United States Drug Patent 4,466,972: Claim Scope, Isradipine Coverage, Expiration and Patent Landscape

U.S. Patent No. 4,466,972 covers a class of 4-aryl-1,4-dihydropyridine calcium-channel blockers bearing benzoxadiazole or benzothiadiazole substituents. Its most commercially significant subject matter is isradipine, including the racemic active ingredient used in DynaCirc. The patent issued on August 21, 1984, and its original 17-year term expired in 2001. The claims no longer create a U.S. blocking right, but they remain important for understanding isradipine’s original composition-of-matter and therapeutic-use protection.

What drug does U.S. Patent 4,466,972 protect?

The patent’s principal commercial compound is isradipine, a dihydropyridine calcium-channel blocker.

Isradipine is commonly identified chemically as:

4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl 1-methylethyl ester

In the claim language supplied, this structure corresponds to the benzoxadiazole series, with:

Structural position	Isradipine substituent
Dihydropyridine nitrogen, R1'	Hydrogen
2- and 6-positions, R2' and R5'	Methyl
3- and 5-positions	One methyl ester and one isopropyl ester
4-position	Benzoxadiazole-4-yl group
Heteroatom, X	Oxygen

Claim 9 expressly covers the isradipine structure:

“4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3-isopropyloxycarbonyl-pyridine-5-carboxylic acid methyl ester.”

The patent also covers related benzoxadiazole and benzothiadiazole analogs with different ester groups, aminoalkyl ester groups, N-substitution and N-alkylation patterns.

What is the legal status and expiration date of U.S. Patent 4,466,972?

U.S. Patent 4,466,972 expired in 2001 under the pre-Uruguay Round patent term regime.

Event	Date or status
U.S. patent number	4,466,972
Issue date	August 21, 1984
Original U.S. term	17 years from issue
Expected original expiration	August 21, 2001
Current enforceability	Expired
Current blocking effect	None for new U.S. manufacture, sale or use
Current Paragraph IV significance	None for this expired patent

The patent issued before the 20-year-from-earliest-effective-filing-date regime became applicable to most later U.S. applications. Its operative term was therefore generally measured from issuance rather than from the earliest priority filing date. The patent expired decades ago and cannot presently support an infringement action against a generic isradipine product.

Patent expiration does not erase the historical scope of the claims. It eliminates the exclusionary right.

How broad is independent claim 1?

Claim 1 is a Markush composition-of-matter claim. It covers a large genus of substituted 1,4-dihydropyridines rather than a single drug.

The core structure contains:

A 1,4-dihydropyridine ring.
A 4-position fused benzoxadiazole or benzothiadiazole aryl substituent.
Substituents at the 2- and 6-positions that may be hydrogen or C1-C6 alkyl.
Ester or amino-substituted ester groups at the 3- and 5-positions.
Optional N-substitution at the dihydropyridine nitrogen.
Optional pharmaceutically acceptable acid-addition salts for basic compounds.

The principal breadth comes from the independent alternatives.

R1' substitution

R1' may be hydrogen or C1-C6 alkyl. This captures:

The unsubstituted dihydropyridine nitrogen found in isradipine.
N-methyl, N-ethyl and other N-alkyl analogs.
Claim 22, which specifically identifies the N-propyl derivative.

Claim 2 narrows the genus to compounds with hydrogen at the ring nitrogen.

R2' and R5' substitution

Each of R2' and R5' may independently be hydrogen or C1-C6 alkyl. Claim 3 narrows both positions to alkyl groups, while claim 4 specifies methyl at both positions.

The 2,6-dimethyl configuration is the commercially relevant configuration for isradipine and many established dihydropyridine calcium-channel blockers.

R3' and R4' ester substitution

The 3- and 5-positions may independently carry:

A carboxylate ester, COOR7'; or
An aminoalkyl ester-type group represented by the second formula in claim 1.

R7' may be:

C1-C6 alkyl;
C3-C7 cycloalkyl;
C7-C10 phenylalkyl; or
C3-C6 alkoxyalkyl.

This creates substantial substituent coverage. The listed claims identify methyl, ethyl, tert-butyl, isobutyl, isopropyl, cyclopentyl, benzyl, phenethyl and alkoxyalkyl ester variants.

