US Patent 4,335,125: Ketoconazole Claims, Scope, Expiration and Patent Landscape

US Patent 4,335,125 is the foundational US composition-of-matter patent for ketoconazole and related substituted dioxolane imidazole compounds. It covers a broad Markush genus, several specifically claimed ketoconazole derivatives, pharmaceutical salts and stereoisomers, and antimicrobial compositions containing the compounds. The patent issued June 15, 1982, and its original 17-year term expired June 15, 1999. It no longer blocks generic manufacture, sale or use in the United States.[1]

The patent is commercially important because claims 3, 8 and 9 identify ketoconazole or its cis form, the active pharmaceutical ingredient in Nizoral tablets, cream and shampoo. The patent does not, on the face of the supplied claims, claim a particular dosage regimen, topical vehicle, shampoo formulation, tablet excipient system, manufacturing process or method of treating a named disease.

What drug does US Patent 4,335,125 protect?

US Patent 4,335,125 protects ketoconazole and a broad family of related imidazole-containing 1,3-dioxolane compounds.

Ketoconazole is the compound identified in claims 3 through 9 as a substituted phenyl-piperazine derivative containing:

A 2,4-dichlorophenyl-substituted 1,3-dioxolane ring
An imidazol-1-ylmethyl substituent
A phenoxy-linked piperazine or morpholine group
A para-substituted phenyl ether linkage
Various piperazine N-substituents in the claimed analogs

The core ketoconazole structure is commonly represented as:

cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine.

The patent is assigned to Janssen Pharmaceutica, the Johnson & Johnson pharmaceutical business associated with development and commercialization of Nizoral.[1][2]

What is the relationship between the patent and Nizoral?

Nizoral is the original ketoconazole brand. FDA-approved dosage forms included oral tablets, topical cream and shampoo products. The patent's compound claims provided the principal early US exclusivity for ketoconazole as an active ingredient.

FDA labeling identifies ketoconazole as an imidazole antifungal agent. The oral product was approved for systemic fungal infections, while topical products were approved for dermatologic and seborrheic conditions. Oral ketoconazole later became subject to major FDA safety restrictions because of hepatotoxicity and adrenal effects.[2][3]

How broad are the claims of US Patent 4,335,125?

The patent contains three principal claim layers:

Broad chemical genus claims.
Narrower chemical subgenus claims.
Specific compound and antimicrobial composition claims.

Claims 1 and 2: Markush chemical genus

Claim 1 covers an azole derivative defined by a formula in which:

Q is CH.
Ar is phenyl or substituted phenyl.
The phenyl ring may contain up to three halo, lower-alkyl or lower-alkoxy substituents.
A is a substituted dioxolane-linked aryl radical.
Z may be a direct bond, CH2, oxygen or N-R4.
R is hydrogen.
The compounds may exist as pharmaceutically acceptable acid-addition salts and stereoisomeric forms.

This is a classic Markush claim. It protects a potentially large chemical genus rather than one commercial molecule. The breadth comes from the permitted variation at Ar, Z and R4.

Claim 2 narrows claim 1 by limiting Z to N-R4. The R4 group remains broad and includes alkyl, hydroxyalkyl, acyl, sulfonyl, carbamoyl, carbamate, phenyl, benzyl and benzoyl-type substituents.

The practical scope of claims 1 and 2 depends on the exact structural drawings, the specification's definitions of "lower alkyl" and related terms, and the prosecution history. The text supplied omits the chemical figures represented by ##STR##; those figures are essential to a complete literal claim chart.

Claims 3 through 7: Named compound species

Claims 3 through 7 identify specific derivatives:

Claim	Compound identified	Commercial relevance
3	1-acetyl piperazine ketoconazole derivative	Ketoconazole species
4	Morpholine analog	Noncommercial or development analog
5	N-methyl piperazine carboxamide analog	Noncommercial or development analog
6	Ethyl piperazine carboxylate analog	Noncommercial or development analog
7	Methyl piperazine carboxylate analog	Noncommercial or development analog

Claim 3 is the principal species claim for ketoconazole. It covers the compound and its pharmaceutically acceptable acid-addition salts and stereoisomeric forms.

Claims 4 through 7 cover structurally related compounds in which the piperazine acetyl group is replaced by morpholine, carboxamide or carbamate substituents.

