
- The active pharmaceutical ingredient must be cabozantinib.
- The counterion must be malate.
- The salt must be crystalline.
- The product must be a pharmaceutical composition containing an excipient.
The claim does not expressly limit the composition to tablets, capsules, a particular dose, a particular excipient, a specific polymorph, a particular particle-size distribution, or a manufacturing process.
The use of “comprising” makes the claim open-ended. A product can contain additional active ingredients, excipients, coatings, processing aids, stabilizers or other materials without avoiding the claim solely because of those additions.
A product containing amorphous cabozantinib malate, a non-malic-acid salt, or the free base would not satisfy the express crystalline cabozantinib malate limitation. Those alternatives could still implicate other patents or regulatory barriers.
Does the patent cover Cabometyx and Cometriq?
Yes, the claims are directed to the active salt used in both products.
Cabometyx contains cabozantinib (S)-malate in tablet form. Because L-malate is within claim 3 and crystalline cabozantinib malate is within claim 1, the marketed tablet product is the commercial product most directly aligned with the patent claims.[2]
Cometriq also uses cabozantinib (S)-malate, but its capsule formulation and approved indication differ from Cabometyx. The claims are composition claims and do not depend on the product’s indication. A capsule formulation can fall within the claims if it contains the claimed crystalline salt and a pharmaceutically acceptable excipient.
What is the patent term and expected expiration date?
US Patent 11,091,440 was issued on August 17, 2021. The patent is an additional solid-state protection layer for cabozantinib malate, separate from the earlier patents covering cabozantinib itself and its therapeutic uses.[1]
The expected statutory expiration is approximately April 2035, based on the relevant 20-year patent term calculated from the applicable nonprovisional or PCT filing date. The operative expiration date should be determined from the USPTO patent-term record, including any patent-term adjustment, terminal disclaimer or other term event.
| Patent |
Primary subject matter |
Expected term position |
| US 7,906,470 |
Cabozantinib compound and related compounds |
Approximately 2026, before adjustment |
| US 8,877,776 |
Cabozantinib-related compound protection |
Approximately 2026 |
| US 11,091,440 |
Crystalline cabozantinib malate compositions |
Approximately April 2035 |
| Later use or formulation patents |
Specific indications, regimens or formulations |
Potentially later than the basic compound patents |
The crystalline-salt patent therefore has a materially later nominal expiration than the basic compound patents. That difference is commercially important because a generic applicant may face a later barrier even after the earliest cabozantinib compound patents expire.
What formulation patents are relevant to cabozantinib?
US Patent 11,091,440 is a solid-state and composition patent. It does not appear, from the supplied claims, to require a particular tablet architecture or excipient combination.
The key protected formulation characteristic is the crystalline salt. The patent therefore differs from a conventional formulation patent that claims:
- A specific dissolution profile.
- A defined tablet hardness or friability range.
- A particular coating.
- A controlled-release system.
- A specific ratio of excipients.
- A particle-size or granulation process.
- A fixed-dose combination.
The patent may be difficult to design around while preserving the same active ingredient and salt. A manufacturer could investigate an amorphous form, a different salt, the free base, or a non-malic-acid crystalline form. Each alternative would require separate pharmaceutical development and regulatory work, and each could encounter other cabozantinib patents.
How does the patent affect an ANDA and Paragraph IV challenge?
A generic applicant seeking approval of cabozantinib tablets or capsules would normally assess listed patents in the FDA Orange Book and submit one of the statutory patent certifications for each applicable patent.[3]
For US Patent 11,091,440, the relevant certification would generally be:
- Paragraph III, if the applicant accepts that the patent has not expired.
- Paragraph IV, if the applicant asserts that the patent is invalid, unenforceable or will not be infringed.
- A section viii statement, only if the listed patent claims an indication or method of use that the applicant seeks to omit. Section viii generally does not avoid a composition claim covering the active salt in the product.
A Paragraph IV notice alleging that the proposed product does not contain crystalline cabozantinib malate would likely require detailed solid-state evidence. Relevant evidence could include:
- Powder X-ray diffraction.
- Differential scanning calorimetry.
- Thermogravimetric analysis.
- Infrared or Raman spectroscopy.
- Solid-state nuclear magnetic resonance.
- Karl Fischer water analysis.
- Microscopy and particle characterization.
- Batch-level manufacturing controls.
Because the claims do not identify a single named polymorph in the text supplied, the central dispute could concern the meaning of “crystalline” and whether the proposed product contains the claimed salt at the point of manufacture, during storage, or in the final dosage form.
What is the Orange Book status of US Patent 11,091,440?
The FDA Orange Book is the controlling source for listed patents and regulatory exclusivity associated with approved drug products.[3] A patent can be relevant to Cabometyx or Cometriq only if it is properly listed against the applicable product and indication under FDA rules.
US Patent 11,091,440 is commercially relevant as a product patent because it claims the active crystalline salt in a pharmaceutical composition. It is not a pure method-of-use patent. Its listing status, associated product number, and current expiration entry must be checked against the current FDA Orange Book record rather than inferred solely from the patent claims.
The distinction between the two products matters. A patent listed for Cabometyx may not automatically have the same listing position for Cometriq if the FDA records assign different product numbers, dosage forms, or regulatory entries.
What litigation and settlement risks affect generic cabozantinib?
Cabozantinib is exposed to the standard litigation sequence for a branded small molecule:
- An ANDA applicant files a Paragraph IV certification.
