Details for Patent: 5,767,115

« Back to Dashboard

Summary for Patent: 5,767,115

Title:	Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
Abstract:	Hydroxy-substituted azetidinone hypocholesterolemic agents of the formula or a pharmaceutically acceptable salt thereof, wherein: Ar1 and Ar2 are aryl or R4-substituted aryl; Ar3 is aryl or R5-substituted aryl; X, Y and Z are -CH2-, -CH(lower alkyl)- or -C(dilower alkyl)-; R and R2 are -OR6, -O(CO)R6, -O(CO)OR9 or -O(CO)NR6R7; R1 and R3 are H or lower alkyl; q is 0 or 1; r is 0 or 1; m, n and p are 0-4; provided that at least one of q and r is 1, and the sum of m, n, p, q and r is 1-6; and provided that when p is O and r is 1, the sum of m, q and n is 1-5; R4 is selected from lower alkyl, R5, -CF3, -CN, -NO2 and halogen R5 is selected from -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylene)COOR6 and -CH=CH-COOR6; R6, R7 and R8 are H, lower alkyl, aryl or aryl-substituted Ic R9 is lower alkyl, aryl or aryl-substituted lower alkyl; are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, pharmaceutical compositions containing them; and a process for preparing them.
Inventor(s):	Stuart B. Rosenblum, Sundeep Dugar, Duane A. Burnett, John W. Clader, Brian A. McKittrick
Assignee:	Merck Sharp and Dohme LLC , Schering Plough Corp
Application Number:	US08/617,751
Patent Claim Types: see list of patent claims	Use; Composition;

United States Patent 5,767,115: Claim Scope, Ezetimibe Coverage, Expiration, and Patent Landscape

U.S. Patent No. 5,767,115 is a core Schering-Plough patent covering substituted 2-azetidinone compounds that inhibit intestinal cholesterol absorption. Its claims encompass ezetimibe, the active ingredient in Zetia and a component of Vytorin and Inegy. The patent issued June 16, 1998, and its ordinary U.S. patent term expired in December 2014, subject to any applicable pediatric extension. The patent is therefore no longer an effective barrier to generic ezetimibe entry.

What does U.S. Patent 5,767,115 cover?

The patent covers a broad chemical genus of substituted beta-lactams, also called 2-azetidinones, together with pharmaceutical compositions and methods for treating atherosclerosis or reducing plasma cholesterol.

The claim architecture has three layers:

Claim	Subject matter	Scope
1	Markush genus of azetidinone compounds and pharmaceutically acceptable salts	Broad chemical composition claim
2	Restricted aryl substitution pattern	Phenyl-based subset
3	Halogen and alkoxy substitution pattern	Narrower preferred substitution pattern
4	Hydroxy-substituted azetidinones with defined ring-linker structure	Functional and structural limitation
5	Specific ring-substitution pattern	Narrow subgenus
6	Alternative specific ring-substitution pattern	Narrow subgenus
7	Enumerated individual compounds	Product-by-species claims
8	Pharmaceutical composition	Composition claim
9	Therapeutic method	Atherosclerosis and cholesterol-reduction method

The claims are directed to compounds containing:

• A 2-azetidinone ring.
• One or more aryl groups attached to the ring.
• Hydroxy, ester, carbonate, carbamate or related oxygen-containing substituents.
• Defined stereochemical configurations in the individual compounds listed in claim 7.
• A pharmaceutically acceptable salt where applicable.

The patent does not claim all cholesterol-lowering compounds. Its scope depends on the interaction of the azetidinone core, aryl substitution, linker topology, oxygenation pattern and stereochemistry.

Does Patent 5,767,115 cover ezetimibe?

Yes. Claim 7 expressly recites the compound corresponding to ezetimibe:

3(R)-[3(S)-(4-fluorophenyl)-3-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-1-(4-fluorophenyl)-2-azetidinone.

Ezetimibe is commonly identified chemically as:

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one.

The claim therefore provides direct species-level coverage, independent of the broader Markush language in claim 1.

