United States Patent 4,335,139: Scope, Claims, Expiration, and Prostacyclin Formulation Landscape

U.S. Patent No. 4,335,139 covers alkaline, amino-acid-buffered formulations of prostacyclin and specified prostacyclin analogs. The core technical concept is stabilization against hydrolysis of prostacyclin’s enol ether moiety by using an amino-acid buffer at pH 9 or higher. The claims extend to formulations, preparation methods, stabilization methods, and therapeutic uses.

The patent is no longer an enforceable barrier to commercialization. Based on its 1982 issue date and the pre-Uruguay Round 17-year patent term applicable to the patent, the ordinary term ended in 1999, subject to any patent-term adjustment, terminal disclaimer, or prosecution-history issue not apparent from the claim text. The patent therefore has historical and freedom-to-operate relevance, but it does not create current United States exclusivity for epoprostenol or the claimed formulation architecture.

What does U.S. Patent 4,335,139 cover?

The patent covers pharmaceutical compositions containing one of four active ingredients:

Prostacyclin, also known as epoprostenol or PGI2.
15-methylprostacyclin.
16,16-dimethylprostacyclin.
A pharmaceutically acceptable salt of one of those compounds.

The formulation must include an amino-acid-based buffer with a pH of at least 9. The buffer may be combined with water, a solvent, sodium chloride, mannitol, or another pharmaceutically acceptable excipient.

The specification’s central formulation objective is chemical stabilization. Prostacyclin is susceptible to hydrolysis, particularly through degradation of its enol ether structure. The patent claims that alkaline amino-acid buffering reduces this degradation sufficiently to produce injectable, infusible, frozen, or freeze-dried pharmaceutical products.

Core claim architecture

Claim group	Subject matter	Principal limitations
Claims 1-17	Pharmaceutical formulations	Prostacyclin or specified analog; amino-acid buffer; pH at least 9
Claims 18-19	Manufacturing method and resulting formulation	Bringing active ingredient into association with the buffer
Claims 20-24	Therapeutic methods	Platelet inhibition, vasodilation, thrombosis, hypertension, gastric lesions
Claim 25	Stabilization method	Preventing hydrolysis of the enol ether moiety
Claims 26-27	Broader formulation claims	Amino-acid principal buffering agent; pH at least 9; optional base
Claims 28-34	Prostacyclin-specific composition claims	Arginine, valine, alanine, glycine, water, injection, sodium salt

The commercial importance is concentrated in claims 1, 26, 28, and 33. These are the principal composition claims. Claims 2-17 and 29-34 narrow those claims by specifying solvents, dosage forms, amino acids, concentrations, excipients, or salts.

How broad are the independent formulation claims?

Claim 1 is broad in active ingredient and excipient selection but narrow in buffering conditions. It requires:

One of the listed prostacyclin compounds or salts;
A pharmaceutically acceptable amino-acid-based buffer;
A pH of at least 9; and
Optionally, an additional carrier.

The claim does not require a specific amino acid, concentration, dosage form, route of administration, or stabilizing excipient. A formulation could therefore fall within claim 1 without containing glycine, mannitol, sodium chloride, or water, provided the amino-acid buffer and pH limitations are met.

Claim 26 is similar but uses the expression “principal buffering agent” and does not include the same express wording concerning a “pharmaceutically acceptable buffer” found in claim 1. Claim 27 adds a base. The presence of a base would not necessarily avoid infringement if the composition still has an amino acid as the principal buffering agent and maintains a pH of at least 9.

Claim 28 narrows the active ingredient to prostacyclin or a pharmaceutically acceptable salt. It is significant because it excludes the two expressly named methylated prostacyclin analogs from the claim’s literal scope.

Claim 33 is the narrowest and most product-relevant composition claim. It requires:

The sodium salt of prostacyclin;
Glycine;
An amino-acid-based buffer;
A pH of at least 9.

Claim 34 adds an injectable form containing water.

Which formulation elements create the principal infringement risk?

The highest-risk combination under the claim language is an epoprostenol sodium formulation containing glycine, adjusted to an alkaline pH of at least 9, particularly when supplied as an injectable aqueous product.

A product need not duplicate every dependent limitation. For example:

A glycine-buffered epoprostenol product at pH 10.5 could implicate claim 1 even if it lacks mannitol.
A formulation containing arginine instead of glycine could implicate claims 1 and 28-29, but not claim 33.
A formulation containing glycine at approximately 0.025 M and pH 10.2-10.8 could implicate claims 1, 7-9, 11, 17, 28, and 33, depending on the active ingredient and salt.
A neutral-pH epoprostenol product would fall outside the express pH limitation of the composition claims.
A formulation containing treprostinil, iloprost, selexipag, or another non-listed prostacyclin-pathway drug would not literally satisfy the claimed active-ingredient limitation.