- Exelixis receives notice of the certification.
- Exelixis may sue within the statutory period.
- FDA approval may be subject to a 30-month stay, subject to statutory exceptions.
- The parties may litigate validity, enforceability and infringement.
- The dispute may end in judgment, license, or settlement with a permitted launch date.
A settlement may allow an authorized or licensed generic launch before patent expiration while preserving the branded company’s principal exclusivity period. Publicly reported cabozantinib patent disputes have involved multiple generic applicants and have focused on the compound, formulation, method-of-use and salt-related patent portfolio rather than on a single patent in isolation.
The practical launch date can therefore differ from the expiration date of US 11,091,440. A settlement may establish a negotiated launch date, while a court decision may invalidate the patent, narrow its scope, or uphold it through the full term.
How strong is the patent estate for cabozantinib?
The estate has several layers:
| Protection layer |
Commercial purpose |
Relevance to US 11,091,440 |
| Basic compound patents |
Protect cabozantinib chemical structure |
Separate, earlier-expiring protection |
| Salt and crystalline-form patents |
Protect the marketed active form |
Directly relevant |
| Formulation patents |
Protect dosage-form performance or composition |
Potentially overlapping |
| Method-of-use patents |
Protect indications and treatment regimens |
Relevant to ANDA labeling |
| Regulatory exclusivity |
Restrict FDA approval independent of patent term |
Product- and approval-specific |
| Manufacturing patents |
Protect preparation, crystallization or purification |
May create process risk |
US 11,091,440 is strongest against products that use cabozantinib L-malate or D-malate in crystalline form. It is less directly applicable to a generic using a different salt or a demonstrably amorphous material. Its commercial strength also depends on whether the patent remains listed, whether its claims survive litigation, and whether the generic product’s final dosage form contains the claimed crystalline material.
How does cabozantinib compare with competing kinase inhibitors?
Cabozantinib competes with other tyrosine kinase inhibitors in renal cell carcinoma, hepatocellular carcinoma and related oncology markets. Relevant competitors include axitinib, lenvatinib, pazopanib, regorafenib and tivozanib.
Cabozantinib differs from many competitors because its commercial product uses a defined malate salt and has separate tablet and capsule products. That creates a more specific solid-state patent target. By contrast, a competitor protected primarily through a compound patent or conventional formulation patent may present a different generic-entry profile.
Cabozantinib is a small molecule, not a biologic. Biosimilar approval pathways do not apply. Generic applicants would use the ANDA pathway, subject to patent certifications and any litigation-related stay.
What licensing arrangements affect cabozantinib commercialization?
Exelixis has retained substantial cabozantinib rights in the United States. It has entered into regional commercialization and licensing arrangements outside the United States, including arrangements involving Ipsen and Takeda for specified territories and products.[4,5]
Those agreements can affect revenue allocation, territorial enforcement and control of patent litigation. They do not change the literal scope of US Patent 11,091,440, but they may determine which party controls enforcement or receives royalties in a particular market.
Key Takeaways
- US Patent 11,091,440 claims pharmaceutical compositions containing crystalline cabozantinib malate.
- Claim 1 is the broadest claim and covers crystalline cabozantinib malate without limiting the malate stereochemistry.
- Claim 2 covers crystalline DL-malate.
- Claim 3 covers crystalline L-malate or D-malate.
- Cabometyx and Cometriq use cabozantinib (S)-malate, corresponding to the commercially relevant L-malate form.
- The patent is a salt and solid-state protection layer, not a basic compound patent.
- The expected term extends to approximately 2035, subject to the USPTO term record.
- An ANDA applicant would face a composition patent that generally cannot be avoided through a section viii labeling carve-out.
- Solid-state characterization will be central to any non-infringement or invalidity challenge.
- Cabozantinib has no biosimilar pathway because it is a small molecule; generic entry proceeds through the ANDA framework.
- The ultimate launch date may be controlled by litigation or settlement rather than the patent’s nominal expiration date.
FAQs About US Patent 11,091,440 and Cabozantinib
Does US Patent 11,091,440 cover cabozantinib free base?
No. The supplied claims require cabozantinib malate, and the salt must be crystalline. Cabozantinib free base is outside the literal wording of these claims.
Does the patent cover cabozantinib hydrochloride or another non-malic-acid salt?
No. The claims identify malate as the counterion. A different salt would not satisfy the claimed salt limitation, although another patent could protect that alternative.
Does claim 3 cover cabozantinib S-malate?
Yes. Cabozantinib S-malate corresponds to the L-malate form identified in claim 3, provided the salt is crystalline and present in a pharmaceutical composition with an acceptable excipient.
Can a generic avoid the patent by changing the excipients?
Usually not if the generic still contains crystalline cabozantinib malate. The claims require an excipient but do not require a particular excipient or excipient combination.
Is US Patent 11,091,440 a method-of-use patent?
No. The supplied claims are composition claims. They do not require treatment of renal cell carcinoma, hepatocellular carcinoma, medullary thyroid cancer or any other disease.
References
- United States Patent and Trademark Office. (2021). US Patent No. 11,091,440, crystalline cabozantinib malate pharmaceutical compositions.
- U.S. Food and Drug Administration. (2024). Cabometyx (cabozantinib) prescribing information. Exelixis, Inc.
- U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
- Exelixis, Inc. (2024). Form 10-K annual report.
- Ipsen S.A. (2024). Universal registration document and annual financial report.
