# United States Drug Patent 8,637,553: Regorafenib Claims, Expiration, Orange Book Status, and Generic Risk

US Patent No. 8,637,553 covers regorafenib, the active pharmaceutical ingredient in Bayer’s Stivarga. Its claims extend beyond the active compound to specified acid-addition salts, metabolites, pharmaceutical compositions, and the underlying chemical genus represented by Formula (I). The patent is the principal composition-of-matter patent associated with regorafenib in the United States.

The patent’s commercial importance is substantial because composition claims generally create the strongest barrier to generic entry. Regorafenib is approved for colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma. FDA labeling identifies Stivarga as regorafenib tablets marketed by Bayer HealthCare Pharmaceuticals Inc. [1]

What drug does US Patent 8,637,553 protect?

US 8,637,553 protects regorafenib and related chemical forms. Regorafenib is chemically identified as:

4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide.

The structure contains five commercially important elements:

Structural element	Patent relevance
4-Chloro-3-trifluoromethyl phenyl group	Forms one side of the diaryl urea pharmacophore
Urea linkage	Connects the substituted aniline to the central aromatic ring
3-Fluorophenoxy group	Distinguishes regorafenib from sorafenib
2-Pyridine carboxamide	Provides the heteroaromatic terminal group
N-Methyl carboxamide	Is expressly identified in the narrower compound claims

Regorafenib is a multikinase inhibitor that targets VEGFR1-3, TIE2, KIT, RET, RAF kinases, BRAF, PDGFR-beta, and FGFR pathways. FDA approved Stivarga in 2012 for metastatic colorectal cancer and later expanded its indications to gastrointestinal stromal tumors and hepatocellular carcinoma. [1, 2]

What are the principal claim categories in US 8,637,553?

The supplied claims fall into six legal and commercial categories.

Claims	Subject matter	Commercial significance
1, 13	Formula (I) compounds and isolated stereoisomers	Broad chemical genus
2, 4, 15	Pharmaceutically acceptable salts	Extends protection to salt forms
3, 5	Regorafenib and specified salts	Direct composition claims
6-9, 14, 16	Pharmaceutical compositions	Covers drug products containing the protected compound or salt
10-12	Metabolites and metabolite salts	Covers certain in vivo or laboratory-generated derivatives
13-16	Repeated compound and salt claims	Independent or parallel protection to the Formula (I) subject matter

Claims 3 and 5 are the most commercially focused claims because they identify regorafenib or particular regorafenib salts. Claims 1 and 13 can be broader, depending on the precise definition of Formula (I), its substituent variables, and the prosecution history.

How broad are the Formula (I) claims?

Claims 1 and 13 potentially cover a genus of substituted diaryl ureas rather than only regorafenib. Their scope depends on the missing structural definition of Formula (I), including:

The permitted substituents on the aryl and heteroaryl rings.
The identity and position of halogen and trifluoromethyl groups.
The scope of the pyridine carboxamide substituent.
Whether the formula includes stereochemical alternatives.
The definition of pharmaceutically acceptable salts.
Any Markush variables and fallback embodiments in the specification.

Claim 1 covers a compound of Formula (I), a pharmaceutically acceptable salt, or an isolated stereoisomer of a salt. Claim 13 separately claims a compound of Formula (I). Claim 15 separately claims a salt of a Formula (I) compound.

Because the user-supplied text does not reproduce the Formula (I) drawing or its substituent definitions, the exact outer boundary of claims 1, 13, and 15 cannot be determined from the claim text alone. The named regorafenib claims provide the clearest enforceable commercial scope.

What do claims 3 and 5 cover?

Claim 3 covers regorafenib itself and its pharmaceutically acceptable salts. Claim 5 narrows the salt coverage to:

Hydrochloride;
Benzenesulfonate; and
Methanesulfonate.

These claims are directed to the active molecular entity rather than a specific tablet strength, excipient system, dissolution profile, or manufacturing process.

Claim 5 is particularly relevant to salt-selection strategies. A generic applicant using one of the expressly named salts could face literal infringement risk if the claim remains enforceable and the product otherwise satisfies the claim limitations.

What salts are protected by US 8,637,553?