Claims 8 and 9: Cis ketoconazole

Claims 8 and 9 focus on the cis form of the acetyl-piperazine compound.

The two claims are materially similar, but claim 8 refers to pharmaceutically acceptable acid-addition salts, while claim 9 expressly includes stereochemically isomeric forms. The overlap may reflect drafting or prosecution history rather than a deliberate attempt to create two commercially distinct products.

For infringement analysis, a product containing cis-ketoconazole would be the central target of these claims. A product containing only a different stereoisomer could raise a separate claim-construction and equivalence analysis, but the patent's explicit treatment of stereoisomers broadens the relevant coverage.

Claims 10 and 11: Antimicrobial compositions

Claims 10 and 11 cover compositions comprising:

An inert carrier material; and
An effective amount of a claimed azole derivative, salt or stereoisomer.

The composition must be directed to combating a microorganism selected from fungus and bacterium.

These claims are narrower in application than the compound claims because they require a composition and an antimicrobial purpose. They could reach pharmaceutical, veterinary or other antimicrobial preparations if the accused composition falls within the claim language and the patent's disclosure.

They do not expressly require:

A particular dosage form
A particular concentration
A particular route of administration
A named fungal species
A particular carrier
A particular formulation excipient

The phrase "inert carrier material" may limit the claims to compositions in which the carrier is pharmacologically or chemically inactive relative to the claimed antimicrobial compound.

Which claims cover ketoconazole most directly?

Claims 3, 8 and 9 are the strongest direct ketoconazole claims.

Claim	Direct coverage of ketoconazole	Scope
3	Yes	Ketoconazole, salts and stereoisomers
8	Yes, cis form	Cis-ketoconazole and acid-addition salts
9	Yes, cis form	Cis-ketoconazole, salts and stereoisomeric forms
10	Yes, if formulated as claimed	Broad antimicrobial composition
11	Yes, if formulated as claimed	Narrower composition claim tied to Z=N-R4
1	Potentially	Genus claim that includes ketoconazole
2	Potentially	N-R4 subgenus that includes ketoconazole
4-7	No	Related analogs rather than ketoconazole

Claim 3 is the cleanest product claim because it names the acetyl-piperazine compound without relying on the breadth of the Markush definitions. Claims 8 and 9 add stereochemical focus.

When did US Patent 4,335,125 expire?

The patent's original US term expired June 15, 1999, based on the 17-year term applicable to pre-URAA patents measured from the issue date.[1][4]

Event	Date
US patent issued	June 15, 1982
Original patent term	17 years from issue
Patent expiration	June 15, 1999
Current enforceability	Expired
Current generic blocking effect	None

The patent predates the modern 20-year term measured from the earliest effective nonprovisional filing date. Patent term adjustment and patent term extension regimes did not create a later enforceable term for this patent.

Patent expiration is distinct from FDA regulatory exclusivity. Any New Drug Application exclusivity associated with the original Nizoral approval was temporary and expired decades ago. The patent itself is no longer an enforceable barrier.

What was the Orange Book status of ketoconazole?

The Orange Book historically listed patents associated with approved Nizoral products and related ketoconazole products. US Patent 4,335,125 was the core early compound patent associated with ketoconazole's original approval-era exclusivity.

It is not a current enforceable Orange Book barrier. A patent listing does not extend the patent term, and an expired patent cannot support a current injunction against an otherwise lawful generic launch.

FDA's Orange Book system distinguishes among:

Drug substance patents
Drug product or formulation patents
Method-of-use patents
Pediatric exclusivity
New chemical entity exclusivity
Other regulatory exclusivities

The original ketoconazole compound patent was a drug substance patent. The supplied claims do not identify a formulation-specific product claim comparable to a modern tablet, cream or shampoo patent.[5]

Did ketoconazole have regulatory exclusivity separate from the patent?

Yes, but any original NCE or approval-related exclusivity expired long before the current market.

Ketoconazole was approved in the United States in 1981. The regulatory exclusivity period associated with the original approval was shorter than the patent term and did not preserve exclusivity after the late 1990s. FDA later approved generic ketoconazole products through the abbreviated drug application pathway.[2][5]

What formulation patents protect ketoconazole products?

US Patent 4,335,125 primarily protects the active compound and antimicrobial compositions. It does not expressly claim the commercial formulation characteristics of every Nizoral dosage form.

