United States Patent 4,539,333: Prostacyclin Claims, Scope, Expiration, and Patent Landscape

US Patent 4,539,333 is the foundational U.S. patent for prostacyclin, also known as prostaglandin I2 or PGI2. It covers isolated prostacyclin, therapeutic uses involving thrombosis, platelet aggregation, gastric lesions, wounds, and vasodilation, and a biological method for producing prostacyclin from prostaglandin endoperoxides. The patent issued on September 3, 1985, and its original 17-year patent term expired on September 3, 2002. It is no longer an enforceable barrier to generic or competing prostacyclin-based products.

The patent is historically important but commercially weak today because its claims are expired. Its main continuing relevance is technical and historical: it established the use of prostacyclin as an antithrombotic, antiplatelet, vasodilatory, gastric-protective, and wound-treatment agent.

What does US Patent 4,539,333 cover?

US 4,539,333 covers four claim categories:

Claim category	Claims	Subject matter
Product	1	Prostacyclin substantially free from other biological material
Therapeutic methods	2-7	Treatment or prevention of thrombosis, platelet aggregation, gastric lesions, wounds, and vasoconstriction-related conditions
Biological production	8	Production of prostacyclin by incubating mammalian tissue microsomes with a prostaglandin endoperoxide
Specific biological production	9	Use of aortic microsomes with PGG2 or PGH2

The patent identifies prostacyclin as (5-Z)-5,6-didehydro-9-deoxy-6,9α-epoxyprostaglandin F1α. The compound is chemically unstable and rapidly hydrolyzes to 6-keto-PGF1α in aqueous environments. That instability later drove development of stabilized formulations, administration systems, and chemically distinct prostacyclin analogs.

The patent was assigned to The Wellcome Foundation Limited and is associated with the prostacyclin research of Salvador Moncada, Ryszard Gryglewski, Stuart Bunting, and John Vane. The patent’s technical disclosure reflects the discovery that prostacyclin is produced by vascular tissue and has strong platelet-inhibitory and vasodilatory effects.

When did US Patent 4,539,333 expire?

US Patent 4,539,333 expired on September 3, 2002, based on the 17-year term applicable to pre-June 8, 1995 U.S. patent applications. The patent was issued on September 3, 1985. No current patent-term extension can revive the original patent after expiration.

Event	Date
Earliest priority period	1976
U.S. patent issued	September 3, 1985
Original U.S. term	17 years from issue
Expiration	September 3, 2002
Current enforceability	Expired

The expiration applies to all nine claims. A party cannot currently be sued for practicing the claimed product, therapeutic methods, or biological manufacturing method solely under US 4,539,333.

What does claim 1 protect?

Claim 1 covers:

“Prostacyclin substantially free from other biological material.”

This is a product claim directed to isolated or purified prostacyclin. The phrase “substantially free from other biological material” distinguishes the claimed product from prostacyclin existing in mammalian tissue or in an unpurified biological mixture.

Claim 1 scope

The claim potentially reaches:

Isolated native prostacyclin;
Purified prostacyclin obtained from biological tissue;
Prostacyclin produced enzymatically and separated from the microsomal reaction mixture;
Preparations containing prostacyclin with only limited biological contaminants.

The claim does not expressly recite:

A specific salt;
A specific dosage form;
A specific concentration;
A specific stabilizer;
A specific route of administration;
Epoprostenol analogs such as iloprost or treprostinil;
A particular pharmaceutical carrier.

The scope of the term “prostacyclin” would ordinarily be limited to the claimed molecule and its legally recognized forms. It would not automatically extend to structurally different prostacyclin analogs. Epoprostenol sodium is the pharmaceutical sodium salt of prostacyclin, but the precise treatment of a salt under this claim would have depended on claim construction and the patent’s specification. That issue has no current enforcement consequence because the claim expired.

How broad are claims 2 through 7?

Claims 2 through 7 are method-of-treatment claims. They do not require a particular formulation, dose, concentration, route, disease stage, or patient subgroup.

