United States Drug Patent 4,358,449: Claim Scope, Expiration, and Patent Landscape

U.S. Patent No. 4,358,449 is an early Janssen-related patent covering substituted azole antifungal compounds built around a 2,4-dichlorophenyl-1,3-dioxolane pharmacophore. Its claims cover a broad chemical genus, five specifically identified compounds, pharmaceutically acceptable acid-addition salts, stereoisomers, and microorganism-control compositions. The patent issued in 1982 and expired under the pre-URAA 17-year patent term in 1999. It does not create a current barrier to generic entry, ANDA approval, or commercial development.

What compounds does U.S. Patent 4,358,449 protect?

The patent protects azole derivatives containing the following core elements:

Structural element	Claimed requirement
Heteroaromatic azole	Q is nitrogen, corresponding to a 1,2,4-triazol-1-yl group
Aromatic substituent	Phenyl or substituted phenyl
Permitted phenyl substituents	One to three halo, lower-alkyl, or lower-alkoxy groups
Dioxolane framework	A substituted 1,3-dioxolane ring
Aryl ether or related linker	A radical containing a direct bond, methylene, oxygen, or substituted nitrogen
Nitrogen substituent	Hydrogen or one of a wide range of alkyl, acyl, sulfonyl, carbamoyl, benzyl, benzoyl, and related groups
Terminal stereochemistry	Hydrogen at the specified position, with stereoisomeric forms expressly included
Salt form	Pharmaceutically acceptable acid-addition salts

The claim language is characteristic of a Markush genus. It attempts to capture numerous chemical variants that share the same antifungal scaffold while allowing substitution at the aryl and nitrogen-containing portions of the molecule.

The missing structural drawings identified in the patent as “STR57” through “STR60” are important to the precise interpretation of the Markush formula. The textual limitations nevertheless establish the principal scope: substituted triazolylmethyl dioxolane derivatives with an aryl-containing side chain and specified nitrogen substitution.

How broad is claim 1 of U.S. Patent 4,358,449?

Claim 1 is the principal compound claim and has the broadest chemical scope. It covers:

The defined azole derivative genus.
Pharmaceutically acceptable acid-addition salts.
Stereochemically isomeric forms.

The claim is broader than claims 2 through 6 because it is not limited to the five named compounds. It covers compounds selected from the specified structural class, subject to every limitation in the Markush definition.

Scope of the Markush substitutions

The claim permits substitution on the phenyl ring by halo, lower alkyl, or lower alkoxy groups. “Halo” ordinarily includes fluorine, chlorine, bromine, and iodine unless the specification narrows the term. “Lower alkyl” and “lower alkoxy” generally refer to short-chain groups, commonly containing up to six carbon atoms, but the patent specification controls the precise interpretation.

The nitrogen-linked variable R4 is particularly important. It includes:

Hydrogen
Lower alkyl
Hydroxyalkyl
Alkoxyalkyl
Lower alkanoyl
Lower alkylsulfonyl
Phenylmethylsulfonyl
Alkoxycarbonyl
Alkoxycarbonylmethyl
Phenoxycarbonyl
Aminocarbonyl
Mono- and dialkylaminocarbonyl
Aminocarbonylmethyl
Alkylaminocarbonylmethyl
Alkylaminothioxomethyl
Alkylthiothioxomethyl
Phenyl
Benzyl
Benzoyl
Substituted benzoyl

This list is broad in functional-group terms, but it is not unlimited. A candidate compound must satisfy the full combination of the claimed azole, dioxolane, aryl, linker, and nitrogen-substitution requirements.

What compounds are specifically covered by claims 2 through 6?

Claims 2 through 6 identify individual compounds. Each claim also covers the corresponding pharmaceutically acceptable acid-addition salts and stereoisomeric forms.

Claim	Specifically identified compound	Key terminal group
2	Cis-methyl 4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazine-carboxylate	Methyl carbamate
3	Cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}piperazine	Secondary piperazine
4	Cis-4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinecarboxaldehyde	Formyl carbamate
5	4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}morpholine	Morpholine
6	Cis-1-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-4-(1-methylethyl)piperazine	N-isopropyl piperazine

The five claims are narrower than claim 1 because they identify fixed chemical structures rather than a variable genus. They may provide stronger literal infringement positions against the exact named compounds, but they have less reach against structurally distinct analogs.

What does claim 7 protect?

Claim 7 is a composition claim. It covers a composition for combating a microorganism selected from fungus and bacterium that contains:

An inert carrier material; and
An effective amount of a compound within the claim 1 genus.

The composition claim is not a general claim to every use of the compounds. It requires a microorganism-control composition and an inert carrier. The claim also incorporates the full structural limitations of the compound genus.