What do the dependent claims protect?

The dependent claims define formulation and product variants that were likely intended to capture practical pharmaceutical presentations.

Amino-acid limitations

Claims 6 and 7 limit the amino acid to a sulfur-free amino acid and identify glycine, alanine, arginine, and valine. Claim 33 specifically selects glycine for prostacyclin sodium.

The amino-acid limitation is material. A buffer based only on phosphate, citrate, acetate, carbonate, or another non-amino-acid system would not literally meet the amino-acid requirement. A mixed buffer could still fall within the claims if the amino acid is the principal buffering acid or principal buffering agent, depending on the claim.

Concentration limitations

Claims 8 and 9 specify a total amino-acid concentration of 0.02 to 0.03 M or approximately 0.025 M. These claims are narrower than claim 1 and require a concentration analysis that includes the amino acid and its salts.

A product outside that concentration range may still implicate claim 1, claim 26, claim 28, or claim 33 if the remaining limitations are met.

pH limitations

Claim 1 requires a pH of at least 9. Claim 11 narrows the range to 10.2-10.8. The pH limitation is likely measured in the final formulation, although the applicable measurement point can depend on the formulation’s physical state and reconstitution instructions.

A freeze-dried product presents a technical issue: the solid cake does not have a conventional pH until reconstituted. Claim 5 covers a solution containing the active compound and buffer that is freeze-dried or frozen. For such products, the relevant pH would likely be assessed in the solution before freezing or after reconstitution, consistent with the product’s formulation and manufacturing records.

Carrier and excipient limitations

Claims 2, 3, 10, 12, and 13 address:

Solvents;
Water;
Sodium chloride;
Excipients generally; and
Mannitol specifically.

These claims do not require the carrier unless the dependent claim is being asserted. Water and mannitol are particularly relevant to injectable prostacyclin products because they support reconstitution, tonicity, cake formation, and product stability.

What methods and therapeutic uses are claimed?

Manufacturing claims

Claim 18 covers the method of bringing the active compound into association with the alkaline amino-acid buffer. The method is functional and does not require a specific mixing order, temperature, equipment configuration, or sterilization technique.

Claim 19 covers a formulation prepared by the method of claim 18. Its practical value is limited because it may overlap substantially with the composition claims and may raise product-by-process interpretation issues.

Stabilization claim

Claim 25 covers stabilizing prostacyclin or the named analogs against hydrolysis of the enol ether moiety by association with the amino-acid buffer at pH 9 or higher.

This claim is broader in purpose than a claim limited to an injectable vial. It could potentially reach a stabilized intermediate, bulk solution, frozen product, or manufacturing-stage composition if the claimed active, buffer, and pH conditions are present.

The functional phrase “against hydrolysis” creates proof issues. A patentee would generally need to establish that the accused composition meets the structural and pH limitations and provides the claimed stabilization result. The claim does not specify a minimum stability period or degradation threshold.

Therapeutic claims

Claims 20-24 cover methods involving:

Inhibition of platelet aggregation;
Vasodilation;
Treatment or prophylaxis of thrombosis;
Reduction of blood pressure; and
Treatment or prophylaxis of gastric lesions.

These claims are formulation-dependent because each requires administration or use of a formulation according to claim 1. They do not independently cover treatment with any form of prostacyclin.

Their current commercial significance is limited by patent expiry. They also would have presented proof challenges because terms such as “effective,” “non-toxic,” “therapeutic,” and “prophylactic” require clinical or pharmacological evidence tied to the claimed formulation.

When did U.S. Patent 4,335,139 lose exclusivity?

U.S. Patent 4,335,139 issued on June 15, 1982. Under the historical 17-year term applicable to patents of that era, the ordinary term would have ended on June 15, 1999, subject to any applicable adjustment or disclaimer. The patent is therefore expired.

Event	Date or status
U.S. patent issue	June 15, 1982
Ordinary pre-1995 patent term	17 years from issue
Expected ordinary expiration	June 15, 1999
Current enforceability	Expired
Current U.S. composition exclusivity from this patent	None

The 20-year term measured from the earliest effective nonprovisional filing date generally applies to later-filed U.S. applications, not to a patent issued in 1982 under the former term regime. The patent’s exact continuity, reexamination, reissue, and terminal-disclaimer history would control any historical term adjustment, but none would ordinarily restore present-day exclusivity decades after the expected 1999 expiration.

What is the Orange Book status of U.S. Patent 4,335,139?

U.S. Patent 4,335,139 should not be treated as a current Orange Book patent barrier.

