United States Patent 7,235,576: Sorafenib Patent Scope, Claims, Expiration and Generic Entry Risk

U.S. Patent No. 7,235,576 is the principal composition-of-matter patent associated with sorafenib and Nexavar. It covers pharmaceutically acceptable salts of selected diaryl urea compounds, including sorafenib tosylate, and method-of-treatment claims directed to RAF-kinase-mediated cancers. The patent issued on June 26, 2007, and its ordinary U.S. patent term expired on December 21, 2020, based on the patent family’s priority structure. Its core commercial claims are no longer enforceable against new U.S. generic entry, although later formulation, crystalline-form, manufacturing and method-of-use patents may have affected launch timing. [1][2][3]

What drug does U.S. Patent 7,235,576 protect?

The commercially important compound in the patent is sorafenib, also known as BAY 43-9006. The marketed product is sorafenib tosylate, sold by Bayer and Onyx Pharmaceuticals as Nexavar.

Sorafenib is a multikinase inhibitor that inhibits RAF kinases, VEGFR kinases, PDGFR-beta and other kinase targets. The FDA-approved product is an oral 200 mg tablet. Approved indications have included unresectable hepatocellular carcinoma, advanced renal cell carcinoma and radioactive iodine-refractory differentiated thyroid carcinoma. [2]

The compound corresponding to sorafenib in the supplied claims is:

N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea

The patent also covers four related diaryl urea compounds. The claim set therefore includes a small chemical genus, but it is not a broad claim to all RAF inhibitors or all diphenyl ureas.

Principal compounds identified in the claims

Compound category	Structural description	Commercial relevance
Compound 1	tert-Butyl, methoxy and methoxy-N-methylcarbamoyl substituted diaryl urea	Research compound; not the Nexavar active moiety
Compound 2	Trifluoromethyl anisole urea linked to N-methylcarbamoyl pyridyloxy phenyl	Research compound
Compound 3	Chloro-trifluoromethyl phenyl urea linked to carbamoyl pyridyloxy phenyl	Related analog
Compound 4	Chloro-trifluoromethyl phenyl urea linked to N-methylcarbamoyl pyridyloxy phenyl	Sorafenib
Compound 5	Chloro-trifluoromethyl anisole urea linked to N-methylcarbamoyl pyridyloxy phenyl	Related analog

What are the independent claims in U.S. Patent 7,235,576?

The principal independent claims are directed to composition and therapeutic-use categories.

Claim 1: selected compounds and salts

Claim 1 covers a pharmaceutically acceptable salt of any one of five identified diaryl urea compounds. Because the claim is compound-specific, infringement generally requires the accused product to contain one of the listed molecular structures or a pharmaceutically acceptable salt of that structure.

The claim does not cover:

Every RAF kinase inhibitor;
Every diaryl urea;
Every compound containing a pyridyloxy phenyl group;
Every sorafenib analog;
Regorafenib solely because it is chemically related to sorafenib.

A generic product containing sorafenib tosylate falls within the chemical scope of claim 1.

Claim 2: first listed compound

Claim 2 narrows the coverage to a pharmaceutically acceptable salt of the first compound, the tert-butyl and methoxy-substituted diaryl urea.

Claims 3 and 9, 11 and 37: salt classes

These claims identify broad classes of acceptable acid and base salts. Listed acids include hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic and several carboxylic acids. The claims also identify alkaline, alkaline-earth, ammonium, substituted ammonium and aromatic substituted ammonium cations.

The drafting contains terminology errors. For example, the claims refer to “basic salts of organic acids and inorganic acids” and “acid salts of organic and inorganic bases,” although the intended categories appear to be acid-addition salts and basic salts. The issued patent, its prosecution history and any certificates of correction control over the transcribed text supplied here.

Claims 4 through 11: additional listed compounds

These claims cover salts of the remaining listed compounds, including the sorafenib structure and related chloro- and trifluoromethyl-substituted analogs. Claims 7 and 10 specifically address tosylate salts. The tosylate limitation is commercially important because Nexavar is marketed as sorafenib tosylate.

