Details for Patent: 8,318,802

Which drugs does patent 8,318,802 protect, and when does it expire?

Patent 8,318,802 protects VELETRI and is included in one NDA.

This patent has nineteen patent family members in fifteen countries.

Summary for Patent: 8,318,802

Title:	Epoprostenol formulation and method of making thereof
Abstract:	This invention relates to a stable epoprostenol composition that can be combined with commercially available IV fluids and can be administered in its reconstituted and/or diluted form under ambient conditions of about 15-30° C. for greater than 24 hours. The composition preferably contains (a) epoprostenol or a salt thereof; (b) a alkalinization agent; and (c) a base, such that when reconstituted or in solution, the solution has a pH>11. Methods for making the lyophilized composition are also disclosed.
Inventor(s):	Naglesh R. Palepu
Assignee:	Actelion Pharmaceuticals Ltd
Application Number:	US12/278,061
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,318,802
Patent Claim Types: see list of patent claims	Composition; Formulation;

US Patent 8,318,802: Epoprostenol Lyophilized Formulation Claims and Patent Landscape

US Patent 8,318,802 protects defined lyophilized epoprostenol formulations containing arginine and sodium hydroxide, made from a bulk solution at pH 13 or higher and intended for intravenous reconstitution. The strongest claim scope is concentrated in the combination of four technical features: a 0.5 mg or 1.5 mg unit dose, arginine, sodium hydroxide, and an alkaline bulk solution with pH of at least 13. The dependent claims narrow protection to specific arginine ratios, 50 mg of arginine, and sucrose or mannitol bulking agents.

The patent does not broadly cover every epoprostenol injectable, every lyophilized prostacyclin, or every formulation containing sodium hydroxide. A potentially infringing product would generally need to satisfy the claimed composition, lyophilization, alkaline bulk-solution, and intravenous-use limitations.

What does US Patent 8,318,802 protect?

The patent has two principal independent claim groups:

Claim group	Independent claim	Protected subject matter
Lyophilized pharmaceutical composition	1	A unit-dose lyophilized epoprostenol composition
Lyophilisate formed from bulk solution	11	A lyophilisate made from an alkaline aqueous solution

Claim 1 requires all of the following:

1. Epoprostenol or an epoprostenol salt.
2. A unit dose of 0.5 mg or 1.5 mg.
3. Arginine.
4. Sodium hydroxide.
5. A lyophilized pharmaceutical composition.
6. Formation from a bulk solution having a pH of 13 or higher.
7. Capability for reconstitution with an intravenous fluid for intravenous administration.

Claim 11 is broader in some respects and narrower in others. It does not specify a 0.5 mg or 1.5 mg unit dose, but it expressly requires a bulk solution containing epoprostenol or its salt, arginine, sodium hydroxide, and water. The pH must be at least 13, and the resulting lyophilisate must be capable of intravenous reconstitution.

The patent therefore combines composition limitations with manufacturing-history and functional limitations. The central technical concept is the stabilization and presentation of epoprostenol in a freeze-dried product made under strongly alkaline conditions.

How should the independent claims be construed?

Claim 1: unit-dose lyophilized composition

Claim 1 is a combination claim. Every listed element must be present for literal infringement. The unit-dose limitation is material. A product containing 1.0 mg or 2.0 mg of epoprostenol would not fall within claim 1 solely because it contains the same excipients and was made at pH 13 or higher.

The claim uses the alternative “0.5 mg or 1.5 mg.” A product with both strengths marketed in separate vials could implicate the claim on a vial-by-vial basis. The relevant issue would be the amount in each unit dose, not merely the total amount in a package.

The phrase “formed from a bulk solution having a pH of 13 or higher” adds a process-related limitation. Because the lyophilized product is dry, its final pH may not be directly measurable in the same way as the liquid bulk solution. Manufacturing records, batch records, development reports, and analytical reconstruction of the reconstituted material could become important in an infringement dispute.

Claim 11: lyophilisate formed from an alkaline solution

Claim 11 omits the unit-dose restriction but requires the bulk solution to include water and to have a pH of at least 13. This creates a potentially broader claim for dosage strength and a potentially narrower claim for proof of the claimed solution composition and pH.

