Details for Patent: 8,377,933

Which drugs does patent 8,377,933 protect, and when does it expire?

Patent 8,377,933 protects LETAIRIS and is included in one NDA.

This patent has seventeen patent family members in fourteen countries.

Summary for Patent: 8,377,933

Title:	Method for treating a pulmonary hypertension condition
Abstract:	A method for treating a pulmonary hypertension condition such as pulmonary arterial hypertension (PAH) in a subject comprises administering to the subject a therapeutically effective amount of ambrisentan, wherein, at baseline, time from first diagnosis of the condition in the subject is not greater than about 2 years.
Inventor(s):	Michael J. Gerber, Christopher Dufton
Assignee:	Gilead Sciences Inc
Application Number:	US13/162,137
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,377,933
Patent Claim Types: see list of patent claims	Use; Dosage form;

US Patent 8,377,933: Scope, Claim Analysis, Expiration, and PAH Combination-Therapy Landscape

US Patent 8,377,933 protects a specific treatment strategy for pulmonary arterial hypertension: starting ambrisentan together with sildenafil, tadalafil, or vardenafil no later than about two years after the patient’s first PAH diagnosis. The patent is a method-of-treatment patent, not a patent on ambrisentan, a PDE5 inhibitor, or a particular tablet formulation.

Its commercial significance is concentrated in combination use of Letairis or generic ambrisentan with a PDE5 inhibitor during the early post-diagnosis period. The broadest claim does not require simultaneous dosing, a fixed-dose combination, a particular PAH etiology, or a specific ambrisentan dose. Dependent claims narrow the population, diagnostic criteria, tadalafil use, dosage range, and administration format.

What does US Patent 8,377,933 protect?

US 8,377,933 protects a method comprising four principal elements:

1. A human subject has pulmonary arterial hypertension.
2. The subject receives a therapeutically effective amount of ambrisentan.
3. The subject receives a therapeutically effective amount of sildenafil, tadalafil, or vardenafil.
4. Initiation of administration of ambrisentan and the PDE5 inhibitor occurs within about two years after first diagnosis of PAH.

The patent therefore covers an early combination-treatment protocol rather than all use of ambrisentan in PAH. A treatment using ambrisentan alone falls outside claim 1. A combination with a PDE5 inhibitor not identified in claim 1 also falls outside the literal scope of the claim.

The principal protected combinations are:

Endothelin receptor antagonist	Permitted PDE5 inhibitor
Ambrisentan	Sildenafil
Ambrisentan	Tadalafil
Ambrisentan	Vardenafil

The claim does not expressly require Letairis. Generic ambrisentan can satisfy the ambrisentan limitation if the product is used in the claimed method.

How should claim 1 of US 8,377,933 be construed?

Claim 1 is a treatment-method claim with a timing limitation. Each limitation must be satisfied for literal infringement.

“Treating pulmonary arterial hypertension”

The method must be directed to PAH, not pulmonary hypertension generally. The claim is focused on pulmonary arterial disease, which is characterized by pulmonary vascular pathology and elevated pulmonary arterial pressure and pulmonary vascular resistance.

Treatment of other pulmonary hypertension groups, such as isolated left-heart pulmonary hypertension or lung-disease-associated pulmonary hypertension, would not automatically satisfy the PAH limitation. The factual diagnosis and the intended use of the drug regimen would be central to infringement analysis.

“In a human subject”

The claim is limited to treatment of a human. Animal studies, in vitro work, and nonhuman veterinary treatment are outside the literal claim.

“Therapeutically effective amount”

The claim does not specify a numerical dose. The amount must be effective for treating the patient’s PAH. This limitation creates a clinical-use requirement but does not limit the claim to the approved 5 mg or 10 mg Letairis dose.

The dependent claims identify an ambrisentan daily dose of approximately 1 mg to 25 mg and, more narrowly, approximately 2.5 mg to 10 mg. Those ranges strengthen the relevance of standard clinical dosing but do not narrow claim 1 unless a dependent claim is asserted.

“Selected from sildenafil, tadalafil and vardenafil”

The language creates a closed selection of three PDE5 inhibitors. Other PDE5 inhibitors are not expressly covered.

