US Patent 7,612,208: Lenvatinib Crystal Forms, Process Claims, and Generic-Entry Landscape
US Patent 7,612,208 protects multiple crystalline and solvated forms of lenvatinib salts, including lenvatinib mesylate Forms A, B, C, F and I and lenvatinib ethanesulfonate Forms alpha and beta. Its strongest commercial relevance is the product-by-property protection for lenvatinib mesylate crystal forms used in pharmaceutical manufacture. The patent also contains narrower solvent, drying, heating and humidification process claims and a composition claim directed to the ethanesulfonate Form beta.
The patent issued Nov. 3, 2009, to Eisai Co., Ltd. The US patent term is generally reported to expire March 17, 2026, subject to any applicable patent-term adjustment or extension. Lenvatinib is marketed as LENVIMA, primarily as the mesylate salt. The patent is therefore a small-molecule formulation and solid-state patent, not a biologic patent and not a patent on the underlying kinase-inhibitor molecule itself (USPTO, 2009; FDA, 2025).
What drug and active ingredient does US Patent 7,612,208 cover?
The claimed compound is lenvatinib, also known as E7080, in specified salt and solid-state forms.
| Attribute |
Description |
| Active ingredient |
Lenvatinib |
| Marketed form |
Lenvatinib mesylate |
| Brand |
LENVIMA |
| Sponsor |
Eisai Inc. and Eisai Co., Ltd. |
| Chemical class |
Oral multi-kinase inhibitor |
| Principal targets |
VEGFR1-3, FGFR1-4, PDGFR-alpha, RET and KIT |
| FDA dosage forms |
Capsules and oral solution products |
| Patent focus |
Polymorphs, hydrates, solvates, salt forms and preparation processes |
| Patent number |
US 7,612,208 B2 |
| Issue date |
Nov. 3, 2009 |
| Reported patent expiration |
March 17, 2026 |
The full chemical name in the claims corresponds to lenvatinib. The patent does not broadly claim every lenvatinib formulation, every lenvatinib salt, or every method of treating cancer with lenvatinib. It claims identified solid forms and processes that produce them.
What crystalline forms are protected by US 7,612,208?
Claims 1 through 15 protect specific solid-state forms by analytical characteristics. The claims are grouped as follows:
| Claims |
Form |
Salt or solvate |
Analytical limitation |
| 1 |
Form A |
Methanesulfonate |
PXRD peaks at 9.65° and 18.37° 2θ |
| 2 |
Form A |
Methanesulfonate |
Solid-state 13C NMR shifts at about 162.4, 128.0, 102.3 and 9.9 ppm |
| 3 |
Form A |
Methanesulfonate |
IR bands at 1161 ±1 and 1044 ±1 cm⁻¹ |
| 4 |
Form B |
Methanesulfonate |
PXRD peaks at 5.72° and 13.84° 2θ |
| 5 |
Form B |
Methanesulfonate |
IR bands at 1068 ±1 and 918 ±1 cm⁻¹ |
| 6 |
Form C |
Methanesulfonate |
PXRD peaks at 14.20° and 17.59° 2θ |
| 7 |
Form C |
Methanesulfonate |
Solid-state 13C NMR shifts at about 160.2, 126.6, 105.6 and 7.8 ppm |
| 8 |
Form C |
Methanesulfonate |
IR bands at 1324 ±1 and 579 ±1 cm⁻¹ |
| 9 |
Form F |
Methanesulfonate hydrate |
PXRD peaks at 8.02° and 18.14° 2θ |
| 10 |
Form I |
Methanesulfonate acetic-acid solvate |
PXRD peaks at 9.36° and 12.40° 2θ |
| 11 |
Form I |
Methanesulfonate acetic-acid solvate |
IR bands at 1750 ±1 and 1224 ±1 cm⁻¹ |
| 12 |
Form alpha |
Ethanesulfonate |
PXRD peaks at 15.70° and 17.18° 2θ |
| 13 |
Form alpha |
Ethanesulfonate |
IR bands at 1320 ±1 and 997 ±1 cm⁻¹ |
| 14 |
Form beta |
Ethanesulfonate |
PXRD peaks at 6.48° and 9.58° 2θ |
| 15 |
Form beta |
Ethanesulfonate |
IR bands at 1281 ±1 and 985 ±1 cm⁻¹ |
How do the PXRD, NMR and IR claims operate?
Claims 1 through 15 are product claims drafted in a product-by-property format. Each claim identifies a crystalline form by a combination of:
- The chemical identity of the lenvatinib salt or solvate; and
- One or more analytical signatures.
The Form A, Form B and Form C claim sets overlap functionally but use different analytical methods. For example, Form A is claimed independently through PXRD, solid-state NMR and IR. A material that satisfies the chemical identity and the relevant PXRD limitation may infringe claim 1 even if the patent owner proves infringement through PXRD rather than NMR or IR.
