Details for Patent: 4,277,479

Summary for Patent: 4,277,479

Title:	Tetrazolylalkoxycarbostyril derivatives and pharmaceutical compositions containing them
Abstract:	Novel tetrazolylalkoxycarbostyril derivative of the formula (I): (I) wherein R1 is a hydrogen atom, a lower alkyl group, a low alkenyl group, a lower alkanoyl group, a benzoyl group or phenylalkyl group; R2 is a hydrogen atom, a lower alkyl group or a group of the formula R3 is a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a phenyl group or a phenylalkyl group; A is a lower alkylene group; the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is either single or double bond; and the substituted position of a group of the formula, in the carbostyril skeleton is either 4-, 5-, 6-, 7- or 8-position provided that the only one such group of the formula can be substituted in the whole carbostyril skeleton, thus when R2 in 4-position is a group of the formula then 5-, 6-, 7- or 8-position will have no such substituted group; furthermore, the phenyl group in the above-mentioned benzoyl group, phenylalkyl group or phenyl group may have substituted group(s). The above-mentioned novel tetrazolylalkoxycarbostyril derivatives have pharmacological activities such as platelet aggregation inhibitory action, antiinflammatory action, antiulcer action, vasodilatory action and phosphodiesterase inhibitory action and are useful as anti-thrombosis agent, cerebral blood flow improving agent, antiinflammatory agent, antiulcer agent, anti-hypertensive agent and anti-asthmatic agent.
Inventor(s):	Takao Nishi, Kazuyuki Nakagawa
Assignee:	Otsuka Pharmaceutical Co Ltd
Application Number:	US06/070,710
Patent Claim Types: see list of patent claims	Composition; Compound;

United States Patent 4,277,479: Scope, Claims, Expiration, and Cilostazol Patent Landscape

U.S. Patent 4,277,479 covers a broad class of tetrazole-substituted carbostyril derivatives, including the compound now known as cilostazol and related analogues. Its claims include composition-of-matter claims, specific chemical species, and pharmaceutical compositions directed to platelet aggregation inhibition, phosphodiesterase inhibition, improved cerebral blood flow, and antihypertensive activity. The patent issued on July 7, 1981, and its original U.S. patent term expired no later than July 7, 1998 under the pre-1995 17-year-from-grant framework. It therefore does not create a current U.S. blocking right for cilostazol or the claimed chemical class. [1]

What does U.S. Patent 4,277,479 cover?

The patent covers substituted carbostyril compounds bearing a tetrazole-containing alkoxy side chain. The central structure consists of:

• A carbostyril nucleus, which may be unsaturated or partially hydrogenated.
• An alkoxy linker, represented by the variable lower alkylene group A.
• A tetrazole ring attached through its 5-position.
• An N-substituent on the tetrazole ring, represented by R3.
• Optional substitution on the carbostyril nitrogen and ring system.

The patent's claim architecture is layered:

Claim group	Subject matter	Scope
Claim 1	Broad chemical genus	Covers the general formula and permitted substituent combinations
Claims 2-10	Subgenus claims	Narrow the position of the side chain and the identity of R3
Claims 11-24	Individual compounds	Cover named chemical species
Claims 25-28	Pharmaceutical compositions	Cover compositions for four stated therapeutic uses

The most commercially important structural member is the 6-substituted, 3,4-dihydrocarbostyril compound with a cyclohexyl-substituted tetrazole and a four-carbon linker. That compound is cilostazol.

What chemical class is protected by claim 1?

Claim 1 is a genus claim covering compounds with the following principal variables:

Variable	Claimed alternatives
R1	Hydrogen, lower alkyl, lower alkenyl, lower alkanoyl, benzoyl, or phenyl-C1-4 alkyl
R2	Hydrogen, lower alkyl, or the specified tetrazole-containing substituent
R3	Lower alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-4 alkyl, phenyl, or phenyl-C1-4 alkyl
A	Lower alkylene
Carbostyril 3,4 bond	Single or double bond
Side-chain position	4-, 5-, 6-, 7-, or 8-position
Aryl substitution	Lower alkoxy, lower alkyl, halogen, di-lower alkylamino, nitro, or lower alkenedioxy

The claim also imposes an important positional limitation: only one tetrazole-containing substituent may be attached to the carbostyril skeleton. If the group is attached at the 4-position, the 5-, 6-, 7-, and 8-positions cannot carry another group of the same formula.

