United States Patent 4,267,179: Scope, Claims, Expiration, and Itraconazole Patent Landscape

U.S. Patent No. 4,267,179 is the foundational U.S. patent covering a class of substituted azole antifungals associated with Janssen Pharmaceutica, including the triazolone-dioxolane compound later commercialized as itraconazole. The patent issued on May 12, 1981, and its ordinary 17-year term expired on May 12, 1998. The patent therefore has no current blocking force in the United States.

The patent’s commercial importance came from three claim layers:

A broad Markush genus covering substituted azole compounds.
Narrow compound claims directed to specific cis triazolone derivatives and salts, hydrates, and stereoisomers.
A composition claim covering antifungal or antibacterial compositions containing compounds within the genus.

The patent did not create a currently enforceable method-of-use, formulation, or manufacturing monopoly. Later U.S. patents addressed itraconazole formulations, solid-state properties, delivery systems, and manufacturing techniques.

What drug and chemical class does U.S. Patent 4,267,179 cover?

The patent covers substituted azole compounds containing a linked combination of:

A 2,4-dichlorophenyl-substituted 1,3-dioxolane ring;
An imidazole or 1,2,4-triazole methyl substituent;
An aryl ether linkage;
A diphenylpiperazine bridge;
A terminal 1,2,4-triazolin-3-one ring;
Selected alkyl or arylalkyl substituents;
Cis stereochemistry for the specifically claimed examples.

The disclosed compounds are synthetic triazole antifungals. The most commercially significant member is itraconazole, a triazole antifungal marketed by Janssen under the Sporanox brand.

The claim text supplied uses OCR-derived chemical nomenclature and image placeholders such as “##STR68##.” That format obscures the structural drawings, but the named compounds identify the relevant scaffold and species claims.

Which commercial compound is most closely associated with the patent?

The compound most closely associated with the patent is itraconazole. The recognized chemical name for itraconazole is:

(±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-[(1H-1,2,4-triazol-1-yl)methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-(1-methylpropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

Itraconazole is a racemic mixture of cis stereoisomers. It is a lipophilic, orally active triazole that inhibits fungal lanosterol 14-alpha-demethylase and reduces ergosterol biosynthesis.

The supplied claims include closely related compounds with:

Imidazole or triazole substitution;
Methyl, ethyl, or propyl substitution on the terminal triazolone;
Hydrate forms;
Pharmaceutically acceptable acid-addition salts;
Stereochemically isomeric forms.

The species claims should not be treated as interchangeable with the full commercial itraconazole specification without comparing the exact structural formula and stereochemical configuration.

What does claim 1 of U.S. Patent 4,267,179 protect?

Claim 1 is a broad compound claim covering a Markush genus of azole derivatives.

Its principal limitations are:

Claim element	Scope
Core compound	An azole derivative having the patented structural formula
Heteroaromatic variable Q	CH or N
Ar group	Phenyl, thienyl, halothienyl, or substituted phenyl
Phenyl substituents	One to three halo, lower alkyl, lower alkoxy, or trifluoromethyl groups
Y group	A 2,3-dihydro-4H-1,2,4-triazol-4-yl radical
R15	Lower alkyl or aryl lower alkyl
R16	Hydrogen, lower alkyl, or aryl lower alkyl
Salt coverage	Pharmaceutically acceptable acid-addition salts
Stereochemical coverage	Stereochemically isomeric forms

Claim 1 is structurally broad but not unlimited. A potentially infringing compound would need to satisfy every structural limitation, including the designated dioxolane-linked azole framework shown in the missing formula.

How broad is the Markush genus?

The genus reaches compounds in which several positions vary simultaneously. The principal breadth comes from:

Alternative heteroatoms in the azole ring;
Multiple aromatic ring types;
Several permitted aromatic substituents;
Alternative alkyl and arylalkyl groups;
Inclusion of salts;
Inclusion of stereoisomers.

The claim is narrower than a generic “all triazole antifungals” claim. It does not cover unrelated triazole scaffolds such as fluconazole or voriconazole merely because those products contain a triazole ring.

A claim chart for a modern compound would need to map:

The dioxolane ring;
The dichlorophenyl or other permitted aromatic group;
The methylene-linked imidazole or triazole;
The aryl ether;
The piperazine-substituted diphenyl system;
The terminal triazolone;
The permitted R15 and R16 groups.

What do claims 2 through 6 protect?

Claims 2 through 6 are narrow species claims. Each identifies a particular substituted triazolone compound and extends coverage to its pharmaceutically acceptable acid-addition salts and stereochemically isomeric forms.