Claim 2 lists a broad group of organic and inorganic acids. The list includes hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, tosylate, naphthalenesulfonates, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate, succinate, fumarate, maleate, benzoate, salicylate, phenylacetate, and mandelate salts.

The salt claims create two different layers of protection:

A broad listed-acid category under claim 2.
A narrower express claim to hydrochloride, benzenesulfonate, and methanesulfonate salts under claim 5.

A salt not expressly listed may still fall within a broader claim if it qualifies as a pharmaceutically acceptable salt under the claim construction adopted by a court. A novel crystalline form, polymorph, hydrate, or solvate may also raise separate claim-construction and infringement issues, depending on the claim language and the manufacturing route.

What metabolites are protected?

Claims 10-12 extend the patent beyond regorafenib itself. They cover metabolites involving modification at:

Either urea nitrogen;
The pyridine nitrogen;
The N-methylamide functionality; or
Combinations of those sites.

Claim 11 identifies several specific transformations:

Metabolic transformation	Covered example
Urea N-hydroxylation	Either urea nitrogen carries a hydroxyl group
Pyridine N-oxidation	Oxidation of the pyridine nitrogen
N-demethylation	Conversion of the N-methylamide to the corresponding amide
Combined changes	N-oxidation, N-demethylation, and urea hydroxylation in specified combinations

Claim 12 names three compounds, including the N-demethylated amide and pyridine N-oxide derivatives. These claims may be relevant to metabolite reference standards, pharmacokinetic studies, impurity characterization, and analytical products. They are less likely than the composition claims to block a conventional generic tablet unless the generic product contains or produces a claimed metabolite in a legally relevant manner.

What pharmaceutical compositions are protected?

Claims 6-9, 14, and 16 cover compositions containing a Formula (I) compound or salt with a physiologically acceptable carrier.

These claims are composition claims, but the supplied language is broad. It does not require:

A particular tablet dose;
A defined excipient;
A specific dissolution profile;
A particular release mechanism;
A particular particle size;
A specified polymorph; or
A defined manufacturing process.

The claims could therefore reach conventional oral dosage forms containing regorafenib or a covered salt. They do not, on the supplied language, appear limited to Bayer’s commercial formulation.

A generic applicant may still challenge composition claims through an ANDA Paragraph IV certification, a non-infringement position, an invalidity defense, or a product design that uses a nonclaimed salt or form. The viability of those strategies depends on the full patent record, including prosecution amendments and issued-claim construction.

When does US Patent 8,637,553 lose exclusivity?

The patent has a 2025 patent-term endpoint associated with the regorafenib composition patent. The relevant date must be determined from the USPTO patent-term calculation and any applicable patent-term adjustment or pediatric extension. The FDA Orange Book is the controlling commercial reference for the listed patent and expiration information. [3, 4]

Exclusivity right	Expected relevance
US 8,637,553 composition patent	Principal regorafenib patent barrier
Patent-term adjustment	May alter the ordinary 20-year term endpoint
Pediatric exclusivity	Can add six months if granted and applicable
FDA chemical exclusivity	No longer the principal barrier for a 2012 small-molecule approval
Method-of-use patents	May affect indication-specific launch risk
Formulation patents	May affect product-specific rather than molecule-wide risk

Patent expiration and FDA exclusivity are separate concepts. A patent may expire after regulatory exclusivity has ended, while a generic may remain exposed to listed method-of-use patents even after the composition patent expires.

What is the Orange Book status of Stivarga and regorafenib?

Stivarga is an FDA-listed drug product containing regorafenib. The Orange Book identifies patents associated with approved Stivarga products and provides the regulatory framework for ANDA certifications. [3]

A generic applicant seeking approval before all listed patents expire would generally assess:

Paragraph I certification if no patent information is listed;
Paragraph II certification if the patent has expired;
Paragraph III certification if the applicant will wait for expiration; or
Paragraph IV certification asserting that the patent is invalid, unenforceable, or not infringed.

For the principal composition patent, Paragraph IV litigation would ordinarily focus on claim construction, validity, written description, enablement, obviousness, and the exact generic salt or active ingredient. For method-of-use patents, a section viii statement may be available if the generic labeling can omit the patented indication without creating a direct infringement theory.

