US Patent 10,335,388: HIF-2α Inhibitor and Immunotherapy Combination Patent Analysis

US Patent 10,335,388 protects methods of treating melanoma, renal cell carcinoma, and colorectal cancer by combining a structurally defined HIF-2α inhibitor with a PD-1 or CTLA-4 inhibitor. The broadest independent claim is a treatment-method claim. It does not claim HIF-2α inhibitors alone, checkpoint inhibitors alone, or the compounds as chemical entities.

The commercial relevance centers on HIF-2α inhibitors such as belzutifan, marketed by Merck as Welireg, and checkpoint inhibitors including pembrolizumab, nivolumab, ipilimumab, and tremelimumab. The patent can create combination-use risk where a product label, clinical protocol, promotional activity, or prescribing pattern supports the claimed cancer indication and combination.

The principal limitations are the named cancer types, the required immunotherapy class, and the Formula I-C structural genus. Claims 2 through 21 narrow the genus by adding synergy, sequencing, mechanism, substituent, scaffold, and named-agent limitations.

What does US Patent 10,335,388 cover?

The patent covers administering a qualifying HIF-2α inhibitor together with a PD-1 or CTLA-4 inhibitor to treat one of three cancers:

Claim element	Scope
Treatment	Administration of an effective amount
HIF target	HIF-2α
Immunotherapy	PD-1 inhibitor or CTLA-4 inhibitor
Cancer	Melanoma, renal cell carcinoma, or colorectal cancer
Chemical requirement	Compound of Formula I-C or pharmaceutically acceptable salt
Timing	Before, simultaneously with, or after immunotherapy under claim 3
Mechanistic limitations	HIF-2α/HIF1β heterodimerization, target-gene expression, VEGF expression, or VEGF secretion
Named agents	Nivolumab, pembrolizumab, tremelimumab, and ipilimumab under claim 21

Claim 1 is the central infringement claim. A potentially infringing treatment must satisfy every limitation. The claim is not infringed merely because a physician administers an HIF-2α inhibitor and a checkpoint inhibitor to a cancer patient. The cancer must fall within the listed group, and the HIF-2α inhibitor must fall within the claimed chemical genus.

How broad is claim 1 of US 10,335,388?

Claim 1 is broad in therapeutic and chemical coverage but narrow in its required combination.

The therapeutic breadth comes from three cancer categories and two immunotherapy classes. The chemical breadth comes from Formula I-C, which permits multiple heterocyclic and carbocyclic alternatives:

X and Y may independently be carbon or nitrogen.
Z may be oxygen, sulfur, a substituted methylene group, nitrogen, or absent.
R1 may be alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, acyl, or cyano.
R4 covers multiple polar and electronically diverse substituents, including cyano, halo, sulfinyl, sulfonyl, sulfoximinyl, and sulfonamidyl groups.
R13 may include hydrogen, fluoro, chloro, hydroxy, alkyl, or heteroalkyl.
Two R13 groups may form a ring.
The variable n ranges from zero to four.

This is a genus claim. Its practical scope depends on whether the accused molecule is within the disclosed Formula I-C embodiments, not merely whether it has HIF-2α activity.

A key limitation is that claim 1 requires the combination to include a Formula I-C inhibitor. A structurally unrelated HIF-2α inhibitor would fall outside claim 1 even if it binds the same PAS-B pocket and produces the same pharmacology.

Which dependent claims materially narrow the patent?

The most commercially relevant dependent claims are claims 2, 3, 10, 17, 20, and 21.

Claim	Narrowing feature	Commercial significance
2	Synergistic treatment effect	Creates a potentially difficult proof issue because synergy must be supported by evidence
3	HIF-2α inhibitor administered before, during, or after immunotherapy	Reduces sequencing-based design-around options
4	Inhibition of specified HIF-2α biological effects	Adds pharmacological limitations
5	Blocks HIF-2α/HIF1β but not HIF1α/HIF1β	Provides a selective mechanism limitation
6	Binds the HIF2α PAS-B domain cavity	Links the claim to the known HIF-2α allosteric binding site
8	Specific R4, R11, and R12 requirements	Narrows the chemical genus toward particular lead-like structures
10	Formula I-H, I-I, I-J, or I-K	Depends on the patent’s more specific structural drawings
17	Fluoroalkyl or sulfonyl R4, oxygen Z, hydroxy R11, hydrogen R12	Potentially important for specific clinical compounds
20	Listed compounds	Potentially the strongest claim for a particular molecule, but the structures are omitted from the supplied claim text
21	Nivolumab, pembrolizumab, tremelimumab, or ipilimumab	Directly relevant to branded checkpoint combinations

Claim 21 is narrower than claim 1 but commercially clearer. It identifies four checkpoint inhibitors rather than the full PD-1 and CTLA-4 classes.

