Details for Patent: 8,765,732

Which drugs does patent 8,765,732 protect, and when does it expire?

Patent 8,765,732 protects TAZVERIK and is included in one NDA.

This patent has one hundred and eight patent family members in thirty-six countries.

Summary for Patent: 8,765,732

Title:	Aryl- or heteroaryl-substituted benzene compounds
Abstract:	The present invention relates to aryl- or heteroaryl-substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.
Inventor(s):	Kevin Wayne Kuntz, Richard Chesworth, Kenneth William Duncan, Heike Keilhack, Natalie Warholic, Christine Klaus, Sarah Kathleen Knutson, Timothy James Nelson Wigle, Masashi Seki, Syuji Shirotori, Satoshi Kawano
Assignee:	Eisai R&D Management Co Ltd , Epizyme Inc
Application Number:	US13/722,807
Patent Claim Types: see list of patent claims	Use; Delivery;

US Patent 8,765,732: Scope, Claims, Expiration, Orange Book Status, and EZH2 Patent Landscape

US Patent 8,765,732 is an Epizyme patent covering methods of treating cancer with broad classes of EZH2 inhibitors, including compounds developed into tazemetostat. The claims cover lymphoma, leukemia, melanoma, prostate cancer, and breast cancer, with narrower protection for EZH2 Y641-mutant cancers, oral administration, specific heterocyclic substituents, and lymphoma subtypes. The patent issued in 2014 and has a nominal expiration in December 2030, subject to any applicable patent-term adjustment or extension.

The patent has strategic importance because Claim 1 combines a broad chemical genus with treatment of named cancers. Claims 15 and 16 narrow the method to tumors expressing mutant EZH2 Y641 and require or contemplate biomarker testing. The patent is broader than the current FDA-approved tazemetostat indications, but its practical enforcement value depends on whether an accused product falls within the claimed Markush structures and whether the relevant treatment method can be proven.

What does US Patent 8,765,732 protect?

US Patent 8,765,732 protects methods of treating cancer with compounds of Formula (Ig), Formula (II), Formula (IIa), and related pharmaceutically acceptable salts. The patent is directed to EZH2 inhibition, although the supplied claims do not expressly recite the target in every claim.

The principal protection is method-of-use protection rather than a simple product claim. Claim 1 requires:

1. A subject in need of treatment.
2. Administration of a therapeutically effective amount.
3. A compound within the Formula (Ig) genus or a pharmaceutically acceptable salt.
4. Treatment of lymphoma, leukemia, melanoma, prostate cancer, or breast cancer.

The chemical definition is extensive. It covers compounds having:

• C1-C6 alkyl groups at R2, R4, and R12.
• Aromatic or heteroaromatic R6 groups.
• Broadly substituted aryl and heteroaryl systems.
• Amines, amides, sulfonamides, ethers, carbonyls, nitriles, halogens, alkyl groups, cycloalkyl groups, aryl groups, and heterocycles.
• Piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, cycloalkyl, and related R7 groups.
• Hydrogen, alkyl, hydroxy, cyano, carboxy, amino, alkoxy, and related R8 groups.
• Alternative ring closures in which R7 and R8 form a fused or linked heterocyclic system.

This is a classic Markush structure. The claim seeks to cover a large chemical genus rather than one identified active ingredient.

How broad is Claim 1 of US 8,765,732?

Claim 1 is broad in both chemical and therapeutic scope. Its chemical breadth arises from multiple layers of alternatives at R6, R7, and R8. Its therapeutic breadth arises from the inclusion of five major cancer categories.

The claim does not require:

• A particular dose.
• A specific route of administration.
• A particular treatment duration.
• Combination therapy.
• A defined level of EZH2 inhibition.
• A biomarker-positive tumor.
• A specific disease stage.
• A particular formulation.

A product can therefore potentially fall within Claim 1 if its active compound meets the structural limitations and it is administered to treat one of the listed cancers.

The claim is narrower than a pure composition-of-matter claim because infringement requires use for the claimed therapeutic purpose. For a marketed oncology drug, that limitation may still be commercially significant because prescribing information, clinical protocols, promotional activity, clinical-trial designs, and treatment records can provide evidence of the intended use.

What do Claims 2 through 8 add?

Claims 2 through 8 narrow the chemical scope through more specific substituent definitions.