This is a relatively broad small-molecule genus. It reaches more than one product candidate because it varies:

1. The carbostyril ring position.
2. The degree of hydrogenation of the carbostyril nucleus.
3. The length of the alkylene linker.
4. The N-substituent on the tetrazole.
5. Substitution on the carbostyril nitrogen.
6. Optional substitution on phenyl groups.

Which claims cover cilostazol?

Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone. It is commonly described as a quinolinone derivative and is marketed in the United States as Pletal. [2]

The claim mapping is:

Cilostazol feature	Patent limitation
3,4-Dihydrocarbostyril nucleus	Claim 1 permits a single bond between positions 3 and 4
6-position side chain	Claim 1 and claim 5
Four-carbon oxyalkyl linker	Claim 1 through the lower alkylene variable; expressly recited in claim 19
Tetrazole ring	Claim 1 general formula
N-cyclohexyl substitution	Claim 1 and claim 3 subgenus
Named compound	Claim 19

Claim 19 is the most direct species claim for cilostazol:

"6-[4-(1-Cyclohexyltetrazol-5-yl)butoxy]carbostyril."

The supplied claim text identifies claim 19 as a carbostyril compound. The commercial drug is generally represented as the 3,4-dihydrocarbostyril form. The patent's broader claim 1 and the patent's structural disclosure are therefore important in addition to the literal species claim.

How do claims 2 through 10 narrow the genus?

Claims 2 through 10 divide the genus by ring position and tetrazole N-substitution.

Claims 2-4: 5-position derivatives

Claim 2 limits the tetrazole-containing side chain to the 5-position of the carbostyril nucleus. Claims 3 and 4 then divide the R3 substituent:

• Claim 3: cycloalkyl or cycloalkylalkyl.
• Claim 4: phenylalkyl, phenyl, or lower alkyl, with permitted aromatic substitutions.

Claims 5-7: 6-position derivatives

Claim 5 limits the side chain to the 6-position. This is the commercially significant branch because cilostazol is a 6-substituted compound. Claims 6 and 7 divide the R3 alternatives in the same general manner as claims 3 and 4.

Claims 8-10: 4-, 7-, and 8-position derivatives

Claim 8 covers substitution at the 4-, 7-, or 8-position. Claims 9 and 10 again divide the tetrazole N-substituent into cycloalkyl/cycloalkylalkyl and aromatic or lower-alkyl categories.

The dependent claims therefore do more than identify preferred compounds. They preserve fallback positions if the broad genus claim is challenged for lack of novelty, obviousness, or inadequate written description.

What specific compounds are claimed in claims 11 through 24?

Claims 11 through 24 identify individual species. They cover variations in ring position, linker length, tetrazole N-substituent, and carbostyril hydrogenation.

Claim	Named compound or structural variation
11	6-propoxy compound with N-cyclohexyl tetrazole
12	6-propoxy compound with N-benzyl tetrazole
13	5-propoxy, 3,4-dihydro compound with N-cyclohexyl tetrazole
14	6-propoxy compound with N-phenyl tetrazole
15	4-methyl-6-propoxy compound with N-cyclohexyl tetrazole
16	6-propoxy compound with N-cyclohexylmethyl tetrazole
17	6-propoxy compound with N-cyclooctyl tetrazole
18	6-propoxy compound with N-cyclopentyl tetrazole
19	6-butoxy compound with N-cyclohexyl tetrazole
20	6-propoxy, 3,4-dihydro compound with N-cyclohexyl tetrazole
21	6-propoxy, 3,4-dihydro compound with N-cyclohexylmethyl tetrazole
22	7-propoxy, 3,4-dihydro compound with N-cyclohexyl tetrazole
23	8-propoxy, 3,4-dihydro compound with N-cyclohexyl tetrazole
24	4-propoxy compound with N-cyclohexyl tetrazole

The species claims provide narrower protection than claim 1 but are typically more defensible in litigation because they identify a defined molecule rather than a large chemical genus.

