United States Drug Patent 4,680,291: Claim Scope, Expiration, Patent Landscape, and Generic Risk

United States Patent No. 4,680,291 is an expired pre-URAA pharmaceutical patent directed to substituted allylamine and related amine compounds, pharmaceutical compositions, and antifungal treatment methods. The claims cover a large Markush genus that includes naphthylmethyl-substituted allylamines, heteroaryl analogues, cyclic amines, enamines, and related compounds. The patent issued on July 14, 1987, and its ordinary 17-year patent term expired on July 14, 2004, absent an unusual term adjustment or extension. The patent therefore presents no current U.S. blocking right.

The claim set has historical importance because it appears to encompass compounds associated with the early allylamine antifungal field, including structures related to naftifine-type chemistry. Patent expiration eliminates direct infringement risk under this patent, but separate later patents, regulatory exclusivities, trademarks, formulation rights, and patents covering particular commercial products must be assessed independently.

What does U.S. Patent 4,680,291 cover?

The patent covers four principal subject-matter categories:

Substituted amine compounds defined by extensive Markush structures.
Pharmaceutical compositions containing those compounds.
Methods for treating mycoses in animals.
Specifically identified chemical species and subgenera.

The core chemical architecture is an amine-containing molecule in which one substituent is an aryl, heteroaryl, fused-ring, or related hydrophobic group and another substituent contains an unsaturated carbon chain terminating in an aromatic, heteroaromatic, carbonyl, cyclic, or substituted alkyl group.

The claim language allows substantial variation in:

The N-substituted aryl group, including naphthyl, benzothiophene, acenaphthene, phenalenyl, tetralinyl, and related fused-ring systems.
N-alkyl substitution, principally hydrogen or lower alkyl.
The carbon chain connecting the amine to the second substituent.
E/Z or cis/trans alkene geometry in expressly identified compounds.
Heteroaryl groups, including thiophene, furan, and pyridine derivatives.
Carbonyl, ester, amide, cycloalkyl, phenyl, and phenylalkyl substituents.
Cyclic amines formed when two substituents join through an alkylene chain.
Chemotherapeutically acceptable salts.

The broadest independent chemical claim is claim 1. Claims 3 through 6 and 8 through 11 identify selected compounds or narrower structural classes. Claims 12 through 24 focus on specific formulas, including acyclic allylamines and cyclic compounds. Claims 25 through 29 identify additional named compounds. Claims 30 through 42 narrow the substituent classes or restate particular structural alternatives.

How broad is claim 1 of U.S. Patent 4,680,291?

Claim 1 is a large Markush claim with two principal alternatives.

Alternative 1: acyclic or cyclic amine structures

Under paragraph (a), the claim covers compounds where:

R1 is an aromatic or heteroaromatic radical defined through formulas IIa to IIe; and
R2 is hydrogen or lower alkyl; or
R1 and R2 jointly form a cyclic radical under formulas IIf or IIg.

The R1 definitions include substituted phenyl-like systems, fused aromatic structures, heterocycles, oxygen- or sulfur-containing rings, nitrogen-containing rings, and polymethylene-linked structures.

The R6 substituent at the opposite end of the molecule is also broad. It can be:

An optionally substituted five-membered heteroaromatic ring.
A substituted aromatic radical.
A carbonyl-containing group.
An alkyl, alkenyl, alkynyl, cycloalkylalkyl, phenylalkyl, phenyl, phenylalkoxy, or aminoalkyl group.
A substituted cyclic or fused-ring structure.
A formula IIIf or IIIg radical containing additional alkyl, aryl, or heteroaryl substitution.

The claim contains a proviso excluding certain combinations. Those exclusions matter because they prevent the claim from covering every theoretical combination of the listed R1 and R6 groups.

Alternative 2: fused or ring-closed structures

Under paragraph (b), R1 remains an aromatic or heteroaromatic radical, while R3 and R4 together form an alkylene bridge of one to eight carbon atoms. This captures cyclic or partially cyclic amine structures.

The practical claim scope is therefore broader than a single marketed molecule. It covers a chemical platform with several structural series.

Which specific compounds are expressly claimed?

The patent separately claims multiple named or structurally defined compounds.

Claim	Representative subject matter
3	Formula Ig compounds with 1-naphthyl-type R1 groups and selected ester, substituted aromatic, or cyclic R6 groups
4	Formula Ih compounds with specified heteroaryl and substituted aromatic R1 groups
5	Formula Ii compounds excluding selected cyclic R3/R4 arrangements
6	N-(3-cyclohex-1-en-1-yl-2-trans-propenyl)-N-methyl-N-(1-naphthylmethyl)amine
7	Antifungal treatment method in animals
8	4-[N-methyl-N-(1-naphthylmethyl)]aminocrotonic acid ethyl ester
9	Cis-cyclohexenyl propenyl naphthylmethylamine
10	Cyclohexyl propenyl naphthylmethylamine
11	Methylthiophenyl propenyl naphthylmethylamine
12	Formula Ie: R1-CH2-N(CH3)-CH2-CH=CH-R6
13-19	Formula Ie species involving naphthyl, benzothienyl, thiophenyl, pyridyl, cycloalkenyl, and related groups
20-24	Formula If compounds, including naphthyl and phenyl species with three- to five-carbon bridges
25-29	Additional named fused-ring and phenyl-substituted amines
30-35	Selected R6 subgenus limitations
36	Ring-closed R3/R4 embodiments
37-42	Additional formula, substituent, and fused-ring subgenera

The claims supplied contain apparent transcription or formatting errors, including inconsistent formula labels and a malformed alkylene notation in claim 36. The issued patent drawings and official claim text control over any OCR-derived version. Those errors do not change the patent’s expiration status.