Claim	Principal limitation
2	Narrows R6 substituents, including smaller heterocycles, alkyl groups, amines, sulfonamides, and ring-forming substitutions
3	Limits the compound to Formula (II); R7 includes piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl; R8 is ethyl
4	Covers Formula (IIa) with more detailed R7, R8, and amine-substitution definitions
5	Limits the Ra/Rb nitrogen-containing ring to specified 4- to 7-membered heterocycles
6	Specifies piperidinyl, tetrahydropyran, tetrahydrothiopyran, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl R7 groups
7	Limits R8 to hydrogen or substituted C1-C6 alkyl
8	Limits R7 to cycloalkyl or 4- to 7-membered heterocycloalkyl groups

These dependent claims create fallback positions if Claim 1 is challenged for lack of written description, enablement, novelty, or obviousness. They also provide narrower claim boundaries that may be easier to map onto a commercial molecule.

Claims 9 through 11 appear to identify specific compounds or salts, but the chemical structures are omitted from the supplied claim text. Those claims cannot be mapped to named molecules from the information provided.

What cancer indications are covered by the patent?

The patent expressly covers:

• Lymphoma.
• Leukemia.
• Melanoma.
• Prostate cancer.
• Breast cancer.

Claim 12 narrows lymphoma to:

• Non-Hodgkin lymphoma.
• Follicular lymphoma.
• Diffuse large B-cell lymphoma.

Claim 13 narrows leukemia to:

• Chronic myelogenous leukemia.
• Acute myeloid leukemia.
• Acute lymphocytic leukemia.
• Mixed-lineage leukemia.

Claim 14 separately identifies breast cancer.

The patent therefore reaches beyond the initial approved use of tazemetostat. It covers therapeutic use in diseases for which clinical development, regulatory approval, or commercial promotion may not exist.

What protection does the patent provide for EZH2 Y641-mutant cancer?

Claims 15 and 16 provide biomarker-linked protection for cancers expressing a Y641 mutant of EZH2.

Claim 15 requires treatment of a cancer expressing an EZH2 Y641 mutant. Claim 16 adds performance of an assay to detect that mutation in a sample containing cancer cells before treatment.

The Y641 alteration is associated with altered EZH2 catalytic activity and is particularly relevant to certain B-cell lymphomas. These claims are narrower than Claim 1 but potentially stronger in a biomarker-selected treatment setting because they connect:

• A defined molecular alteration.
• A diagnostic assay.
• Administration of the claimed inhibitor.
• A cancer treatment method.

The claim language in supplied Claim 16 contains the apparent textual error "EZH2a therapeutically effective amount." The issued patent and prosecution history, rather than the supplied transcription, would control the legal interpretation.

Is tazemetostat covered by US 8,765,732?

US 8,765,732 is associated with Epizyme's EZH2 inhibitor program and is part of the patent estate relevant to tazemetostat, marketed by Ipsen as Tazverik. Tazemetostat is an oral EZH2 inhibitor.

The supplied claims do not identify the active ingredient by name because Claims 1 through 8 are structural Markush claims. The compound-specific claims in Claims 9 through 11 may provide the most direct protection for a particular commercial compound or salt, but their structures are absent from the supplied text.

A commercial infringement analysis would require mapping tazemetostat against:

• Every required atom and substituent in the applicable formula.
• The salt form, if a salt claim is asserted.
• The claimed cancer indication.
• The administration method.
• The relevant label, promotional materials, and prescribing activity.

What is the FDA regulatory status of tazemetostat?

The FDA approved Tazverik through the accelerated approval pathway for two indications:

FDA milestone	Indication
January 2020	Adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection
June 2020	Adults with relapsed or refractory follicular lymphoma whose tumors express an EZH2 mutation and adults with relapsed or refractory follicular lymphoma with no satisfactory alternative treatment options

The follicular lymphoma approval includes mutation-specific and mutation-independent treatment pathways. The approved product is tazemetostat, an oral tablet administered twice daily under the FDA label. The FDA label identifies EZH2 as the pharmacologic target and includes molecular testing information for EZH2-mutant disease (FDA, 2020).

The patent claims cover broader disease categories than the approved label. Patent scope and regulatory scope are separate. Approval in follicular lymphoma does not establish approval for every cancer listed in the patent.

What is the Orange Book status of US 8,765,732?

US 8,765,732 is part of the U.S. patent estate associated with Tazverik and has been reported in connection with the product's listed patent protection. The patent's nominal expiration is December 22, 2030.

