Details for Patent: 9,957,232

Which drugs does patent 9,957,232 protect, and when does it expire?

Patent 9,957,232 protects STIVARGA and is included in one NDA.

This patent has forty-one patent family members in thirty-seven countries.

Summary for Patent: 9,957,232

Title:	4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate
Abstract:	The present invention relates to 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate, to processes for its preparation, to pharmaceutical compositions comprising it and to its use in the control of disorders.
Inventor(s):	Alfons Grunenberg, Juergen Stiehl, Katharina Tenbieg, Birgit Keil
Assignee:	Bayer Intellectual Property GmbH , Bayer Healthcare LLC
Application Number:	US12/444,974
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,957,232
Patent Claim Types: see list of patent claims	Use; Composition;

US Patent 9,957,232: Regorafenib Monohydrate Claims, Patent Scope, Exclusivity and Generic Entry Risk

US Patent 9,957,232 protects a solid-state form of regorafenib, the active ingredient in Bayer’s Stivarga product. The claims cover the compound identified as formula II, pharmaceutical compositions containing it, cancer-treatment methods, combination therapies, conversion processes, and analytical markers including an X-ray diffraction peak at 21.2° 2θ, a far-infrared peak at 353 cm⁻¹, and approximately 3.6% water by weight. The patent is materially narrower than the original regorafenib compound patent because it focuses on a defined crystalline or hydrated form and products made with that form.

What drug does US Patent 9,957,232 protect?

The protected compound is regorafenib in a specified solid-state form. The chemical name recited in the process claims is:

4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide.

Regorafenib is a multikinase inhibitor marketed in the United States as Stivarga. FDA-approved indications include:

• Metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, where applicable, an anti-EGFR therapy.
• Unresectable or metastatic gastrointestinal stromal tumor after prior imatinib and sunitinib.
• Hepatocellular carcinoma previously treated with sorafenib.[2]

The patent does not claim regorafenib in every possible physical form. Its central commercial relevance is the claimed form II material and products containing that material.

What are the principal claims of US Patent 9,957,232?

The claims fall into six functional groups.

Claim group	Claims	Subject matter	Commercial relevance
Compound	1, 19, 20, 25	Formula II compound, XRPD and FIR characteristics, water content	Defines the solid-state active ingredient
Pharmaceutical compositions	2, 5, 11, 14, 15, 21, 26-29	Compositions containing formula II, including aqueous and oily suspensions	Covers finished dosage forms and injectable or suspension products
Treatment methods	3, 4, 6, 16, 17, 22-24	Treatment of hyper-proliferative disorders, digestive tumors and colorectal cancer	Creates method-of-use exposure for products using the claimed form
Combination therapy	7-10	Formula II with cytotoxic agents, signal-transduction inhibitors, anticancer agents or antiemetics	Extends coverage to combination regimens
Manufacturing processes	12, 13	Conversion or precipitation of another regorafenib form into formula II	Creates process-specific infringement risk
Disease subtypes	18	Detailed tumor, lymphoma, sarcoma and leukemia categories	Expands method claims across named cancers

Claim 1 is the foundational product claim. Claims 2 through 18 largely depend on the compound claim or repeat it in composition, method, disease, and combination formats. Claims 19, 20 and 25 add physical identity requirements that may be important in abbreviated new drug application litigation.

What solid-state characteristics are protected?

The patent identifies formula II through three principal markers:

1. An X-ray powder diffraction peak maximum at 21.2° 2θ.
2. A far-infrared spectrum peak maximum at 353 cm⁻¹.
3. Water content of approximately 3.6% by weight.

These limitations are consistent with a defined hydrated or crystalline regorafenib form. Claims 19 and 20 use analytical characteristics to identify the compound. Claim 25 expressly requires water content of 3.6% by weight.

The analytical claims can be important because a generic applicant may attempt to avoid infringement by using an anhydrous form, a different polymorph, a different hydrate, or an amorphous material. The result would depend on whether the generic product nevertheless contains the claimed form, either as the principal material or as a component of the drug substance.

Why the 21.2° XRPD peak matters

An XRPD peak at 21.2° 2θ is a fingerprint limitation, but a single peak normally must be assessed with the complete diffraction pattern and testing conditions. Peak position can vary with instrument calibration, sample preparation, hydration state and measurement parameters.

A generic product with a coincident peak may face an infringement allegation, but the peak alone may not establish that the entire claimed crystalline form is present. Conversely, a material with a shifted peak could still present infringement issues under an equivalence theory, depending on the patent’s specification and litigation record.

