US Patent 4,359,578: Enoxacin Claims, Scope, Expiration, and Patent Landscape

US Patent 4,359,578 is a core composition-of-matter patent covering enoxacin, a fluorinated 1,8-naphthyridine antibacterial agent, together with specified pharmaceutical salts. The patent issued on November 16, 1982, and its ordinary pre-URAA patent term expired on November 16, 1999. The patent does not create a current barrier to generic enoxacin development, FDA approval, or manufacture in the United States.

The claims supplied identify the protected active ingredient as enoxacin and specifically cover its hydrochloride and methanesulfonate salts. The patent’s commercial significance was highest during the development and launch of Penetrex, the former U.S. enoxacin product.

What drug does US Patent 4,359,578 protect?

The compound in claims 3 and 4 is enoxacin.

Attribute	Description
Active ingredient	Enoxacin
Chemical class	Fluoroquinolone-related 1,8-naphthyridine-3-carboxylic acid
Core structure	1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-1,8-naphthyridine-3-carboxylic acid
U.S. brand	Penetrex
Original U.S. sponsor	Rhone-Poulenc Rorer
FDA regulatory category	Small-molecule antibacterial
Patent	U.S. Patent 4,359,578
Patent grant date	November 16, 1982
Ordinary expiration	November 16, 1999

Enoxacin differs structurally from ciprofloxacin, norfloxacin, and other quinolone antibacterials because its fused bicyclic nucleus is a 1,8-naphthyridine rather than a quinoline. The additional ring nitrogen is the defining structural distinction.

The compound has also been identified by the CAS number 74011-58-8. Enoxacin was developed for urinary tract and other susceptible bacterial infections but is no longer a significant U.S. commercial product.

What do the claims of US Patent 4,359,578 cover?

The claims form a descending scope hierarchy.

Claim 1: Formula-based compound and salts

Claim 1 covers:

A 1,8-naphthyridine compound of the formula shown in the patent, or a nontoxic pharmaceutically acceptable salt thereof.

This is the principal composition claim. Its exact breadth depends on the structural formula in the patent drawing, including the positions and permitted substituents represented by the formula. The text-only claim supplied does not reproduce that structure, so the full Markush boundaries cannot be determined from the claim language alone.

For the identified commercial compound, claim 1 reaches enoxacin and its pharmaceutically acceptable salts. Composition claims of this type generally create product-level rights independent of the manufacturing process, formulation, dosage, or treatment method.

Claim 2: Hydrochloride and methanesulfonate salts

Claim 2 narrows claim 1 to salts that are:

Hydrochloride; or
Methanesulfonate, commonly called mesylate.

A salt claim can protect a drug product even when the free acid or free base is separately described. Its commercial value depends on whether the salt has improved stability, crystallinity, solubility, handling, bioavailability, or formulation performance.

Claim 2 does not cover every possible enoxacin salt. It is limited to the two listed salt forms.

Claim 3: Enoxacin free acid

Claim 3 expressly claims:

1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid.

This is the free-acid form of enoxacin. It is a species claim and is narrower than a formula-based genus claim. A valid species claim can remain enforceable even if a broader genus claim is later narrowed or invalidated, although both claims expired in 1999.

Claim 4: Enoxacin methanesulfonate

Claim 4 covers the methanesulfonate salt of the compound in claim 3. It is the narrowest claim supplied because it requires:

The enoxacin molecular structure; and
The methanesulfonate counterion.

Claim 4 would not, by its wording, cover enoxacin hydrochloride, sodium enoxacin, or another pharmaceutically acceptable salt.

How broad is the patent’s chemical scope?

The patent contains three legally distinct levels of protection.

Claim level	Protected subject matter	Relative breadth
Claim 1	Formula-defined 1,8-naphthyridine compound and pharmaceutically acceptable salts	Broadest
Claim 2	Hydrochloride or methanesulfonate salts falling within claim 1	Intermediate
Claim 3	Enoxacin free acid	Narrow species
Claim 4	Enoxacin methanesulfonate	Narrowest

The principal commercial protection came from claims 1 and 3. Claim 1 could potentially cover related compounds within the illustrated formula, while claim 3 directly identifies enoxacin. Claims 2 and 4 add salt-specific coverage.

The patent does not, based on the claims supplied, expressly claim:

A particular tablet, capsule, suspension, or injectable formulation;
A specific excipient combination;
A controlled-release dosage form;
A manufacturing process;
A crystalline polymorph;
A particle-size distribution;
A method of treating a named infection;
A dosing schedule;
A combination therapy; or
A particular pharmaceutical composition.

Those rights would require separate claims elsewhere in the patent or in related patents.

When did US Patent 4,359,578 expire?

The patent issued on November 16, 1982. Under the pre-Uruguay Round patent term applicable to this patent, the ordinary term was 17 years from issuance.

Event	Date
Patent issued	November 16, 1982
Ordinary expiration	November 16, 1999
Current status	Expired
Current enforceability	None for future conduct

Patent term adjustment did not apply to this patent’s original term framework. Patent term extension under 35 U.S.C. § 156 was introduced after the patent issued and is not reflected in the standard public patent record for this patent. The patent therefore does not provide a current U.S. exclusivity period.