This distinction is important. A generic manufacturer seeking approval for ezetimibe would face a direct product claim, not merely an argument that the generic product falls within a broad chemical genus.

How broad is claim 1?

Claim 1 is a structurally broad Markush claim. It covers compounds in which:

• Ar1 and Ar2 are aryl or substituted aryl;
• Ar3 is aryl or substituted aryl;
• X, Y and Z are methylene or substituted methylene units;
• R and R2 are hydroxy-derived or acylated oxygen substituents;
• R1 and R3 are hydrogen, lower alkyl or aryl;
• The variables m, n, p, q and r define the spacing and connectivity of the substituents;
• At least one of q and r is 1;
• The total linker and ring-substitution count falls within specified numerical limits.

The claim reaches substantially more compounds than ezetimibe. It can cover:

• Hydroxy compounds;
• Acetate and other ester prodrugs;
• Carbonate and carbamate derivatives;
• Compounds with phenyl, substituted phenyl or naphthyl groups;
• Multiple stereochemical arrangements, depending on the claim construction and disclosed embodiments.

The breadth is constrained by several cumulative limitations. A compound must satisfy the aryl identity requirements, the permitted linker definitions, the oxygen-substituent definitions and the numerical restrictions on the ring and side-chain variables. A compound that differs only by an impermissible linker, substitution position or functional group may fall outside the literal wording of claim 1.

What do claims 2 through 6 add?

Claims 2 through 6 narrow the genus but do not materially change the invention’s commercial center of gravity.

Claim 2: phenyl-based aryl groups

Claim 2 requires Ar1 and Ar2 to be phenyl or substituted phenyl and requires Ar3 to be substituted phenyl. This excludes many nonphenyl embodiments potentially covered by claim 1.

Claim 3: halogen and alkoxy substitution

Claim 3 narrows the preferred groups to:

• Halogen-substituted Ar1;
• Halogen- or alkoxy-substituted Ar2;
• Alkoxy- or hydroxy-substituted Ar3.

This claim is closely aligned with the substitution pattern used in ezetimibe, which contains two 4-fluorophenyl groups and one 4-hydroxyphenyl group.

Claim 4: hydroxy-containing compounds

Claim 4 requires:

• X, Y and Z to be methylene;
• R1 and R3 to be hydrogen;
• R and R2 to be hydroxy;
• The total value of m, n, p, q and r to be 2, 3 or 4.

This claim focuses on unesterified hydroxy compounds rather than prodrug derivatives.

Claims 5 and 6: defined topology

Claim 5 requires m, n and r to be zero, q to be 1 and p to be 2.

Claim 6 requires p, q and n to be zero, r to be 1 and m to be 2 or 3.

These are alternative structural arrangements for placing the hydroxy-bearing side chain relative to the azetidinone core. They have narrower literal scope but can be valuable against close analogues that avoid the most specific species claims.

What compounds are specifically listed in claim 7?

Claim 7 contains approximately two dozen individual compounds and stereoisomers. The listed compounds include:

• Hydroxyphenyl-substituted azetidinones;
• Methoxyphenyl and fluorophenyl analogues;
• Acetoxy derivatives;
• Benzyloxy derivatives;
• Chlorophenyl compounds;
• Naphthyl-containing compounds;
• Multiple R/S stereoisomers.

The commercial relevance of claim 7 is highest for the ezetimibe species. Other listed compounds appear to represent research compounds, intermediates, stereoisomers or alternative drug candidates rather than products with established commercial status.

The claim language contains transcription and formatting defects, including missing parentheses and inconsistent stereochemical notation. Patent interpretation would ordinarily rely on the issued patent, specification, drawings and prosecution history rather than the normalized text reproduced in the question.

What are the pharmaceutical composition and method claims?

Claim 8: pharmaceutical composition

Claim 8 covers a pharmaceutical composition containing an effective amount of a claim 1 compound in a pharmaceutically acceptable carrier. The stated uses are:

• Treatment of atherosclerosis;
• Prevention of atherosclerosis;
• Reduction of plasma cholesterol levels.