Potentially separate formulation patent categories include:

Oral tablet formulations
Topical creams and gels
Shampoos and surfactant systems
Enhanced-solubility formulations
Particle-size or crystallinity forms
Combination antifungal products
Delivery systems for skin or scalp administration

A formulation patent must be assessed independently from the compound patent. A later formulation patent could expire after US 4,335,125, but it would cover only the claimed formulation features, not ketoconazole as a molecule.

For a generic applicant, the relevant analysis is whether the proposed product practices an unexpired formulation claim, not whether it contains ketoconazole. FDA-approved generic tablets or topical products demonstrate that the historical compound patent did not remain a practical barrier after expiration.

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

The supplied patent does not contain a conventional method-of-treatment claim. Claims 10 and 11 are composition claims directed to combating fungi or bacteria.

A method-of-use patent would typically recite:

Administering ketoconazole to a patient
Treating a named condition
A dosage amount or treatment schedule
A specific patient population
A particular route or formulation

Ketoconazole's later regulatory history created commercial importance around use restrictions, especially for systemic treatment. FDA labeling now limits oral ketoconazole because of potentially severe liver injury, drug interactions and adrenal insufficiency.[3]

Those safety restrictions are regulatory controls. They do not revive or extend US Patent 4,335,125.

Which companies challenged ketoconazole exclusivity?

Ketoconazole generic competition developed after the original compound patent and regulatory exclusivity expired. Generic manufacturers have included companies such as Teva, Mylan and other ANDA sponsors across different dosage forms and markets.

A Paragraph IV certification is relevant only when an ANDA applicant asserts that a listed patent is invalid, unenforceable or not infringed. Because US Patent 4,335,125 expired in 1999, later generic applicants did not need to rely on a current Paragraph IV challenge to overcome that patent.

The main practical pathways were:

Paragraph III certification when a listed patent remained valid but the applicant accepted delayed approval.
Paragraph IV certification when the applicant challenged an unexpired listed patent.
Section viii statement where the applicant carved out a patented method of use.
No patent certification or an equivalent post-expiration pathway when the relevant patent had expired.

No current Paragraph IV risk attaches to US Patent 4,335,125 itself.

What litigation affected the patent?

The supplied information does not establish a current infringement case involving US Patent 4,335,125. Any historical litigation must be separated from current enforceability because the patent expired more than two decades ago.

For present commercial diligence, the critical issue is whether later patents covering formulation, delivery, polymorphism or use were asserted against a particular generic product. Such disputes would not extend the term of the 1982 compound patent.

How strong is the patent estate for ketoconazole?

Historical strength

The estate was historically strong because it combined:

A broad chemical genus claim
A narrower nitrogen-containing subgenus
A specific ketoconazole claim
Cis-form claims
Antimicrobial composition claims

The composition-of-matter claims were the most valuable. They could reach ketoconazole regardless of whether the product was supplied as a tablet, cream or shampoo, subject to claim requirements and applicable legal defenses.

Current strength

The current strength of US Patent 4,335,125 is zero as an exclusionary patent right because the patent has expired.

Factor	Assessment
Compound coverage	Historically broad
Specific ketoconazole coverage	Direct and strong
Formulation coverage	Limited on supplied claims
Method-of-use coverage	Not present in supplied claims
Remaining patent term	None
Generic launch barrier	None from this patent
Biosimilar relevance	None
Current litigation leverage	None

Does biosimilar risk apply to ketoconazole?

No. Ketoconazole is a small-molecule drug, not a biologic. Biosimilar provisions under the Public Health Service Act do not apply.

The relevant competitive pathway is the ANDA generic pathway under section 505(j) of the Federal Food, Drug, and Cosmetic Act. Generic applicants must demonstrate pharmaceutical equivalence and bioequivalence to the relevant reference product, subject to dosage-form and product-specific requirements.[5][6]

What generic launch scenarios exist for ketoconazole?

Oral tablets

Generic oral ketoconazole tablets can compete without overcoming US Patent 4,335,125. Commercial demand is constrained by FDA safety restrictions and the availability of alternative antifungals, including fluconazole and itraconazole.