Claim	Claimed use	Principal limitation
2	Treatment of thrombosis	Effective antithrombotic amount
3	Inhibition of platelet aggregation	Effective platelet antiaggregation amount
4	Prevention of thrombosis	Effective thrombosis-prevention amount
5	Prevention or treatment of gastric lesions	Non-toxic prevention or treatment amount
6	Treatment of wounds	Non-toxic wound-treatment amount
7	Vasodilation	Effective vasodilatory amount

Claims 2 and 4 separately cover treatment and prevention of thrombosis. Claim 3 focuses on platelet aggregation rather than thrombosis itself. This distinction would have allowed the patentee to assert the claim against products used for platelet inhibition even when the commercial indication was not expressly labeled as thrombosis treatment.

Claims 5 and 6 contain apparent typographical errors in the issued text, including “gastric lessions” and “prostacylin.” Those errors would generally be interpreted in context as “gastric lesions” and “prostacyclin.” The claims use functional dosage language rather than a numerical dosage range.

Limitations of the treatment claims

The method claims are broad, but they require actual administration of prostacyclin to a mammal. They do not cover:

Mere possession of prostacyclin;
Research involving non-therapeutic in vitro platelet assays;
Treatment with a structurally different prostacyclin analog;
A formulation that contains no prostacyclin;
A process that produces prostacyclin but does not administer it.

The claims also do not expressly cover every disease associated with pulmonary hypertension, renal disease, peripheral vascular disease, or cardiovascular disease. Coverage depends on whether the asserted use fits the specific functional language of the claim.

What do claims 8 and 9 protect?

Claims 8 and 9 cover biological production of prostacyclin.

Claim 8 recites incubating mammalian tissue microsomes with a prostaglandin endoperoxide to produce (5-Z)-5,6-didehydro-9-deoxy-6,9α-epoxyprostaglandin F1α.

Claim 9 narrows claim 8 by specifying:

Aortic microsomes; and
PGG2 or PGH2 as the prostaglandin endoperoxide substrate.

Process claim hierarchy

Claim	Required biological component	Required substrate
8	Microsomes of mammalian tissue	A prostaglandin endoperoxide
9	Aortic microsomes	PGG2 or PGH2

The claims are directed to an enzymatic conversion pathway. They are not general claims to every chemical synthesis of prostacyclin. A fully synthetic route that does not use mammalian microsomes would fall outside the literal language of claims 8 and 9.

The commercial relevance of these claims diminished as manufacturers adopted chemical synthesis and pharmaceutical stabilization methods. Their expiration in 2002 eliminated any remaining process exclusivity.

What is the FDA and Orange Book status of prostacyclin?

Native prostacyclin is marketed primarily as epoprostenol or epoprostenol sodium because the free compound is unstable. FDA-approved products include Flolan and Veletri for intravenous use in pulmonary arterial hypertension.

Product	Active ingredient	Principal sponsor or manufacturer	Regulatory role
Flolan	Epoprostenol sodium	Originally Glaxo Wellcome; later associated with GlaxoSmithKline	Intravenous pulmonary arterial hypertension treatment
Veletri	Epoprostenol sodium	Actelion, later part of Johnson & Johnson	Stabilized epoprostenol product
Generic epoprostenol sodium products	Epoprostenol sodium	Multiple manufacturers	Generic injectable competition

The FDA approved Flolan in the 1990s for intravenous treatment of pulmonary arterial hypertension. Veletri was later approved as a more stable formulation with different storage and preparation characteristics. The key commercial distinction is that Veletri reduced some of the handling and stability burdens associated with earlier epoprostenol products.

US 4,539,333 is not a current Orange Book exclusivity barrier. Its claims expired before the principal commercial expansion of modern epoprostenol products. Any current Orange Book patents for epoprostenol products would have to arise from later patents covering formulation, container systems, stability, manufacturing, or specific delivery technologies, not from the expired 1985 patent.

What formulation patents replaced the original prostacyclin patent?

Later patent activity concentrated on stability and administration rather than discovery of native prostacyclin. The principal technical problems were:

Rapid hydrolysis at physiologic pH;
Refrigerated storage requirements;
Short solution stability;
Need for continuous intravenous infusion;
Reconstitution and dilution requirements;
Compatibility with infusion pumps and containers;
Avoidance of dosing interruptions.

