United States Patent 4,859,692: Claim Scope, Zafirlukast Coverage, and Leukotriene Antagonist Patent Landscape

US Patent 4,859,692 is an expired composition, pharmaceutical-composition, method-of-treatment, and salt patent covering substituted indole leukotriene antagonists. Its broadest claim is a chemically constrained Markush claim directed to indole-linked benzoyl derivatives bearing acidic groups such as carboxylic acid, tetrazole, or acylsulfonamide. Narrower claims cover indole embodiments and named compounds associated with zafirlukast.

The patent issued on August 22, 1989. Its ordinary 17-year patent term therefore ended on August 22, 2006, subject to any applicable term adjustment or extension. The FDA-approved drug zafirlukast, marketed as Accolate, received approval in 1996. The patent is no longer an effective barrier to generic entry.

What does US Patent 4,859,692 cover?

The patent covers leukotriene antagonist compounds built around a substituted aromatic or indole framework. The claim architecture has four principal elements:

A substituted core represented by formula Ia.
An amidic substituent represented by R1.L-.
A phenylene-linked acidic pharmacophore.
Pharmaceutical compositions and therapeutic use of the compounds.

The central chemical design can be summarized as:

an indole or related aromatic nucleus;
a substituted nitrogen atom, NRd;
an amino, carbamate, thiocarbamate, urea, or related substituent at another aromatic position;
a benzyl or substituted benzyl bridge;
a benzoyl group;
an acidic terminal group, particularly carboxy, tetrazole, or acylsulfonamide.

The patent does not claim every leukotriene antagonist. A potentially infringing compound must satisfy the structural limitations of formula Ia or a dependent claim. A compound with a different core, different linker, or nonconforming acidic group would generally fall outside the literal scope of claim 1.

What is the chemical scope of claim 1?

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

Ra is hydrogen or C1-C4 alkyl;
Rb and Rc are hydrogen or jointly create an unsaturated bond;
Rd is hydrogen, a broad range of substituted C1-C10 alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, or substituted phenylalkyl;
R1.L- is an amidic radical containing carbonyl, thiocarbonyl, oxy, thio, imino, or direct-linkage options;
R2 is hydrogen, halogen, C1-C4 alkyl, or C1-C4 alkoxy;
Q is substituted or unsubstituted phenylene;
A1 is C1-C2 alkylene or vinylene;
A2 is methylene, vinylene, or a direct bond;
M is carboxy, tetrazole, or an acylsulfonamide.

The acidic group M is commercially important. Acylsulfonamides can act as carboxylic-acid bioisosteres and were a recurring design element in leukotriene receptor antagonist programs.

How do claims 2 through 8 narrow the Markush claim?

Claim	Principal limitation	Legal effect
1	Broad formula Ia and permitted substituent classes	Broad genus claim
2	Specific R1, R2, R3, Ra, Rd, A1, A2, Q, and W lists	Narrows the genus to enumerated substituents
3	Further restricted R1, R2, R3, Ra, Rd, A1, A2, Q, and W	Focuses on a smaller preferred subgroup
4	Rb and Rc form an unsaturated linkage	Directs the claim toward indole-type compounds
5	M is carboxy, tetrazole, or phenyl-substituted acylsulfonamide; A1 is methylene and A2 is a direct link	Captures key acidic pharmacophores
6	Para relationship between R1.L- and NRd	Adds a positional limitation on the aromatic ring
7	Indole derivative of formula IIa	Narrows the core structure
8	Selected indole derivatives and acidic groups	Defines preferred compound classes
9	Eight named compounds	Compound-specific fallback coverage
10	One specifically identified compound	Narrow compound claim
11	A second specifically identified compound	Narrow compound claim associated with zafirlukast-type chemistry
12	Pharmaceutical composition	Composition-of-matter use in a formulation
13	Liquid or powdered aerosol	Aerosol dosage-form limitation
14	Method of antagonizing leukotrienes	Therapeutic method claim
15	Allergic, inflammatory, endotoxic, or traumatic shock treatment	Disease-use limitation
16	Allergic asthma	Narrow therapeutic-use claim
17	Pharmaceutically acceptable salts	Salt-form coverage

Which marketed drug is associated with US 4,859,692?

The patent is principally associated with zafirlukast, the leukotriene receptor antagonist marketed by AstraZeneca as Accolate. Zafirlukast is a small-molecule cysteinyl leukotriene receptor antagonist used for prophylaxis and chronic treatment of asthma.

Claim 11 identifies a compound with the following key features:

an indole nucleus;
N-methyl substitution;
a 5-cyclopentyloxycarbonylamino group;
a 3-indolylmethyl substituent;
a 3-methoxybenzoyl group;
a benzenesulfonamide acidic group.

That structural combination corresponds to the zafirlukast chemical series. Claim 9 includes closely related analogues that vary the indole N-substituent, the 5-position substituent, and the sulfonamide aryl group.