What pharmaceutical uses are protected by claims 25 through 28?

Claims 25 through 28 are composition claims. They require:

1. A compound within claim 1.
2. A pharmacologically effective amount.
3. A pharmaceutically acceptable carrier.
4. A specified therapeutic purpose.

Claim	Stated use
25	Platelet aggregation inhibitor
26	Phosphodiesterase inhibitor
27	Cerebral blood flow improver
28	Antihypertensive agent

These are composition claims rather than pure method-of-treatment claims. The claims do not expressly require a particular tablet, capsule, excipient, particle size, polymorph, release profile, or manufacturing process.

For modern U.S. infringement analysis, a product containing a claimed compound may raise different questions from a product marketed with a claimed indication. The composition claims are not equivalent to a later, narrowly drafted method-of-use claim directed to a particular disease or dosing regimen.

What is the patent expiration date of U.S. Patent 4,277,479?

U.S. Patent 4,277,479 issued on July 7, 1981. It was subject to the pre-Uruguay Round patent term rule, under which the ordinary term was 17 years from grant. On that basis, the patent expired on July 7, 1998. [1]

The patent predates the modern 20-year-from-earliest-effective-filing-date regime created by the Uruguay Round Agreements Act. Patent term adjustment and patent term extension statutes do not ordinarily convert an old, already expired patent into a currently enforceable right.

Event	Date or status
U.S. patent issued	July 7, 1981
Ordinary pre-1995 term	17 years from grant
Expected expiration	July 7, 1998
Current enforceability	Expired
Current composition-of-matter blocking right	None from this patent

No current commercial launch analysis should treat this patent as an enforceable U.S. barrier.

What is the Orange Book status of cilostazol and Pletal?

Pletal is the U.S. brand name for cilostazol. The FDA approved Pletal for the reduction of symptoms of intermittent claudication, including increased walking distance. [2]

Patent 4,277,479 is not a current Orange Book exclusivity barrier. The patent expired before the FDA approval of Pletal, which occurred in 1999. FDA Orange Book protection is based on listed patents and regulatory exclusivity associated with an approved drug application. An expired 1981 patent cannot provide current patent exclusivity for the product. [3]

The commercial consequences are:

• No live U.S. composition patent from Patent 4,277,479.
• No current exclusivity period arising from that patent.
• No basis for a present Paragraph IV challenge directed specifically to Patent 4,277,479.
• Any later-listed Pletal patent would need to be analyzed separately by patent number, claims, listing date, and expiration date.

When did cilostazol lose market exclusivity?

Cilostazol lost the protection available from Patent 4,277,479 in 1998, before Pletal's 1999 approval. FDA regulatory exclusivity associated with the original approval was separate from patent rights. The historical Hatch-Waxman status of a generic applicant would depend on the NDA's listed patents and any applicable exclusivity periods, not on the expired 1981 patent alone. [3]

The drug is now a conventional generic product. Cilostazol tablets are available in 50 mg and 100 mg strengths, corresponding to the approved Pletal dosage forms. [2,4]

Which companies challenged or entered against Pletal?

Publicly marketed cilostazol products have been supplied by generic manufacturers after the expiration of the original patent estate. FDA's Approved Drug Products with Therapeutic Equivalence Evaluations identifies approved generic equivalents by product and applicant. [3]

The relevant competitive set has included manufacturers of abbreviated new drug application products rather than biosimilar developers. Cilostazol is a chemically synthesized small molecule, so the relevant FDA pathway is ANDA approval under section 505(j), not the biosimilar pathway under section 351(k).

A current company-by-company litigation conclusion cannot be assigned to Patent 4,277,479 because the patent expired in 1998. Any historical Paragraph IV litigation involving cilostazol would have had to concern other patents, if any, listed for the relevant NDA.

Are biosimilar risks relevant to cilostazol?