The term “lyophilisate formed from” may be litigated as a product-by-process limitation. A court could treat the manufacturing language as limiting, particularly because the claims focus on the pH of the precursor bulk solution. A competing product that has the same final excipients but is manufactured from a lower-pH solution could present a noninfringement position, although the outcome would depend on claim construction and the evidentiary record.

What dependent claims add to the patent scope?

Claims	Limitation	Commercial significance
2, 12	Epoprostenol-to-arginine ratio of about 1:25 to about 1:200	Captures a broad excipient ratio range
3, 13	Bulking agent	Extends the formulation to additional solid-state excipients
4, 14	Enumerated bulking agents, including HES, sorbitol, sugars, dextran, mannitol, trehalose, cyclodextrin, glycine, and PVP	Creates multiple formulation species
5, 15	Bulking agent at about 1% to 10%	Adds concentration-based protection
6, 16	Epoprostenol sodium	Targets the principal commercial salt
7, 17	Dextran, sucrose, or mannitol	Narrows to commercially practical bulking agents
8, 18	Sucrose	Protects a specific formulation alternative
9, 19	Mannitol	Protects another specific formulation alternative
10	Sealed sterile vial	Links the composition to a finished injectable presentation
20	50 mg of arginine	Adds a precise arginine quantity
21	0.5 mg or 1.5 mg epoprostenol, 50 mg arginine, mannitol, and sodium hydroxide	High-value commercial species
22	0.5 mg or 1.5 mg epoprostenol, 50 mg arginine, sucrose, and sodium hydroxide	Alternative high-value commercial species

Claims 21 and 22 are the most commercially focused dependent claims. They define specific vial formulations with either mannitol or sucrose and 50 mg of arginine. A product matching one of those formulations would still need to satisfy the claim 1 requirements, including the pH 13-or-higher bulk solution and intravenous reconstitution limitations.

What formulation ratios are protected?

Claim 2 protects an epoprostenol-to-arginine weight ratio of approximately 1:25 to 1:200. Claim 12 applies a similar ratio to epoprostenol sodium.

The two stated unit doses interact with the 50 mg arginine limitation as follows:

Epoprostenol dose	Arginine dose	Approximate epoprostenol:arginine ratio
0.5 mg	50 mg	1:100
1.5 mg	50 mg	1:33.3

Both ratios fall within the claimed range. The 0.5 mg formulation is centered at 1:100, while the 1.5 mg formulation is closer to the lower-ratio boundary.

The word “about” creates a potential tolerance issue. It does not necessarily permit unlimited variation from the numerical range. In an infringement analysis, the relevant questions would include the specification’s examples, prosecution history, measurement precision, and whether the accused ratio is materially outside the claimed range.

What bulking agents are covered?

The patent claims a broad list of bulking agents and then narrows to specific alternatives.

Broad bulking-agent list

Claims 4 and 14 identify:

• Hydroxyethyl starch, referred to in the claim as “hydroxyl ethyl starch”
• Sorbitol
• Lactose
• Dextran
• Maltose
• Mannose
• Ribose
• Sucrose
• Mannitol
• Trehalose
• Cyclodextrin
• Glycine
• Polyvinylpyrrolidone

The list contains duplicate entries for lactose and dextran. The duplication does not materially expand the claim.

Narrowed bulking-agent claims

Claims 7 and 17 narrow the list to dextran, sucrose, and mannitol. Claims 8 and 18 separately cover sucrose. Claims 9 and 19 separately cover mannitol.

The concentration limitation in claims 5 and 15 requires the bulking agent to be present at about 1% to 10%. The claims do not expressly state whether the percentage is measured weight/volume, weight/weight, or another basis. The specification and prosecution history would be relevant to that interpretation.

How strong is the patent estate for the claimed formulation?

The patent’s strength is concentrated rather than comprehensive.

Stronger elements

The following limitations create meaningful barriers to a close formulation copy:

• The combination of epoprostenol, arginine, and sodium hydroxide.
• A bulk-solution pH of at least 13.
• Specific 0.5 mg and 1.5 mg unit doses.
• 50 mg of arginine.
• Mannitol or sucrose.
• Lyophilization into a sterile injectable vial.
• The claimed epoprostenol-to-arginine ratio.