The Orange Book lists patents submitted for approved drug products and identified by the sponsor as claiming the drug substance, drug product, or an approved method of use. A historical formulation patent may not appear in current Orange Book records even if it once had relevance to an approved product. The Orange Book must be reviewed by specific application and product, not only by patent number.[1]

For epoprostenol products, the current regulatory assessment should distinguish:

The active ingredient, epoprostenol sodium;
The approved product formulation;
Any current FDA-listed formulation patents;
Regulatory exclusivity periods; and
Expired historical patents such as U.S. Patent 4,335,139.

FDA approval of a product containing glycine, mannitol, water, or an alkaline pH does not revive an expired patent. It also does not establish that every formulation element is currently patent-protected.

Which products and competitors are relevant?

Epoprostenol products

Epoprostenol products are the most direct commercial counterparts to the claimed formulations. Flolan and Veletri are prostacyclin products used primarily in pulmonary arterial hypertension. Their labeling describes epoprostenol sodium formulations that use alkaline conditions and excipients such as glycine and mannitol.[2,3]

Those products may resemble the claimed subject matter technically, especially where they contain:

Epoprostenol sodium;
Glycine;
Water after reconstitution;
An alkaline pH; and
Mannitol.

That resemblance has historical relevance but does not create a current infringement risk under an expired patent.

Treprostinil and other prostacyclin-pathway products

Treprostinil products, including Remodulin, Tyvaso, and Orenitram, are not literally within the active-ingredient list of U.S. Patent 4,335,139. Treprostinil is a chemically distinct prostacyclin analog and is not prostacyclin, 15-methylprostacyclin, or 16,16-dimethylprostacyclin as those terms are ordinarily understood.

Other pathway products such as iloprost and selexipag likewise fall outside the literal active-ingredient list. Their patent estates are separate and generally focus on the active compound, salts, formulations, delivery systems, dosage regimens, and methods of treating pulmonary hypertension.

Product or ingredient	Literal coverage under U.S. 4,335,139
Epoprostenol/prostacyclin	Potentially within scope
Epoprostenol sodium	Potentially within scope
15-methylprostacyclin	Potentially within scope
16,16-dimethylprostacyclin	Potentially within scope
Treprostinil	Generally outside literal scope
Iloprost	Outside literal scope
Selexipag	Outside literal scope
Beraprost	Outside literal scope

Are biosimilar or generic challenges relevant?

Biosimilar risk is not applicable. Epoprostenol is a chemically defined small molecule, not a biologic subject to the biosimilar pathway under the Public Health Service Act.

The relevant pathway is abbreviated new drug application approval under section 505(j) of the Federal Food, Drug, and Cosmetic Act. A generic applicant could challenge current listed patents through Paragraph IV certification, but an expired patent cannot block approval or launch.

The practical generic risks are instead determined by:

Current Orange Book patent listings;
Product-specific exclusivity;
Active pharmaceutical ingredient supply;
Sterility and manufacturing controls;
Stability and packaging;
Reconstitution instructions;
Labeling requirements; and
Any later formulation, device, or process patents.

A generic epoprostenol product that uses the same or similar alkaline glycine-buffered architecture would not face a live claim from U.S. Patent 4,335,139. The product could still encounter unrelated current patents covering a particular presentation, container, delivery system, manufacturing process, or approved use.

How strong was the patent estate?

The patent’s historical strength was concentrated in a technically specific formulation problem. It did not claim prostacyclin as a molecule. It claimed a stabilization solution based on three principal parameters:

A listed prostacyclin active ingredient;
An amino-acid-based buffer; and
A pH of at least 9.

Strengths

The core formulation concept is easy to map onto an accused product.
Claim 1 covers multiple amino acids and does not require a specific excipient.
Claims 26 and 28 create overlapping composition coverage.
Claim 33 directly targets prostacyclin sodium with glycine.
Claim 25 extends beyond a finished dosage form to stabilization of the active compound.
Claims 20-24 provide use-claim coverage for several pharmacological effects.

Weaknesses

The claims exclude many prostacyclin-pathway drugs.
The pH threshold and amino-acid requirement create design-around routes.
Dependent claims are narrow and vulnerable to nonmatching concentration or excipient profiles.
Functional terms such as “effective,” “non-toxic,” and “against hydrolysis” create proof burdens.
Broad composition claims may face prior-art issues if alkaline stabilization and amino-acid buffering were known.
The patent is expired, eliminating current enforcement value.

The estate was commercially meaningful for early epoprostenol products but is now a historical formulation patent rather than a live exclusivity asset.

What generic launch scenarios exist?

