US Drug Patent 4,551,456: Claim Scope, Expiration, FDA Status, and Patent Landscape

US Patent No. 4,551,456 covers a method of treating ocular bacterial infections with topical ocular doses of specified quinolone antibiotics, particularly norfloxacin. The patent was issued in 1985 and its 17-year pre-URAA term expired in 2002. The claims are therefore no longer enforceable in the United States. The patent does not currently create a generic-entry barrier, Orange Book exclusivity position, Paragraph IV litigation risk, or biosimilar risk.

What does US Patent 4,551,456 cover?

The patent claims a therapeutic method rather than a composition, pharmaceutical product, compound, manufacturing process, or dosage form standing alone.

The core elements of independent claim 1 are:

Claim element	Scope
Disease	Ocular bacterial infection
Administration route	Topical ocular administration
Site	An infected eye
Dose	0.015 to 1.5 mg
Active ingredient	Norfloxacin, ofloxacin, pefloxacin, AT-2266, or Bayer 09867
Chemical forms	Hydrates and ophthalmologically acceptable salts

The listed compounds are quinolone or fluoroquinolone antibacterial agents. Claim 1 is drafted as a Markush method claim. A method falls within the literal scope only if it uses one of the expressly listed active ingredients, or a permitted hydrate or ophthalmologically acceptable salt, in the specified dose range and for the claimed ocular indication.

The claim does not require:

A specific bacterial species.
A particular dosing frequency.
A specific concentration.
A defined treatment duration.
A particular ophthalmic container.
A particular pH, preservative, tonicity agent, or viscosity modifier.
A particular formulation unless claim 4 is practiced.
FDA approval of the product.
A specific clinical outcome.

The dose limitation is central. A topical ocular administration below 0.015 mg or above 1.5 mg would not literally satisfy claim 1, although infringement analysis could still raise equivalents issues in a live patent. Because the patent expired, that issue has no current enforcement consequence.

What does claim 2 add for norfloxacin?

Claim 2 narrows claim 1 to norfloxacin, including a norfloxacin hydrate or ophthalmologically acceptable salt.

The practical scope is:

Treatment of an ocular bacterial infection.
Topical delivery to the infected eye.
Administration of 0.015 to 1.5 mg.
Use of norfloxacin, a hydrate, or an ophthalmologically acceptable salt.

Claim 2 is narrower than claim 1 in active ingredient but broader than claims 3 and 4 because it does not require an aqueous solution or thermogelling carrier.

The claim does not require a particular norfloxacin concentration. A conventional 0.3% ophthalmic solution could fall within the dose range depending on drop volume. For example, a 0.3% solution contains approximately 3 mg/mL. A 50 microliter drop would contain approximately 0.15 mg of norfloxacin, which is within the claimed 0.015 to 1.5 mg range.

What does claim 3 protect?

Claim 3 requires the norfloxacin formulation to be an aqueous solution.

Its limitations are cumulative:

Requirement	Claim 3
Infection	Ocular bacterial infection
Delivery	Topical ocular administration
Dose	0.015 to 1.5 mg
Active ingredient	Norfloxacin, hydrate, or ophthalmologically acceptable salt
Formulation	Aqueous solution

Claim 3 would have reached conventional liquid norfloxacin ophthalmic products, assuming the administered quantity fell within the stated dose range. It would not necessarily cover:

A nonaqueous oil solution.
A suspension.
A dry powder.
An ointment.
A solid insert.
A thermogelling formulation that is not an aqueous solution, depending on its composition and claim construction.

An aqueous thermogelling product could potentially satisfy both claims 3 and 4 if it remains an aqueous solution before administration and also meets the carrier limitations in claim 4.

What formulations are protected by claim 4?

Claim 4 adds a carrier limitation. The carrier must be:

A clear physiologically acceptable liquid; and
A material that forms a semisolid gel at human body temperatures.

This is a temperature-responsive or thermogelling delivery concept. The formulation is administered as a liquid and becomes more viscous or semisolid after contact with the ocular surface.