Cream and topical products

Topical ketoconazole products face formulation, bioequivalence and product-specific regulatory requirements. Their commercial competition depends more on formulation and dermatology-market positioning than on the expired compound patent.

Shampoo

Ketoconazole shampoo competition depends on the approved concentration, vehicle, surfactant system, labeling and reference-product requirements. The expired compound patent does not prevent entry, but a product-specific formulation or method patent would require separate analysis.

How does ketoconazole compare with competing antifungals?

Drug	Class	US patent position	Current competitive issue
Ketoconazole	Imidazole	Foundational patent expired	Safety restrictions and generic pricing
Clotrimazole	Imidazole	Original patents expired	Broad topical generic competition
Miconazole	Imidazole	Original patents expired	OTC and topical competition
Fluconazole	Triazole	Original compound exclusivity expired	Systemic-use standard and generic volume
Itraconazole	Triazole	Later patent estate	Formulation and pharmacokinetic differentiation
Terbinafine	Allylamine	Original patents expired	Oral and topical generic competition

Ketoconazole's historical advantage came from early broad compound protection and multiple dosage forms. Its current weakness is the loss of exclusivity combined with oral safety limitations and competition from newer or better-tolerated antifungals.

What geographic coverage does the patent have?

US Patent 4,335,125 has territorial effect only in the United States. It does not establish rights in Europe, Japan, Canada or other jurisdictions.

The corresponding international patent family would need to be reviewed separately for:

Filing and grant status
National phase coverage
Patent-term differences
Supplementary protection certificates
Opposition or revocation proceedings
Local formulation and use patents

The US expiration date cannot be applied automatically to foreign family members.

What manufacturing and IP barriers remain?

Manufacturing ketoconazole after expiration is generally not blocked by the expired compound patent. Remaining barriers can include:

API manufacturing capability
Control of impurities and residual solvents
Stereochemical and crystallinity control
Particle-size specifications
Bioequivalence
Topical product performance
Stability in shampoo or cream vehicles
FDA facility compliance
DMF and supplier qualification
Later unexpired formulation or process patents

These are commercial, regulatory and technical barriers rather than rights arising from US Patent 4,335,125.

Key Takeaways

US Patent 4,335,125 is the foundational US ketoconazole patent.
Claims 3, 8 and 9 directly cover ketoconazole or its cis form.
Claims 1 and 2 cover broader substituted dioxolane azole genera.
Claims 10 and 11 cover antimicrobial compositions containing the claimed compounds.
The patent issued June 15, 1982, and expired June 15, 1999.
It provides no current US exclusivity or generic-launch barrier.
The patent contains no clear formulation-specific, dosage-regimen or disease-specific method claim in the supplied text.
Ketoconazole is a small molecule; biosimilar law does not apply.
Current competition is governed by ANDA requirements, formulation performance, manufacturing quality and any later product-specific patents.
The patent's commercial significance is historical, not current.

FAQs About US Patent 4,335,125 and Ketoconazole

Is US Patent 4,335,125 still enforceable?

No. Its original US patent term expired June 15, 1999.

Does US Patent 4,335,125 cover Nizoral shampoo?

It covers ketoconazole as an active compound and antimicrobial compositions meeting the claim limitations. It does not, based on the supplied claims, specifically claim every Nizoral shampoo vehicle or surfactant formulation.

Can a company launch generic ketoconazole without challenging US Patent 4,335,125?

Yes. The patent has expired, so it no longer requires a Paragraph IV invalidity or noninfringement challenge.

Does ketoconazole have biosimilar competition?

No. Ketoconazole is a chemically synthesized small molecule and competes through generic drug pathways, not biosimilar pathways.

Are claims 8 and 9 identical?

They are substantially overlapping cis-ketoconazole claims. Claim 8 limits the listed salts differently, while claim 9 expressly includes stereochemically isomeric forms. The prosecution record would control the precise legal effect of the overlap.

References

United States Patent and Trademark Office. (1982). US Patent No. 4,335,125: Substituted dioxolane derivatives. U.S. Department of Commerce.
U.S. Food and Drug Administration. (1981). Nizoral (ketoconazole) approval and prescribing information. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (2013). FDA drug safety communication: FDA limits usage of Nizoral oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal problems. U.S. Department of Health and Human Services.
Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284 (2011).
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.
Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(j).

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
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,335,125

Summary for Patent: 4,335,125