X as oxygen or sulfur

X defines the heteroatom in the fused benzoxadiazole or benzothiadiazole ring:

X	Covered heteroaryl class
Oxygen	Benzoxadiazole derivatives
Sulfur	Benzothiadiazole derivatives

Claim 3 specifically selects sulfur. Claims 6 through 23 identify individual oxygen- and sulfur-containing compounds.

Which claims specifically cover isradipine?

Claim 9 is the strongest direct claim to isradipine based on the supplied text.

Claim	Subject matter
Claim 1	Broad genus of benzoxadiazole and benzothiadiazole dihydropyridines
Claim 2	Claim 1 compounds with N-H
Claim 3	N-H; 2,6-dialkyl; ester groups; sulfur heteroaryl
Claim 4	2,6-dimethyl; methyl, ethyl or tert-butyl ester groups
Claim 5	Ethyl ester limitation
Claim 9	Benzoxadiazole compound with methyl and isopropyl ester groups
Claims 24-28	Pharmaceutical compositions and listed cardiovascular indications
Claims 30-34	Treatment methods using a claim 1 compound

Claim 9 identifies the asymmetric diester substitution pattern associated with isradipine: one methyl ester and one isopropyl ester. That asymmetry distinguishes isradipine from the diethyl and dimethyl diesters recited in claims 6 and 7.

What formulations are protected by the patent?

The patent does not claim a detailed dosage form, release profile, tablet coating, capsule shell or manufacturing process. Claims 24 through 28 are broad pharmaceutical-composition claims.

They require:

A pharmaceutically acceptable carrier or diluent.
A therapeutically effective amount of a claim 1 compound or salt.
Use for one of the listed conditions.

The listed therapeutic categories are:

Coronary insufficiency.
Intermittent claudication.
Cerebrovascular accidents.
Muscular spasms.
Hypertension.

These claims cover compositions containing the active compound, but they do not appear to require a particular excipient, dissolution profile, particle size, polymorph, dosage strength or route of administration.

A conventional isradipine tablet or capsule would have historically implicated these claims if it contained a compound falling within claim 1. Since the patent expired, the formulation claims no longer restrict commercial manufacture.

What method-of-use claims does U.S. Patent 4,466,972 contain?

Claims 30 through 34 are treatment-method claims directed to administering a claim 1 compound to an animal in need of treatment.

Claim	Indication
Claim 30	Coronary insufficiency
Claim 31	Intermittent claudication
Claim 32	Cerebrovascular accidents
Claim 33	Muscular spasms
Claim 34	Hypertension

These claims are narrower than a pure composition-of-matter claim because they require an administration step and a specified therapeutic purpose. They also depend on the broad chemical definition of claim 1.

The claims use the term “animal,” which was common in older pharmaceutical patents. The claims do not specify dose, route, dosage form, treatment duration or patient population. The absence of those limitations increases their historical breadth but also leaves the claims dependent on the compound falling within the chemical genus.

How many patents cover isradipine?

The foundational U.S. composition-of-matter patent supplied here is U.S. Patent 4,466,972. Isradipine’s commercial exclusivity also depended on regulatory exclusivity, trademarks, manufacturing know-how and any later patents directed to formulations or processes.

The relevant protection categories are distinct:

Protection category	Relevance to isradipine
Composition of matter	Covered by the benzoxadiazole dihydropyridine genus and specific species claims
Pharmaceutical composition	Covered broadly by claims 24-28
Method of treatment	Covered by claims 30-34
Formulation technology	Not specifically detailed in the supplied claims
Manufacturing process	Not claimed in the supplied claims
Regulatory exclusivity	Separate from patent rights
Trademark	DynaCirc branding, separate from patent rights

A precise count of all related U.S. patents requires a complete patent-family and continuation review. The supplied claim set alone establishes one foundational patent, not the full worldwide patent estate.

What was the Orange Book status of isradipine?

Isradipine was approved by the FDA as DynaCirc, associated with Novartis predecessor Sandoz. The FDA-approved product was indicated for hypertension. The approval relied on the safety and efficacy record for isradipine as a dihydropyridine calcium-channel blocker.

The Orange Book treats approved drug products, listed patents and generic applications separately from the general patent record. An expired composition-of-matter patent may remain visible in historical FDA records while no longer blocking approval or launch.