Patent expiration eliminates the enforceable exclusionary right. It does not erase historical infringement exposure occurring before expiration, nor does it invalidate separate, later-issued patents covering formulations, processes, polymorphs, or other distinct subject matter.

What was the FDA status of enoxacin?

Enoxacin was approved in the United States under the Penetrex brand. The product was associated with Rhone-Poulenc Rorer and was approved for susceptible bacterial infections, including urinary tract infections. FDA labeling identified enoxacin as an oral fluoroquinolone-type antibacterial.

The U.S. product is no longer a major marketed antibacterial. FDA’s Orange Book is principally relevant to approved drug products and the patents listed for those products. An expired composition patent cannot support a current Orange Book patent block.

Regulatory issue	Assessment
FDA-approved active ingredient	Yes, historically
Current commercial importance in the U.S.	Limited
Current marketed brand	No significant current U.S. brand presence
Current patent exclusivity from 4,359,578	None
Biosimilar pathway	Not applicable
Generic pathway	ANDA pathway historically applicable
Current Paragraph IV significance	None for this expired patent

Because enoxacin is a small molecule, biosimilar provisions under the Public Health Service Act do not apply. Any generic applicant would ordinarily use the abbreviated new drug application pathway rather than a biosimilar application.

What is the Orange Book status of US Patent 4,359,578?

The patent’s current Orange Book significance is effectively zero because it expired in 1999. Any historical listing associated with an enoxacin product could not now block an ANDA based on the patent’s composition claims.

A Paragraph IV certification would have had commercial significance only while the patent was listed and unexpired. After expiration, an applicant would not need to establish that the patent was invalid or not infringed to launch on the basis of this patent. A Paragraph III certification, if applicable during the remaining term, would have required waiting until expiration.

No current regulatory exclusivity can be derived from claims 1 through 4.

Were there Paragraph IV challenges or patent litigation?

The supplied patent claims do not establish a Paragraph IV challenge, ANDA filing, district-court case, or settlement. Patent litigation cannot be inferred from the existence of a patent or from the later availability of generic products.

The relevant legal timing was:

Before November 16, 1999, an ANDA applicant could have faced a patent certification issue if the patent was listed for the reference product.
A Paragraph IV certification could have triggered patent litigation under the Hatch-Waxman framework.
After November 16, 1999, the patent no longer created a live infringement barrier.
Any later dispute would need to rely on a different patent, trademark, regulatory exclusivity right, or product liability theory.

There is no basis in the supplied material to identify a settlement agreement involving this patent. A settlement would require separate court, FDA, SEC, or company-record evidence.

What formulations are protected by this patent?

The supplied claims are composition claims, not formulation claims.

They cover enoxacin itself and specified salts. They do not expressly require a dosage form, excipient, release profile, coating, or manufacturing process. A generic manufacturer could therefore avoid the patent’s expired claims by using an alternative formulation, but avoidance is no longer necessary because the claims have expired.

Potential formulation subject matter that could have been protected by separate patents includes:

Immediate-release tablets;
Film-coated tablets;
Oral suspensions;
Stabilized salt formulations;
Solubility-enhanced products;
Crystalline or amorphous forms;
Controlled-release formulations;
Specific excipient systems; and
Manufacturing or crystallization processes.

No such formulation claim appears in the four claims supplied.

Did the patent cover methods of use?

The four supplied claims do not include a method-of-treatment claim. They claim chemical products and salts.

A method-of-use patent would typically recite treatment of a bacterial infection by administering an effective amount of enoxacin. A method claim could have created a separate patent barrier after expiration of the composition patent, subject to its own validity, enforceability, and term. The supplied claims do not provide that protection.

The absence of a method claim also means that the patent’s scope did not depend on whether the product was used for urinary tract infection, respiratory infection, gastrointestinal infection, gonorrhea, or another indication. Product claims generally apply regardless of the intended therapeutic indication.

How does enoxacin compare with competing fluoroquinolone patent estates?

Enoxacin competed in a crowded class that included norfloxacin, ciprofloxacin, ofloxacin, and later-generation fluoroquinolones. The compounds share several pharmacophore elements, but their patent estates were molecule-specific.

Drug	Core structural distinction	Commercial patent profile
Enoxacin	1,8-naphthyridine nucleus; piperazinyl substituent	Core U.S. patent 4,359,578 expired in 1999
Norfloxacin	Quinoline nucleus; piperazinyl substituent	Separate composition and formulation estate
Ciprofloxacin	Cyclopropyl substitution; quinolone nucleus	Broader later commercial estate, including formulation and process rights
Ofloxacin	Fused oxazine-containing quinolone	Separate composition, process, and stereochemical issues
Levofloxacin	Active S-enantiomer of ofloxacin	Separate stereochemistry and formulation estate

Structural similarity does not establish infringement. A competitor’s compound would infringe only if it falls within every limitation of an asserted claim. Enoxacin’s 1,8-naphthyridine nucleus is particularly important in distinguishing it from quinoline-based drugs.

How strong is the patent estate for enoxacin?