Later formulation and delivery patents generally sought protection for:

More stable epoprostenol formulations.
Alkaline-buffered solutions.
Freeze-dried or lyophilized compositions.
Specific sodium or other pharmaceutically acceptable salt forms.
Ready-to-use infusion solutions.
Container and pump systems.
Storage conditions and reconstitution procedures.

These later rights were narrower than claim 1 because they typically required defined excipients, pH ranges, concentration ranges, packaging conditions, or stability profiles. They could block a particular product design without covering all prostacyclin products.

How does prostacyclin compare with prostacyclin analogs?

The main competitive landscape consists of native prostacyclin products and chemically distinct analogs.

Drug	Relationship to prostacyclin	Administration	Main commercial distinction
Epoprostenol	Native prostacyclin or its sodium salt	Continuous IV infusion	Strong efficacy but substantial stability and administration burden
Treprostinil	Stable prostacyclin analog	IV, subcutaneous, inhaled, oral	Longer half-life and multiple delivery options
Iloprost	Prostacyclin analog	Inhaled or IV, depending on product	Intermittent administration potential
Selexipag	Oral prostacyclin receptor agonist prodrug	Oral	Avoids continuous infusion
Beraprost	Oral prostacyclin analog in certain markets	Oral	Geographic availability varies

US 4,539,333 does not claim treprostinil, iloprost, or selexipag as chemical compounds. Its method claims could theoretically have raised issues only if a product actually administered prostacyclin, rather than a different analog. Later analog patents created separate patent estates with their own composition, formulation, method-of-use, and manufacturing claims.

Which companies challenged or licensed the patent?

There is no current Paragraph IV litigation risk from US 4,539,333 because the patent expired in 2002. Paragraph IV certifications are relevant only to unexpired Orange Book-listed patents. Generic manufacturers may have had historical freedom-to-operate issues before expiration, but a present-day abbreviated new drug application cannot be blocked by this patent.

The commercial history indicates that Wellcome-related entities developed and commercialized epoprostenol products, while later companies including Actelion commercialized stabilized formulations. Public product histories show commercial succession and corporate ownership changes, but US 4,539,333 should not be treated as a current licensing asset.

No current settlement agreement can preserve exclusivity under an expired patent. Any historic license, collaboration, or settlement involving prostacyclin products would have no ability to extend the statutory life of the patent.

What patent litigation affects epoprostenol products?

US 4,539,333 presents no current litigation exposure. Any relevant modern dispute would more likely involve:

Later formulation patents;
Patent listings for epoprostenol sodium products;
Stability specifications;
Infusion-device compatibility;
Manufacturing processes;
Patent-term calculations for later patents;
Regulatory exclusivity independent of patent rights.

The original patent’s broad therapeutic claims would not support an active infringement action because claims 2 through 7 expired together with the patent.

What generic launch risks exist for epoprostenol?

Generic launch risk is driven primarily by regulatory and technical execution, not by US 4,539,333.

Low patent risk

The expired patent creates no blocking patent position for:

Generic epoprostenol sodium;
Alternative infusion formulations;
Non-infringing manufacturing processes;
Products using different excipients or storage conditions;
Competing prostacyclin analogs.

Technical and regulatory barriers

The more important barriers are:

Demonstrating pharmaceutical equivalence;
Controlling degradation products;
Matching potency and stability;
Establishing container-closure compatibility;
Validating sterile manufacturing;
Supporting infusion-device use;
Meeting FDA requirements for injectable products.

These barriers can delay launch even when the foundational composition patent has expired.

How strong is the patent estate for prostacyclin?

The original estate was strong historically because it combined a product claim with broad therapeutic-use claims and a biological-production process. Its weaknesses were chemical instability and the absence of claims directed to modern commercial formulations.

Estate characteristic	Assessment
Foundational molecule	Strong historically
Product claim breadth	Broad for isolated native prostacyclin
Method-of-use breadth	Broad functional claims
Formulation coverage	Limited in the supplied claims
Manufacturing coverage	Narrow biological process
Current enforceability	None
Biosimilar relevance	None
Generic relevance	Historical only
Geographic coverage	U.S. rights only for US 4,539,333

The patent is not a biologic patent. Epoprostenol is a chemically defined small molecule, and biosimilar rules do not apply. Competing products are evaluated under generic-drug or drug-product regulatory pathways rather than the FDA biosimilar pathway.

