US Patent 5,151,444: Scope, Claims, Expiration, Orange Book Status, and Unoprostone Patent Landscape

US Patent 5,151,444 covers topical ophthalmic compositions and treatment methods using a broad genus of 13,14-dihydro-15-keto prostaglandins, including 13,14-dihydro-15-keto-20-ethyl-PGE2 alpha-isopropyl ester, the active ingredient commonly associated with unoprostone isopropyl. The patent issued on September 29, 1992, and its original 17-year term expired on September 29, 2009. The patent therefore presents no current US blocking risk.

The claims historically covered composition, formulation, and therapeutic-use subject matter. The commercial product Rescula, an unoprostone isopropyl ophthalmic solution, received FDA approval but was later discontinued in the United States. There is no current biosimilar issue because unoprostone is a synthetic small molecule, not a biologic. Any remaining US market-entry barriers would arise from regulatory, manufacturing, formulation, or commercial factors rather than enforceable rights under US 5,151,444.

What does US Patent 5,151,444 protect?

US 5,151,444 protects two principal categories:

Topical ocular compositions containing specified 13,14-dihydro-15-keto prostaglandins.
Methods for treating ocular hypertension or glaucoma by administering those compounds.

The patent uses a Markush structure. Instead of claiming only one named molecule, it claims a broad chemical genus defined by substituent variables designated R, Y, and Z.

Claim group	Subject matter	Commercial relevance
Claim 1	Topical ocular composition containing an effective amount of a formula I compound and a pharmaceutically acceptable carrier	Covers ophthalmic formulations
Claims 2-5	Ester forms, 20-alkyl forms, glaucoma treatment, and eye-drop dosage form	Narrows composition protection
Claim 6	Method of treating ocular hypertension	Broad therapeutic-use claim
Claim 7	Method of treating glaucoma	Disease-specific method claim
Claims 8-9	Alkyl ester and 20-alkyl limitations	Narrows claim 6
Claim 10	Specific 13,14-dihydro-15-keto-20-ethyl-PGE2 alpha-isopropyl ester	Most commercially relevant compound-specific claim
Claims 11-15	Topical administration, glaucoma, ester, and 20-alkyl limitations	Narrows treatment claims

The claims contain typographical errors, including “slats,” “prostaglanlin,” “unsatured,” and “hypothensive.” Those errors do not necessarily invalidate the claims. Courts generally assess whether the claim language, specification, and prosecution history provide a legally workable meaning.

What chemical compounds fall within the patent claims?

The claimed formula includes a prostaglandin core characterized by:

A 13,14-dihydro structure.
A 15-keto group.
R substituents independently selected from hydroxy, hydroxy C1-C3 alkyl, or C1-C2 alkyl.
A Y chain containing two to six carbon atoms, saturated or unsaturated.
A Z group containing one to ten carbon atoms, configured as a straight chain, branched chain, or ring.
Optional substitution of Y or Z with oxo, halogen, alkyl, alkoxy, hydroxyl, phenyl, or phenoxy groups.
Physiologically acceptable salts.
Broad classes of carboxylic acid esters.

The ester language is commercially important. It includes straight-chain and branched-chain alkyl esters, cycloalkyl esters, benzyl, phenyl, hydroxyalkyl, alkoxyalkyl, alkylsilyl, and tetrahydropyranyl esters.

The claim is therefore broader than a single product claim. It reaches selected analogs, prodrug forms, and formulation-ready derivatives, subject to the structural limitations of formula I and the ocular-use limitations.

Does US 5,151,444 specifically cover unoprostone isopropyl?

Yes, claim 10 expressly identifies 13,14-dihydro-15-keto-20-ethyl-PGE2 alpha-isopropyl ester. This compound is generally identified as unoprostone isopropyl or unoprostone isopropyl ester and was marketed in the United States as Rescula.

Claim 14 repeats the same specific compound in the glaucoma-treatment claim set. Claims 5, 11, and 15 add topical eye administration or eye-drop limitations.

The most direct historical coverage of the commercial product was therefore found in:

Claim 10, for the method using the named compound.
Claim 14, for glaucoma treatment using the named compound.
Claim 1, if the marketed formulation satisfied the formula and carrier limitations.
Claim 5, if the composition was characterized as a topical eye drop.
Claims 11 and 15, for topical administration of the named compound in the relevant method context.