Claim 4 is not limited to norfloxacin. Because it depends directly on claim 1, it potentially covers any of the listed antibiotics when used with the specified thermogelling carrier:

Norfloxacin.
Ofloxacin.
Pefloxacin.
AT-2266.
Bayer 09867.

The claim does not expressly specify:

The gelation temperature.
Gel duration.
Polymer concentration.
Gel viscosity.
Residence time on the ocular surface.
A particular polymer or excipient.
A particular antibiotic concentration.

The phrase “at human body temperatures” supplies a functional limitation. A formulation that remains a liquid on the eye would be outside the literal scope of claim 4. A formulation that is already a semisolid before administration could also raise a claim-scope issue because the claim describes a liquid that forms a semisolid gel at body temperature.

When did US Patent 4,551,456 expire?

US Patent No. 4,551,456 was issued on November 5, 1985. It was subject to the pre-URAA patent-term rule, which generally provided 17 years from issuance for utility patents filed before June 8, 1995.

Event	Date
Patent issued	November 5, 1985
Standard statutory term	17 years from issuance
Expiration	November 5, 2002
Current enforceability	Expired

The patent’s expiration means that no current U.S. product or method can infringe it. An expired patent cannot support a new infringement action, damages claim, injunction, or Paragraph IV settlement.

The expiration analysis assumes no unusual terminal disclaimer or enforceable patent-term adjustment altered the term. The patent’s 1985 issuance date places it well before the modern 20-year-from-earliest-effective-filing-date regime created by the Uruguay Round Agreements Act.

What is the Orange Book status of US Patent 4,551,456?

US Patent 4,551,456 does not provide a current Orange Book barrier.

The patent claims a method of treating ocular bacterial infection. FDA Orange Book listings can include method-of-use patents when they are submitted for an approved drug and meet applicable listing requirements. However, any historical listing associated with a norfloxacin ophthalmic product would no longer have legal effect because the patent expired in 2002.

The relevant regulatory distinction is:

Issue	Status
Patent type	Method-of-use patent
Drug category	Small-molecule antibacterial
Orange Book relevance	Historically possible; no current exclusionary effect
Current patent term	Expired
Current Paragraph IV risk	None from this patent
Current 30-month stay potential	None from this patent
Biosimilar relevance	None

FDA approval and patent enforceability are separate. FDA approval of a norfloxacin ophthalmic product did not extend the patent term.

What FDA products and indications relate to the patent?

Norfloxacin ophthalmic products were developed for bacterial infections of the eye, including conjunctivitis and corneal ulcer-related indications. Chibroxin, a norfloxacin ophthalmic solution, is the principal branded product historically associated with topical ophthalmic norfloxacin in the United States.

The patent’s claim language is broader than any single approved label in several respects. It covers five named quinolone agents and does not limit treatment to a particular label indication, pathogen, dosing schedule, or approved product name.

FDA regulatory status does not revive the patent. Even if an approved norfloxacin ophthalmic product remains marketed, the expired patent does not block an FDA-approved generic from entering the market.

How does the patent compare with formulation and compound patents?

US 4,551,456 is narrower than a compound patent but potentially broader than a narrowly drafted product patent during its term.

Patent category	Typical protection	Relationship to US 4,551,456
Compound patent	Chemical molecule and salts	4,551,456 does not claim the compounds themselves
Composition patent	Formulation and ingredients	4,551,456 claims treatment, with formulation limits only in claim 4
Method-of-use patent	Use of a product for a disease	Primary category of 4,551,456
Dosage patent	Specific dose, schedule, or patient group	4,551,456 includes a dose range
Manufacturing patent	Process for making drug or dosage form	Not claimed
Device patent	Container, insert, applicator, or delivery device	Not claimed
Regulatory exclusivity	FDA approval-based market protection	Separate from the patent

The patent’s method format could have covered a manufacturer’s labeled use, a physician’s treatment, or other conduct depending on the applicable direct and induced infringement facts. It would not automatically cover every sale of norfloxacin because the claims require a particular therapeutic administration.

How strong was the patent estate?

The patent estate was commercially useful during the 1980s and early 1990s but structurally limited.