How broad are the method-of-treatment claims?

Claims 12 through 42 cover administering a pharmaceutically acceptable salt of one of the listed compounds to treat cancerous cell growth mediated by RAF kinase.

The method claims are arranged in descending levels of specificity:

RAF-kinase-mediated cancer;
Individual listed compounds;
Solid cancers;
Carcinomas, myeloid disorders or adenomas;
Lung, pancreatic, thyroid, bladder or colon carcinoma;
Myeloid leukemia or villous colon adenomas;
Specific salt classes;
Specific tosylate salts.

Claims 13 through 17 are compound-specific method claims. Claims 18 through 36 add disease categories. Claims 38 through 42 focus on administration of tosylate salts.

Therapeutic scope

The claims are broader than the original FDA indications in some respects. They recite:

Solid tumors;
Carcinomas;
Myeloid disorders;
Adenomas;
Myeloid leukemia;
Villous colon adenomas;
Lung, pancreas, thyroid, bladder and colon cancers.

A method claim is not limited to the exact FDA label unless the claim language or prosecution history imposes that limitation. The patent claims use RAF kinase mediation as the biological mechanism and do not require a particular mutation, biomarker, dose, treatment line or combination partner.

Does U.S. Patent 7,235,576 cover sorafenib tosylate?

Yes. Sorafenib tosylate is within the patent’s salt and compound claims, particularly the claims directed to the sorafenib structure and its tosylate salt.

The commercially relevant claim pathway is:

Claim category	Coverage
Selected compound claim	Sorafenib molecular structure
Pharmaceutically acceptable salt claim	Sorafenib salts, including acid-addition salts
Tosylate claim	Sorafenib p-toluenesulfonate salt
Method claim	Use of sorafenib salt for RAF-mediated cancer
Disease-specific method claim	Certain solid cancers, carcinomas and related disorders

The patent does not require the product to be sold under the Nexavar brand. A generic manufacturer marketing sorafenib tosylate would have implicated the same composition claims before expiration.

What is the patent expiration date for U.S. Patent 7,235,576?

The ordinary U.S. patent term expired on December 21, 2020. The patent issued on June 26, 2007, from a family claiming priority to December 21, 2000. For modern utility patents, the relevant term is generally 20 years from the earliest effective nonprovisional filing date, subject to patent-term adjustment, terminal disclaimers and patent-term extension. [1][4]

Exclusivity timeline

Event	Date or period
Earliest claimed priority	December 21, 2000
U.S. patent grant	June 26, 2007
Nexavar FDA approval	December 2005
New chemical entity exclusivity	Approximately through November 2010
Composition patent expiration	December 21, 2020
Post-expiration generic risk	High for the core compound and salt claims

The FDA’s five-year new chemical entity exclusivity and the patent term were separate rights. NCE exclusivity restricted certain abbreviated applications during the exclusivity period. It did not extend the patent beyond the applicable patent-term calculation. [2][4]

What was the Orange Book status of Nexavar and patent 7,235,576?

Nexavar was listed in the FDA Orange Book under NDA 021923. U.S. Patent 7,235,576 was the principal listed composition patent for the product. The Orange Book also reflected later patents associated with formulation, crystalline form or other product characteristics. [3]

The Orange Book distinction is important:

Patent 7,235,576 protected the active compound and salts.
Later-listed patents may have addressed formulations, solid forms or other product attributes.
Orange Book listing does not itself establish patent validity.
An ANDA applicant could submit a Paragraph IV certification against a listed patent.
A timely infringement action could trigger a 30-month stay of FDA approval under the Hatch-Waxman framework. [5]

After December 21, 2020, patent 7,235,576 could no longer independently block approval or commercial launch based on its expired claims. Any remaining barrier had to arise from another unexpired patent, regulatory exclusivity, injunction, settlement term or product-specific legal issue.

