US Patent 6,756,033: Scope, Claims, Expiration, and Treprostinil Patent Landscape

US Patent 6,756,033 protects inhaled delivery of benzindene prostaglandins, principally treprostinil, using aerosol droplets or powder particles smaller than 10 micrometers. The patent covers method of treatment claims rather than the treprostinil molecule, a specific device, or a particular disease. Its principal commercial relevance was Tyvaso, United Therapeutics’ inhaled treprostinil product.

The patent’s 20-year term ran from the nonprovisional filing date of December 14, 1999, placing the expected expiration in December 2019, subject to any patent-term adjustment. The patent is therefore expired and cannot presently block generic or competing inhaled treprostinil products. Its former claim scope remains relevant for historical Orange Book analysis, freedom-to-operate reviews, and interpretation of later treprostinil patents.

What does US Patent 6,756,033 protect?

The patent protects a method of administering a benzindene prostaglandin to a mammal by inhalation when the formulation contains particles or droplets smaller than 10 micrometers.

The independent claims divide the technology into two delivery formats:

Claim	Delivery format	Particle limitation	Active ingredient scope
1	Aerosolized liquid formulation	Droplets less than 10 µm	Benzindene prostaglandin
2	Aerosolized liquid formulation	Droplets less than 10 µm	Specifically identifies UT-15
6	Powder formulation	Particles less than 10 µm	Benzindene prostaglandin
7	Powder formulation	Particles less than 10 µm	Specifically identifies UT-15

The claims are method claims. An accused product would generally need to be used or marketed for administering the claimed prostaglandin by inhalation. The patent does not claim treprostinil as a chemical compound in the abstract.

The central technical limitation is pulmonary delivery of respirable material. A formulation with droplets or particles measuring 10 micrometers or larger would fall outside the literal size limitation, although measurement methodology and infringement under the doctrine of equivalents could have been disputed while the patent was enforceable.

What is the active ingredient covered by the patent?

The principal compound is UT-15, the development code for treprostinil.

Claim 2 identifies UT-15 by a lengthy chemical name corresponding to treprostinil:

"9-deoxy-2',9-alpha-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-1,3,14-trihydro-prostaglandin F1."

Treprostinil is a prostacyclin analogue used to treat pulmonary arterial hypertension. It is marketed in several dosage forms, including:

Remodulin, an injectable formulation;
Tyvaso, an inhalation solution;
Orenitram, an extended-release oral formulation; and
Tyvaso DPI, a dry-powder inhalation product.

Patent 6,756,033 is most directly relevant to inhaled treprostinil. It does not by itself cover injectable or oral administration.

How broad are claims 1 and 6?

Claims 1 and 6 are the broadest claims in the patent.

Claim 1: liquid aerosol delivery

Claim 1 requires:

A mammal in need of treatment;
A therapeutically effective amount of a benzindene prostaglandin;
Administration by inhalation;
A formulation containing droplets smaller than 10 micrometers.

The claim does not require:

A particular pulmonary disease;
Treprostinil specifically;
A particular dose;
A named nebulizer;
A specified liquid carrier;
Sustained release;
A particular treatment duration; or
A limitation requiring no effect on heart rate.

The use of the term "benzindene prostaglandin" creates a genus-level limitation. Claim construction would determine which compounds fall within that category. Claim 2 narrows the genus to UT-15.

Claim 6: powder delivery

Claim 6 covers inhaled powder formulations with particles smaller than 10 micrometers. It is structurally similar to claim 1 but applies to a powder rather than aerosolized liquid droplets.

The powder claim is significant because it is directed to dry-powder inhalation rather than nebulized delivery. Claim 7 narrows it to UT-15.

A dry-powder product could raise separate questions concerning whether the relevant particle-size measurement is the geometric particle diameter, aerodynamic diameter, emitted dose particle size, or another formulation metric. Those issues would have affected infringement analysis before expiration.

What do the dependent claims add?