A competing product that reproduces the commercial presentation and uses the same alkaline manufacturing approach would face the greatest risk.

Weaker or contestable elements

Potentially contestable features include:

• Whether the accused product was actually formed from a bulk solution at pH 13 or higher.
• Whether the final product is legally a “lyophilisate” within the claim.
• Whether “capable of being reconstituted” imposes a meaningful limitation.
• The interpretation of “about” in the weight ratio and bulking-agent concentration.
• Whether the product-by-process language limits the claims to products made by the specified process.
• Whether a different epoprostenol salt falls within the claims, particularly where the product does not use epoprostenol sodium.

The presence of a different buffer or excipient does not necessarily avoid infringement. The claims use “comprising,” which generally allows additional ingredients unless the added ingredient changes another required limitation or creates a separate legal defense.

When does US Patent 8,318,802 lose exclusivity?

The patent was granted on November 27, 2012. Its term depends on the effective nonprovisional filing date, any patent-term adjustment, and any terminal disclaimer recorded in the patent file. The underlying patent record should be used for the controlling expiration calculation.[1]

The patent’s expected ordinary term is in the 2027 period based on the relevant priority and filing chronology. The precise expiration date should be taken from the USPTO patent file and the applicable Orange Book entry, if the patent is listed for an approved epoprostenol product.

Patent expiration is separate from FDA regulatory exclusivity. FDA approval of an epoprostenol product does not itself extend the patent term. Conversely, expiration of the patent does not eliminate any remaining regulatory exclusivity, pediatric exclusivity, or other statutory protections.

What is the Orange Book status of the patent?

Epoprostenol is a small molecule, so the relevant FDA pathway for a generic is generally an abbreviated new drug application, not a biosimilar application under the Biologics Price Competition and Innovation Act.

A patent listed in the Orange Book for an epoprostenol product can create a Paragraph IV certification issue for an ANDA applicant. The listing would need to be evaluated against the specific reference-listed drug, dosage form, strength, and NDA. FDA’s Orange Book identifies patent listings and associated use codes where applicable.[2]

The practical Orange Book questions are:

Issue	Relevance
Listed patent	Determines whether a Paragraph IV certification may trigger the Hatch-Waxman notice and litigation framework
Listed use code	Limits the relevance of a method-of-use listing
Product strength	Important because claims 1, 21, and 22 focus on 0.5 mg and 1.5 mg unit doses
Dosage form	A lyophilized vial may not be interchangeable with a different presentation for listing purposes
Patent expiration	Determines the earliest ordinary patent-based generic launch date
30-month stay	May delay approval if the NDA holder or patent owner timely files suit after a Paragraph IV notice

The claims supplied are formulation claims, not conventional method-of-use claims. They would generally be more relevant to a formulation or product certification than to a therapeutic-use certification.

Which companies could challenge the patent?

Potential challengers would include generic manufacturers developing epoprostenol sodium for injection, contract manufacturers supplying an ANDA applicant, and sponsors seeking approval of an alternative lyophilized presentation.

A challenger could use one or more of the following positions:

1. Noninfringement based on a bulk-solution pH below 13.
2. Noninfringement based on a unit dose outside 0.5 mg and 1.5 mg.
3. Noninfringement based on the absence of arginine.
4. Noninfringement based on another salt or another active ingredient form.
5. Noninfringement based on a non-lyophilized formulation.
6. Invalidity based on anticipation or obviousness.
7. Invalidity based on indefiniteness of “about,” “capable of,” or the bulking-agent percentage.
8. Lack of written description or enablement for the full range of claimed excipients and ratios.

The most commercially credible design-around would likely change the formulation architecture rather than merely substitute a minor excipient. Removing arginine, using a lower-pH manufacturing process, or adopting a different dosage form could materially reduce literal infringement risk.

What prior-art and invalidity issues are most relevant?

The principal prior-art categories are:

• Earlier epoprostenol sodium injectable formulations.
• Earlier alkaline stabilization methods for epoprostenol.
• Lyophilized prostacyclin compositions.
• Arginine-containing injectable formulations.
• Formulations using sodium hydroxide to stabilize labile prostacyclin compounds.
• Products containing mannitol, sucrose, glycine, or related bulking agents.
• Earlier disclosures of 0.5 mg and 1.5 mg epoprostenol vials.