The claim does not distinguish branded and generic products. Revatio and Viagra contain sildenafil; Adcirca and Cialis contain tadalafil; Levitra contains vardenafil. The relevant active ingredient, intended treatment, and manner of use would determine whether the drug satisfies the limitation.

“Initiation ... not greater than about 2 years from first diagnosis”

This is the most important limiting feature. It requires the combination regimen to begin within approximately two years after the patient’s first PAH diagnosis.

The claim does not require:

• Initiation on the day of diagnosis.
• Simultaneous first doses.
• Prior treatment failure.
• Hospitalization.
• Disease progression.
• A particular baseline six-minute walk distance.
• A specified right-heart catheterization result.
• Use of a fixed-dose combination product.

The phrase “initiation of administration of ambrisentan and the PDE5 inhibitor” can support sequential use, provided the initiation of the relevant combination falls within the claimed period. Claims 10 and 11 confirm that the patent contemplates both same-time administration and separate administration at different times.

The word “about” creates a fact-sensitive boundary around the two-year period. A regimen initiated materially after the second anniversary presents a stronger non-infringement position than one initiated shortly after that date.

What do claims 2 through 11 add?

Claim	Added limitation	Practical effect
2	WHO Functional Class II, III, or IV	Excludes subjects outside those specified functional classes
3	Idiopathic PAH	Covers idiopathic disease
4	Non-idiopathic PAH	Covers secondary PAH
5	Scleroderma, systemic lupus erythematosus, anorexigen use, or HIV infection	Identifies specific secondary causes
6	Hemodynamic criteria involving mean PAP, PVR, PCWP, or LVEDP	Adds objective disease-definition criteria
7	PDE5 inhibitor is tadalafil	Narrows the combination to ambrisentan plus tadalafil
8	Ambrisentan dose of approximately 1 mg to 25 mg daily	Broad dose range
9	Ambrisentan dose of approximately 2.5 mg to 10 mg daily	Narrower clinically relevant range
10	Same dosage form and same-time administration	Covers a single dosage form administered at the same time
11	Separate administration at different times	Covers coadministration without a single dosage form

Claim 6 uses “and/or.” On its face, satisfaction of at least one listed hemodynamic condition may be enough, subject to the remaining claim limitations and the interpretation of the claim language.

What PAH patients and disease categories are covered?

The patent expressly reaches both idiopathic and non-idiopathic PAH.

The specified secondary forms include PAH associated with:

• Scleroderma.
• Systemic lupus erythematosus.
• Anorexigen exposure.
• HIV infection.

Claim 2 narrows the method to WHO Functional Class II, III, or IV. Claim 1 itself does not contain that class limitation, so a patient in another functional class could potentially fall within claim 1 if all other limitations are satisfied.

The hemodynamic limitations in claim 6 refer to:

• Mean pulmonary artery pressure of at least approximately 25 mmHg at rest or approximately 30 mmHg during exercise.
• Pulmonary vascular resistance of at least approximately 3 mmHg/L/min.
• Pulmonary capillary wedge pressure or left ventricular end-diastolic pressure of no more than approximately 15 mmHg.

These measurements distinguish precapillary pulmonary vascular disease from pulmonary venous or left-heart causes. The statutory and regulatory relevance of these thresholds depends on the applicable diagnostic standard and the clinical evidence recorded for the patient.

What dosage forms and administration methods are protected?

US 8,377,933 covers more than a fixed-dose combination concept.

Same dosage form

Claim 10 covers ambrisentan and the PDE5 inhibitor in one dosage form for administration at the same time. A single tablet, capsule, multiparticulate product, or other combined dosage form could be relevant if it contains both active ingredients and is used within the claimed early-treatment period.

The claim does not expressly require a particular excipient, release profile, tablet strength, coating, or manufacturing process.

Separate products or separate times

Claim 11 covers administration of ambrisentan and the PDE5 inhibitor separately at different times. This is commercially important because standard PAH therapy commonly uses separate products rather than a fixed-dose combination.

A patient receiving ambrisentan in the morning and tadalafil at another time could potentially satisfy claim 11, assuming the other limitations are met. Separate prescriptions do not avoid the claim merely because the products come from different manufacturers.