Claim	Added limitation	Legal effect
2	UT-15 in a pharmacologically acceptable liquid carrier	Narrows claim 1 to treprostinil liquid aerosol delivery
3	Human patient	Narrows the mammal limitation
4	Sustained-release formulation	Adds controlled-release formulation limitation
5	No effect on heart rate	Adds a functional treatment-result limitation
7	UT-15	Narrows claim 6 to treprostinil powder delivery
8	Human patient	Narrows claim 6 to human use
9	Sustained-release formulation	Adds controlled-release powder limitation
10	No effect on heart rate	Adds a functional treatment-result limitation

Claims 3 and 8 have limited commercial value because the independent claims already cover administration to a mammal, and human treatment would ordinarily fall within that broader category.

Claims 4 and 9 are more technically significant. They extend the patent’s reach to sustained-release inhaled formulations, but they require proof that the formulation has the claimed sustained-release characteristic.

Claims 5 and 10 introduce an outcome-based limitation: administration must have no effect on heart rate. This limitation could create proof problems because heart-rate response can depend on dose, baseline condition, concomitant drugs, measurement timing, and patient population.

What formulations are protected by US 6,756,033?

The patent reaches two primary formulation categories.

Nebulized liquid formulations

The liquid claims cover formulations delivered as inhaled droplets below 10 micrometers. A nebulized aqueous or other pharmacologically acceptable carrier containing treprostinil could fall within the claim structure if the other limitations were satisfied.

Tyvaso inhalation solution is the clearest commercial product associated with this technology. FDA labeling identifies Tyvaso as treprostinil inhalation solution administered using a nebulizer system. The approved product is indicated for pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease [2][3].

Dry-powder formulations

The powder claims cover treprostinil particles below 10 micrometers delivered by inhalation. The claim does not require a specific dry-powder inhaler, excipient, carrier, capsule, blister, or dose-loading mechanism.

Tyvaso DPI was approved substantially later than the patent’s filing date. The product uses a dry-powder inhalation platform and represents the type of product that would have been commercially relevant to claims 6 and 7, although later patents, regulatory exclusivities, and other intellectual-property rights determine its current protection [4].

When did US Patent 6,756,033 expire?

The patent was filed on December 14, 1999, and issued on June 29, 2004. Under the modern US patent-term statute, the ordinary term is 20 years from the earliest effective nonprovisional filing date, not 20 years from issuance [1].

Event	Date
US nonprovisional filing	December 14, 1999
Patent issuance	June 29, 2004
Expected statutory term end	December 14, 2019
Current status	Expired

Any patent-term adjustment would have altered the precise end date. The patent’s enforceable term nevertheless ended no later than the period generally associated with late 2019 or early 2020. The patent is no longer a live barrier to market entry.

The expiration analysis differs from FDA regulatory exclusivity. Patent expiration does not establish that a generic product is approved, therapeutically substitutable, or immediately launchable. It removes one patent-based exclusion right.

What was the Orange Book status of US 6,756,033?

Patent 6,756,033 was associated with the inhaled treprostinil product franchise and was relevant to Orange Book patent-listing analysis for Tyvaso. The patent’s subject matter was a method of use involving inhalation, not a compound claim.

For an Orange Book-listed method patent, an ANDA applicant could address the patent through a Paragraph IV certification if the applicant sought approval before expiration and contended that the patent was invalid, unenforceable, or would not be infringed. A section viii statement could also be relevant where the applicant carved out the patented method from its proposed labeling, depending on the scope of the listed use and the proposed labeling [5].

Because 6,756,033 has expired, it no longer creates a current Paragraph IV launch risk. FDA Orange Book status must still be distinguished from the broader patent estate. Other unexpired patents may cover:

Treprostinil formulations;
Nebulizer systems;
Dry-powder inhalers;
Specific dosing regimens;
Treatment of particular pulmonary conditions;
Manufacturing methods; and
Drug-device combinations.

Which companies challenged or could challenge the patent?

No current Paragraph IV challenge can create a launch block based solely on patent 6,756,033 because the patent has expired.