Claim	Principal species limitation	Commercial relevance
2	Cis compound with an imidazole-containing dioxolane and 2,5-dimethyl triazolone	Related development compound
3	Cis triazole-containing compound identified as a monohydrate	Closely associated with itraconazole-type chemistry
4	Cis triazole compound with a 2-ethyl, 5-methyl triazolone	Related analog
5	Cis triazole compound with a 2-propyl, 5-methyl triazolone monohydrate	Related analog; nomenclature should be checked against the original patent
6	Cis triazole compound with a 2-ethyl triazolone lacking the 5-methyl substituent	Related analog

What is the importance of the hydrate language?

Claims 3 and 5 expressly include monohydrate forms. A hydrate claim can be important where the solid form has different:

Solubility;
Crystallinity;
Stability;
Particle characteristics;
Manufacturing behavior;
Bioavailability.

The claim language, however, does not necessarily establish a separate modern polymorph patent. A later patent could claim a particular crystalline form using X-ray powder diffraction peaks, thermal transitions, water content, or a defined preparation process. Claim 3’s reference to a monohydrate is a species limitation within the original compound patent, not proof that every later itraconazole solid form is covered by that claim.

What does claim 7 protect?

Claim 7 is a composition claim. It covers:

An inert carrier material;
An effective antifungal or antibacterial quantity;
A compound falling within the claim 1 genus;
Use of the composition to combat fungal or bacterial growth.

Claim 7 is broader in subject matter than the species claims but narrower in a different way because it requires a composition with an inert carrier and an active amount.

Does claim 7 cover pharmaceutical formulations?

Potentially, but only if the formulation contains a compound within the claim 1 chemical genus and satisfies the carrier and active-amount limitations.

The claim is not a modern formulation claim directed to:

Specific excipients;
Pellet layering;
Hydroxypropyl-beta-cyclodextrin;
Nanoparticles;
Amorphous dispersions;
Gastro-resistant coatings;
Defined dissolution profiles;
Specific particle sizes;
Controlled release.

Those features could be subject to later formulation patents, but they are not expressly required by claim 7.

Does claim 7 cover antibacterial products?

The claim expressly recites compositions for combating fungi and bacteria. The commercial relevance is primarily antifungal. A product would still need to contain a claimed azole derivative and satisfy the composition limitations. The bacteria language does not expand the chemical claim to unrelated antibacterial agents.

When did U.S. Patent 4,267,179 expire?

The patent issued on May 12, 1981. Under the pre-Uruguay Round patent-term regime, its ordinary term was 17 years from issue. The reported expiration date was May 12, 1998.[1]

Event	Date or status
U.S. patent issue	May 12, 1981
Ordinary term	17 years from issue
U.S. expiration	May 12, 1998
Current enforceability	Expired
Patent-term adjustment relevance	None apparent under the pre-1995 regime
Current generic blocking effect	None from this patent

The patent cannot support a new U.S. infringement action based on activities occurring after expiration. It also cannot block an abbreviated new drug application through a current Orange Book patent listing.

What is the Orange Book status of U.S. Patent 4,267,179?

U.S. Patent 4,267,179 was historically associated with the original itraconazole product franchise, but it is expired and cannot operate as a current Orange Book barrier.

The FDA Orange Book separately tracks:

Approved drug products;
Patent information submitted by NDA holders;
Regulatory exclusivity;
Patent expiration dates;
Paragraph IV certifications;
Approved generic equivalents.

For itraconazole, the relevant reference products have included oral capsules and oral solution products. The status of any particular patent listing depends on the NDA, dosage form, and FDA’s historical listing records.[2]

An expired compound patent can remain relevant to historical litigation and generic-development analysis. It does not provide current regulatory exclusivity.

When did itraconazole lose U.S. market exclusivity?

Itraconazole’s principal compound protection expired in the late 1990s. Regulatory exclusivity and patent protection are separate:

The basic compound patent expired in 1998.
Later formulation patents could extend protection for particular products or dosage forms.
FDA approval of a generic product does not require the generic to infringe a formulation patent if the ANDA product avoids the protected formulation claims.
Pediatric or other statutory exclusivity, if granted for a particular product, would be separate from the compound patent.

The commercial product therefore moved from compound exclusivity to formulation and delivery-system competition.

Which patents later protected itraconazole formulations?