The claim is not limited to a particular tablet, capsule, dosage strength, excipient, release profile or combination product. It is therefore broader than a conventional formulation patent but narrower than a claim to any pharmaceutical use.

Claim 9: method of treatment

Claim 9 covers administering an effective amount of a claim 1 compound to a mammal to:

• Treat atherosclerosis;
• Prevent atherosclerosis;
• Reduce plasma cholesterol levels.

The claim is an early therapeutic-use claim and is not limited to a particular patient population or LDL-cholesterol threshold. It does not expressly require combination treatment with a statin.

When did U.S. Patent 5,767,115 expire?

Event	Date
U.S. application filing	December 1994, based on the patent family record
Patent issued	June 16, 1998
Standard patent term under applicable U.S. term rules	December 2014
Potential six-month pediatric extension	Dependent on FDA pediatric-use qualification
Current status	Expired

The patent was filed during the transition from the former 17-year-from-issuance regime to the 20-year-from-earliest-effective-filing regime. Public patent records identify December 2014 as the ordinary expiration period for the patent. FDA pediatric exclusivity, where applicable to the listed product and patent, could extend enforcement of the relevant patent or regulatory protection for six months. That extension did not create a continuing patent barrier after the pediatric period ended.

Patent term adjustment, terminal disclaimers and any patent-specific term determination should be confirmed against the USPTO maintenance and term records for a litigation-grade opinion. The patent itself is no longer enforceable as a live exclusion right.

What was the Orange Book status of Patent 5,767,115?

The patent was listed in the FDA Orange Book for ezetimibe products, including Zetia. It was one of the principal patents cited in connection with generic abbreviated new drug applications for ezetimibe.

The relevant regulatory framework was:

• An NDA holder listed the patent in the Orange Book.
• A generic applicant submitting an ANDA certified under Paragraph IV that the patent was invalid, unenforceable or would not be infringed.
• The NDA holder could file patent litigation within 45 days.
• A Paragraph IV lawsuit could trigger a 30-month stay of ANDA approval under the Hatch-Waxman Act, subject to statutory exceptions and court developments.

Orange Book listing did not extend the patent term. It created a regulatory litigation mechanism while the patent remained listed and enforceable.

Which companies challenged the ezetimibe patent estate?

Generic manufacturers challenged the Zetia patent estate through ANDA filings and Paragraph IV certifications. Public litigation and regulatory records identify challenges involving major generic companies, including Teva, Mylan and other ANDA applicants.

The principal commercial issue was not whether generic ezetimibe could be technically manufactured. It was whether the generic product could obtain FDA approval before the expiration or settlement date for the listed patents.

After the key compound patent expired, FDA approved generic ezetimibe products. The launch environment also depended on later patents and settlement arrangements involving formulation, crystalline form, manufacturing or combination-product claims.

What other patents protected ezetimibe?

The commercial patent estate extended beyond U.S. Patent 5,767,115. It included later patents and patent-family members directed to narrower compounds, formulations, manufacturing processes and combination products.

Patent category	Typical subject matter	Commercial purpose
Core compound patents	Ezetimibe and related azetidinones	Prevent direct generic substitution
Stereochemical claims	Defined enantiomers and diastereomers	Protect the active clinical species
Formulation claims	Tablets, excipients and dosage forms	Delay formulation-specific competition
Process patents	Chemical preparation and purification	Create manufacturing leverage
Combination patents	Ezetimibe with simvastatin or other statins	Protect Vytorin-type products
Polymorph or solid-state patents	Crystalline or solid forms	Address product quality and process reproducibility
Method-of-use patents	Cholesterol reduction and cardiovascular use	Support narrower regulatory or litigation positions

The later estate was more commercially relevant after expiration of the core compound patent. However, a later patent could block only the specific claimed formulation, process, combination or use. It could not restore an expired genus or species patent.

What formulation patents protect ezetimibe products?