No. Cilostazol is not a biologic and does not create biosimilar risk. The competitive risk is generic substitution.

Issue	Cilostazol position
Product type	Small-molecule drug
FDA abbreviated pathway	ANDA
Biosimilar pathway	Not applicable
Primary competitive threat	Generic cilostazol tablets
Key approval standard	Pharmaceutical equivalence and bioequivalence
Manufacturing differentiation	Usually limited unless supported by formulation or process IP

What formulation patents protect cilostazol?

Patent 4,277,479 does not claim a specific commercial formulation. Claims 25 through 28 require a pharmacologically effective amount of a claimed compound and a pharmaceutically acceptable carrier, but they do not specify:

• A particular excipient system.
• A controlled-release matrix.
• An enteric coating.
• A particle-size distribution.
• A solid-state form.
• A dissolution profile.
• A manufacturing process.
• A specific tablet strength.

The patent therefore has broad pharmaceutical-composition language but no detailed formulation platform in the claims supplied. A later formulation patent could protect a distinct dosage form without reviving Patent 4,277,479. Conversely, a generic product using the same active ingredient would not automatically infringe a later formulation patent unless it practices the later patent's limitations.

What method-of-use patents are covered?

Claims 25 through 28 are directed to compositions for four stated pharmacological uses. They do not recite a patient, dose, treatment duration, administration schedule, or disease-specific treatment step.

The claimed uses are:

• Platelet aggregation inhibition.
• Phosphodiesterase inhibition.
• Improvement of cerebral blood flow.
• Antihypertensive treatment.

The approved U.S. indication for Pletal is intermittent claudication. [2] That indication is narrower than the full therapeutic-use language in claims 25 through 28. Because the patent expired before approval, these claims have no current blocking effect.

How strong was the patent estate for cilostazol?

Historically, the estate was structurally strong because it combined a broad genus claim with narrower fallback claims and individual species claims.

Strength factor	Assessment
Broad genus coverage	High on the face of claim 1
Species coverage	High for expressly named compounds
Positional coverage	Broad across 4-, 5-, 6-, 7-, and 8-positions
N-substituent coverage	Broad across alkyl, cycloalkyl, aryl, and aralkyl groups
Use coverage	Broad pharmacological composition claims
Formulation coverage	Limited in the supplied claims
Manufacturing coverage	Not apparent in the supplied claims
Current enforceability	None; expired

The principal weakness from a present commercial standpoint is expiration. Patent strength has no remaining exclusionary value after the patent term ends.

What manufacturing and intellectual-property barriers remain?

Patent 4,277,479 does not create a current manufacturing barrier. A generic manufacturer must still satisfy FDA requirements for:

• API identity and impurity control.
• Tablet content uniformity.
• Dissolution.
• Stability.
• Bioequivalence.
• Current good manufacturing practice.
• Labeling and serialization requirements.

Those are regulatory and operational barriers, not surviving rights under Patent 4,277,479.

The patent's chemistry may nevertheless remain relevant as technical prior art. It can affect the validity of later patents directed to:

• New salts.
• New polymorphs.
• Particle engineering.
• Modified-release dosage forms.
• Combination products.
• New dosing regimens.
• New therapeutic indications.
• Improved synthetic processes.

A later patent must distinguish over the disclosed compounds and uses in Patent 4,277,479 under novelty and obviousness standards.

How does Patent 4,277,479 compare with a modern generic patent estate?

Estate element	Patent 4,277,479	Typical modern generic or innovator estate
Core molecule	Yes	Sometimes
Species claims	Yes	Often
Formulation claims	Minimal	Common
Polymorph claims	Not shown	Common
Method-of-use claims	Broad composition-use claims	Often indication-specific
Manufacturing claims	Not shown	Often included
Regulatory listing relevance	Historical	May remain current
Current enforceability	Expired	Depends on expiration
Biosimilar relevance	None	Depends on biologic status

The patent is best characterized as an early chemical platform patent, not as a modern lifecycle-management estate.

What generic launch scenarios existed for cilostazol?