Which companies challenged the Nexavar patent estate?

Generic manufacturers typically approached the Nexavar estate through ANDA filings and Paragraph IV certifications. Publicly reported generic applicants and suppliers included major companies such as Teva, Mylan, Cipla and other abbreviated-application sponsors. The relevant challenge would have targeted the listed patents, including the composition patent and later product patents, rather than only the brand name.

The principal Paragraph IV arguments available against a compound patent of this type include:

Anticipation by an earlier publication or patent;
Obviousness based on known RAF inhibitors and diaryl urea analogs;
Lack of written description for the selected salt scope;
Lack of enablement across all listed salts and compounds;
Indefiniteness caused by malformed or missing structural language;
Noninfringement based on a different active ingredient, salt, solid form or use.

The strongest practical defense for the patent holder was the narrow identification of specific molecules combined with experimental kinase and antitumor data. The strongest generic arguments would have focused on obviousness and the routine nature of making pharmaceutically acceptable salts, particularly where the asserted product was a known compound salt rather than a new chemical entity.

How strong was the patent estate for sorafenib?

The estate was strong during the period in which the composition patent remained enforceable. A valid composition-of-matter patent generally provides broader protection than a formulation or method patent because it reaches the active ingredient regardless of dosage form, manufacturer or indication.

Strengths

Direct coverage of sorafenib;
Coverage of pharmaceutically acceptable salts;
Specific coverage of sorafenib tosylate;
Method claims linked to RAF-mediated cancers;
Long period between FDA approval and composition-patent expiration;
Commercial product aligned closely with the claimed compound.

Weaknesses

Salt formation can be attacked as routine or obvious;
Some claims contain apparent drafting and transcription defects;
The claims cover a limited set of compounds rather than a broad RAF inhibitor genus;
Method claims can be vulnerable to divided-infringement and induced-infringement defenses;
Expiration eliminated the principal barrier to generic sorafenib.

The claim set had high historical blocking value but little current exclusionary value for ordinary U.S. sorafenib products because the patent has expired.

What formulation and solid-form patents may have extended Nexavar protection?

A branded product may have a layered patent estate beyond its composition patent. For sorafenib, later patents and patent applications addressed matters such as:

Sorafenib tosylate crystalline forms;
Particle size and solid-state characteristics;
Tablet formulations;
Manufacturing processes;
Stability and dissolution properties;
Combination therapies;
Specific clinical uses.

These patents do not automatically extend the term of U.S. Patent 7,235,576. They must be assessed separately by patent number, claim scope, expiration date and Orange Book listing.

A generic manufacturer can avoid a later formulation patent by using a different excipient system, particle-size distribution, manufacturing process or solid form, if the resulting product remains bioequivalent and does not practice the asserted claims. A crystalline-form patent can therefore delay a specific generic product without preserving exclusivity over the active ingredient generally.

What generic launch scenarios existed after patent expiration?

After expiration of the core patent, the main launch scenarios were:

Scenario	Commercial consequence
No unexpired blocking patent	Immediate or near-immediate generic competition after approval
Unexpired formulation or solid-form patent	Possible delayed launch or design-around
Paragraph IV settlement	Entry date controlled by settlement terms
Authorized generic	Earlier price pressure without independent ANDA competition
Multiple ANDA approvals	Rapid erosion of Nexavar volume and price
Limited manufacturing capacity	Temporary supply constraints despite legal availability

For sorafenib, the expiration of the composition patent materially reduced the legal barrier to entry. The remaining questions concerned the status of later Orange Book patents, FDA approval timing, manufacturing readiness and settlement agreements.

How does sorafenib compare with regorafenib?

Sorafenib and regorafenib are related Bayer diaryl urea kinase inhibitors, but they are not the same compound.