Regulatory issue	Isradipine status
Active ingredient	Isradipine
Drug class	Dihydropyridine calcium-channel blocker
Reference product	DynaCirc
FDA indication	Hypertension
Historical patent relevance	U.S. 4,466,972
Current patent barrier from this patent	None
Generic pathway	Abbreviated New Drug Application
Biosimilar pathway	Not applicable

Isradipine is a small molecule, not a biologic. Biosimilar approval under section 351(k) of the Public Health Service Act is therefore irrelevant. Generic applicants would use the ANDA pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act.

Were Paragraph IV challenges relevant to this patent?

Paragraph IV challenges could have been relevant before expiration if a generic applicant asserted that the patent was invalid, unenforceable or would not be infringed. They have no current commercial significance because the patent expired in 2001.

A Paragraph IV certification against an expired patent does not create the same launch barrier as a certification against an unexpired listed patent. The principal current generic issues for isradipine are product approval, bioequivalence, manufacturing capability and commercial demand, not U.S. patent clearance under U.S. 4,466,972.

No current litigation or settlement rights can arise solely from this expired patent.

Which companies challenged or competed with the isradipine patent estate?

The competitive landscape includes branded and generic calcium-channel blockers rather than only direct isradipine substitutes.

Drug	Active ingredient	Drug class	Principal competitive position
DynaCirc	Isradipine	Dihydropyridine calcium-channel blocker	Reference isradipine product
Procardia/Adalat	Nifedipine	Dihydropyridine	Earlier major class competitor
Plendil	Felodipine	Dihydropyridine	Long-acting hypertension competitor
Norvasc	Amlodipine	Dihydropyridine	Major commercial competitor
Cardene	Nicardipine	Dihydropyridine	Hypertension and intravenous-use competitor
Nimotop	Nimodipine	Dihydropyridine	Cerebrovascular-focused competitor
Sular	Nisoldipine	Dihydropyridine	Hypertension competitor

The closest chemical competitors are other 1,4-dihydropyridines with substituted ester groups and aryl or heteroaryl groups at the 4-position. Their patents generally protected different molecular species or separate genera. They would not automatically invalidate U.S. 4,466,972 merely because they occupy the same pharmacological class.

How strong was the patent estate?

The original patent had strong historical composition-of-matter characteristics because it covered both a broad chemical genus and individually named species.

Strengths

Claim 1 covers a wide substituent matrix.
Claim 9 directly identifies the isradipine ester pattern.
Claims 6 through 23 provide species-level fallback positions.
Composition claims generally provide stronger protection than method claims.
The patent covers both benzoxadiazole and benzothiadiazole analogs.
The patent includes pharmaceutical compositions and treatment methods.

Limitations

The patent term expired in 2001.
The supplied claims do not cover a defined controlled-release system.
They do not claim a specific polymorph, crystal form or particle-size distribution.
They do not recite a manufacturing process.
Method claims depend on the compound satisfying the broad chemical definition.
The patent does not provide current regulatory exclusivity.

The patent was therefore historically strong as a small-molecule discovery patent but has no remaining exclusionary value in the United States.

What generic launch risks exist for isradipine?

A generic isradipine applicant does not face a patent-launch risk from U.S. Patent 4,466,972. The main risks are regulatory and commercial.

Regulatory risks

Demonstrating bioequivalence to the reference product.
Matching the approved dosage form and strength.
Addressing any inactive-ingredient differences.
Satisfying current manufacturing and quality requirements.
Maintaining product consistency for a relatively low-volume drug.

Commercial risks

Limited market size compared with amlodipine and other high-volume calcium-channel blockers.
Established physician familiarity with competing products.
Potentially modest reimbursement incentives.
Manufacturing economics for a lower-volume active ingredient.
Channel and wholesaler interest in stocking the product.

Litigation risk

The expired patent does not create a viable infringement claim. Litigation risk would depend on later unexpired patents, trade secrets, regulatory exclusivity or unrelated commercial conduct.

Does the patent cover isradipine salts, metabolites or prodrugs?

The claims cover pharmaceutically acceptable acid-addition salts only for basic compounds within the claimed chemical genus. Isradipine itself is generally treated as a neutral ester-containing dihydropyridine, so the salt language is more relevant to basic aminoalkyl ester analogs, such as the compounds recited in claims 13 and 23.

The patent does not automatically cover:

Isradipine metabolites lacking the claimed structure.
New prodrugs with materially different covalent structures.
Unclaimed polymorphs as independent chemical inventions.
Formulations that contain no claim 1 compound.
Other calcium-channel blockers outside the claimed genus.