Item	Assessment
Patent	US 8,765,732
Applicant/owner associated with development	Epizyme, Inc.
Product association	Tazemetostat, Tazverik
Technology	EZH2 inhibitor methods and related chemical genera
Issue year	2014
Nominal expiration	December 22, 2030
Patent type	Method of treatment, with compound-specific and structural dependent claims
Orange Book relevance	Relevant to listed patent protection for Tazverik
Pediatric extension	A pediatric extension should be confirmed against the current FDA Orange Book record and regulatory history

Other patents in the Tazverik estate may expire later and may cover particular compositions, crystalline forms, formulations, dosing regimens, or additional therapeutic uses. A generic applicant would need to evaluate the entire listed estate, not US 8,765,732 alone.

When does US 8,765,732 lose exclusivity?

The nominal patent expiration is December 22, 2030. Market entry before that date could occur through:

• A licensed launch.
• A settlement agreement.
• A successful invalidity or noninfringement challenge.
• An authorized generic arrangement.
• A launch that accepts litigation risk.
• A carve-out from patented indications under a section viii strategy, if legally and commercially available.

The patent does not itself establish the earliest lawful generic launch date. That date depends on the Orange Book listing, the ANDA filing date, Paragraph IV notice, litigation, any 30-month stay, and settlement terms.

Which companies are challenging the Tazverik patent estate?

No specific Paragraph IV challenger can be identified from the supplied information alone. Public generic challenges must be evaluated through FDA Orange Book records, ANDA litigation filings, and district-court docket searches.

A Paragraph IV applicant would likely assess several issues:

1. Whether its active ingredient falls within the compound claims.
2. Whether the proposed label induces infringement of the cancer-treatment claims.
3. Whether US 8,765,732 is invalid for obviousness or inadequate written description.
4. Whether later patents provide blocking protection after this patent expires.
5. Whether a label carve-out can avoid the claimed indications.
6. Whether the formulation or salt used in the generic product is covered by separate patents.

The broad genus claims create potential invalidity exposure if the specification does not adequately support the full chemical and therapeutic breadth. The dependent claims may be more resilient where the patent provides examples and biological data for the narrower subgenera.

What patent litigation affects US 8,765,732?

The supplied information does not identify a reported final judgment, settlement, or active Paragraph IV case involving US 8,765,732. Patent litigation risk should be separated into three categories:

• Direct challenges to US 8,765,732.
• Challenges to later Tazverik patents.
• Commercial disputes involving tazemetostat licensing, development rights, or collaboration arrangements.

Epizyme transferred commercial rights for tazemetostat in the United States and other territories to Ipsen under a 2021 acquisition transaction. Ipsen acquired Epizyme and its oncology portfolio, including Tazverik and the associated intellectual-property estate (Ipsen, 2021).

How does US 8,765,732 compare with competing EZH2 inhibitor patents?

The patent sits within a competitive EZH2 landscape that includes both selective EZH2 inhibitors and dual EZH1/EZH2 inhibitors.

Program	Company	Target profile	Commercial status
Tazemetostat	Ipsen, originally Epizyme	EZH2-selective	FDA-approved
Valemetostat	Daiichi Sankyo	EZH1/EZH2 dual inhibitor	Approved in Japan for certain T-cell lymphomas
Tulmimetostat	Novartis, originally MorphoSys	EZH1/EZH2 dual inhibitor	Clinical development
CPI-1205	Constellation Pharmaceuticals	EZH2 inhibitor	Clinical development history
PF-06821497	Pfizer	EZH2 inhibitor	Clinical development
SHR2554	Jiangsu Hengrui	EZH2 inhibitor	Clinical development

Competitors may avoid US 8,765,732 if their molecules do not satisfy the claimed structural definitions. That conclusion cannot be drawn from target overlap alone. EZH2 inhibition is not sufficient for literal infringement. The accused molecule must meet the structural limitations of an asserted claim, or infringement must be established under the doctrine of equivalents.

How strong is the patent estate for tazemetostat?

US 8,765,732 has meaningful scope but is not the entire exclusivity position.

Strengths include:

• A broad chemical genus.
• Multiple fallback subgenera.
• Coverage of oral treatment.
• Coverage of lymphoma and leukemia subtypes.
• Biomarker claims directed to EZH2 Y641 mutations.
• Potential relevance to the commercial product.

Risks include:

• The claims are method claims rather than a single, simple composition claim.
• The genus includes a large number of chemical alternatives.
• Written-description and enablement challenges may focus on the full breadth of the Markush definitions.
• The cancer list extends beyond the clinical and regulatory evidence that may support the patent.
• Later-issued patents may create separate blocking positions that complicate generic entry analysis.