Dose ranges

Claims 8 and 9 are directed to ambrisentan dose ranges. They do not specify a dose range for the PDE5 inhibitor. A regimen using standard tadalafil, sildenafil, or vardenafil dosing could therefore be relevant to claim 1 or claim 7 without satisfying the narrower ambrisentan-dose claims.

When does US Patent 8,377,933 lose exclusivity?

The patent has a nominal US patent term tied to the earliest effective nonprovisional filing date, subject to patent-term adjustment. Public patent records identify US 8,377,933 as a Gilead-related PAH method patent with an expiration period in the late 2020s. The operative expiration date is the expiration date shown in the USPTO Patent Center record after accounting for patent-term adjustment.

Exclusivity issue	Analysis
Patent type	US method-of-treatment patent
Active ingredient	Ambrisentan used with a specified PDE5 inhibitor
Patent term basis	20 years from the applicable earliest nonprovisional filing date
Patent-term adjustment	May extend the ordinary 20-year term
Patent-term extension	Must be assessed from the USPTO and FDA records
Geographic scope	United States only
Regulatory exclusivity	Separate from patent exclusivity
Biosimilar exclusivity	Not applicable because ambrisentan is a small molecule

A patent expiration date does not eliminate other patents covering ambrisentan, formulations, manufacturing processes, or separate methods of use. A generic entrant must evaluate the full patent and regulatory package, not only US 8,377,933.

Is US 8,377,933 listed in the Orange Book?

The Orange Book analysis must distinguish the patent from the approved product.

Ambrisentan is marketed in the United States as Letairis and approved for PAH. FDA Orange Book listings are product-specific and may include compound, method-of-use, formulation, or other patents submitted by the NDA holder. A patent can be relevant to generic certification only if it is listed for the applicable reference-listed drug and associated with a use or product covered by the ANDA.

For this patent, the key Orange Book questions are:

• Whether US 8,377,933 is listed against the Letairis NDA.
• Whether it is listed for a method of use relevant to the proposed ANDA labeling.
• Whether the generic applicant carves out the protected combination-use language.
• Whether the applicant submits a Paragraph IV certification.
• Whether the NDA holder brings suit within 45 days.

FDA approval and Orange Book listing do not themselves establish patent validity or infringement. Listing is an administrative notice mechanism under the Hatch-Waxman framework. The patent holder must still prove infringement and withstand validity challenges under the Patent Act.

How could a generic company design around the patent?

Potential design-around positions depend on the proposed label and clinical use.

Label-based design around

A generic ambrisentan applicant could seek a label that omits the patented early combination regimen, subject to FDA requirements and the feasibility of a section viii statement. The applicant could state that the product is not approved for use in combination with sildenafil, tadalafil, or vardenafil within two years of PAH diagnosis.

The viability of a carve-out depends on whether the protected use is separable from the approved labeling and whether the remaining label still supports the proposed product.

Timing-based design around

A regimen initiated more than approximately two years after first diagnosis may avoid the timing limitation. This strategy is clinically restrictive because the patent is aimed at early combination treatment.

Drug-selection design around

Use with a PDE5 inhibitor other than sildenafil, tadalafil, or vardenafil would not satisfy the closed drug-selection limitation as written. A different pharmacologic class would also fall outside the express claim.

Disease-definition design around

A treatment for a form of pulmonary hypertension that is not PAH, or that does not meet the claimed disease characterization, may avoid the claim. This position would require consistency between the label, patient diagnosis, clinical records, and actual promotional conduct.

What Paragraph IV risks exist for ambrisentan generics?

A generic applicant seeking approval before relevant patent expiration may file:

• A Paragraph III certification, accepting delayed approval until patent expiration.
• A Paragraph IV certification, alleging that the patent is invalid, unenforceable, or not infringed.
• A section viii statement carving out a patented method of use.
• A certification strategy combining a label carve-out with noninfringing product instructions.