An obviousness challenge would likely combine references directed to epoprostenol stability, alkaline pH, arginine as a stabilizer or excipient, and conventional lyophilization practice. The patent owner’s strongest response would be evidence of unexpected stability, improved shelf life, reduced degradation, or a manufacturing advantage associated with the claimed pH and arginine combination.

The dependent claims may provide fallback positions if the broad claims are vulnerable. Claims directed to 50 mg arginine with mannitol or sucrose may be more fact-specific, but they also face prior-art risks if those exact commercial formulations or close examples were publicly disclosed.

How does the patent relate to FDA-approved epoprostenol products?

Epoprostenol sodium is used as an intravenous prostacyclin for pulmonary arterial hypertension and related clinical settings. FDA-approved products have historically included lyophilized vial presentations requiring reconstitution and dilution before infusion. Product labeling identifies active and inactive ingredients, storage conditions, reconstitution instructions, and approved strengths.[3]

The patent claims are technically aligned with a commercial lyophilized injectable presentation because they address:

• Unit-dose vial strength.
• Lyophilized solid-state form.
• Reconstitution with an intravenous fluid.
• Alkaline formulation conditions.
• Bulking agents used to produce a stable cake or lyophilisate.
• Sterile sealed-vial packaging.

FDA approval does not establish patent infringement. The regulatory product description can, however, provide useful evidence concerning composition, strength, reconstitution, and dosage form. Manufacturing pH and batch-process details may not appear in the public label.

Are biosimilar risks relevant?

No. Epoprostenol is a chemically synthesized small molecule rather than a biologic. A competing sponsor would normally pursue an ANDA or another small-molecule pathway, not a 351(k) biosimilar application.

The relevant competitive risks are therefore:

• ANDA filings.
• Paragraph IV certifications.
• Formulation-based patent litigation.
• Product-by-process claim construction.
• State and federal launch injunctions.
• Substitution and procurement competition after approval.

What patent litigation and settlement issues should be reviewed?

The relevant litigation search should cover:

• District-court cases involving US 8,318,802.
• Federal Circuit appeals.
• Inter partes review or post-grant proceedings.
• Paragraph IV notices involving epoprostenol sodium.
• Settlement agreements with generic applicants.
• Authorized-generic arrangements.
• License agreements covering epoprostenol formulations or intravenous prostacyclin products.

A settlement could alter the practical launch date without changing the patent’s nominal expiration date. It could permit an authorized generic, a licensed generic, or a delayed entry date. Public patent databases, PACER, FDA litigation listings, and SEC filings are the principal sources for identifying such events.[1,2,4]

What geographic coverage does the patent have?

US Patent 8,318,802 provides protection only in the United States. Equivalent foreign applications, grants, abandonments, and expiration dates must be analyzed separately.

The relevant geographic workstreams are:

Jurisdiction	Key question
United States	Patent term, Orange Book listing, ANDA litigation
European Union	EP prosecution, validation countries, opposition, SPC exposure
United Kingdom	UK national rights and post-Brexit litigation
Canada	Canadian formulation claims and regulatory linkage
Japan	National patent term and generic approval timing
China	National phase status and manufacturing exposure
India	Local formulation claims and export-manufacturing risk

A US patent does not block manufacture or sale outside the United States. It can still affect global supply chains where an active ingredient, finished vial, or manufacturing step is imported into the US.

What manufacturing and IP barriers remain after patent expiration?

Patent expiration would remove the ordinary patent barrier, but commercial entry may still depend on:

• Demonstrating pharmaceutical equivalence.
• Matching the reference product’s dosage form and strength.
• Establishing stability through reconstitution and infusion.
• Validating aseptic filling and lyophilization.
• Controlling degradation of epoprostenol.
• Meeting container-closure and sterility requirements.
• Obtaining an ANDA approval.
• Resolving any remaining listed patents or regulatory exclusivity.
• Qualifying suppliers for epoprostenol sodium and sterile vials.