Scenario 1: Generic epoprostenol matches the historical formulation

A generic product containing epoprostenol sodium, glycine, water, mannitol, and an alkaline pH could resemble claims 1, 13, 16, 17, 28, 33, and 34. The expired status of the patent means those claims do not prevent launch.

Scenario 2: Generic epoprostenol uses a different buffer

A phosphate-, citrate-, or other non-amino-acid-buffered product would avoid the literal amino-acid limitation. It would still require FDA demonstration of stability, sterility, compatibility, and bioequivalence or applicable product-specific equivalence.

Scenario 3: Generic epoprostenol changes pH

A formulation below pH 9 would avoid the express pH limitation. That approach may be technically difficult because prostacyclin stability is central to the product design.

Scenario 4: Alternative prostacyclin-pathway drug

Treprostinil, iloprost, or selexipag does not fall within the listed active-ingredient scope. These products face separate patent and regulatory analyses.

What manufacturing and geographic barriers remain?

The patent does not create current geographic exclusivity in the United States. Its historical rights were U.S.-specific, and corresponding foreign patents would need to be assessed independently by country.

For current development, the more significant barriers are technical and regulatory:

Maintaining epoprostenol stability during manufacture and storage;
Controlling alkaline pH after reconstitution;
Preventing adsorption or degradation in infusion systems;
Establishing acceptable shelf life;
Validating sterile manufacture;
Controlling freeze-drying or frozen storage;
Qualifying the active ingredient supplier; and
Demonstrating compatibility with approved administration systems.

Expired patent claims may still be useful as prior-art markers. They can also help identify formulation design choices that were historically associated with prostacyclin stability, but they do not support a current licensing royalty or exclusionary position.

Key takeaways

U.S. Patent 4,335,139 covers alkaline amino-acid-buffered formulations of prostacyclin and three specified prostacyclin analogs.
The strongest claim focus is epoprostenol sodium with an amino-acid buffer, especially glycine, at pH 9 or higher.
Claims 8, 9, and 11 narrow the scope through amino-acid concentration and pH ranges.
Claim 25 covers stabilization against hydrolysis of the enol ether moiety.
Claims 20-24 cover therapeutic uses involving platelet aggregation, vasodilation, thrombosis, blood pressure, and gastric lesions.
Treprostinil, iloprost, selexipag, and other non-listed pathway drugs are outside the literal active-ingredient scope.
The patent’s ordinary term ended in 1999 under the historical 17-year patent term.
No current Paragraph IV strategy is needed against this expired patent.
Biosimilar analysis is inapplicable because epoprostenol is a small molecule.
Current risk for generic epoprostenol depends on later Orange Book listings, product-specific exclusivity, manufacturing controls, and newer formulation or delivery patents.

FAQs

Does U.S. Patent 4,335,139 cover Flolan?

The claims technically read on formulations containing prostacyclin or epoprostenol sodium with an alkaline amino-acid buffer. Flolan formulations may share those characteristics. The patent is expired and therefore does not currently block Flolan manufacture, generic entry, or formulation development.

Does the patent cover treprostinil?

No. Treprostinil is not one of the active compounds expressly identified in the claims. Treprostinil products require a separate patent and regulatory analysis.

Does a glycine-buffered epoprostenol formulation infringe the patent?

It could have fallen within the claim language during the patent term if it also satisfied the alkaline pH and other required limitations. The expired patent cannot support an infringement action today.

Is mannitol required by the patent?

No. Mannitol appears in dependent claim 13. The independent claims do not require mannitol. A product without mannitol could still satisfy a broader composition claim if the active ingredient, amino-acid buffer, and pH limitations are met.

Can an amino-acid buffer at pH 8.5 fall within the claims?

It would not literally satisfy the express “pH of at least 9” limitation. The expired status also makes the question commercially irrelevant for current U.S. freedom to operate, absent a separate later patent.

References

U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book. https://www.accessdata.fda.gov/scripts/cder/ob/
U.S. Food and Drug Administration. (n.d.). Flolan (epoprostenol sodium) prescribing information.
U.S. Food and Drug Administration. (n.d.). Veletri (epoprostenol sodium) prescribing information.
United States Patent and Trademark Office. (1982). U.S. Patent No. 4,335,139, pharmaceutical compositions.
U.S. Food and Drug Administration. (n.d.). Drug approval package and labeling resources for epoprostenol products.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
United Kingdom	20175/78	May 17, 1978

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	365926	⤷ Start Trial
Austria	4411	⤷ Start Trial
Austria	A363479	⤷ Start Trial
Australia	4704279	⤷ Start Trial
Australia	525695	⤷ Start Trial
Belgium	876296	⤷ Start Trial
Canada	1141661	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Summary for Patent: 4,335,139