Practical scope of claim 7

Claim 7 could historically have reached:

Agricultural antifungal compositions
Veterinary antifungal compositions
Topical or environmental antimicrobial preparations
Other compositions using an inert carrier and an active compound within the claimed genus

The claim does not expressly limit the carrier to a particular dosage form, route of administration, concentration, or manufacturing process. It also does not include a method-of-treatment format. Its enforceability against a particular product would have depended on whether the product contained the claimed active compound and satisfied the carrier and effective-amount limitations.

When did U.S. Patent 4,358,449 expire?

U.S. Patent 4,358,449 issued on January 12, 1982. Because it is a pre-June 8, 1995 patent, its ordinary term was generally 17 years from issuance under the law then in effect. On that basis, the patent expired on January 12, 1999, absent a terminal disclaimer or unusual term adjustment.

Event	Date
Patent issuance	January 12, 1982
Ordinary patent term	17 years from issuance
Expected expiration	January 12, 1999
Current status	Expired
Current blocking effect	None as an enforceable U.S. patent right

The Hatch-Waxman patent-term extension provisions do not normally create a new term for an old compound patent unless the patent and approved product satisfy the statutory requirements. No current enforceable term should be attributed to this patent based solely on the claim language supplied. Patent term adjustment also generally does not alter the term of a patent issued under the pre-URAA framework in a manner that would extend it into the present period. (35 U.S.C. §§ 154, 156.)

What is the Orange Book status of U.S. Patent 4,358,449?

U.S. Patent 4,358,449 has no current Orange Book blocking significance because it expired in 1999. FDA Orange Book listings can identify patents submitted for approved drug products, but an expired patent cannot support a current patent-based delay of ANDA approval.

The patent also does not appear, from the claim language supplied, to be a modern product-specific Orange Book patent directed to a currently marketed dosage form. Its claims are primarily directed to chemical compounds and a broad microorganism-control composition.

An applicant evaluating a later generic product would therefore not face a live Paragraph IV challenge against this patent. A Paragraph IV certification is relevant to an unexpired listed patent that the applicant asserts is invalid, unenforceable, or not infringed. For an expired patent, the relevant certification would ordinarily be that the patent has expired, rather than a conventional Paragraph IV validity or infringement challenge. (FDA, 2024a; 21 U.S.C. § 355(j)(2)(A)(vii).)

Are there method-of-use or formulation patents in this patent?

No method-of-use patent is presented in the supplied claims. Claim 7 is a composition claim, not a method claim. It requires an active azole compound, an inert carrier, and use in a composition for combatting fungus or bacterium.

The patent also does not claim:

A specific tablet formulation
A capsule formulation
A particular oral solution
A spray-dried dispersion
A cyclodextrin complex
A nanoparticle or amorphous solid dispersion
A controlled-release system
A specific excipient combination
A manufacturing process
A dosage regimen
A treatment method for a named disease

Any such rights would have to arise from separate patents or applications in the relevant family or from later formulation and product-development patents.

How does this patent compare with later azole antifungal patents?

The patent belongs to the earlier generation of triazole antifungal chemistry. Its key technical motif is a 2,4-dichlorophenyl-substituted 1,3-dioxolane connected through an aryl ether to a nitrogen-containing heterocycle.

Later azole patents often narrowed one or more of the following:

Patent strategy	Difference from U.S. 4,358,449
Specific active ingredient	Claims one defined molecule rather than a broad genus
Enantiomer or cis isomer	Limits the stereochemical configuration
Salt or polymorph	Targets a solid-state or salt form
Formulation	Claims bioavailability, dissolution, or delivery technology
Manufacturing process	Claims a particular reaction sequence or purification step
Indication	Claims treatment of a defined fungal disease
Combination therapy	Claims an azole with another active ingredient
Improved exposure	Claims a formulation or dosage form that raises systemic exposure

A generic developer must separate the expired genus patent from any later active patents covering a particular commercial active ingredient, salt, polymorph, formulation, or manufacturing process. The expiration of U.S. 4,358,449 removes one historical layer of protection but does not establish freedom to operate for every later azole product.

Does the patent cover itraconazole?

The claimed chemistry is structurally related to the triazole-dioxolane class associated with later commercial antifungals, including compounds developed by Janssen. The claims supplied do not, on their face, expressly identify itraconazole by name.

The listed compounds in claims 2 through 6 have methyl carbamate, unsubstituted piperazine, formyl, morpholine, or N-isopropyl piperazine terminal groups. Itraconazole has a more complex substituted piperazine-triazolone architecture. Whether a particular itraconazole structure falls within claim 1 depends on the omitted structural formulas and the precise definition of the variable A and Z groups in the issued patent.

Accordingly, the five specifically named compounds should not be treated as itraconazole. The broad genus claim may be chemically relevant to the same research program, but direct coverage requires a complete claim chart against the issued drawings and every limitation of claim 1.

Which patent-law risks remain for a commercial product?