Historically, the relevant challenger class consisted of ANDA applicants seeking approval for generic treprostinil inhalation solution. Potential challengers would have had three principal options:

Paragraph IV certification that the patent was invalid, unenforceable, or not infringed;
Paragraph III certification accepting delayed approval until patent expiration; or
Section viii carve-out of the patented inhalation method, where legally and commercially feasible.

A Paragraph IV notice concerning an expired patent has no practical injunction value today. Litigation could continue for damages or historical issues, but it would not preserve a current exclusion period.

No biosimilar pathway applies. Treprostinil is a chemically synthesized small molecule, not a biologic. A competing product would use the ANDA pathway or, for a clinically different product, another small-molecule FDA pathway. FDA approval of a generic inhalation product would depend on pharmaceutical equivalence, bioequivalence, device performance, labeling, manufacturing controls, and any remaining patent rights [5].

How strong was the patent estate for inhaled treprostinil?

Patent 6,756,033 had strong early commercial relevance but limited residual value after expiration.

Factor	Assessment
Claim type	Method of treatment
Core technology	Inhalation of sub-10-micrometer droplets or particles
Compound coverage	Broad genus in independent claims; treprostinil in dependent claims
Disease limitation	None in the independent claims
Device limitation	None
Formulation limitation	Liquid aerosol or powder; sustained release in dependent claims
Geographic coverage	United States only
Current enforceability	None after expiration
Historical commercial relevance	High for inhaled treprostinil
Current blocking value	None

The patent’s breadth came from its omission of a disease limitation and specific inhaler limitation. Its weaknesses included reliance on a size threshold, functional terms such as "therapeutically effective amount," and a genus term that could have raised written-description or claim-construction issues for compounds beyond treprostinil.

The patent did not create a complete product monopoly. A competitor could have designed around it by changing the delivery route, using particles outside the claimed size range, developing a non-inhaled dosage form, or relying on a different active compound. Those design-around options would have been assessed against the full patent portfolio, not this patent alone.

What patent litigation affects inhaled treprostinil?

The principal litigation risk during the patent’s term would have involved generic or competing inhaled treprostinil products. The typical dispute would have addressed:

Whether the proposed formulation contained droplets or particles below 10 micrometers;
Whether the product was intended for a claimed inhalation method;
Whether treprostinil qualified as the claimed benzindene prostaglandin;
Whether a sustained-release limitation was met;
Whether the heart-rate limitation was satisfied;
Whether the patent was enabled across the claimed genus; and
Whether the patent was obvious in view of prostacyclin inhalation and aerosol literature.

The expired status materially changes the litigation posture. Current competitors focus on later patents and regulatory exclusivities. Patent 6,756,033 may remain relevant to prosecution history, claim-priority analysis, and the technical background of subsequent patent families, but it is not an active injunction asset.

How does US 6,756,033 compare with later Tyvaso patents?

Patent 6,756,033 is an early platform patent. Later rights are more likely to focus on narrower commercial implementations.

Category	US 6,756,033	Later Tyvaso-related rights
Primary subject	Inhaled benzindene prostaglandins	Product-specific formulations, devices, dosing, or uses
Delivery	Liquid aerosol and powder	Often tied to a particular inhaler or formulation
Compound	Genus plus UT-15 dependent claims	Frequently treprostinil-specific
Particle limitation	Less than 10 µm	May use different particle, dose, or device parameters
Status	Expired	Some later rights may remain active
Commercial role	Foundational inhaled-delivery protection	Follow-on lifecycle and product protection

The relevant competitive landscape includes United Therapeutics, generic-drug manufacturers, inhalation-device developers, and companies developing alternative pulmonary arterial hypertension therapies. Competing drugs include inhaled iloprost, oral prostacyclin-pathway agents, endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors. These products are not necessarily substitutes from an intellectual-property perspective because their active ingredients, delivery systems, and FDA indications differ.

What generic launch risks remain after expiration?

Expiration of 6,756,033 removes the patent’s direct barrier but does not guarantee immediate generic entry.

Remaining issues may include:

Unexpired formulation or device patents;
FDA regulatory exclusivity;
Limited availability of an FDA-reference-listed drug pathway;
Complex bioequivalence requirements for inhaled products;
Device comparability and human-factors testing;
Manufacturing controls for low-dose prostacyclin formulations;
Patent rights covering pulmonary hypertension indications; and
Commercial difficulty establishing an inhalation-device supply chain.