Why the 3.6% water limitation matters

The 3.6% water limitation links the claim to a hydrated solid form. Water content is sensitive to:

• Relative humidity.
• Drying conditions.
• Storage duration.
• Karl Fischer testing conditions.
• Residual solvent and excipient content.
• Conversion between hydrate and anhydrate forms.

A formulation manufacturer may therefore need to control solid-state handling from crystallization through tableting and packaging.

What formulations are protected by US Patent 9,957,232?

The patent claims broad composition categories and narrower dosage-form embodiments.

Oral and general pharmaceutical compositions

Claims 2, 5, 11, 14, 15 and 21 cover formula II combined with pharmaceutically suitable or inert, nontoxic excipients. The disease references include solid tumors, lymphomas, sarcomas, leukemias and cancers of numerous organs.

The language is broad and does not limit the composition to a particular tablet strength, release profile or excipient system. A product containing the claimed form in a conventional pharmaceutical composition could fall within these claims if the other limitations are met.

Aqueous formulations

Claims 26 and 27 identify water as the excipient and specify a sterile injectable aqueous suspension. These claims are narrower than the general composition claims and would apply only to a product meeting the injectable suspension limitations.

The approved Stivarga dosage form is an oral tablet, not a sterile injectable aqueous suspension.[2] Claims 26 and 27 therefore appear less important to the marketed Stivarga product than claims directed to the compound and oral composition.

Oily suspensions

Claims 28 and 29 cover compositions using vegetable oil, arachis oil, olive oil, sesame oil, coconut oil, mineral oil or liquid paraffin, including an oily suspension. These claims may be relevant to alternative formulations, preclinical products or formulation development programs, but they do not appear to describe the approved Stivarga tablet presentation.

What diseases and methods of use are covered?

Claims 3, 4 and 6 cover administration of the claimed composition for hyper-proliferative disorders. Claims 14 through 18 and 21 through 24 target digestive tract tumors and colorectal cancer with greater specificity.

Claim 18 enumerates a wide set of diseases, including:

• Breast cancer.
• Small-cell and non-small-cell lung cancer.
• Brain tumors.
• Prostate, testicular, cervical, ovarian and uterine cancers.
• Colon, colorectal, gastric, pancreatic and rectal cancers.
• Kidney, bladder and urinary tract cancers.
• Liver cancers.
• Melanoma and other skin cancers.
• Head-and-neck cancers.
• Hodgkin and non-Hodgkin lymphoma.
• Acute and chronic leukemias.
• Osteosarcoma and other sarcomas.

The breadth of the disease list does not itself establish clinical efficacy for every listed cancer. For infringement purposes, however, a method claim can create exposure where a product is promoted or administered for a claimed indication and the other claim elements are satisfied.

Does the patent cover combination therapy?

Yes. Claims 7 through 10 cover formula II with one or more additional pharmaceutical agents. The listed categories include:

• Cytotoxic agents.
• Signal-transduction inhibitors.
• Anticancer agents.
• Antiemetics.
• Other anti-hyper-proliferative agents.

These claims can be relevant to clinical trials, combination-labeling strategies and co-packaged products. The claims do not identify a single named partner drug. That increases breadth but may also create claim-construction and written-description issues if a challenger argues that the specification does not adequately support every combination within the generic categories.

What manufacturing processes are protected?

Claims 12 and 13 cover two conversion routes.

Precipitation process

Claim 12 requires dissolving a specified non-form-II regorafenib material in an inert solvent and adding water until precipitation occurs.

Aqueous conversion process

Claim 13 requires suspending the specified starting material in an aqueous solvent and stirring or shaking until conversion to formula II occurs.

These process claims are directed to making the claimed solid form rather than merely using regorafenib. They may be significant in discovery because a generic applicant’s process information can reveal whether it converts an existing regorafenib form into formula II.

Process claims can be avoided by using a different crystallization route, producing a different polymorph, or purchasing the drug substance from a supplier using a non-infringing process. They can also create supply-chain risk if the active pharmaceutical ingredient manufacturer uses the claimed conversion steps outside the United States and imports the resulting product.

When does US Patent 9,957,232 lose exclusivity?

The patent issued on May 1, 2018, from U.S. Application No. 14/396,815.[1] Its earliest claimed priority is in the 2012 period. A standard 20-year patent term measured from the earliest effective nonprovisional or international filing date would place expiration in approximately 2033, subject to patent-term adjustment, terminal disclaimers or other USPTO events.