Formulation patents generally address:

• Tablet composition;
• Particle size and mixing;
• Excipients;
• Dissolution and bioavailability;
• Manufacturing conditions;
• Fixed-dose combinations with statins.

Zetia is an immediate-release oral tablet. Its commercial formulation is not protected merely because it contains ezetimibe. A formulation patent must claim a sufficiently specific composition or process. Generic manufacturers can often avoid such claims through a different excipient system, manufacturing route or product design.

For an ANDA applicant, the relevant question is whether the proposed product practices each limitation of the listed formulation claim. A Paragraph III certification, Paragraph IV certification, or section viii statement may be available depending on the patent listing and the use being sought.

How does the patent estate compare with statin patents?

Ezetimibe’s patent strategy differed from the estates for atorvastatin, rosuvastatin and simvastatin.

Feature	Ezetimibe	Typical statin estate
Core structure	Synthetic azetidinone	HMG-CoA reductase inhibitor
Primary mechanism	Cholesterol absorption inhibition	Hepatic cholesterol synthesis inhibition
Core product patent	Directly covered ezetimibe species	Usually covered the statin molecule or salt
Biosimilar exposure	None	None for small-molecule statins
Generic pathway	ANDA	ANDA
Combination exposure	Ezetimibe/statin products	Statin combinations and salts
Main litigation risk	Compound, formulation, combination and process claims	Compound, polymorph, formulation and process claims

Ezetimibe is often used with statins, but that does not make it biologic-like or subject to biosimilar regulation.

Is there biosimilar risk for ezetimibe?

No. Ezetimibe is a chemically synthesized small molecule. Competing products use the ANDA generic-drug pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act, not the 351(k) biosimilar pathway under the Public Health Service Act.

The relevant competitive threats are:

• Generic ezetimibe tablets;
• Generic ezetimibe/simvastatin combinations;
• Authorized generics;
• Formulation and manufacturing workarounds.

Biosimilar development is not relevant to the product’s exclusivity analysis.

What manufacturing and intellectual-property barriers remain?

After expiration of the core compound patent, technical barriers remain but are lower than the original patent barrier.

Key manufacturing issues include:

• Control of azetidinone stereochemistry;
• Selective preparation of the 3R,4S ring configuration;
• Control of the hydroxy-bearing side-chain stereocenter;
• Removal of regioisomeric and diastereomeric impurities;
• Control of residual solvents and degradation products;
• Reproducible particle size and dissolution;
• Demonstration of bioequivalence for the finished tablet.

The process must also avoid infringement of any unexpired process or solid-state patent. A generic applicant can reduce risk by using an independent route, producing a nonclaimed solid form or relying on a different formulation.

What was the revenue exposure from Patent 5,767,115?

Patent 5,767,115 protected the active ingredient underlying Zetia and contributed to the exclusivity value of Vytorin and related products. Merck and Schering-Plough generated multi-billion-dollar annual sales from the broader ezetimibe franchise at peak commercial performance.

The patent’s economic importance was high because it covered the active molecule rather than a limited dosage form. Once the core product patent expired, the market became vulnerable to direct generic substitution, price erosion and formulary pressure.

A reasonable valuation framework separates:

1. Revenue protected by the core ezetimibe species claim.
2. Revenue protected by later formulation and combination patents.
3. Revenue subject to settlement-based launch timing.
4. Revenue retained through brand loyalty, authorized generic strategy and fixed-dose combinations.

How strong was the patent estate?

The patent was strong during its enforceable life because claim 7 directly identified ezetimibe and claim 1 covered a broad genus around the commercial compound. The principal strengths were:

• Direct species coverage;
• Broad Markush genus;
• Stereochemical specificity;
• Composition and method claims;
• Orange Book listing;
• Ability to trigger Hatch-Waxman litigation.

The main weaknesses were:

• Expiration of the core patent term;
• Potential validity challenges based on prior art, obviousness and written description;
• Limited ability of composition claims to block noninfringing formulations after expiration;
• Dependence on later patents for post-expiration protection.

The patent estate was therefore strong as a pre-generic barrier but no longer has meaningful exclusionary strength for ordinary ezetimibe products.