The claims use "having" language. That generally indicates that the listed peaks or bands are required characteristics, while additional peaks or bands may also be present. The two listed PXRD peaks in each claim are not necessarily intended to define the entire diffraction pattern. In a patent dispute, identity would normally be established through a full analytical comparison, including peak positions, relative intensities, crystallinity, solvent or water content and salt stoichiometry.
How broad are the product claims?
The product claims are narrower than a claim to lenvatinib mesylate generally but broader than a claim limited to a particular manufacturing batch.
A material may fall within the claims if it has the claimed:
- Lenvatinib molecular structure;
- Mesylate or ethanesulfonate counterion;
- Hydrate or acetic-acid solvate status, where specified;
- Crystalline form; and
- PXRD, NMR or IR characteristics.
The claims do not require a particular particle size, tablet strength, excipient, capsule shell, dissolution profile, storage condition or manufacturing site. A generic manufacturer could therefore face product-claim risk even if it uses a different crystallization process, provided the resulting commercial material is the claimed form.
The patent does not appear from the supplied claims to cover:
- Amorphous lenvatinib;
- Every lenvatinib mesylate polymorph;
- A different lenvatinib salt not identified in the claims;
- A formulation containing a nonclaimed lenvatinib form;
- A treatment method based solely on administering lenvatinib; or
- A process that produces a genuinely different, nonclaimed solid form.
What preparation processes are protected?
Claims 16 through 27 protect specific preparation routes. They are narrower than the product claims because infringement generally requires performance of each material process step.
| Claims |
Resulting form |
Claimed process |
| 16 |
Mesylate Form A |
Dissolving lenvatinib, methanol and methanesulfonic acid |
| 17 |
Mesylate Form A |
Dissolving lenvatinib, acetic acid and methanesulfonic acid, then adding ethanol |
| 18 |
Mesylate Form B |
Drying acetic-acid solvate Form I at 30°C for 3 hours and 40°C for 16 hours |
| 19 |
Mesylate Form C |
Heating the dimethyl-sulfoxide solvate at 115°C for 10 hours |
| 20 |
Mesylate Form C |
Mixing acetic-acid solvate Form I with ethanol |
| 21 |
Mesylate Form C |
Dissolving lenvatinib, acetic acid and methanesulfonic acid, then adding 2-propanol |
| 22 |
Mesylate Form C |
Humidifying mesylate Form B |
| 23 |
Mesylate Form F |
Dissolving lenvatinib, acetic acid and methanesulfonic acid, then adding ethyl acetate |
| 24 |
Mesylate Form I |
Dissolving lenvatinib, acetic acid and methanesulfonic acid, then adding 1-propanol |
| 25 |
Ethanesulfonate Form alpha |
Dissolving lenvatinib, dimethyl sulfoxide and ethanesulfonic acid |
| 26 |
Ethanesulfonate Form beta |
Mixing ethanesulfonate Form alpha with ethanol |
| 27 |
Ethanesulfonate Form beta |
Dissolving lenvatinib, acetic acid and ethanesulfonic acid, then adding 2-propanol and water |
Claim 21 contains an apparent textual omission: the chemical name recites "4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-methoxy-6-quinolinecarboxamide" rather than the repeated "7-methoxy" nomenclature used elsewhere. The omission may create a claim-construction and prosecution-history issue. It does not automatically invalidate the claim, but it can affect interpretation, correction and enforceability.
Can a different process avoid the process claims?
Potentially, but a different process does not avoid the product claims if it produces a claimed crystalline form. A manufacturer using a new solvent system, altered temperature profile or continuous crystallization route may avoid a particular process claim while still producing Form A, B, C, F or I.
The process claims are most valuable as manufacturing-specific fallback protection. They can support infringement theories against a producer whose process is confidential if discovery, import records, process parameters or product transformation evidence establishes the claimed steps. For imported products, US law can also create exposure for products made abroad by a patented process under 35 U.S.C. § 271(g).
What does claim 28 protect?
Claim 28 is a pharmaceutical composition claim dependent on claim 15. It covers a tablet, powder, granule, capsule or lozenge containing:
- Lenvatinib ethanesulfonate Form beta; and
- A pharmaceutically acceptable carrier.
This claim is materially narrower than a general lenvatinib formulation claim. It does not expressly cover lenvatinib mesylate Form A, Form B, Form C, Form F or Form I. It also does not cover every dosage form unless the composition contains the specific ethanesulfonate Form beta defined in claim 15.
The composition claim may have limited relevance to LENVIMA if the marketed product uses lenvatinib mesylate rather than the claimed ethanesulfonate. Its principal value is protection against a formulation that adopts the claimed beta ethanesulfonate solid form.
What is the Orange Book status of US 7,612,208?