Does US 10,335,388 cover belzutifan and Welireg?

The supplied claim text does not include the structures listed in claim 20. A definitive mapping of belzutifan to Formula I-C or claim 20 cannot be made from the text alone.

Belzutifan is an orally administered HIF-2α inhibitor developed by Peloton Therapeutics and acquired by Merck. It is marketed in the United States as Welireg. The FDA approved Welireg for certain von Hippel-Lindau disease-associated tumors and later for advanced renal cell carcinoma after prior PD-1 or PD-L1 inhibitor and VEGF-TKI therapy.[2]

The patent creates potential belzutifan combination risk only if:

Belzutifan falls within Formula I-C or one of the specific structures in claim 20;
The treatment concerns melanoma, renal cell carcinoma, or colorectal cancer;
The immunotherapy is a PD-1 or CTLA-4 inhibitor; and
The relevant use is within the territorial and temporal scope of the patent.

The current Welireg label does not by itself establish infringement. A label can be relevant to induced-infringement analysis, but the approved indication, promotional language, clinical-trial activity, and actual use must be evaluated separately.

What formulations are protected by US Patent 10,335,388?

The patent claims treatment methods, not a tablet, capsule, injectable formulation, excipient system, or manufacturing process.

The claims do not expressly require:

A particular dosage form;
Oral administration;
A specific dose;
A fixed-dose combination;
A co-formulated product;
A particular pharmaceutical excipient;
A specific pharmacokinetic profile;
A specific schedule beyond the alternatives in claim 3.

A separately formulated HIF-2α inhibitor and checkpoint antibody can fall within the claim if they are administered as the claimed combination. A co-packaged or fixed-dose product is not required.

The absence of a formulation limitation increases method-of-use breadth. It also means the patent does not, on its face, block a formulation containing the HIF-2α inhibitor when that formulation is sold for an unrelated use.

What is the Orange Book status of US 10,335,388?

The patent is a method-of-treatment patent relating to a combination of an HIF-2α inhibitor and checkpoint immunotherapy. It is not a patent on the Welireg active ingredient alone.

Orange Book listing depends on whether the patent is submitted for an approved drug product and whether it claims the approved drug or an approved method of use under FDA listing rules. The FDA Orange Book should be checked for the current listing status of US 10,335,388 against Welireg and any other relevant product.[1]

The practical distinction is important:

Issue	Implication
Listed against Welireg	A generic applicant may need to address the patent in an ANDA certification
Not listed against Welireg	The patent may still create litigation exposure but may not generate an Orange Book Paragraph IV pathway
Combination method not in approved label	Listing and induced-infringement theories become more fact-dependent
Checkpoint product separately listed	The patent may not be relevant to the checkpoint product’s own regulatory exclusivity

Because claim 1 covers a combination method rather than a stand-alone HIF-2α product, the patent’s Orange Book importance may be lower than that of a compound patent, depending on FDA listing treatment and the approved labeling.

When does US Patent 10,335,388 expire?

US Patent 10,335,388 issued on July 2, 2019. Its patent term is generally measured from the earliest effective nonprovisional filing date, subject to patent-term adjustment, patent-term extension, terminal disclaimers, and any applicable disclaimer or correction.

The family is associated with HIF-2α inhibitor combination technology developed by Peloton Therapeutics. A projected term based on a 2016-era nonprovisional filing would generally extend into 2036, but the enforceable expiration date must be confirmed from the USPTO patent record and the patent’s term-adjustment calculation.[3]

A practical exclusivity timeline is:

Event	Date or period
Patent grant	July 2, 2019
Expected base-term horizon	Approximately 2036, subject to the effective filing date
Regulatory exclusivity for Welireg	Separate from this patent and dependent on the approved indication
Generic or follow-on entry	Dependent on patent term, Orange Book listing, certifications, litigation, and regulatory exclusivity

The patent term cannot be inferred solely from the grant date. A 20-year term from issuance would be incorrect.