What generic launch scenarios existed?

The main launch scenarios were:

Scenario	Result
Paragraph III certification	Approval deferred until patent expiration
Paragraph IV certification without suit	Approval could proceed after FDA review
Paragraph IV certification with timely suit	Potential 30-month stay
Settlement with licensed launch date	Entry controlled by negotiated date and terms
Successful invalidity or noninfringement challenge	Earlier launch possible
Core patent expiration with no blocking patent	Broad generic entry

Ezetimibe ultimately entered the U.S. generic market after expiration or resolution of the principal patent barriers. The commercial outcome was consistent with the expected lifecycle of an expired small-molecule compound patent.

What is the geographic coverage of Patent 5,767,115?

The patent provides rights only in the United States. Corresponding foreign applications and patents may have existed in Europe, Canada, Japan and other jurisdictions, but each foreign right had its own:

• Priority chain;
• Claim scope;
• Patent term;
• Supplementary protection certificate status;
• Opposition or invalidity history;
• Regulatory linkage rules.

A U.S. expiration date cannot be applied to foreign markets. For global diligence, the U.S. patent should be mapped against the relevant national and regional family members rather than treated as a worldwide right.

Key Takeaways

• U.S. Patent 5,767,115 is a core Schering-Plough patent for substituted 2-azetidinone cholesterol-absorption inhibitors.
• Claim 7 directly covers ezetimibe.
• Claim 1 covers a broad genus of related aryl-substituted azetidinones, hydroxy compounds and prodrug derivatives.
• Claims 8 and 9 cover pharmaceutical compositions and cholesterol-reduction or atherosclerosis treatment methods.
• The patent was listed in the Orange Book for ezetimibe products.
• Its ordinary U.S. patent term expired in December 2014, subject to any applicable pediatric extension.
• Ezetimibe is a small molecule, so generic competition proceeds through ANDA litigation rather than biosimilar review.
• Later formulation, process, solid-state and combination patents were relevant to post-expiration lifecycle management.
• The patent had high historical revenue value but no continuing exclusionary force against ordinary generic ezetimibe products.

FAQs About U.S. Patent 5,767,115

Does Patent 5,767,115 cover the ezetimibe molecule itself?

Yes. Claim 7 lists the ezetimibe stereoisomer by chemical name. Claim 1 also covers ezetimibe through its broader Markush structure.

Can an expired Patent 5,767,115 block a new ezetimibe ANDA?

No. An expired patent cannot independently block approval or commercial marketing. A generic applicant would need to assess any separate unexpired patents listed for the relevant product.

Is Patent 5,767,115 a formulation patent?

No. It is primarily a compound patent with related pharmaceutical composition and method claims. It does not function as a narrow tablet-excipient patent.

Does Patent 5,767,115 cover Vytorin?

It covers the ezetimibe component used in Vytorin. Separate patents and claims may apply to the fixed-dose ezetimibe/simvastatin combination and its formulation.

Was a Paragraph IV challenge required for generic ezetimibe?

A Paragraph IV certification was one possible route when listed patents remained unexpired. A generic applicant could also use a Paragraph III certification and defer approval until patent expiration, or submit a section viii statement for a patented use that it did not seek to market.

References

1. U.S. Patent No. 5,767,115. (1998). 2-Azetidinone compounds useful as hypocholesterolemic agents. United States Patent and Trademark Office.

2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. FDA.

3. U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs. FDA.

4. U.S. Patent and Trademark Office. (n.d.). Patent term adjustment and patent term information. USPTO.

5. Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355.

6. Public Health Service Act, 42 U.S.C. § 262.

Drugs Protected by US Patent 5,767,115

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate

International Family Members for US Patent 5,767,115

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0720599		300132	Netherlands
European Patent Office	0720599		0390018-0	Sweden
European Patent Office	0720599		92545	Luxembourg
European Patent Office	0720599		SPC/GB03/023	United Kingdom
European Patent Office	0720599		SZ 20/2003	Austria