For a present-day product, U.S. 4,358,449 presents no ordinary infringement risk because the patent is expired. The main residual issues are historical and transactional:

Patent-family diligence

A company reviewing a compound associated with this patent should identify:

Continuations
Divisionals
Continuations-in-part
Foreign counterparts
Later patents claiming selected species
Patents claiming commercial salts or formulations
Regulatory exclusivity associated with an approved product

A patent family may contain later-issued patents with different expiration dates even when the original genus patent has expired.

Manufacturing and process rights

A process patent can create a separate barrier even when the compound patent is expired. Relevant risks include:

Enantioselective synthesis
Cis/trans isomer separation
Crystallization
Salt formation
Purification
Intermediate compounds
Solid-state forms
Improved yield or impurity-control processes

Biosimilar risk

Biosimilar analysis is not applicable to the claimed compounds as small-molecule azole drugs. These are chemically synthesized small molecules, not biologic products subject to the abbreviated licensure pathway under the Public Health Service Act. The relevant competitive pathway is generally ANDA approval or, for an unapproved active ingredient, a full NDA or other applicable FDA pathway.

Which companies challenged U.S. Patent 4,358,449?

No current Paragraph IV litigation can arise against U.S. Patent 4,358,449 because the patent expired more than two decades ago. The supplied record does not establish a current infringement action, ANDA challenge, or settlement agreement involving this patent.

Any historical litigation search should distinguish this patent from later Janssen patents covering specific triazole products, formulations, or manufacturing processes. A settlement involving a related patent would not automatically apply to U.S. 4,358,449.

How strong is the patent estate today?

The patent’s historical claim breadth was substantial, but its present commercial strength is zero as an enforceable U.S. right.

Factor	Assessment
Chemical genus breadth	Broad
Named species coverage	Moderate to strong for exact structures
Stereochemical coverage	Expressly included
Salt coverage	Expressly included
Formulation coverage	Limited
Method-of-use coverage	Not present in supplied claims
Manufacturing coverage	Not present in supplied claims
Current U.S. enforceability	None
Orange Book blocking value	None based on expiration
Generic entry impact	No current delay or patent barrier

Key Takeaways

U.S. Patent 4,358,449 claims a broad genus of substituted triazole-containing 1,3-dioxolane compounds.
Claims 2 through 6 identify five specific cis or unsubstituted compounds with piperazine or morpholine substituents.
Claim 7 covers microorganism-control compositions containing a claimed compound and an inert carrier.
The patent does not, based on the supplied claims, directly claim a specific dosage form, manufacturing process, treatment method, or biologic.
The patent issued on January 12, 1982, and its ordinary 17-year term expired on January 12, 1999.
It has no current Paragraph IV, Orange Book, generic-delay, or biosimilar significance.
Freedom-to-operate analysis must still review later patents covering specific active ingredients, salts, polymorphs, formulations, manufacturing processes, and therapeutic uses.
The omitted structural drawings are material to any definitive claim chart for claim 1 and to determining coverage of a specific later-developed azole compound.

FAQs

Does an expired patent still affect FDA approval?

An expired patent does not block FDA approval or trigger a current 30-month stay. FDA may still require the applicant to address listed patents for the reference product, but an expired patent cannot provide a current patent-based delay.

Can a company practice the exact compound in claim 2 today?

In the United States, the expired patent no longer prevents practice of the claimed compound. Separate active patents, regulatory controls, trade secrets, or contractual restrictions could still affect commercialization.

Are acid-addition salts independently covered?

Yes. Claims 1 through 6 expressly include pharmaceutically acceptable acid-addition salts of the claimed compounds.

Does claim 7 cover a method of treating a fungal infection?

No. Claim 7 is drafted as a composition claim. It requires a composition containing an inert carrier and an effective amount of a claimed compound for combating a fungus or bacterium.

Is a later polymorph automatically covered by this patent?

Not automatically. A polymorph may contain the same claimed compound, but the expired status of this patent eliminates current enforcement. Any separate polymorph protection would have to come from a later patent with its own claim limitations and term.

References

U.S. Patent No. 4,358,449. (1982). Azole derivatives and compositions containing them. United States Patent and Trademark Office.
U.S. Food and Drug Administration. (2024a). Approved drug products with therapeutic equivalence evaluations. FDA.
U.S. Food and Drug Administration. (2024b). Approved drug product patent and exclusivity information. FDA.
21 U.S.C. § 355. (2024). New drugs and abbreviated applications.
35 U.S.C. § 154. (2024). Contents and term of patent; provisional rights.
35 U.S.C. § 156. (2024). Extension of patent term.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	366683	⤷ Start Trial
Austria	A63678	⤷ Start Trial
Australia	3285078	⤷ Start Trial
Australia	521329	⤷ Start Trial
Belgium	863382	⤷ Start Trial
Canada	1094559	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,358,449

Summary for Patent: 4,358,449