US 7,612,208 has been associated with LENVIMA and lenvatinib mesylate in FDA patent-listing materials. Its commercial significance comes from the possibility that an ANDA applicant must address the listed patent through a Paragraph IV certification or wait until patent expiry, depending on the product, listing and certification strategy (FDA, 2025a).
| Regulatory issue |
Assessment |
| FDA-approved drug |
Yes, LENVIMA |
| NDA holder |
Eisai Inc. |
| Small-molecule product |
Yes |
| Biosimilar pathway |
Not applicable |
| ANDA pathway |
Applicable |
| NCE exclusivity |
Five-year period began with the first approval, subject to statutory exceptions |
| Orphan exclusivity |
Applied to certain approved indications, not to all lenvatinib uses |
| Patent role |
Solid-state and manufacturing protection |
| Reported expiration |
March 17, 2026 |
FDA approval of LENVIMA began with radioactive iodine-refractory differentiated thyroid cancer in 2015. Subsequent approvals expanded use into renal cell carcinoma, hepatocellular carcinoma and endometrial cancer, including combinations with everolimus and pembrolizumab (FDA, 2025b).
Regulatory exclusivity and patent exclusivity operate separately. The five-year new chemical entity period does not extend the life of US 7,612,208. Orphan-drug exclusivity is indication-specific and does not create a general prohibition on all abbreviated applications for lenvatinib.
When does lenvatinib lose exclusivity?
The principal dates are:
| Event |
Date or period |
| LENVIMA first FDA approval |
Feb. 13, 2015 |
| Five-year NCE exclusivity |
Generally ended Feb. 13, 2020 |
| Seven-year orphan exclusivity for the original orphan indication |
Generally ran into February 2022 |
| US 7,612,208 reported patent expiration |
March 17, 2026 |
| Earliest ordinary generic-entry date based on this patent |
After patent expiry, unless a successful Paragraph IV or other legal pathway permits earlier entry |
A Paragraph IV certification can allow litigation before expiry and can produce a 30-month stay if the NDA holder sues within the statutory period. A successful Paragraph IV challenge can permit earlier launch. A settlement can establish a negotiated entry date earlier than patent expiry, although settlement terms depend on the specific parties and patents.
The patent text itself identifies no ANDA filer, Paragraph IV notice, litigation docket or settlement agreement. Those facts are not determined by the issued claims.
Which patents compete with US 7,612,208 in the LENVIMA estate?
US 7,612,208 is one component of a broader LENVIMA estate. The estate can include separate patents directed to the active compound, pharmaceutical compositions, treatment methods, combinations and later formulations.
| Estate category |
Relationship to US 7,612,208 |
| Base compound patents |
May protect lenvatinib independent of its crystal form |
| Salt or polymorph patents |
Directly adjacent and potentially overlapping |
| Formulation patents |
May cover capsules, oral solutions, excipients or release properties |
| Method-of-use patents |
May protect cancer indications or combination therapy |
| Combination patents |
May cover lenvatinib with everolimus or pembrolizumab |
| Manufacturing patents |
May cover intermediates, reaction sequences or purification |
| US 7,612,208 |
Primarily solid forms and selected preparation routes |
The relevant legal question is not whether a generic copies the branded manufacturing process. It is whether the generic product contains a claimed form or uses a claimed process. A generic applicant can avoid some process claims while remaining exposed under product claims.
How strong is the patent estate?
US 7,612,208 has meaningful product-claim value because crystalline-form claims are composition claims. The main strengths are:
- Multiple forms are claimed;
- The mesylate salt is covered through Forms A, B, C, F and I;
- Several analytical methods provide alternative infringement and proof routes;
- The claims cover the product regardless of who made it;
- Conversion pathways between forms are expressly claimed; and
- The patent reaches hydrate and solvent-containing intermediates relevant to manufacturing.
The principal limitations are:
- The claims require the claimed analytical characteristics;
- The patent does not claim all lenvatinib salts or all solid forms;
- Process claims are route-specific;
- Claim 28 is directed to ethanesulfonate Form beta rather than the principal mesylate product;
- Polymorph claims may face novelty and obviousness attacks based on prior solid-state screening; and
- Analytical peak claims can create disputes over measurement conditions, calibration, peak intensity and sample preparation.
A validity challenge would likely focus on prior disclosure of lenvatinib mesylate, routine polymorph screening, solvent inclusion, predictable solid-state transformations and whether the claimed forms were sufficiently distinguished from known materials. An infringement defense would focus on a nonclaimed polymorph, amorphous material, different salt, analytical mismatch or an alternative manufacturing route.
What generic launch risks exist?