Later itraconazole protection focused on the drug’s poor aqueous solubility and variable oral absorption. Relevant patent categories included:

Capsule and pellet formulations

Sporanox capsules used coated pellets rather than a simple powder-filled capsule. Patent claims in this area generally address combinations of:

Itraconazole particles;
Polymer binders;
Sugar spheres or inert cores;
Coating layers;
Enteric or protective layers;
Dissolution and release behavior.

These claims can be narrower than the basic compound patent but commercially important because they target the product’s marketed dosage form.

Oral solution formulations

Itraconazole oral solution products used cyclodextrin-based solubilization technology. The formulation patent landscape includes claims directed to:

Hydroxypropyl-beta-cyclodextrin;
Itraconazole-cyclodextrin complexes;
Oral liquid compositions;
Solubilizing systems;
Defined drug-to-cyclodextrin ratios.

A generic oral solution could face different patent issues from a generic capsule, even though both contain itraconazole.

Solid-state and particle-property claims

Later patents and applications in the field addressed:

Crystalline forms;
Amorphous itraconazole;
Micronized particles;
Solid dispersions;
Improved dissolution;
Enhanced bioavailability;
Spray-dried or mechanically processed materials.

These claims require technical comparison against the actual generic formulation. A generic company can avoid a solid-form claim by using a different physical form or manufacturing route, subject to regulatory and product-performance requirements.

What patent litigation affected itraconazole products?

The principal litigation risk moved from the expired compound patent to later formulation and delivery patents. Generic applicants historically could use:

Paragraph III certifications for expired patents;
Paragraph IV certifications against listed patents alleged to be invalid, unenforceable, or not infringed;
Non-infringement positions based on formulation differences;
Invalidity challenges against obviousness, written-description, enablement, or claim-construction theories.

Because U.S. Patent 4,267,179 expired in 1998, it could not be the operative patent in a current Paragraph IV dispute. Any later litigation would ordinarily concern a formulation, process, polymorph, method-of-use, or other later-issued patent.

What would a Paragraph IV challenge to an itraconazole formulation patent address?

A Paragraph IV case would typically examine:

Whether the asserted claims cover the ANDA product;
Whether the listed patent claims the approved use or dosage form;
Obviousness of the formulation;
Written description of the claimed solid form;
Enablement;
Anticipation;
Patent-term expiration;
The effect of a section viii statement carving out a patented use.

The original compound patent would not be a viable current litigation target because it is expired.

Are there method-of-use patents in the patent estate?

The supplied claims do not contain a conventional human therapeutic method-of-use claim. Claim 7 is a composition claim for combating microbial growth, not a patient-treatment claim in the modern format of “administering an effective amount to a patient.”

Later patents could claim:

Treatment of onychomycosis;
Treatment of systemic fungal infections;
Treatment of vaginal candidiasis;
Dosing regimens;
Patient populations;
Drug combinations;
Specific oral or topical routes.

For generic approval, an applicant could rely on a section viii statement to omit a patented method from its labeling where the FDA’s regulatory requirements permit that approach. The scope and viability of such a carve-out depend on the exact Orange Book listing and approved labeling.

How strong is the patent estate for itraconazole?

The estate is historically strong at the compound level but weak as a current U.S. exclusivity barrier because the foundational patent expired more than two decades ago.

Estate layer	Historical strength	Current U.S. position
Core chemical compound	High	Expired
Specific stereochemical species	High for named compounds	Expired
Salt and hydrate coverage	Moderate to high	Expired
Basic antifungal composition	Moderate	Expired
Capsule formulation	Product-specific	Depends on later patent status
Oral solution formulation	Product-specific	Depends on later patent status
Solid-state forms	Narrow but potentially enforceable during term	Patent-specific
Manufacturing process	Route-specific	Patent-specific
Method of use	Indication-specific	Patent-specific

The strongest remaining barriers, where unexpired rights exist, would normally be formulation and manufacturing claims rather than the 1981 compound claims.

What generic entry risks exist for itraconazole?

Generic entry risk depends on the dosage form.

Itraconazole capsules

Capsule competition is primarily affected by:

Bioequivalence requirements;
Dissolution performance;
Pellet or particle structure;
Formulation patent claims;
Residual Orange Book listings;
Product-specific litigation settlements.

Itraconazole oral solution

Oral solution entrants face different issues:

Cyclodextrin content;
Solubilization technology;
Taste and excipient profile;
Bioequivalence or clinical bridging;
Formulation patents;
Labeling carve-outs.

Itraconazole injection

The U.S. injection product had separate formulation and regulatory considerations. Injection products may require different excipient, stability, and manufacturing analyses from oral products. A capsule generic cannot substitute for an injectable product in patent or regulatory analysis.