Which companies are challenging regorafenib exclusivity?

Regorafenib generic competition is expected to come primarily from ANDA sponsors seeking approval for generic regorafenib tablets. Public company-by-company conclusions require current FDA ANDA records, Paragraph IV notices, and district-court dockets.

The principal competitive groups are:

Large generic manufacturers with oncology portfolios;
Indian pharmaceutical companies filing abbreviated applications;
US generic companies purchasing or licensing ANDA rights;
Contract manufacturers supporting authorized or independent generic launches.

The absence of a public litigation record does not establish the absence of Paragraph IV activity. ANDA notices are served confidentially on the patent holder and may not become public unless litigation is filed.

What patent litigation affects regorafenib?

Regorafenib litigation risk is concentrated in three areas:

Composition-patent litigation

A challenge to US 8,637,553 would attack the core molecule or a claimed salt. This is the highest-value dispute because success can remove the principal barrier across multiple indications.

Method-of-use litigation

Stivarga’s approved uses include colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma. A later patent may cover one or more treatment methods. Such patents can produce indication-specific risk even after a composition patent expires.

Formulation and manufacturing litigation

A separate patent may cover a solid form, particle-size distribution, formulation, coating, process, or impurity-control method. These patents usually do not prevent every generic route to the active ingredient, but they can delay a particular product design.

No settlement terms should be inferred solely from the existence of an ANDA challenge. A settlement may include a licensed entry date, an authorized-generic arrangement, manufacturing restrictions, or no-admission provisions.

How does regorafenib patent protection compare with sorafenib?

Regorafenib and sorafenib share the diaryl urea pharmacophore and the 4-chloro-3-trifluoromethylphenyl group. Regorafenib has an additional fluorine substitution on the central phenoxy ring.

Issue	Regorafenib	Sorafenib
Brand	Stivarga	Nexavar
Developer	Bayer, with Onyx collaboration	Bayer, with Onyx collaboration
Core class	Multikinase inhibitor	Multikinase inhibitor
Central ring	3-fluorophenoxy substitution	Unfluorinated phenoxy structure
Terminal group	N-methylpyridine-2-carboxamide	N-methylpyridine-2-carboxamide
Patent strategy	Composition, salts, metabolites, compositions, uses	Separate composition and use patent families
Commercial exposure	Colorectal cancer, GIST, liver cancer	Renal cell carcinoma, hepatocellular carcinoma, thyroid cancer

The additional fluorine is legally important. Regorafenib is not automatically covered by every sorafenib claim, and sorafenib patent expiration does not determine regorafenib’s patent status. Each molecule requires separate claim and family analysis.

How strong is the patent estate for regorafenib?

US 8,637,553 has strong claim positioning because it includes the active compound in claims 3 and 5 and also includes broad Formula (I), salt, metabolite, and composition claims.

Estate component	Strength assessment
Named regorafenib compound	High, subject to validity and expiration
Expressly named salts	High for the listed salts
Broad Formula (I) genus	Potentially high, but dependent on formula definitions and prosecution history
Metabolites	Moderate commercial blocking value
Simple pharmaceutical compositions	Moderate, depending on claim construction
Formulation protection	Not established by the supplied claims
Manufacturing protection	Not established by the supplied claims
Method-of-use protection	Must be assessed in separate patent families

The principal weakness is temporal rather than structural: a composition patent near expiration provides limited ability to prevent post-expiry generic entry. The remaining commercial value then shifts to pediatric exclusivity, later-expiring use patents, formulation patents, regulatory exclusivities, supply agreements, and launch settlements.

What generic launch scenarios exist for regorafenib?

Three launch scenarios are commercially plausible.

Delayed launch after composition-patent expiry

The generic waits for the applicable expiration date and files or maintains a Paragraph III position. This reduces litigation exposure but delays revenue capture.

At-risk launch after a Paragraph IV challenge

The generic challenges US 8,637,553 or a later-listed patent and launches before final resolution. The sponsor faces damages and injunction risk if the patent holder prevails.

Carved-out indication launch

The generic omits a patented indication from its labeling under section viii while retaining noninfringing indications. This strategy depends on the exact use claims, FDA labeling, promotional conduct, and whether the remaining label still induces infringement.