The patent does not appear to claim every ophthalmic prostaglandin. It is limited to the defined 13,14-dihydro-15-keto prostaglandin genus. Latanoprost, travoprost, bimatoprost, and tafluprost are structurally distinct molecules and are not automatically covered merely because they are prostaglandin-related glaucoma drugs.

How broad are the composition claims?

Claim 1 is broad in chemical scope but contains several limiting elements.

A product would generally need to satisfy all of the following:

Be a topical ocular composition.
Contain an amount effective as an ocular hypotensive agent.
Contain a compound within formula I.
Include a physiologically acceptable salt or permitted carboxylic acid ester where applicable.
Include a pharmaceutically acceptable carrier.

The claim does not require a specific concentration, preservative, buffer, tonicity agent, viscosity modifier, container, or dosing schedule. This gives the claim substantial historical breadth across conventional ophthalmic liquid formulations.

The claim also does not require that the formulation contain only one active ingredient. A combination product could potentially fall within the claim if it contained a qualifying prostaglandin and satisfied the remaining limitations.

The strongest limitation is the structural formula. A formulation containing an ocular hypotensive compound outside that formula would not infringe claim 1 solely because it lowered intraocular pressure.

What do claims 6 through 15 protect?

Claims 6 through 15 are method claims. They require administration to a human patient needing treatment.

Claim 6 covers treatment of ocular hypertension. Claim 7 narrows the disease context to glaucoma. Claims 10 and 14 identify the specific unoprostone-isopropyl compound. Claims 11 and 15 require topical administration to the eye.

The claim architecture creates several levels of protection:

Protection level	Example	Scope
Broad method	Claim 6	Treating ocular hypertension with the formula I genus
Disease-specific method	Claim 7	Treating glaucoma with the formula I genus
Structural narrowing	Claims 8-9 and 12-13	Alkyl ester or C-20 alkyl forms
Compound-specific method	Claims 10 and 14	Unoprostone-isopropyl compound
Route-specific method	Claims 11 and 15	Topical ocular administration

A generic or follow-on manufacturer using the named compound for glaucoma would historically have faced greater risk under claims 14 and 15 than under the broader genus claims, because the commercial compound is expressly identified.

When did US Patent 5,151,444 expire?

Event	Date
US patent issued	September 29, 1992
Applicable term regime	Pre-TRIPS, 17 years from issue
Base expiration	September 29, 2009
Current enforceability	Expired

US 5,151,444 was filed before the change to the 20-year-from-earliest-effective-filing-date patent term. For patents in this category, the ordinary term was 17 years from issuance, subject to applicable adjustments or terminal disclaimers. Public patent records identify the patent as expired. The patent cannot now support an infringement action for post-expiration activity. (U.S. Patent and Trademark Office, n.d.; Google Patents, n.d.)

No current patent-term extension under the Hatch-Waxman framework can revive the expired patent. Patent-term extension applies to qualifying regulatory review periods, but it does not convert an expired patent into an enforceable right after the statutory term has ended.

What was the FDA regulatory status of the covered product?

The covered commercial product was Rescula, an ophthalmic solution containing unoprostone isopropyl. The product was approved by FDA under NDA 20-579 for reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. FDA labeling identifies unoprostone isopropyl as a prostaglandin-related ocular hypotensive agent. (U.S. Food and Drug Administration, 2000)

Rescula was later discontinued in the United States. The discontinuation was associated with commercial factors rather than a determination that the product was withdrawn for safety or effectiveness reasons. FDA’s discontinued-drug records distinguish commercial discontinuation from withdrawal for safety or efficacy. (U.S. Food and Drug Administration, n.d.-a)

Was there FDA exclusivity for Rescula?

Any FDA marketing exclusivity associated with the original NDA was separate from the patent term. The likely commercial exclusivity window was short relative to the patent term because unoprostone isopropyl was approved as a small-molecule drug rather than a biologic and did not receive biologic reference-product exclusivity.

The relevant regulatory protections were:

NDA approval exclusivity, if applicable under the approval pathway.
Patent protection under US 5,151,444.
Any listed formulation or method patents, if present in the Orange Book during the product’s commercial life.