The patent should therefore be analyzed in two ways:

as a broad historical genus patent covering a research program; and
as a specific compound patent protecting zafirlukast-related embodiments.

What formulations are protected by the patent?

Claim 12 covers a pharmaceutical composition containing an effective amount of a claim 1 compound and a pharmaceutically acceptable carrier or diluent. Claim 13 narrows that protection to liquid or powdered aerosols.

The formulation protection is limited compared with a modern formulation patent. It does not claim:

a specific tablet excipient system;
a particular dissolution profile;
a sustained-release matrix;
a defined particle-size distribution;
a specific salt or polymorph;
a particular bioavailability-enhancing formulation.

The patent therefore primarily protects the active compound rather than a sophisticated dosage-form technology. A conventional oral tablet containing a covered compound could implicate claim 12, while an aerosol formulation could implicate claim 13 if the active ingredient and composition limitations are met.

The FDA label for Accolate identified oral tablets in 10 mg and 20 mg strengths, not an aerosol product (FDA, 2022).

What method-of-use claims does US 4,859,692 contain?

Claims 14 through 16 cover therapeutic use. The broad method claim concerns antagonizing one or more leukotriene actions in a living mammal. Dependent claims identify:

allergic diseases;
inflammatory diseases;
endotoxic conditions;
traumatic shock;
allergic asthma.

These claims would have been relevant to a product using a covered compound for asthma or another leukotriene-mediated condition. They are no longer commercially significant in the United States because the patent term has expired.

The method claims also do not create broad exclusivity over all asthma treatments. They are tied to administering a compound that falls within claim 1 or the relevant dependent claims.

When did US Patent 4,859,692 lose exclusivity?

The patent issued on August 22, 1989, and its ordinary pre-1995 patent term was 17 years from issuance. The base term therefore ended on August 22, 2006.

Event	Date or period
US patent issued	August 22, 1989
Ordinary 17-year expiration	August 22, 2006
Accolate FDA approval	1996
Pediatric exclusivity associated with the NDA	Six months, if applicable
Current patent status	Expired

Any six-month pediatric exclusivity attached to the Accolate NDA would have affected the regulatory exclusivity period, not revived the expired patent. Patent expiration and FDA marketing exclusivity are separate legal mechanisms.

The Orange Book historically listed US 4,859,692 for Accolate. An expired Orange Book patent does not prevent ANDA approval or commercial generic launch (FDA, 2024).

What was the Orange Book status of Accolate?

Accolate was approved under NDA 020547. The FDA approved zafirlukast for chronic treatment and prevention of asthma in adults and children aged five years and older, subject to the labeling limitations applicable to leukotriene receptor antagonists.

The Orange Book listing created a pathway for ANDA applicants to submit Paragraph IV certifications while the patent remained in force. After expiration, a Paragraph IV challenge to US 4,859,692 ceased to provide a meaningful launch advantage because the patent no longer blocked approval or marketing.

The patent was not a biologic patent, and no biosimilar pathway applied. Zafirlukast is a chemically synthesized small molecule regulated through an NDA and ANDA pathway.

Which companies challenged or competed against the patent?

Publicly relevant competitive pressure came from both generic manufacturers and other branded leukotriene therapies.

Generic competition

Potential ANDA applicants for zafirlukast included generic-drug manufacturers operating under the Hatch-Waxman framework. The key legal event for any applicant would have been a Paragraph IV certification against the unexpired patent, followed by possible litigation under 35 U.S.C. § 271(e)(2).

Because the patent expired in 2006, later generic applicants did not face a durable patent barrier from US 4,859,692. The commercial significance of any individual Paragraph IV filing was therefore limited to the period before expiration and any applicable 30-month stay or regulatory exclusivity.

Branded competitive drugs

Drug	Active ingredient	Company or originator	Mechanism	Patent profile
Accolate	Zafirlukast	AstraZeneca	CysLT1 receptor antagonist	US 4,859,692 and related filings
Singulair	Montelukast	Merck	CysLT1 receptor antagonist	Separate montelukast patent estate
Onon	Pranlukast	Ono Pharmaceutical	CysLT1 receptor antagonist	Separate Japanese and international estate
Zyflo	Zileuton	Abbott	5-lipoxygenase inhibitor	Different target and patent estate

Montelukast became the principal US commercial competitor. Its structure and patent estate are distinct from zafirlukast, so a montelukast product would not ordinarily infringe US 4,859,692 merely because both products act on leukotriene pathways.

How strong was the patent estate for zafirlukast?

The estate had meaningful strength during the period before expiration because claim 1 combined:

a relatively broad substituted-indole genus;
multiple permitted linkers;
multiple acidic pharmacophores;
broad N-substituent and aromatic substituent definitions;
composition and therapeutic-use claims;
specific compound claims in claims 9 through 11.