Strengths

It covered multiple quinolone agents in a single independent claim.
It targeted ocular treatment, a commercially defined use.
It included a broad 15 microgram to 1.5 milligram dose range.
It reached both conventional topical treatment and, through claim 4, thermogelling delivery.
It covered norfloxacin salts and hydrates.
It did not depend on a narrow bacterial species or a particular formulation excipient.

Limitations

It was a single U.S. method patent, not a compound-and-formulation estate.
It did not claim the active compounds themselves.
It did not independently claim an ophthalmic composition.
It did not cover every route or dosage form.
Claim 4 was limited to the thermogelling carrier.
The five-compound list limited the claim to specified quinolones.
The patent expired in 2002.

The most commercially important claim was likely claim 3 for aqueous norfloxacin ophthalmic solutions. Claim 4 had greater formulation specificity and would have been relevant to controlled-residence ophthalmic products rather than ordinary drops.

Were there Paragraph IV challenges or patent litigation?

No current Paragraph IV challenge can be based on US 4,551,456 because the patent expired more than two decades ago.

A Paragraph IV certification is relevant when an ANDA applicant asserts that a listed patent is invalid, unenforceable, or will not be infringed. Once the patent expires, an applicant has no practical need to challenge it. A generic applicant can wait for patent expiration or otherwise proceed without triggering the patent’s remaining term.

The patent also cannot support:

A new Hatch-Waxman infringement action under 35 U.S.C. § 271(e)(2).
A 30-month regulatory stay.
A patent-based injunction against generic launch.
A post-expiration damages claim.
A patent settlement restricting generic entry based on this patent.

A historical litigation search would need to distinguish cases involving norfloxacin, ofloxacin, or other fluoroquinolone patents from cases specifically asserting US 4,551,456. The existence of litigation involving the same active ingredient would not establish that this patent was asserted.

Which companies could challenge products protected by this patent?

The patent no longer creates a live challenge target. During its term, potential market participants would have included:

The branded product sponsor for norfloxacin ophthalmic solution.
ANDA applicants seeking approval of generic norfloxacin ophthalmic solution.
Manufacturers developing alternative fluoroquinolone ophthalmic products.
Developers of sustained-release or thermogelling ocular delivery systems.

The competitive landscape also included other ophthalmic fluoroquinolones, including ciprofloxacin, ofloxacin, and later-generation agents. Those products could compete clinically without necessarily practicing the patent, depending on the active ingredient and dosing method.

A product using ciprofloxacin would not fall within claim 1 because ciprofloxacin is not one of the five listed agents. A product using levofloxacin would likewise be outside the literal Markush group. A product using ofloxacin could fall within claim 1 if the dose and topical ocular treatment limitations were satisfied.

What geographic coverage does the patent have?

US Patent 4,551,456 provides rights only in the United States. It does not establish protection in:

Europe.
Japan.
Canada.
China.
India.
Australia.
Any other jurisdiction.

Foreign counterparts would require separate national patents, different claim language, and separate expiration analyses. Because the patent issued in 1985, corresponding foreign rights would generally have expired no later than the late 1990s or early 2000s, subject to national filing dates, patent-term extensions, supplementary protection certificates, and local prosecution history.

There is no basis for treating the U.S. patent as a global patent estate.

What manufacturing and intellectual-property barriers remain?

US 4,551,456 creates no current manufacturing barrier. A company can manufacture a norfloxacin ophthalmic solution or other covered product without infringing this expired patent.

Current barriers, if any, would arise from different sources:

Active ingredient manufacturing controls.
FDA quality requirements.
Sterility validation.
Container-closure integrity.
Preservative compatibility.
Stability and impurity specifications.
Trade secrets concerning formulation or manufacturing.
Regulatory approval requirements.
Other unexpired patents not identified in this patent’s claims.
Trademark rights associated with a branded product.

The patent does not claim a manufacturing process, so it would not block production of norfloxacin or an ophthalmic formulation after expiration.

What generic launch risks exist?