Those protections have expired or ceased to create a current US market barrier.

What is the Orange Book status of unoprostone and Rescula?

The Orange Book records approved drug products and certain patents or exclusivities associated with approved products. For a discontinued product, the Orange Book entry may remain historically visible even though the product is no longer marketed.

The current commercial implications are:

Issue	Status
Reference product	Rescula, unoprostone isopropyl ophthalmic solution
NDA	20-579
Product status	Discontinued in the United States
Patent 5,151,444	Expired
Current blocking patent from 5,151,444	No
Biosimilar pathway	Not applicable
Generic pathway	ANDA pathway theoretically applicable
Current US marketed product	No established branded market presence

An Orange Book listing, if retained historically, does not extend an expired patent. Nor does an inactive NDA create a continuing exclusionary right against a later applicant.

Were there Paragraph IV challenges or patent litigation?

There is no evident current Paragraph IV controversy involving US 5,151,444. Any Paragraph IV certification against this patent would have become commercially relevant before its September 2009 expiration. A Paragraph IV certification is a regulatory statement by an ANDA applicant that a listed patent is invalid, unenforceable, or not infringed.

The patent’s age and expiration materially reduce the significance of any historical challenge. A generic applicant entering after expiration would not need to litigate the patent to establish freedom to operate under that patent.

No current litigation status associated with US 5,151,444 creates an active enforcement risk. A historical case, settlement, or license would not restore patent enforceability after expiration, although contractual restrictions could remain relevant if independently enforceable.

How strong was the patent estate for unoprostone?

The patent was commercially strong during its active term because it combined:

A broad prostaglandin genus.
Ocular composition claims.
Ocular hypertension method claims.
Glaucoma method claims.
Explicit coverage of the commercial unoprostone-isopropyl compound.
Topical administration and eye-drop limitations.

Its current strength is zero as an exclusionary patent because it has expired.

Historical validity risk would have depended on the specification’s support for the full Markush genus, enablement across the claimed chemical breadth, written description, definiteness, and prior-art disclosures. The specific compound claims would generally have presented a narrower validity question than the broad genus claims. Without relying on prosecution-history details, the practical distinction is clear: the broad genus was more vulnerable to enablement and written-description attacks, while claims 10 and 14 were more vulnerable to compound-specific prior art or obviousness arguments.

How does US 5,151,444 compare with competing glaucoma patents?

US 5,151,444 occupied a different chemical and commercial position from the major prostaglandin analog patents for latanoprost, travoprost, and bimatoprost.

Drug	Representative US patent	Drug class	Relationship to US 5,151,444
Unoprostone isopropyl	US 5,151,444	13,14-dihydro-15-keto prostaglandin derivative	Directly covered by specific claims
Latanoprost	US 5,296,504	PGF2 alpha analog	Separate chemical estate
Travoprost	US 5,510,383	Prostaglandin analog	Separate chemical estate
Bimatoprost	US 5,607,978	Prostamide analog	Separate chemical estate
Tafluprost	Later patent families	Fluorinated prostaglandin analog	Separate chemical estate

Patent expiration for competing drugs often depended on later-filed patents, pediatric extensions, formulation patents, and terminal disclaimers. Those products therefore cannot be used as direct expiration comparators without reviewing their individual patent families. (U.S. Patent and Trademark Office, n.d.)

What generic launch risks remain for unoprostone?

A post-expiration generic launch would face limited patent risk from US 5,151,444. The principal remaining issues would be regulatory and commercial:

Whether FDA would accept an ANDA or require another application pathway.
Whether a suitable reference product remains available for bioequivalence comparison.
Whether the discontinued NDA creates practical reference-product problems.
Whether the applicant can reproduce the formulation and stability profile.
Whether manufacturing yields and raw-material supply support a viable product.
Whether ophthalmic sterility, preservative performance, container closure, and dose uniformity can be demonstrated.
Whether market demand justifies development costs.

For a topical ophthalmic generic, formulation equivalence can be more difficult than chemical identity alone suggests. The applicant may need to address pH, osmolality, viscosity, preservative concentration, particle control, droplet size, container compatibility, and delivery performance.

What manufacturing and formulation IP barriers exist?