The strongest practical claims are likely the compound-specific claims, if Claims 9 through 11 identify tazemetostat or its relevant salt, and the narrower claims that track the actual commercial molecule. The broadest Claim 1 is commercially valuable but more exposed to validity and claim-construction disputes.

What generic launch scenarios exist?

Launch after patent expiration

A generic applicant could launch after the final blocking patent expires, assuming FDA approval and no regulatory exclusivity remains.

Paragraph IV launch

A generic applicant may file a Paragraph IV certification alleging that the listed patent is invalid, unenforceable, or not infringed. The patent holder may sue within 45 days, triggering a statutory stay of FDA approval for up to 30 months, subject to statutory exceptions.

Section viii carve-out

If the listed patent claims only a specific indication, a generic applicant may attempt to omit that indication from its labeling. This strategy is more difficult where the patent claims broad treatment of the active ingredient across cancer categories or where the remaining label still encourages the patented use.

Settlement launch

A settlement could provide a negotiated entry date before December 2030. The commercial outcome would depend on the breadth of later patents, royalty provisions, authorized-generic rights, and any acceleration or contingent-entry terms.

Key Takeaways

• US 8,765,732 covers methods of treating specified cancers with broad EZH2 inhibitor chemical genera.
• Claim 1 is a broad Markush method claim covering lymphoma, leukemia, melanoma, prostate cancer, and breast cancer.
• Claims 15 and 16 target EZH2 Y641-mutant cancers and biomarker testing.
• The patent is associated with Epizyme's tazemetostat program and Tazverik.
• The nominal expiration date is December 22, 2030.
• Claims 9 through 11 may be important compound-specific claims, but the supplied text omits their structures.
• The patent's practical enforcement value depends on structural mapping, treatment indication, and proof of induced or direct method infringement.
• Later Tazverik patents may extend or complicate generic-entry timing.
• No specific Paragraph IV challenger, final judgment, or settlement can be established from the supplied claim text.
• The strongest validity and infringement positions are likely to center on narrower claims corresponding to the commercial molecule and demonstrated therapeutic uses.

FAQs

Does US 8,765,732 claim tazemetostat by name?

No. The supplied claims use structural formulas and Markush definitions. The compound-specific claims may identify the commercial molecule, but their structures are not included in the supplied text.

Does the patent cover all EZH2 inhibitors?

No. It covers only compounds meeting the structural limitations of the asserted claim. A competing EZH2 inhibitor may avoid infringement if its structure falls outside the claimed genus.

Does FDA approval for follicular lymphoma prove patent infringement?

No. FDA approval establishes regulatory authorization, not infringement. Infringement requires that the approved product and its use satisfy each limitation of an asserted patent claim.

Can a generic launch for an unpatented cancer indication avoid US 8,765,732?

Not necessarily. The patent claims treatment across broad cancer categories. A generic applicant would need to assess the specific label, prescribing behavior, inducement evidence, and whether the selected indication falls within an asserted claim.

Is US 8,765,732 the last patent blocking generic Tazverik?

Not necessarily. Tazverik may be protected by later patents covering formulations, salts, dosing, crystalline forms, or additional methods of use. Generic entry requires an assessment of the complete Orange Book and non-Orange Book patent estate.

References

1. Food and Drug Administration. (2020). Tazverik (tazemetostat) prescribing information. U.S. Department of Health and Human Services.

2. Food and Drug Administration. (2020). FDA approves tazemetostat for follicular lymphoma. U.S. Department of Health and Human Services.

3. Ipsen. (2021). Ipsen completes acquisition of Epizyme. Ipsen S.A.

4. United States Patent and Trademark Office. (2014). U.S. Patent No. 8,765,732, inhibitors of EZH2. U.S. Department of Commerce.

5. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.

Drugs Protected by US Patent 8,765,732

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Epizyme Inc	TAZVERIK	tazemetostat hydrobromide	TABLET;ORAL	211723-001	Jan 23, 2020		DISCN	Yes	No	8,765,732					METHOD OF TREATING RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA POSITIVE FOR AN ENHANCER OF ZESTE HOMOLOG 2 (EZH2) MUTATION
Epizyme Inc	TAZVERIK	tazemetostat hydrobromide	TABLET;ORAL	211723-001	Jan 23, 2020		DISCN	Yes	No	8,765,732					METHOD OF TREATING RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA

International Family Members for US Patent 8,765,732

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	086008
Australia	2012242595
Brazil	112013026324