Event	Date or period
Earliest priority period	2012
U.S. application	No. 14/396,815
Patent grant	May 1, 2018
Patent number	US 9,957,232 B2
Expected standard term	Approximately 2033
Patent-term adjustment	Must be confirmed from the USPTO patent file
FDA small-molecule exclusivity	Separate from patent term
Product	Stivarga, regorafenib tablets

A definitive expiration date should be taken from the USPTO Patent Examination Data System or the patent’s current bibliographic record. FDA regulatory exclusivity and patent protection are separate rights. Stivarga’s initial FDA approval occurred in 2012, and the product’s five-year new chemical entity exclusivity would have ended before this patent issued.[2][3]

What is the Orange Book status of US Patent 9,957,232?

US 9,957,232 is potentially relevant to Stivarga only if it is listed by the NDA holder in the FDA Orange Book for the approved product. Orange Book listing must be evaluated separately from the patent’s technical scope.

The Orange Book may list patents for:

• The active ingredient.
• The drug product.
• A formulation.
• An approved method of use.

A crystalline-form patent is generally more useful against an ANDA if the listed patent covers the drug substance or drug product as used in the reference product. A patent that only covers an unapproved formulation or an unapproved method may have weaker practical relevance to Stivarga’s marketed tablet.

The FDA’s Orange Book is the controlling public source for current listed-patent status and expiration information.[3]

Which generic entry risks exist?

A generic applicant seeking approval for regorafenib tablets would generally face three principal pathways under the Hatch-Waxman framework:

ANDA certification	Consequence
Paragraph I	No relevant patent information listed
Paragraph II	Listed patent has expired
Paragraph III	Applicant accepts delay until listed patent expiration
Paragraph IV	Applicant asserts the listed patent is invalid, unenforceable or not infringed

A Paragraph IV certification regarding US 9,957,232 could challenge:

• Whether the proposed product contains formula II.
• Whether the product meets the XRPD or FIR limitations.
• Whether the water-content limitation is satisfied.
• Whether the patent claims a patentable polymorph over prior art.
• Whether the specification adequately supports the claimed hydrate and uses.
• Whether the claims are enabled across the full disease and formulation scope.
• Whether a process claim covers the generic manufacturer’s actual process.

The most direct design-around is a non-infringing regorafenib solid form. That strategy may reduce exposure under claims 1, 19, 20 and 25, but it would not automatically eliminate risk from other Orange Book-listed patents covering the active ingredient or approved product.

Are biosimilars relevant to this patent?

No. Regorafenib is a chemically synthesized small-molecule drug, not a biological product. The relevant competitive pathway is an ANDA for a generic drug under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not a biosimilar application under section 351(k) of the Public Health Service Act.[4][5]

Biosimilar exclusivity concepts, interchangeability designations and biologic reference-product protections do not apply to Stivarga or this patent.

What is the competitive patent landscape for regorafenib?

The estate should be separated into four layers:

1. Original composition-of-matter patents covering regorafenib and related substituted pyridine compounds.
2. Solid-state patents covering polymorphs, hydrates and crystalline forms.
3. Formulation patents covering tablets, suspensions, excipients and delivery systems.
4. Method-of-use patents covering specific cancers, treatment lines or combinations.

US 9,957,232 sits primarily in the second layer, with secondary coverage in the third and fourth layers. It does not appear, based on the supplied claims, to be the foundational composition-of-matter patent for all regorafenib.

Relative patent strength

Issue	Assessment
Compound-form coverage	Strong if the marketed drug substance is formula II
Analytical identification	Useful, but dependent on testing methodology and complete characterization
Broad cancer methods	Broad on paper; vulnerable to written-description, enablement and induced-infringement arguments
Specific colorectal claims	Commercially relevant because colorectal cancer is an FDA-approved use
Formulation claims	Strong only for the specified suspension formats; less central to the approved tablet
Process claims	Potentially significant, but avoidable through alternate manufacturing routes
Combination claims	Broad category language; commercial relevance depends on actual labeling and treatment use
Biosimilar relevance	None
Generic challenge	Likely centered on polymorph identity, validity and non-infringement

What litigation or settlement issues affect generic entry?