The principal launch path was an ANDA-based generic entry after the relevant patent and regulatory barriers expired. The commercial scenarios were:

1. Paragraph IV entry: applicable only if a listed, unexpired patent existed and the applicant certified invalidity, unenforceability, or noninfringement.
2. Paragraph III entry: applicable if an unexpired listed patent existed but the applicant accepted delayed approval until expiration.
3. Patent-free entry: applicable where no unexpired listed patent blocked approval.
4. Regulatory-exclusivity delay: possible if FDA exclusivity remained even without an enforceable patent.

For Patent 4,277,479, the applicable position was patent expiration before Pletal approval. The patent itself could not support a later Paragraph IV filing.

What is the geographic coverage of Patent 4,277,479?

The patent is a United States patent. Its enforceability was limited to the United States and its territories under U.S. patent law. Foreign equivalents, if filed and granted, would require separate analysis by country.

The U.S. patent does not establish rights in:

• Japan.
• Europe.
• Canada.
• China.
• India.
• Australia.
• Other jurisdictions.

International protection would depend on corresponding national patents, their claims, prosecution history, term adjustments, maintenance fees, and expiration dates. The U.S. expiration date cannot be used automatically for every foreign counterpart.

Key Takeaways

• U.S. Patent 4,277,479 claims tetrazole-substituted carbostyril compounds and related pharmaceutical compositions.
• Claim 1 is a broad chemical genus covering multiple ring positions, linkers, carbostyril hydrogenation states, and tetrazole N-substituents.
• Claims 11 through 24 identify individual compounds, including the structure associated with cilostazol.
• Claims 25 through 28 cover platelet aggregation inhibition, phosphodiesterase inhibition, cerebral blood-flow improvement, and antihypertensive compositions.
• The patent issued July 7, 1981, and expired on July 7, 1998 under the pre-1995 17-year term.
• The patent is not a current U.S. barrier to generic cilostazol.
• Cilostazol is a small molecule, so generic ANDA competition applies; biosimilar analysis does not.
• The supplied claims do not provide meaningful protection for a specific formulation, polymorph, manufacturing process, or controlled-release system.
• Any current freedom-to-operate assessment must focus on later patents, FDA-listed patents, formulation claims, process claims, and indication-specific patents rather than Patent 4,277,479.

FAQs

Is cilostazol specifically claimed in U.S. Patent 4,277,479?

Yes. The claim set includes a compound corresponding to the cilostazol structure, together with broader genus and subgenus claims that cover related compounds.

Can an expired patent still block a generic cilostazol launch?

No. An expired U.S. patent cannot support an injunction or current patent-based launch block, although it remains relevant as prior art against later patent applications.

Does Patent 4,277,479 claim the Pletal tablet formulation?

No. The supplied composition claims require a claimed active compound and a pharmaceutically acceptable carrier but do not identify the commercial Pletal excipient system or a specific release technology.

Is a cilostazol ANDA subject to biosimilar interchangeability rules?

No. Cilostazol is a chemically synthesized small molecule. The relevant pathway is an ANDA, with bioequivalence and pharmaceutical-equivalence requirements.

Could a new cilostazol patent still be valid after Patent 4,277,479 expired?

Yes, if it claims a patentably distinct subject matter, such as a novel solid form, formulation, manufacturing process, combination, or dosing regimen, and satisfies novelty, nonobviousness, written description, enablement, and other statutory requirements.

References

1. United States Patent and Trademark Office. (1981). U.S. Patent No. 4,277,479: 1-substituted tetrazole derivatives of carbostyril. U.S. Department of Commerce.
2. U.S. Food and Drug Administration. (1999). Pletal (cilostazol) prescribing information.
3. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
4. DailyMed. (2024). Cilostazol tablet labeling. National Library of Medicine.

Drugs Protected by US Patent 4,277,479

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

Foreign Priority and PCT Information for Patent: 4,277,479

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	53/107869	Sep 01, 1978

International Family Members for US Patent 4,277,479

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	229342
Austria	364363
Austria	A584579
Australia	5039779
Australia	538410
Belgium	878548