The principal Paragraph IV arguments against US 8,377,933 would likely include:

1. Lack of novelty based on earlier disclosure of ambrisentan plus a PDE5 inhibitor in early PAH treatment.
2. Obviousness based on known PAH treatment guidelines, combination therapy, and the pharmacology of endothelin receptor antagonists and PDE5 inhibitors.
3. Indefiniteness or lack of written-description support concerning “about two years,” “first diagnosis,” “therapeutically effective amount,” or the scope of “initiation.”
4. Noninfringement based on a label that does not direct the claimed early combination use.
5. Lack of induced infringement where the generic label merely identifies an approved drug without promoting the patented combination.

The patent owner would respond that the claimed timing window and combination produced a clinically meaningful treatment strategy and that the prior art did not provide a sufficient reason to initiate both therapies within two years of first diagnosis.

What clinical evidence supports the commercial relevance of the patent?

The AMBITION trial evaluated initial combination therapy with ambrisentan and tadalafil in patients with PAH. The study reported a reduction in clinical-failure events for initial combination therapy compared with ambrisentan or tadalafil monotherapy. The trial was published in 2015, after the patent’s priority period, and helped establish the commercial and clinical relevance of early combination treatment. [4]

The trial does not determine patent validity by itself. It may, however, be relevant to:

• Written-description and enablement disputes.
• Obviousness arguments concerning expected clinical benefit.
• FDA labeling and promotional conduct.
• Commercial exposure for products used in early combination therapy.

The patent claims three PDE5 inhibitors, while the best-known clinical evidence for initial combination therapy involved ambrisentan plus tadalafil. Claim 7 narrows the patent to that tadalafil combination.

How does this patent compare with other ambrisentan patent categories?

Patent category	Subject matter	Relevance to US 8,377,933
Compound patent	Ambrisentan molecule and chemical derivatives	Separate from the combination-use claims
Composition or formulation patent	Tablet composition, excipients, release characteristics, stability	May create additional generic barriers
Manufacturing patent	Synthesis, purification, crystallization, or process controls	May affect API sourcing
Method-of-use patent	Ambrisentan plus specified PDE5 inhibitor within two years of diagnosis	Core subject of US 8,377,933
Regulatory exclusivity	FDA approval-based exclusivity	Separate from patent rights
Pediatric exclusivity	Six-month extension if granted	Separate from the patent’s substantive scope

The method patent is narrower than a compound patent but can be commercially important if the protected use is prominent in the approved label or treatment guidelines. Its risk is highest for a generic label that expressly instructs early combination use.

Does this patent create biosimilar risk?

No. Ambrisentan is a chemically synthesized small-molecule drug. Generic applicants use the ANDA pathway, not the biosimilar pathway under the Public Health Service Act.

The relevant market-entry issues are:

• ANDA approval.
• Paragraph III or Paragraph IV certification.
• Section viii use carve-out.
• Patent litigation under 35 U.S.C. § 271(e)(2).
• Potential 30-month stay after timely infringement litigation.
• Labeling and induced-infringement exposure.

What litigation or settlement issues matter?

A patent dispute involving US 8,377,933 would likely focus on the interaction between the patent claim and the proposed generic label. The principal litigation questions would be:

• Does the generic label instruct use of ambrisentan with tadalafil, sildenafil, or vardenafil?
• Does it direct initiation within about two years of first diagnosis?
• Does the label identify the relevant PAH populations?
• Can the use be carved out without making the label misleading or incomplete?
• Is the timing limitation definite and supported?
• Was the combination and timing obvious from PAH treatment practice before the patent’s priority date?

A settlement could permit an agreed generic launch date before the asserted patent expiration, potentially with a license or a restricted label. Settlement terms would not alter the claim scope for nonparties and would not establish patent validity.

How strong is the patent estate around early PAH combination therapy?

US 8,377,933 has meaningful claim breadth within a defined clinical scenario:

• It covers three major PDE5 inhibitors.
• It reaches both simultaneous and separate administration.
• It does not require a fixed-dose formulation.
• It does not limit claim 1 to one PAH etiology.
• It captures early treatment rather than only rescue therapy.

Its principal weaknesses are structural:

• The two-year timing limitation materially narrows infringement.
• “First diagnosis” may create evidentiary disputes.
• “About two years” may create boundary disputes.
• Method claims require proof of patient treatment and intent.
• Generic labeling can sometimes avoid direct instruction of the patented use.
• The combination of known PAH drug classes may create obviousness exposure.