A Paragraph IV notice concerning an Orange Book-listed patent can trigger a 45-day period for the NDA holder to file an infringement action. A timely action generally creates a 30-month stay of ANDA approval, subject to statutory exceptions and court decisions.[4]

For this patent, the central litigation questions would likely be:

• Whether Stivarga contains the patented form II material.
• Whether the proposed generic’s regorafenib matches the claimed XRPD and FIR characteristics.
• Whether the generic drug substance has approximately 3.6% water.
• Whether the generic manufacturer’s process practices claim 12 or claim 13.
• Whether a different polymorph remains pharmaceutically equivalent for FDA purposes.
• Whether any settlement restricts launch timing, authorized-generic arrangements or manufacturing.

A patent settlement can establish a generic launch date earlier than patent expiration. Without a verified court docket or settlement filing, the patent’s nominal expiration date should not be treated as the actual generic launch date.

What revenue exposure does the patent create?

The revenue exposure is tied to Stivarga’s remaining U.S. sales, not to every disease listed in the patent. The highest-value risk is a generic regorafenib tablet that can obtain ANDA approval and avoid or defeat the listed-patent estate.

The commercial impact would depend on:

• The number and scope of remaining Orange Book patents.
• Whether a generic uses formula II.
• The availability of an alternative non-infringing polymorph.
• The timing of Paragraph IV litigation.
• The presence of an authorized generic.
• Payer substitution and discounting.
• Regorafenib demand in colorectal cancer, GIST and hepatocellular carcinoma.

A successful generic launch would typically cause rapid price erosion in a small-molecule oral oncology market. The focal patent may delay entry if it is listed and covers the reference product, but it is unlikely to prevent all entry by itself if a generic can use a different solid-state form.

Key Takeaways

• US 9,957,232 is a regorafenib solid-state patent centered on formula II.
• The patent claims a defined hydrate or crystalline form, not every form of regorafenib.
• Key identifiers are a 21.2° 2θ XRPD peak, a 353 cm⁻¹ FIR peak and about 3.6% water by weight.
• Composition, treatment, colorectal-cancer, combination and manufacturing claims extend beyond the core compound claim.
• The approved Stivarga product is an oral tablet, making the compound and general composition claims more commercially important than the injectable and oily-suspension claims.
• The patent is not relevant to biosimilar competition. Regorafenib competitors would use the ANDA pathway.
• Generic risk will turn on Orange Book listing, the generic’s polymorph, analytical characterization and manufacturing process.
• The standard patent term appears to extend into approximately 2033, subject to USPTO term calculations.
• Patent expiration alone does not establish the actual generic launch date because Paragraph IV litigation and settlement terms can alter market entry.

FAQs About US Patent 9,957,232 and Regorafenib

Does US 9,957,232 cover Stivarga tablets?

It may, if the regorafenib drug substance in Stivarga is the claimed formula II form and the patent is listed against the relevant Stivarga NDA. The technical claims are directed to the active form and compositions containing it.

Can a generic avoid US 9,957,232 by using amorphous regorafenib?

Potentially. An amorphous product that does not contain the claimed crystalline or hydrated form could avoid literal infringement, but the generic would still need to address other active-ingredient, drug-product and method patents.

Is claim 18 a colorectal-cancer patent?

Claim 18 lists colorectal cancer as one disease subtype within a broader method claim. Claims 15, 17 and 24 separately target colorectal cancer more directly.

Does the patent protect regorafenib combinations with immunotherapy?

The claims use broad categories such as anticancer agents and signal-transduction inhibitors. Whether a particular immunotherapy falls within the claims would depend on claim construction and the patent specification’s disclosure.

What evidence is needed to test infringement of the solid-state claims?

Relevant evidence includes XRPD, FIR or related spectroscopic data, water-content testing, solid-form characterization, batch records, drug-substance specifications and the manufacturing process used for the proposed generic.

References

1. United States Patent and Trademark Office. (2018). U.S. Patent No. 9,957,232 B2: Crystalline forms of regorafenib.
2. U.S. Food and Drug Administration. (2023). Stivarga (regorafenib) prescribing information. Bayer HealthCare Pharmaceuticals Inc.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
4. Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(j).
5. Public Health Service Act, 42 U.S.C. § 262(k).

Drugs Protected by US Patent 9,957,232

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				Y

Foreign Priority and PCT Information for Patent: 9,957,232

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
	06021296	Oct 11, 2006

PCT Information
PCT Filed	September 29, 2007	PCT Application Number:	PCT/EP2007/008503
PCT Publication Date:	April 17, 2008	PCT Publication Number:	WO2008/043446

International Family Members for US Patent 9,957,232

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2097381		C02097381/01	Switzerland
Argentina	062927
Australia	2007306716