Does the patent cover naftifine or a naftifine-type compound?

The claim set is chemically related to naftifine-type allylamine antifungals, but a product identification requires exact structural comparison.

Naftifine is generally identified as an N-methyl-N-(1-naphthylmethyl)-3-phenyl-2-propen-1-amine structure. Formula Ie in claim 12 has the general arrangement:

R1-CH2-N(CH3)-CH2-CH=CH-R6

When R1 is 1-naphthyl and R6 is phenyl, that formula is chemically consistent with a naftifine-type structure. Claim 12 is therefore the most relevant claim for an ordinary naphthylmethyl-substituted allylamine comparison.

That conclusion should not be extended automatically to every commercial product bearing a similar therapeutic name. Patent infringement depends on the exact molecular structure, stereochemistry, salt form, formulation, and claim construction.

When did U.S. Patent 4,680,291 lose exclusivity?

Event	Date or status
Patent issue	July 14, 1987
Applicable term framework	Pre-URAA, generally 17 years from issue
Ordinary expiration	July 14, 2004
Current status	Expired
Current enforceability	No enforceable exclusionary term under the expired patent
Patent-term extension relevance	No current term remains under this patent

The patent was issued before the transition to the 20-year-from-earliest-effective-filing-date system. Under the pre-URAA framework, the ordinary term was 17 years from grant, subject to historical adjustments and extensions under applicable law [1][2].

Patent expiration places the claimed compounds and methods in the public domain in the United States. It does not invalidate later patents covering a particular formulation, manufacturing process, crystalline form, salt, dosage form, or method of use.

What is the Orange Book status of U.S. Patent 4,680,291?

U.S. Patent 4,680,291 cannot presently create an Orange Book exclusivity barrier because it expired in 2004.

The Orange Book lists patents submitted by an approved drug applicant for an approved drug product. Listing practice distinguishes patents claiming the active ingredient, drug product, formulation, composition, or approved method of use from patents that do not meet the applicable listing standards [3]. A historical patent may have been relevant to an original NDA or branded product, but its current listing would not preserve enforceable exclusivity after expiration.

No Paragraph IV notice directed solely to an expired patent can delay approval under the Hatch-Waxman framework. A generic applicant may still need to address other unexpired patents listed for the reference product.

Are there current Paragraph IV risks under this patent?

No. U.S. Patent 4,680,291 is expired, so it cannot support a current Paragraph IV stay or a valid patent-based launch delay.

For an approved small-molecule antifungal product, current Paragraph IV exposure would instead depend on:

Unexpired Orange Book-listed formulation patents.
Method-of-use patents.
Salt, polymorph, particle-size, or crystalline-form patents.
Delivery-system patents.
Manufacturing-process patents, if listed or otherwise enforceable.
Regulatory exclusivities separate from patent rights.

A generic applicant could still file a Paragraph IV certification against a different unexpired patent. That would be legally unrelated to the expired ’291 patent.

What formulations are protected by U.S. Patent 4,680,291?

Claim 2 covers a pharmaceutical composition containing a therapeutically effective amount of a claim 1 compound with a chemotherapeutically acceptable diluent or carrier.

This is a functional composition claim. It does not identify a specific cream, gel, spray, tablet, capsule, solution, suspension, or transdermal system. The claim is broad at the level of the active compound plus a carrier, but its enforceability ended with patent expiration.

The patent does not, from the supplied claim text, create a durable formulation estate directed to:

Specific excipient ratios.
Particle size.
Cream or gel rheology.
Preservative systems.
Packaging.
Skin-penetration enhancers.
Controlled release.
Specific salt or polymorph forms.

Those subjects would generally require separate claims and separate patent support.

What method-of-use rights does claim 7 provide?

Claim 7 covers administering an antimycotic amount of a claim 1 compound to an animal to combat mycoses in or on the animal.

The claim is not limited to a particular fungal species, anatomical site, dosage form, administration route, or treatment duration. It is broad in therapeutic intent but depends on use of a compound falling within claim 1.

The method claim expired with the patent. It therefore does not block current treatment methods, generic products, veterinary products, or human topical products.

How strong was the patent estate?

The patent was structurally broad but commercially vulnerable to the normal limitations of a large Markush estate.

Strengths

Broad chemical genus covering multiple aromatic, heteroaromatic, cyclic, and fused-ring systems.
Express coverage of pharmaceutical compositions.
Express antifungal method claim.
Multiple dependent claims directed to named compounds.
Coverage of both acyclic and ring-closed amine architectures.
Salt coverage through the “chemotherapeutically acceptable salt” language.