The generic launch risk from US 4,551,456 is zero as a patent matter because the patent expired on November 5, 2002.

A generic applicant seeking approval for norfloxacin ophthalmic solution would still need to address:

FDA bioequivalence or applicable product-specific requirements.
Sterility.
Assay and impurities.
Preservative performance, if applicable.
Container and closure requirements.
Labeling.
Any other unexpired Orange Book patents listed for the reference product.

Those regulatory requirements are separate from the expired patent. The patent does not create a launch delay, exclusivity period, or automatic need for a Paragraph IV certification.

What is the revenue exposure from this patent?

No current revenue is protected by US 4,551,456. The patent’s economic value ended when the term expired in 2002.

During the patent term, exposure would have been concentrated in:

Norfloxacin ophthalmic solution sales.
Potential ofloxacin or pefloxacin ophthalmic products.
Thermogelling ocular formulations using a listed quinolone.
Licensing or partnering transactions involving ophthalmic quinolone delivery.

The patent did not protect systemic norfloxacin products generally. It also did not protect unrelated fluoroquinolone products outside the five named compounds.

Key Takeaways

US Patent 4,551,456 is a method-of-treatment patent for topical ocular use of five specified quinolone antibiotics.
Claim 1 requires 0.015 to 1.5 mg administered topically to an infected eye.
Claim 2 narrows the invention to norfloxacin and permitted forms.
Claim 3 covers norfloxacin aqueous solutions within the dose range.
Claim 4 addresses clear physiologically acceptable liquids that form semisolid gels at human body temperatures.
The patent was issued on November 5, 1985, and expired on November 5, 2002.
It has no current Orange Book, Paragraph IV, litigation, generic-launch, or biosimilar significance.
The patent never claimed the quinolone compounds, manufacturing processes, or ophthalmic compositions independently.
Foreign patent rights would require separate counterpart analysis and cannot be inferred from the U.S. patent.
Current barriers would come from FDA requirements, other patents, formulation know-how, manufacturing controls, or commercial rights, not US 4,551,456.

FAQs

Does US Patent 4,551,456 cover ciprofloxacin eye drops?

No. Claim 1 lists norfloxacin, ofloxacin, pefloxacin, AT-2266, and Bayer 09867. Ciprofloxacin is not included in the claim.

Does a 0.3% norfloxacin eye drop fall within the claimed dose?

It may. A 0.3% solution contains approximately 3 mg/mL. A 50 microliter drop contains approximately 0.15 mg, which falls within the claimed 0.015 to 1.5 mg range.

Does the patent cover an ophthalmic ointment?

Not necessarily. Claim 1 is a method claim and does not require an ointment, but claim 4 requires a clear physiologically acceptable liquid that forms a semisolid gel at human body temperatures. A conventional ointment would not ordinarily meet that carrier limitation.

Can a generic manufacturer rely on patent expiration without a Paragraph IV challenge?

Yes, with respect to this patent. An expired patent does not require a Paragraph IV invalidity or noninfringement certification as a basis for avoiding its term. Other listed patents, if any, must be assessed separately.

Is there biosimilar risk associated with this patent?

No. Norfloxacin, ofloxacin, and the other listed agents are small-molecule antibacterial compounds. The relevant regulatory pathway is generally an ANDA or another small-molecule pathway, not a biosimilar application under the Biologics Price Competition and Innovation Act.

References

United States Patent and Trademark Office. (1985). US Patent No. 4,551,456. U.S. Department of Commerce.
U.S. Food and Drug Administration. (2023). Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.
U.S. Food and Drug Administration. (2024). Orange Book: Approved drug products with therapeutic equivalence evaluations. U.S. Department of Health and Human Services.
United States Code, 35 U.S.C. §§ 154, 271(e)(2), 282.
United States Code, 21 U.S.C. § 355(j).

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	3538084	⤷ Start Trial
Australia	567979	⤷ Start Trial
Canada	1241599	⤷ Start Trial
Denmark	537784	⤷ Start Trial
European Patent Office	0142426	⤷ Start Trial
Spain	537584	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,551,456

Summary for Patent: 4,551,456