The expired patent covers broad formulation use but does not by itself establish protection for every manufacturing process. A separate process patent could have covered synthesis, purification, stereochemical control, esterification, crystallization, or impurity removal. A separate formulation patent could have addressed:

Preservative systems.
Solubilization of unoprostone isopropyl.
Specific concentrations.
Buffer systems.
Multidose packaging.
Container-closure systems.
Stability under accelerated or long-term storage.

Those rights would need independent review. They cannot be inferred from the claims supplied for US 5,151,444. Based on the stated claims, the patent is primarily a composition-and-use patent, not a detailed manufacturing-process patent.

What is the geographic coverage of US 5,151,444?

US 5,151,444 has territorial effect only in the United States. Foreign protection would depend on corresponding national patents or regional applications derived from the same priority filings.

A freedom-to-operate analysis for Europe, Japan, Canada, China, or other markets cannot rely on the US patent’s expiration. Foreign counterparts may have had different:

Filing dates.
Patent terms.
Claim amendments.
Patent-term extensions.
Opposition outcomes.
Lapse or maintenance histories.
Regulatory exclusivity periods.

The US patent’s expiration therefore does not establish freedom to operate outside the United States.

Key Takeaways

US 5,151,444 covers topical ocular compositions and treatment methods using a broad genus of 13,14-dihydro-15-keto prostaglandins.
Claims 10 and 14 specifically identify 13,14-dihydro-15-keto-20-ethyl-PGE2 alpha-isopropyl ester, associated with unoprostone isopropyl.
Claims 1 and 6 are broad composition and ocular-hypertension claims; claims 7 and 14 narrow the use to glaucoma.
The patent issued September 29, 1992, and expired September 29, 2009.
The patent creates no current US infringement barrier.
Rescula was FDA-approved under NDA 20-579 but was later discontinued in the United States.
No biosimilar pathway applies because unoprostone is a synthetic small molecule.
Any current market-entry risk would come from FDA requirements, formulation development, manufacturing capability, or separate patent families, not US 5,151,444.
Foreign freedom to operate requires separate review of national and regional counterparts.

FAQs

Is unoprostone isopropyl still protected by a US patent?

US 5,151,444 no longer protects unoprostone isopropyl because the patent expired on September 29, 2009. Separate later patents would need independent verification.

Can a company launch a generic unoprostone eye drop without challenging US 5,151,444?

Yes. Because the patent has expired, a current applicant does not need to overcome this patent through a Paragraph IV challenge.

Does US 5,151,444 cover latanoprost?

No. Latanoprost is a different prostaglandin analog and is not covered merely because it is used to treat glaucoma.

Is Rescula eligible for a biosimilar application?

No. Unoprostone isopropyl is a chemically synthesized small molecule. A biosimilar application under the Public Health Service Act is not the applicable pathway.

Could a new formulation of unoprostone still receive patent protection?

Potentially. A genuinely novel and nonobvious formulation, delivery system, manufacturing process, or therapeutic-use limitation could be separately patentable. Any such protection would arise from a later patent, not from the expired claims of US 5,151,444.

References

Google Patents. (n.d.). US5151444A: Ophthalmic composition containing prostaglandin derivative. https://patents.google.com/patent/US5151444A/en

U.S. Food and Drug Administration. (2000). Rescula (unoprostone isopropyl ophthalmic solution) prescribing information. FDA.

U.S. Food and Drug Administration. (n.d.-a). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book

U.S. Food and Drug Administration. (n.d.-b). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/

U.S. Patent and Trademark Office. (n.d.). Patent term adjustment and patent term calculation. https://www.uspto.gov/patents/laws/patent-term-calculator-consolidated

U.S. Patent and Trademark Office. (n.d.). Patent Center. https://patentcenter.uspto.gov/

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Japan	62-235890	Sep 18, 1987
Japan	62-334037	Dec 29, 1987

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	0289349	⤷ Start Trial	300135	Netherlands	⤷ Start Trial
European Patent Office	0289349	⤷ Start Trial	SPC/GB04/007	United Kingdom	⤷ Start Trial
European Patent Office	0289349	⤷ Start Trial	C300135	Netherlands	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,151,444

Summary for Patent: 5,151,444