What Paragraph IV challenges could target this patent?

A Paragraph IV challenge would be relevant only if the patent is listed in the Orange Book for an approved product and an ANDA applicant seeks approval for a product or use implicated by the listing.

Potential challenge theories include:

Non-infringement

An applicant could argue that its product is not within Formula I-C, does not satisfy a specific claim 20 structure, or is not labeled for the claimed cancer and immunotherapy combination.

Invalidity for lack of written description

The genus includes multiple ring systems, heteroatoms, substituents, and ring-forming alternatives. A challenger could argue that the specification does not demonstrate possession of the full breadth of the claimed genus.

Enablement

The breadth of Formula I-C may invite an enablement challenge if practicing the full genus requires extensive experimentation, particularly across multiple scaffold classes and therapeutic combinations.

Obviousness

A challenger could combine prior-art HIF-2α inhibitors with known PD-1 or CTLA-4 treatment strategies. The patentee would likely rely on mechanistic distinctions, unexpected synergy, tumor-model data, and the specific HIF-2α/checkpoint combination.

Indefiniteness or claim-construction disputes

Terms such as “effective amount,” “synergistic effect,” and “in combination” may generate claim-construction issues. Claim 2 is especially vulnerable to disputes over the evidentiary standard for synergy.

How strong is the patent estate for HIF-2α and immunotherapy combinations?

The patent is stronger as a combination-use patent than as a standalone HIF-2α asset.

Estate component	Relative position
Compound patent	Typically strongest barrier to generic substitution
Combination patent	Important for labeled combination therapy and clinical development
Method-of-use patent	Can protect a defined indication despite an unpatented treatment component
Formulation patent	Relevant to product substitution and lifecycle management
Manufacturing patent	May create supply-chain barriers without directly blocking clinical use
Biomarker or patient-selection patent	Can protect a narrower precision-medicine strategy

The patent’s main strengths are the defined biological mechanism, the named checkpoint classes, and the sequencing language. Its main vulnerabilities are genus breadth, proof of synergy, and the need to establish that a specific HIF-2α inhibitor falls within the claimed structural formula.

Which companies are most exposed to this patent?

Merck has the greatest direct commercial relevance because it owns Welireg and markets pembrolizumab as Keytruda. Bristol Myers Squibb is relevant through nivolumab and ipilimumab. AstraZeneca is relevant through tremelimumab.

Company	Relevant products	Potential exposure
Merck	Welireg, Keytruda	HIF-2α plus PD-1 combination programs
Bristol Myers Squibb	Opdivo, Yervoy	HIF-2α plus PD-1 or CTLA-4 combinations
AstraZeneca	Imjudo	HIF-2α plus CTLA-4 combination programs
Generic manufacturers	Future HIF-2α or combination products	Dependent on structure, label, listing, and certification
Clinical-stage HIF-2α developers	Other HIF-2α inhibitors	Depends on chemical scope and product-specific claims

The patent does not automatically cover every combination involving these companies’ checkpoint inhibitors. Exposure requires the HIF-2α component to fall within the claimed genus or a specific dependent claim.

What litigation and settlement issues matter?

A Paragraph IV case could produce a 30-month stay if statutory conditions are met, but that outcome depends on Orange Book listing, the ANDA certification, timely notice, and suit within the statutory period.[4]

Potential settlement structures include:

Delayed generic entry;
A license limited to a particular indication;
A carve-out for melanoma or colorectal cancer;
A royalty-bearing combination license;
Restrictions on promotion or clinical-trial use;
Entry after patent expiry but before regulatory exclusivity expires.

A settlement involving a compound patent would not necessarily resolve this combination patent. Conversely, a settlement covering US 10,335,388 may leave separate patents relating to belzutifan, polymorphs, formulations, manufacturing, or other indications intact.

No conclusion on litigation outcome should be drawn from the patent grant alone. Patent validity, enforceability, listing, and infringement are separate questions.

How does US 10,335,388 compare with compound and formulation patents?

US 10,335,388 differs materially from a conventional small-molecule patent.