Limitations

Numerous provisos carve out combinations from the genus.
Structural interpretation depends heavily on the patent’s formula drawings.
The claim set appears to contain transcription inconsistencies.
A compound must satisfy every applicable limitation, including substitution, chain length, ring size, and exclusion clauses.
The patent has been expired for more than two decades.
Later patents could have narrowed commercial protection around particular products.

The patent is therefore relevant as a historical platform patent, not as a current enforcement asset.

What patent litigation or settlement agreements affect the patent?

The supplied record identifies no litigation, Paragraph IV settlement, covenant not to sue, license agreement, or consent judgment involving U.S. Patent 4,680,291.

Because the patent expired in 2004, any historical litigation would have no continuing exclusionary effect unless it produced obligations independent of patent validity, such as a contractual license, royalty provision, or settlement restriction. Patent litigation involving a related antifungal product or a later patent should not be attributed to the ’291 patent without a case-specific record.

Does the patent create biosimilar risk?

No. Biosimilar law applies to biological products, not conventional small-molecule compounds of the type claimed here [4]. Any competitive threat involving these compounds would arise through an ANDA, a 505(b)(2) application, an ordinary abbreviated application, or a commercial product introduced after patent expiration.

What is the geographic coverage of the patent?

U.S. Patent 4,680,291 had territorial effect only in the United States. It did not directly control manufacture, sale, use, or importation in Europe, Japan, Canada, or other jurisdictions.

The related international estate would have required separate national patents. Foreign counterparts may have had different:

Filing dates.
Claim scope.
Patent terms.
Opposition histories.
Validity outcomes.
Supplementary protection certificates.
Expiration dates.

A U.S. expiration analysis does not establish freedom to operate in another country.

What generic launch scenarios exist after expiration?

The principal U.S. launch scenarios are:

A generic compound product relying on the expired compound claims.
A topical product relying on an ANDA or 505(b)(2) pathway, depending on the reference product and dosage form.
A product using a different salt, formulation, or delivery system protected by later patents.
A non-infringing product that avoids later formulation and method claims.
A licensed product where commercial rights, rather than patent rights, control market entry.

The expired patent removes the principal early-platform barrier. Remaining launch risk must be assessed at the product level.

Key Takeaways

U.S. Patent 4,680,291 is an expired pre-URAA patent issued July 14, 1987.
Its ordinary patent term ended July 14, 2004.
Claim 1 covers a broad Markush genus of substituted allylamine and related amine antifungal compounds.
Claims 2 and 7 cover pharmaceutical compositions and antifungal treatment methods.
Claims 6, 8-11, 13-19, 21-29, and 38-42 identify narrower compounds or subgenera.
Formula Ie, particularly the 1-naphthyl/N-methyl allylamine series, is the most relevant portion for naftifine-type chemistry.
The patent cannot support a current Paragraph IV stay or Orange Book exclusivity.
Biosimilar law is not relevant because the claimed products are small molecules.
Later formulation, salt, polymorph, manufacturing, delivery, or method-of-use patents require a separate freedom-to-operate analysis.
The U.S. expiration does not determine the status of foreign counterpart patents.

FAQs About U.S. Patent 4,680,291

Is U.S. Patent 4,680,291 still enforceable?

No. Its ordinary 17-year term expired on July 14, 2004.

Does the patent cover a compound with a 1-naphthylmethyl-N-methyl allylamine structure?

Potentially. Formula Ie and related claims cover multiple 1-naphthylmethyl-N-methyl allylamine embodiments, but exact coverage depends on the R6 substituent, alkene arrangement, and applicable provisos.

Can an expired patent be used in a Paragraph IV certification?

A generic applicant may identify an expired patent in an ANDA certification record, but the expired patent cannot create a current statutory stay or prevent approval.

Are topical antifungal formulations protected by claim 2?

Claim 2 broadly covers a composition containing a claim 1 compound and a carrier. It does not preserve current exclusivity because the claim expired and does not specify a modern commercial formulation.

Does U.S. expiration mean the corresponding European patents also expired?

No. Each foreign patent must be reviewed separately. National filing dates, term rules, supplementary protection certificates, and prosecution histories can produce different outcomes.

References

U.S. Patent No. 4,680,291. (1987). Substituted amine compounds, pharmaceutical compositions, and methods for combating mycoses. United States Patent and Trademark Office.
United States Code, 35 U.S.C. § 154. (2024). Contents and term of patent; provisional rights.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (2024). Biological product and biosimilar regulatory framework. U.S. Department of Health and Human Services.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Switzerland	10203	Aug 19, 1977
Switzerland	10202	Aug 19, 1977
Sweden	12909	Oct 24, 1977
Switzerland	12910	Oct 24, 1977

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	366659	⤷ Start Trial
Austria	366660	⤷ Start Trial
Austria	375063	⤷ Start Trial
Austria	A602578	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,680,291

Summary for Patent: 4,680,291