Revenue exposure is concentrated in Bayer’s Stivarga sales and in the oncology distribution channel. After core composition protection ends, price erosion can be substantial, although oncology products may retain value through restricted distribution, reimbursement complexity, manufacturing requirements, and physician familiarity.

What geographic coverage does the patent provide?

US 8,637,553 provides protection only in the United States. Related applications and patents may exist in Europe, Japan, China, Canada, and other jurisdictions, but foreign rights require separate review of:

National-phase filings;
Grant and lapse status;
Supplementary protection certificates;
Patent-term extensions;
Opposition or invalidity proceedings;
Local claim scope;
Local regulatory linkage rules.

The US patent does not create worldwide protection for regorafenib, and foreign expiration dates may differ materially.

Key Takeaways

US 8,637,553 is a principal US composition patent for regorafenib, the active ingredient in Stivarga.
Claims 3 and 5 directly identify regorafenib and specified hydrochloride, benzenesulfonate, and methanesulfonate salts.
Claims 1 and 13 may cover a broader Formula (I) chemical genus, but the exact scope depends on the full structural formula and prosecution history.
Claims 6-9, 14, and 16 cover pharmaceutical compositions containing the compound or salts.
Claims 10-12 cover specified metabolites, including urea hydroxylation, pyridine N-oxidation, and N-demethylation products.
The principal patent term reaches a 2025 endpoint, subject to the controlling USPTO and Orange Book calculations and any applicable extension.
Generic risk depends on more than the core patent. Later method-of-use, formulation, solid-form, or manufacturing patents may affect specific launch strategies.
Regorafenib and sorafenib share a pharmacophore but have separate patent estates and separate expiration analyses.

FAQs

Does US 8,637,553 cover regorafenib tablets?

Yes. The patent’s composition claims cover regorafenib and its salts, while the pharmaceutical-composition claims cover compositions containing the protected compound with a physiologically acceptable carrier.

Can a generic avoid US 8,637,553 by using a different regorafenib salt?

Possibly, but not automatically. Claims 1, 2, 4, and 15 may reach a broader range of pharmaceutically acceptable salts. A different salt requires claim construction, infringement analysis, and review of the complete patent specification.

Are regorafenib metabolites relevant to generic approval?

They can be relevant to impurity specifications, pharmacokinetic testing, reference standards, and analytical methods. The metabolite claims are less likely to block a standard tablet solely because the human body generates a metabolite after administration.

Does regorafenib have biosimilar risk?

No. Regorafenib is a chemically synthesized small molecule, so the relevant competitive pathway is an ANDA generic application rather than a biosimilar application under the Public Health Service Act.

Can a company launch generic regorafenib before patent expiration?

A company may seek an at-risk launch after a Paragraph IV challenge, subject to litigation and injunction risk. It may also pursue a section viii carve-out if later patents cover only particular indications and FDA labeling can lawfully omit those uses.

References

U.S. Food and Drug Administration. (2024). Stivarga (regorafenib) prescribing information. Bayer HealthCare Pharmaceuticals Inc.
U.S. Food and Drug Administration. (2012). FDA approves Stivarga for metastatic colorectal cancer. FDA.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: The Orange Book. FDA.
United States Patent and Trademark Office. (2014). U.S. Patent No. 8,637,553, compounds, pharmaceutical compositions, and methods of use. U.S. Department of Commerce.

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	STIVARGA	regorafenib	TABLET;ORAL	203085-001	Sep 27, 2012		RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial	Y	Y			⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	1663978	⤷ Start Trial	C300620	Netherlands	⤷ Start Trial
European Patent Office	1663978	⤷ Start Trial	92300	Luxembourg	⤷ Start Trial
European Patent Office	1663978	⤷ Start Trial	CA 2013 00056	Denmark	⤷ Start Trial
European Patent Office	1663978	⤷ Start Trial	13C0060	France	⤷ Start Trial
European Patent Office	1663978	⤷ Start Trial	C20130034 00099	Estonia	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,637,553

Which drugs does patent 8,637,553 protect, and when does it expire?

Summary for Patent: 8,637,553