At-risk launch before March 2026
An ANDA applicant seeking entry before the reported patent expiry would likely need to pursue a Paragraph IV strategy against the listed patent or rely on a noninfringement position. The principal technical design-around options would include:
- Producing a nonclaimed lenvatinib polymorph;
- Using an amorphous form, if commercially and pharmaceutically viable;
- Selecting a different salt;
- Demonstrating that the final dosage form does not contain the claimed crystal form; or
- Using a process outside claims 16 through 27.
A design-around must account for transformation during drying, milling, granulation, encapsulation and storage. A noninfringing starting form can convert into a claimed form during manufacturing or shelf life.
Launch after patent expiry
After expiry, the patent should no longer block ordinary US manufacture, sale or importation based solely on the claimed subject matter, assuming no applicable extension or separate enforceable patent covers the product. Other LENVIMA patents may still affect specific indications, combinations, formulations or manufacturing methods.
How does lenvatinib compare with competing kinase inhibitors?
| Drug |
Principal commercial use |
Solid-state risk relative to US 7,612,208 |
| Lenvatinib |
Thyroid, kidney, liver and endometrial cancers |
Direct risk because the patent covers lenvatinib forms |
| Sorafenib |
Liver, kidney and thyroid cancers |
No direct chemical infringement; separate estate |
| Pazopanib |
Renal cell carcinoma and soft-tissue sarcoma |
No direct chemical infringement |
| Cabozantinib |
Renal cell, liver and thyroid cancers |
No direct chemical infringement |
| Axitinib |
Renal cell carcinoma |
No direct chemical infringement |
| Tivozanib |
Renal cell carcinoma |
No direct chemical infringement |
These drugs compete clinically and commercially but do not create biosimilar risk for LENVIMA. Lenvatinib is a chemically synthesized small molecule, so the relevant competitive threat is generic entry through an ANDA, not biosimilar substitution under the Biologics Price Competition and Innovation Act.
What geographic coverage does the patent provide?
US 7,612,208 provides US rights only. It can cover:
- US manufacture;
- US sale and offer for sale;
- US importation;
- Certain foreign-made products imported into the US when made by a patented process; and
- Conduct involving the claimed products or processes within the United States.
It does not independently prevent manufacture or sale in Europe, Japan, China, India or other jurisdictions. Eisai’s international protection depends on corresponding national patents and their local term, claim scope and litigation history. A global launch analysis must therefore separate US product claims from foreign family members.
Key Takeaways
- US 7,612,208 is a lenvatinib solid-state patent, not a broad claim to every lenvatinib product.
- Claims 1 through 15 cover Forms A, B, C, F and I of lenvatinib mesylate and Forms alpha and beta of lenvatinib ethanesulfonate.
- Claims 16 through 27 cover specified solvent, drying, heating and humidification processes.
- Claim 28 covers dosage forms containing lenvatinib ethanesulfonate Form beta.
- The mesylate product claims are commercially more important to LENVIMA than the ethanesulfonate composition claim.
- The reported US expiration date is March 17, 2026.
- Generic applicants face product-form risk even if they use a different manufacturing process.
- No biosimilar pathway applies because lenvatinib is a small molecule.
- The patent does not itself identify Paragraph IV challengers, litigation or settlements.
- A complete freedom-to-operate analysis must evaluate the entire LENVIMA patent estate, not US 7,612,208 alone.
FAQs About US Patent 7,612,208 and Lenvatinib
Does US 7,612,208 cover lenvatinib free base?
No. The claims are directed to specified crystalline salt, hydrate and solvate forms. They do not claim lenvatinib free base in general.
Can a generic avoid US 7,612,208 by using a different solvent?
A different solvent may avoid a specific process claim, but it does not avoid the product claims if the resulting material is Form A, B, C, F or I mesylate or another claimed form.
Is lenvatinib subject to biosimilar competition?
No. Lenvatinib is a chemically synthesized small molecule. Generic competition proceeds through the ANDA pathway.
Does claim 28 cover a LENVIMA mesylate capsule?
Not on its face. Claim 28 depends on claim 15 and requires lenvatinib ethanesulfonate Form beta. A mesylate capsule would not satisfy that limitation solely because it contains lenvatinib.
What testing is most important in a lenvatinib patent dispute?
Testing normally includes PXRD, infrared spectroscopy, solid-state NMR, thermogravimetric analysis, differential scanning calorimetry, water or solvent determination and salt-stoichiometry analysis. PXRD comparison is particularly important because several claims use specified diffraction peaks.
References
-
Eisai Co., Ltd. (2009). Crystalline forms of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate and processes for preparation thereof (U.S. Patent No. 7,612,208 B2). United States Patent and Trademark Office.
-
U.S. Food and Drug Administration. (2025a). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.
-
U.S. Food and Drug Administration. (2025b). LENVIMA (lenvatinib mesylate) prescribing information. FDA.
-
United States Congress. (2011). Hatch-Waxman Amendments, 21 U.S.C. §§ 355 and 271.