What is the geographic coverage of US 4,539,333?

The patent provides rights only in the United States. Foreign counterparts would have required separate national patents and may have had different expiration dates, claim scope, maintenance histories, and legal outcomes.

The international patent landscape for prostacyclin included related filings in major pharmaceutical markets, but the U.S. expiration date does not establish the status of corresponding rights in Europe, Japan, Canada, or other jurisdictions. Any cross-border freedom-to-operate review must analyze each national family member independently.

Key Takeaways

US 4,539,333 covers isolated prostacyclin, therapeutic administration, and a microsome-based production method.
The patent issued on September 3, 1985, and expired on September 3, 2002.
Claim 1 is a broad product claim to prostacyclin substantially free from biological material.
Claims 2 through 7 cover thrombosis, platelet aggregation, gastric lesions, wounds, and vasodilation.
Claims 8 and 9 cover production using mammalian microsomes, particularly aortic microsomes with PGG2 or PGH2.
The patent does not directly claim treprostinil, iloprost, selexipag, or other structurally distinct analogs.
Current epoprostenol competition depends on later formulation, stability, manufacturing, and delivery patents.
The expired patent creates no current Paragraph IV, Orange Book, biosimilar, or patent litigation barrier.
Generic launch risk is primarily technical and regulatory because epoprostenol is an unstable sterile injectable product.

FAQs About US Patent 4,539,333 and Prostacyclin Exclusivity

Does US Patent 4,539,333 cover epoprostenol sodium?

It covers prostacyclin as the claimed active compound. Whether a particular epoprostenol sodium formulation historically fell within claim 1 would have depended on claim construction and the patent specification. The issue is now moot because the patent expired in 2002.

Can a generic manufacturer launch epoprostenol without licensing US 4,539,333?

Yes. US 4,539,333 is expired and cannot require a current license. A manufacturer must still comply with FDA requirements and evaluate later patents covering the proposed formulation or delivery system.

Does the patent cover pulmonary arterial hypertension?

The supplied claims do not expressly recite pulmonary arterial hypertension. Claim 7 covers producing a vasodilatory action in mammalian blood vessels. The patent’s use claims are functional and do not specifically identify the modern pulmonary arterial hypertension indication.

Are treprostinil and iloprost covered by this patent?

No, not as claimed compounds. Treprostinil and iloprost are structurally distinct prostacyclin analogs with separate patent and regulatory histories.

Is prostacyclin a biologic subject to biosimilar competition?

No. Epoprostenol is a chemically defined small-molecule drug. Competing products proceed through generic-drug or other small-molecule regulatory pathways, not the FDA biosimilar pathway.

References

United States Patent and Trademark Office. (1985). US Patent No. 4,539,333: Prostacyclin. https://patents.google.com/patent/US4539333
U.S. Food and Drug Administration. (n.d.). Orange Book: Approved drug products with therapeutic equivalence evaluations. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Food and Drug Administration. (n.d.). Drugs@FDA: FDA-approved drugs. https://www.accessdata.fda.gov/scripts/cder/daf/
U.S. Food and Drug Administration. (2019). Flolan prescribing information. https://www.accessdata.fda.gov
U.S. Food and Drug Administration. (2019). Veletri prescribing information. https://www.accessdata.fda.gov
U.S. Code, 35 U.S.C. § 154. Patent term. https://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title35-section154
Moncada, S., Gryglewski, R. J., Bunting, S., & Vane, J. R. (1976). An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature, 263, 663-665. https://doi.org/10.1038/263663a0

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	19384	May 11, 1976
United Kingdom	34151	Aug 17, 1976
United Kingdom	36547	Sep 03, 1976

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	366382	⤷ Start Trial
Austria	380879	⤷ Start Trial
Austria	A306881	⤷ Start Trial
Austria	A333177	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 4,539,333

Summary for Patent: 4,539,333