The manufacturing process may also contain unexpired trade secrets. The patent does not disclose every operational parameter needed to reproduce a commercial product at scale.

What generic launch scenarios exist?

Launch before patent expiration

A pre-expiration launch would generally require one of four paths:

• A successful Paragraph IV challenge.
• A court ruling of noninfringement or invalidity.
• A license or settlement permitting earlier entry.
• A product design that avoids the asserted claims.

Launch at patent expiration

This is the lowest litigation-risk scenario, assuming no other listed patents, regulatory exclusivity, or unresolved approval issues block entry.

Launch with a formulation design-around

A competing sponsor could target a different strength, omit arginine, use another stabilizer system, change the pH of the precursor solution, or adopt a non-lyophilized presentation. Each approach would require separate stability and regulatory validation.

Key Takeaways

• US 8,318,802 is a formulation patent directed to lyophilized epoprostenol compositions for intravenous use.
• Claims 1 and 11 are the core independent claims.
• The central limitations are epoprostenol, arginine, sodium hydroxide, lyophilization, and formation from a bulk solution at pH 13 or higher.
• Claims 21 and 22 target specific 0.5 mg or 1.5 mg formulations containing 50 mg arginine with mannitol or sucrose.
• A product using the same excipients but a different manufacturing pH may have a noninfringement position, subject to claim construction.
• Epoprostenol is a small molecule, so generic challenges proceed through the ANDA and Paragraph IV framework rather than a biosimilar pathway.
• The expected patent term falls in the 2027 period, but the controlling expiration date requires review of the USPTO term calculation and any applicable Orange Book listing.
• The patent’s practical strength depends heavily on proof of the bulk-solution pH and the meaning of the product-by-process language.
• Formulation patents, manufacturing records, stability data, and any Paragraph IV settlement are more commercially important than the broad therapeutic indication.

FAQs About US Patent 8,318,802

Does US 8,318,802 cover all epoprostenol sodium injections?

No. The claims require a particular combination of excipients, lyophilized form, alkaline bulk-solution condition, and intravenous reconstitution capability.

Can a product avoid the patent by replacing arginine with glycine?

Potentially. Removing arginine eliminates a central claim limitation, although other patents, contractual rights, or doctrine-of-equivalents arguments could remain relevant.

Does a 1.0 mg epoprostenol vial fall within claim 1?

Not literally, because claim 1 specifies a unit dose of 0.5 mg or 1.5 mg. Other claims, including claim 11, do not contain the same explicit unit-dose limitation.

Is a product with mannitol automatically infringing?

No. Mannitol alone is insufficient. The product must satisfy the applicable independent claim and all required limitations, including arginine, sodium hydroxide, lyophilization, and the pH condition where applicable.

Is an epoprostenol biosimilar needed to compete with the patented product?

No. Epoprostenol is a small molecule. The principal US regulatory route for a generic competitor is an ANDA, with patent certifications governed by the Hatch-Waxman framework.

References

1. United States Patent and Trademark Office. (2012). U.S. Patent No. 8,318,802, Pharmaceutical compositions comprising epoprostenol.
2. U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations: Orange Book.
3. U.S. Food and Drug Administration. (n.d.). Veletri (epoprostenol sodium) for injection prescribing information.
4. U.S. Food and Drug Administration. (n.d.). Paragraph IV patent certifications and patent litigation information.

Drugs Protected by US Patent 8,318,802

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Actelion	VELETRI	epoprostenol sodium	INJECTABLE;INJECTION	022260-002	Jun 28, 2012	AP2	RX	Yes	No			Y
Actelion	VELETRI	epoprostenol sodium	INJECTABLE;INJECTION	022260-001	Jun 27, 2008	AP2	RX	Yes	Yes			Y

Foreign Priority and PCT Information for Patent: 8,318,802

PCT Information
PCT Filed	February 02, 2007	PCT Application Number:	PCT/US2007/002948
PCT Publication Date:	August 16, 2007	PCT Publication Number:	WO2007/092343

International Family Members for US Patent 8,318,802

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Brazil	PI0707488
Canada	2641393
Canada	2868998
China	101410119
Cyprus	1117128
Denmark	1993557
European Patent Office	1993557