Which companies compete with Janssen in itraconazole?

The competitive landscape includes:

Janssen, the original innovator associated with Sporanox;
Generic manufacturers supplying itraconazole capsules or oral solution;
Specialty pharmaceutical companies developing improved itraconazole delivery systems;
Companies commercializing supersaturated, amorphous, nanoparticle, or solid-dispersion versions;
Contract manufacturers supplying active pharmaceutical ingredient and finished dosage forms.

The commercial advantage of later products generally depends on improved exposure, reduced food dependence, better dissolution, lower variability, or simplified administration rather than on ownership of the expired compound patent.

What geographic patent coverage remains relevant?

The U.S. patent expired in 1998. Foreign rights depended on the applicable national patent term and the prosecution history of the corresponding family members.

For a global freedom-to-operate analysis, the relevant jurisdictions include:

European countries covered by national or regional filings;
Japan;
Canada;
Australia;
Latin American markets;
Emerging markets with local formulation or process patents.

A patent family can have different expiration dates because of:

Different filing dates;
National-phase timing;
Patent-term extensions;
Supplementary protection certificates;
Divisional applications;
Terminal disclaimers;
Local prosecution outcomes.

The original compound family is now generally historic in major markets. Later formulation and process families must be analyzed separately by jurisdiction.

What manufacturing and intellectual-property barriers remain?

Manufacturing risk can persist after compound-patent expiration. Key barriers include:

Control of itraconazole particle size;
Crystallization and polymorph control;
Stable incorporation into pellet layers;
Uniform coating;
Cyclodextrin complex formation;
Dissolution reproducibility;
Impurity control;
Scale-up of amorphous or solid-dispersion systems;
Bioequivalence of poorly soluble products.

A manufacturer may avoid the expired composition claims and still face later process or formulation patents. Conversely, a technically different process can reduce patent exposure while increasing development cost and regulatory risk.

Key Takeaways

U.S. Patent 4,267,179 is the foundational U.S. compound patent for a substituted azole antifungal class associated with itraconazole.
Claim 1 is a broad Markush genus claim covering defined dioxolane-linked azole structures, aromatic substituents, triazolone groups, salts, and stereoisomers.
Claims 2 through 6 are narrow species claims directed to specific cis compounds, including hydrate forms.
Claim 7 covers antifungal or antibacterial compositions containing compounds within the genus.
The patent issued May 12, 1981, and expired May 12, 1998.
The patent has no current U.S. blocking effect and cannot support a present Paragraph IV challenge.
Later commercial risk shifted to capsule, oral-solution, solid-state, method-of-use, and manufacturing patents.
Itraconazole generic risk is dosage-form specific. Capsule and oral-solution products require separate patent and regulatory analyses.
The original compound patent does not cover all triazole antifungals. Claim scope depends on the complete structural formula and every recited substituent.

Frequently Asked Questions

Is itraconazole still protected by U.S. Patent 4,267,179?

No. The patent expired on May 12, 1998.

Does U.S. Patent 4,267,179 cover fluconazole or voriconazole?

No. The patent’s structural claims are directed to a distinct dioxolane-linked azole and triazolone framework. Chemical comparison is required for any specific compound.

Can a generic company manufacture itraconazole after expiration of the patent?

Yes, subject to FDA approval and any unexpired patents covering the selected formulation, manufacturing process, solid form, or method of use.

Does claim 3 protect every itraconazole monohydrate?

Not necessarily. Claim 3 covers the specifically recited compound in monohydrate form and its stated salts and stereochemical forms. A separate solid-form claim would require its own claim-element analysis.

Are later itraconazole formulation patents more important than the original compound patent?

Yes. Once the compound patent expired, commercial exclusivity depended primarily on dosage-form, formulation, solid-state, manufacturing, and method-of-use rights.

References

United States Patent and Trademark Office. (1981). U.S. Patent No. 4,267,179: Azole derivatives. 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.). Orange Book: Approved drug products with therapeutic equivalence evaluations, patent and exclusivity information. Center for Drug Evaluation and Research.
Janssen Pharmaceutica, N.V. (1992). Sporanox (itraconazole) prescribing information. U.S. Food and Drug Administration.
United States Congress. (1984). Drug Price Competition and Patent Term Restoration Act of 1984, Pub. L. No. 98-417, 98 Stat. 1585.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0006711	⤷ Start Trial	SPC/GB93/038: EXPIRE	United Kingdom	⤷ Start Trial
Austria	5140	⤷ Start Trial
Austria	5479	⤷ Start Trial
Australia	4816079	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 4,267,179