Patent type	Protected subject matter	Design-around potential
Compound patent	Chemical entity or defined Markush genus	Often limited
Combination method patent	Two-agent treatment for specified cancers	Substitute agent, indication, or sequence may avoid claim
Formulation patent	Dosage form, excipients, release profile	Alternate formulation may avoid claim
Method-of-use patent	Treatment of a disease or patient group	Label carve-out or different indication may help
Manufacturing patent	Process or intermediate	Alternate process may avoid infringement

The strongest design-around options are a non-Formula I-C HIF-2α inhibitor, a non-listed cancer indication, or a checkpoint mechanism outside PD-1 and CTLA-4. Those options may not be clinically or commercially equivalent.

What generic launch risks exist?

A generic or follow-on HIF-2α product faces several possible launch scenarios:

Launch outside the three claimed cancers and without a PD-1 or CTLA-4 combination indication.
Launch with a label carve-out excluding the patented combination use, if FDA rules permit.
Challenge the patent through Paragraph IV if it is Orange Book-listed.
Launch after expiration while other compound or regulatory barriers remain.
Accept a license or settlement with restricted combination-use rights.

A skinny label does not eliminate all risk if the product is marketed, promoted, or used in a manner that supports induced infringement. Physician prescribing alone also requires a fact-specific analysis.

Key Takeaways

US Patent 10,335,388 is a combination method-of-treatment patent.
Claim 1 requires a Formula I-C HIF-2α inhibitor, a PD-1 or CTLA-4 inhibitor, and treatment of melanoma, renal cell carcinoma, or colorectal cancer.
Claim 21 specifically names nivolumab, pembrolizumab, tremelimumab, and ipilimumab.
The patent does not independently claim all HIF-2α inhibitors, all checkpoint inhibitors, or a pharmaceutical formulation.
Claim 3 prevents a simple sequencing design-around because it covers administration before, during, or after immunotherapy.
Claims 2, 4, 5, and 6 introduce synergy and mechanism limitations that may create proof and claim-construction disputes.
Belzutifan coverage cannot be conclusively mapped from the supplied text because the structures in claim 20 are omitted.
The expected patent-term horizon is approximately 2036, subject to the USPTO term calculation and any adjustment or disclaimer.
Orange Book significance depends on whether the patent is listed against an approved product and whether the approved labeling overlaps the claimed combination.
The principal competitive risks are combination-label expansion, clinical-trial use, induced infringement, and overlap with separate compound, formulation, and manufacturing patents.

FAQs About US Patent 10,335,388

Does the patent cover pembrolizumab by itself?

No. Pembrolizumab is relevant only when used with a qualifying Formula I-C HIF-2α inhibitor for one of the claimed cancers.

Does the patent cover renal cell carcinoma treatment with any HIF-2α inhibitor?

No. The inhibitor must fall within the claimed Formula I-C genus or a relevant narrower claim.

Can a company avoid the patent by administering the drugs on different days?

Not necessarily. Claim 3 expressly covers administration before, simultaneously with, or after the immunotherapeutic agent.

Is synergy required for infringement?

No. Synergy is required by claim 2, but claim 1 does not include the synergy limitation.

Does the patent block HIF-2α inhibitor monotherapy?

Not on the face of the supplied claims. The claims require combination with a PD-1 or CTLA-4 immunotherapeutic agent.

References

U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (2023). Welireg (belzutifan) prescribing information. Merck Sharp & Dohme LLC.
United States Patent and Trademark Office. (2019). U.S. Patent No. 10,335,388, Combination therapies comprising HIF-2α inhibitors.
United States Code. (2023). 21 U.S.C. § 355(j): Abbreviated applications for new drugs.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Merck Sharp Dohme	WELIREG	belzutifan	TABLET;ORAL	215383-001	Aug 13, 2021		RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial				IN COMBINATION WITH PEMBROLIZUMAB OR PEMBROLIZUMAB/BERAHYALURONIDASE ALFA, FOR ADJUVANT TREATMENT OF ADULTS WITH CCRCC AT INTERMEDIATE-HIGH OR HIGH RISK OF RECURRENCE FOLLOWING (1) NEPHRECTOMY OR (2) NEPHRECTOMY AND RESECTION OF METASTATIC LESIONS	⤷ 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
World Intellectual Property Organization (WIPO)	2016168510	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 10,335,388

Which drugs does patent 10,335,388 protect, and when does it expire?

Summary for Patent: 10,335,388