A metabolite or prodrug would require a separate infringement analysis against the literal language and any applicable doctrine-of-equivalents theory. That issue is historical because the patent has expired.

What licensing deals and settlement agreements affected the patent?

The patent’s commercial development is associated with Sandoz and the DynaCirc product. The supplied claim text does not establish a specific license, assignment chain, Paragraph IV settlement or co-promotion agreement.

Patent ownership, product commercialization and regulatory sponsorship are separate questions. Sandoz’s development and commercialization of isradipine do not, by themselves, prove that every party involved held title to the patent or licensed each claim.

Because U.S. Patent 4,466,972 expired in 2001, any historical license or settlement would no longer create a current U.S. exclusionary barrier against generic isradipine.

What is the geographic coverage of the patent?

U.S. Patent 4,466,972 has territorial effect only in the United States. It does not directly control:

European manufacture or sale.
Japanese commercial activity.
Canadian products.
Emerging-market launches.
Importation into countries where corresponding patents expired or were never granted.

The benzoxadiazole and benzothiadiazole dihydropyridine invention may have been pursued through foreign priority filings and national patent applications. Those rights must be analyzed jurisdiction by jurisdiction. U.S. expiration does not establish the status of corresponding foreign patents.

For current freedom-to-operate work, the relevant question is whether an unexpired patent exists in the target country covering isradipine, its formulation, a manufacturing process or a specific use.

What manufacturing and intellectual-property barriers remain?

The expired patent does not prevent manufacture of isradipine in the United States. Practical barriers may remain:

Sourcing qualified starting materials.
Controlling regioisomer and stereoisomer composition.
Reproducing the active pharmaceutical ingredient specification.
Managing ester hydrolysis and impurity formation.
Establishing a validated analytical method.
Demonstrating stability over the proposed shelf life.
Qualifying a commercial-scale synthetic process.
Meeting FDA current good manufacturing practice requirements.

Isradipine contains a 1,4-dihydropyridine ring and ester substituents. Those features can create sensitivity to oxidation, light, hydrolysis and process-related impurities. These are manufacturing and quality issues, not continuing rights under U.S. Patent 4,466,972.

Key Takeaways

U.S. Patent 4,466,972 covers a broad class of benzoxadiazole and benzothiadiazole 1,4-dihydropyridines.
Claim 9 directly covers the isradipine structure identified in the supplied claims.
Claims 24 through 28 cover broad pharmaceutical compositions for cardiovascular and related indications.
Claims 30 through 34 cover treatment methods for the same general indication set.
The patent issued on August 21, 1984, and its original term expired in 2001.
The patent creates no current U.S. patent barrier to generic isradipine.
Isradipine is a small molecule and has no biosimilar pathway.
Current launch risk is primarily regulatory, manufacturing and commercial.
Foreign patent status cannot be inferred from U.S. expiration.
Later formulation, process or polymorph patents would require a separate patent-family review.

FAQs

Is U.S. Patent 4,466,972 still enforceable?

No. The patent’s original U.S. term expired in 2001.

Does claim 9 cover isradipine?

Yes. Claim 9 recites the benzoxadiazole dihydropyridine with methyl and isopropyl ester groups associated with isradipine.

Can a company manufacture generic isradipine in the United States?

The expired patent does not prevent manufacture. The company must still obtain FDA approval and comply with applicable quality, manufacturing and labeling requirements.

Is isradipine protected by a biologic exclusivity period?

No. Isradipine is a chemically synthesized small molecule. Biologic exclusivity and biosimilar rules do not apply.

Are isradipine metabolites covered by the patent?

Not automatically. A metabolite must independently satisfy the structural limitations of the claims. A metabolite with a materially different structure would generally require a separate infringement analysis.

References

United States Patent and Trademark Office. (1984). U.S. Patent No. 4,466,972: 4-Aryl-1,4-dihydropyridines. U.S. Department of Commerce.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (n.d.). DynaCirc prescribing information: Isradipine. Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
U.S. Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	7520/77	Jun 20, 1977
Switzerland	2865/78	Mar 16, 1978
Switzerland	5627/79	Jun 15, 1978
Switzerland	12835/78	Dec 18, 1978
Switzerland	12888/78	Dec 18, 1978

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	376220	⤷ Start Trial
Austria	A443178	⤷ Start Trial
Australia	3725278	⤷ Start Trial
Australia	524000	⤷ Start Trial
Australia	536055	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,466,972

Summary for Patent: 4,466,972