The historical estate was strongest at the active-ingredient level and weakest at the lifecycle-management level based on the claims supplied.

Estate category	Coverage in supplied claims	Current position
Active ingredient	Yes	Expired
Pharmaceutically acceptable salts	Yes	Expired
Hydrochloride salt	Yes	Expired
Methanesulfonate salt	Yes	Expired
Free acid	Yes	Expired
Formulation	No express claim	No conclusion from supplied claims
Method of use	No express claim	No conclusion from supplied claims
Manufacturing process	No express claim	No conclusion from supplied claims
Polymorph or crystal form	No express claim	No conclusion from supplied claims
Biosimilar protection	Not applicable	Not applicable

The patent was commercially important because it covered the active molecule itself. Once that composition patent expired, the core barrier disappeared unless separate, unexpired patents existed.

What generic entry risks existed?

Before expiration, the main generic-entry risk was a composition-patent challenge. An ANDA applicant would have needed to address the patent through a Paragraph IV, Paragraph III, or other applicable certification.

After expiration, the principal risks shifted away from this patent:

Separate formulation patents;
Process patents;
Salt or polymorph patents;
Regulatory exclusivity;
Manufacturing know-how;
Supply-chain constraints;
Product liability;
Market withdrawal by the reference sponsor; and
Limited commercial demand.

For an old antibacterial with limited current U.S. sales, commercial entry risk is more likely to arise from market size, manufacturing economics, FDA quality requirements, and supply reliability than from US Patent 4,359,578.

What geographic rights did the patent provide?

US Patent 4,359,578 provided rights only in the United States. It did not establish protection in Europe, Japan, Canada, or other jurisdictions.

The international landscape would depend on corresponding national applications, grants, continuations, divisional applications, and local patent-term rules. Foreign patents based on the same invention would have had separate expiration dates and separate validity analyses. U.S. expiration does not prove that every foreign counterpart expired on the same day, although patents filed from the same priority family often have broadly similar historical timing.

Were there licensing deals involving the patent?

The patent itself does not establish a license or assignment history. Commercial development of enoxacin involved relationships among the originating research company, regulatory sponsor, and marketing entities, but a definitive licensing conclusion requires review of assignment records, SEC filings, transaction documents, and company disclosures.

The public commercial association between enoxacin and Rhone-Poulenc Rorer does not, by itself, prove that Rhone-Poulenc Rorer owned US Patent 4,359,578 or held an exclusive license. Patent ownership and product sponsorship are separate issues.

Key Takeaways

US Patent 4,359,578 is a core enoxacin composition patent.
Claim 1 covers the formula-defined 1,8-naphthyridine compound and pharmaceutically acceptable salts.
Claim 2 specifically covers hydrochloride and methanesulfonate salts.
Claim 3 covers enoxacin free acid.
Claim 4 covers enoxacin methanesulfonate.
The patent issued November 16, 1982, and ordinarily expired November 16, 1999.
The claims supplied do not expressly cover formulations, manufacturing processes, polymorphs, or methods of treatment.
Enoxacin is a small molecule, so biosimilar law does not apply.
The patent has no current U.S. blocking effect on generic entry.
Any present-day barrier would need to arise from a separate unexpired patent, regulatory right, or commercial constraint.
A complete Markush analysis of claim 1 requires the structural formula shown in the original patent drawing.

FAQs

Is enoxacin still protected by US Patent 4,359,578?

No. The patent’s ordinary term expired on November 16, 1999.

Does claim 4 cover enoxacin hydrochloride?

No. Claim 4 is limited to enoxacin methanesulfonate. Claim 2 separately identifies hydrochloride and methanesulfonate salts.

Can a generic company launch enoxacin without a Paragraph IV challenge?

Yes, with respect to US Patent 4,359,578, because the patent expired. A separate analysis would be required for any other unexpired patent or regulatory exclusivity.

Is enoxacin a biosimilar product?

No. Enoxacin is a chemically synthesized small-molecule drug. A generic drug pathway, not a biosimilar pathway, is applicable.

Does the patent cover ciprofloxacin or norfloxacin?

No. The claims identify a specific 1,8-naphthyridine structure. Ciprofloxacin and norfloxacin have different core structures and are covered, if at all, by separate patents.

References

United States Patent and Trademark Office. (1982). U.S. Patent No. 4,359,578: 1,8-Naphthyridine derivatives. U.S. Department of Commerce.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations. Center for Drug Evaluation and Research.
U.S. Food and Drug Administration. (1991). Penetrex (enoxacin) prescribing information. Center for Drug Evaluation and Research.
National Center for Biotechnology Information. (2024). PubChem compound summary for enoxacin. PubChem.
United States Code, 35 U.S.C. §§ 154, 156, 271, and 355.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	53/104235	Aug 25, 1978
Japan	157939	Dec 20, 1978
Japan	53/162095	Dec 29, 1978

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Argentina	223983	⤷ Start Trial
Argentina	225195	⤷ Start Trial
Argentina	227529	⤷ Start Trial
Australia	5004979	⤷ Start Trial
Australia	530052	⤷ Start Trial
Canada	1168241	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,359,578

Summary for Patent: 4,359,578