Attribute	Sorafenib	Regorafenib
Brand	Nexavar	Stivarga
Core class	Diaryl urea multikinase inhibitor	Diaryl urea multikinase inhibitor
Key commercial uses	Liver, kidney and thyroid cancers	Colorectal cancer, gastrointestinal stromal tumors and liver cancer
Patent relevance	Covered by U.S. 7,235,576	Protected by a separate patent estate
Automatic coverage under 7,235,576	Yes, for sorafenib salts	No, absent a claim covering the distinct structure

The chemical relationship between the products does not make the regorafenib molecule an infringing sorafenib product. Each product requires separate composition, formulation, method and regulatory analysis.

What licensing deals affected sorafenib commercialization?

Bayer and Onyx entered into a collaboration covering development and commercialization of sorafenib. Bayer led development and held major commercial rights, while Onyx participated in development and received economic rights under the collaboration. Amgen later acquired Onyx in 2013, making Amgen the successor to Onyx’s economic interest in the product. [6]

The licensing structure affected revenue allocation and commercial control, but it did not change the legal scope or expiration date of U.S. Patent 7,235,576.

What is the current litigation and commercial risk?

The core composition patent presents no current U.S. launch risk because it expired in December 2020. Any present dispute would more likely concern:

Later Orange Book patents;
Infringement of a specific formulation or crystalline form;
Manufacturing-process patents;
Patent settlement restrictions;
Product labeling and induced infringement;
Regulatory exclusivity unrelated to the expired composition patent.

For a generic manufacturer, the principal legal risk is no longer infringement of U.S. Patent 7,235,576 itself. The principal risk is practicing a separate unexpired claim while manufacturing or selling sorafenib tablets.

Key Takeaways

U.S. Patent 7,235,576 is the foundational sorafenib composition patent.
It covers sorafenib and pharmaceutically acceptable salts, including sorafenib tosylate.
Claims 12 through 42 cover RAF-kinase-mediated cancer treatment methods.
The patent does not cover all RAF inhibitors or all diaryl ureas.
Sorafenib tosylate is the commercial compound most directly implicated.
The patent expired on December 21, 2020.
FDA NCE exclusivity ended years earlier and did not extend the patent term.
Later formulation, solid-form and method patents required separate analysis.
Generic entry after expiration depended primarily on the status of later patents and FDA approvals.
Regorafenib is chemically related but is not automatically covered by this patent.

FAQs About U.S. Patent 7,235,576

Is sorafenib tosylate still protected by U.S. Patent 7,235,576?

No. The patent’s ordinary U.S. term expired on December 21, 2020. Later patents could have protected specific formulations or solid forms, but they are separate rights.

Does U.S. Patent 7,235,576 cover sorafenib free base?

The claims are directed to pharmaceutically acceptable salts of the identified compounds. A product containing a different physical or chemical form must be analyzed against the issued claim language and any applicable doctrine of equivalents.

Does the patent cover treatment of every cancer with sorafenib?

No. The claims recite RAF-kinase-mediated cancer growth and specified disease categories. The exact scope depends on the asserted claim, the administered salt, the disease and the infringement theory.

Can a generic company avoid the patent by using a non-tosylate sorafenib salt?

Not necessarily. Several claims cover pharmaceutically acceptable salts broadly. Avoiding the tosylate claim would not automatically avoid broader salt claims.

Does expiration of this patent eliminate all Nexavar patent risk?

No. Expiration eliminates the core patent’s exclusionary effect, but later patents covering formulations, crystalline forms, manufacturing methods or approved uses may create separate risks.

References

United States Patent and Trademark Office. (2007). U.S. Patent No. 7,235,576, substituted diphenyl ureas as Raf kinase inhibitors.
U.S. Food and Drug Administration. (2005). Nexavar prescribing information, NDA 021923.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
United States Code. (2024). 35 U.S.C. §§ 154 and 156.
United States Code. (2024). 21 U.S.C. § 355(j).
Amgen Inc. (2013). Annual report for the fiscal year ended December 31, 2013.

Details for Patent: 7,235,576

Summary for Patent: 7,235,576