The patent is stronger against a product expressly promoted for early ambrisentan plus tadalafil treatment than against a product with a carved-out label and no instructions for the patented regimen.

Key Takeaways

• US 8,377,933 is a US method-of-treatment patent covering early combination therapy for PAH.
• Claim 1 requires ambrisentan plus sildenafil, tadalafil, or vardenafil.
• The combination must be initiated within about two years after first PAH diagnosis.
• The claim does not require simultaneous dosing or a single dosage form.
• Claims 10 and 11 cover both co-formulated and separately administered regimens.
• Claim 7 specifically targets ambrisentan plus tadalafil.
• Claims 2 through 6 narrow the patient population by functional class, etiology, and hemodynamic criteria.
• The patent does not cover ambrisentan monotherapy or every possible PAH combination.
• Generic risk is principally an ANDA, Paragraph IV, label-carve-out, and induced-infringement issue.
• Biosimilar analysis is irrelevant because ambrisentan is a small molecule.
• The patent’s commercial value depends on its operative expiration date, Orange Book status, approved labeling, generic certifications, and any related formulation or manufacturing patents.

FAQs About US Patent 8,377,933

Does US 8,377,933 cover Letairis alone?

No. The independent claim requires ambrisentan to be administered in combination with sildenafil, tadalafil, or vardenafil.

Does taking ambrisentan and tadalafil on the same day infringe the patent?

Not necessarily. The claim requires initiation of the combination within about two years after first PAH diagnosis and requires a therapeutically effective treatment regimen. Same-day dosing may satisfy the administration relationship, but all other limitations must also be met.

Does the patent cover generic tadalafil with generic ambrisentan?

Potentially. The claim is directed to active ingredients and treatment conditions, not to the Cialis or Adcirca brands. Generic substitution does not by itself avoid the claim.

Is a fixed-dose ambrisentan-tadalafil tablet required?

No. Claim 1 is broad enough to cover separate products. Claim 10 addresses administration in one dosage form, while claim 11 addresses separate administration at different times.

Can a generic applicant avoid the patent by omitting tadalafil from its label?

Potentially, if the resulting label does not instruct or encourage the patented combination use and the use can lawfully be carved out. The outcome depends on the final label, FDA requirements, and the facts supporting any induced-infringement claim.

References

1. United States Patent and Trademark Office. (2013). US Patent No. 8,377,933 B2, Methods of treating pulmonary arterial hypertension. U.S. Department of Commerce.

2. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book. U.S. Department of Health and Human Services.

3. U.S. Food and Drug Administration. (2019). Letairis (ambrisentan) prescribing information. Gilead Sciences, Inc.

4. Galiè, N., Barberà, J. A., Frost, A. E., Ghofrani, H.-A., Hoeper, M. M., McLaughlin, V. V., Peacock, A. J., Simonneau, G., Vachiery, J.-L., Grunig, E., Oudiz, R. J., Vonk-Noordegraaf, A., White, R. J., Chan, M., Rubin, L. J., & AMBITION Investigators. (2015). Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. New England Journal of Medicine, 373(9), 834-844. https://doi.org/10.1056/NEJMoa1413687

5. United States Code. (2024). 35 U.S.C. §§ 271, 282, 283, 284, and 355. U.S. Government Publishing Office.

Drugs Protected by US Patent 8,377,933

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Gilead	LETAIRIS	ambrisentan	TABLET;ORAL	022081-001	Jun 15, 2007	AB	RX	Yes	No	8,377,933					FOR THE TREATMENT OF PULMONARY HYPERTENSION (PAH) IN COMBINATION WITH TADALAFIL
Gilead	LETAIRIS	ambrisentan	TABLET;ORAL	022081-002	Jun 15, 2007	AB	RX	Yes	Yes	8,377,933					FOR THE TREATMENT OF PULMONARY HYPERTENSION (PAH) IN COMBINATION WITH TADALAFIL

International Family Members for US Patent 8,377,933

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
European Patent Office	2101777		300813	Netherlands
European Patent Office	2101777		PA2016018	Lithuania
European Patent Office	2101777		93081	Luxembourg