For Tyvaso, the greatest entry risk is likely to come from later product and device patents rather than from 6,756,033. For Tyvaso DPI, the dry-powder inhaler and formulation platform may present a different patent profile from the original nebulized solution.

What is the revenue exposure associated with the patent?

The commercial exposure was substantial because inhaled treprostinil became one of United Therapeutics’ leading products. United Therapeutics reported approximately $1.15 billion in Tyvaso net product revenue for 2023 [6].

That revenue was not protected by patent 6,756,033 alone. The product’s market protection depended on the combined effect of:

The original inhalation patent;
Later formulation and device patents;
FDA approval and labeling;
Manufacturing know-how;
Distribution infrastructure; and
Clinical adoption in pulmonary hypertension.

Once 6,756,033 expired, the revenue risk shifted from a single foundational patent to the remaining portfolio and the practical barriers to developing an equivalent inhaled product.

Key Takeaways

US Patent 6,756,033 covers inhaled delivery of benzindene prostaglandins in droplets or particles smaller than 10 micrometers.
The patent specifically reaches treprostinil, also known as UT-15, through claims 2 and 7.
Claim 1 covers aerosolized liquid delivery; claim 6 covers powder delivery.
Claims 4 and 9 address sustained-release formulations.
Claims 5 and 10 require no effect on heart rate and are narrower, fact-intensive limitations.
The patent is a method patent, not a compound patent or general treprostinil composition patent.
The expected patent term ended in December 2019, subject to any patent-term adjustment.
The patent no longer creates a current Paragraph IV or injunction risk.
Treprostinil is a small molecule, so competing products follow the ANDA framework rather than the biosimilar pathway.
Current commercial risk depends mainly on later formulation, device, dosing, manufacturing, and method-of-use patents.
United Therapeutics’ Tyvaso franchise generated approximately $1.15 billion in net product revenue in 2023.

FAQs

Does US Patent 6,756,033 cover Tyvaso DPI?

It covers the claimed method of administering a treprostinil powder with particles smaller than 10 micrometers. Tyvaso DPI may also be subject to later patents covering its specific powder formulation, inhaler, dosing system, or manufacturing process.

Is treprostinil protected by a biosimilar patent strategy?

No. Treprostinil is a chemically synthesized small molecule. The relevant regulatory pathway is generally an ANDA or another small-molecule application, not a biosimilar application under the Public Health Service Act.

Could a generic treprostinil product launch after expiration of 6,756,033?

Yes, expiration removes this patent as a blocking right. Launch timing may still depend on FDA approval, remaining patents, device requirements, formulation equivalence, and commercial manufacturing capacity.

Does the patent cover injectable Remodulin?

No. The asserted claims require administration by inhalation. Injectable treprostinil products do not satisfy that route-of-administration limitation.

What is the most important limitation for infringement analysis?

The sub-10-micrometer limitation is central. For liquid products, the analysis concerns aerosol droplets. For powder products, it concerns particles. The applicable particle-size measurement and the product’s intended method of use would have been key technical issues during the patent term.

References

United States Patent and Trademark Office. (2004). U.S. Patent No. 6,756,033, Inhalation of benzindene prostaglandins.
U.S. Food and Drug Administration. (2022). Tyvaso (treprostinil) inhalation solution: Prescribing information. United Therapeutics Corporation.
U.S. Food and Drug Administration. (2022). Tyvaso approved labeling for pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease.
U.S. Food and Drug Administration. (2022). Tyvaso DPI (treprostinil) inhalation powder: Prescribing information. United Therapeutics Corporation.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations.
United Therapeutics Corporation. (2024). Annual report pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934 for the fiscal year ended December 31, 2023.

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	245979	⤷ Start Trial
Australia	4082700	⤷ Start Trial
Canada	2365890	⤷ Start Trial
China	1196479	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 6,756,033

Summary for Patent: 6,756,033