The strongest commercial protection likely came from the specific compound claims and the preferred indole claims rather than from the full breadth of claim 1. Broad Markush claims are vulnerable to validity attacks based on:

anticipation by earlier leukotriene antagonist disclosures;
obviousness over related indole and benzoyl compounds;
inadequate written description for the full substituent universe;
enablement challenges across a large chemical genus;
claim-construction disputes over functional and structural terminology.

The narrow claims provided fallback positions if the broad genus was narrowed or invalidated. Claim 11 was particularly important because it identified a specific zafirlukast-type compound rather than relying solely on a broad Markush definition.

What manufacturing and intellectual-property barriers applied?

The patent did not claim a unique manufacturing process in the claims provided. It therefore created a compound and use barrier, not a process-specific barrier.

A generic manufacturer would still need to address:

chemical synthesis and impurity control;
solid-state form and stability;
bioequivalence;
tablet formulation;
analytical methods;
active pharmaceutical ingredient sourcing;
FDA ANDA requirements.

Those technical issues could delay entry without extending the patent term. A separate process, polymorph, formulation, or intermediate patent could have created additional barriers, but the supplied claims do not establish such protection.

What generic launch risks existed?

Before August 22, 2006, a generic zafirlukast applicant faced several potential risks:

Literal infringement of claims 9, 10, or 11.
Infringement of claim 1 or claim 7 under the claimed structural formula.
Infringement of composition claim 12 through an oral dosage form.
Method-of-use exposure if the product labeling included a patented asthma indication while the method claims remained enforceable.
Regulatory delay from an Orange Book patent certification.
Possible induced-infringement arguments based on labeling or product promotion.

After patent expiration, the principal risk shifted from patent infringement to regulatory and commercial execution. The patent estate no longer supported a blocking strategy against an ANDA applicant.

What is the current commercial value of the patent?

US 4,859,692 has no current blocking value in the United States. Its economic value is historical and evidentiary:

it documents the original zafirlukast-related discovery program;
it may remain relevant to freedom-to-operate analyses involving historical acts;
it can inform validity, inventorship, priority, and prosecution-history research;
it does not prevent current generic manufacture or sale based solely on the claims provided.

The revenue exposure associated with the patent was concentrated in the Accolate franchise during the period from FDA approval through patent expiry. After 2006, generic entry risk increased sharply, while montelukast had already established a strong competing position in the asthma market.

Key Takeaways

US 4,859,692 is an expired leukotriene antagonist patent issued August 22, 1989.
The ordinary patent term ended August 22, 2006.
The patent covers a broad genus of substituted indole and related aromatic compounds.
Claims 9 through 11 identify specific compounds associated with the zafirlukast series.
Claim 12 covers pharmaceutical compositions; claim 13 covers aerosol compositions.
Claims 14 through 16 cover leukotriene antagonism, allergic disease, and allergic asthma.
The patent was relevant to Accolate, the AstraZeneca zafirlukast product.
Zafirlukast is a small molecule; biosimilar analysis does not apply.
Any Paragraph IV strategy is now historical because the patent has expired.
The patent does not, from the claims supplied, create a current process, polymorph, or formulation barrier.

FAQs About US Patent 4,859,692

Is US Patent 4,859,692 still enforceable?

No. Its ordinary 17-year term from the August 22, 1989 issue date ended in 2006.

Does US 4,859,692 cover montelukast?

No. Montelukast is structurally distinct and is protected by a separate patent estate.

Does US 4,859,692 cover zafirlukast salts?

Yes. Claim 17 expressly covers salts of compounds within specified claims, including zafirlukast-related compounds.

Was US 4,859,692 a biologic or biosimilar patent?

No. It covers chemically synthesized small molecules and was relevant to the NDA/ANDA framework rather than the biologic-license and biosimilar framework.

Could a generic manufacturer launch zafirlukast after patent expiry?

Yes, subject to FDA approval, bioequivalence, manufacturing compliance, and any separate unexpired regulatory or intellectual-property barriers.

References

AstraZeneca. (1996). Accolate (zafirlukast) tablets: Prescribing information. U.S. Food and Drug Administration.
Food and Drug Administration. (2022). Accolate (zafirlukast) prescribing information. U.S. Department of Health and Human Services.
Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, 44th ed. U.S. Department of Health and Human Services.
United States Patent and Trademark Office. (1989). U.S. Patent No. 4,859,692: Indole derivatives. U.S. Department of Commerce.
U.S. Code, 21 U.S.C. §§ 355, 355(j).
U.S. Code, 35 U.S.C. §§ 154, 271(e)(2).

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	85/09882	Apr 17, 1985
United Kingdom	85/25658	Oct 17, 1985

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0199543	⤷ Start Trial	SPC/GB98/033	United Kingdom	⤷ Start Trial
European Patent Office	0199543	⤷ Start Trial	97C0031	Belgium	⤷ Start Trial
Argentina	242569	⤷ Start Trial
Austria	70053	⤷ Start Trial
Austria	74127	⤷ Start Trial
Australia	5616486	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,859,692

Summary for Patent: 4,859,692