United States Patent 5,739,152: Scope, Claims, Expiration, and Clevidipine Patent Landscape

U.S. Patent No. 5,739,152 protects intravenous lipid emulsions containing a short-acting dihydropyridine calcium-channel blocker, including clevidipine-related compounds. Its core claims cover the formulation architecture, specified dihydropyridine structures, concentration ranges, and perioperative blood-pressure-control use. The patent issued on April 14, 1998, and its ordinary 20-year term expired in 2015. It is no longer a blocking patent for new clevidipine products. Later patents, regulatory exclusivities, formulation know-how, and manufacturing controls remain relevant to commercial entry. [1]

What does U.S. Patent 5,739,152 protect?

The patent protects an intravenous emulsion comprising four essential components:

A short-acting dihydropyridine compound with a plasma half-life below 30 minutes.
A lipid phase.
An emulsifier.
Water or a buffer.

The independent formulation claim is claim 1. Claim 10 repeats the same basic formulation for short-term blood-pressure reduction. Claim 9 covers intravenous administration of the formulation during surgery and postoperatively.

The patent is directed to rapidly titratable intravenous antihypertensive therapy. Its technical premise is that a short plasma half-life allows clinicians to increase or discontinue blood-pressure effects quickly, while a lipid emulsion enables intravenous delivery of poorly water-soluble dihydropyridines.

Claim structure

Claim	Subject matter	Practical scope
1	IV emulsion containing short-acting dihydropyridine, lipid, emulsifier, and water or buffer	Broadest formulation claim
2	Claim 1 formulation using a defined Markush class of substituted 1,4-dihydropyridines	Structural limitation
3	Claim 1 formulation using six expressly identified compounds	Compound-specific limitation
4	Active compound at 0.001-20 wt%	Concentration limitation
5	Lipid phase comprising triglycerides	Lipid limitation
6	Lipid phase at 1-35 wt%	Concentration limitation
7	Emulsifier comprising a phospholipid	Emulsifier limitation
8	Emulsifier at 0.01-2 times the lipid-phase weight	Ratio limitation
9	IV method for short-term blood-pressure reduction during and after surgery	Method-of-use claim
10	Formulation for short-term blood-pressure reduction	Use-linked formulation claim

The use of “comprises” makes the claims open-ended. An accused product could contain additional excipients, stabilizers, tonicity agents, or preservatives and still fall within the claim if every required limitation is present.

How broad is claim 1 of U.S. Patent 5,739,152?

Claim 1 is broad in formulation terms but narrower than a general intravenous antihypertensive claim. It requires the following combination:

The active ingredient must be a dihydropyridine.
The active ingredient must have a plasma half-life below 30 minutes.
The dosage form must be an emulsion.
The formulation must contain a lipid phase.
The formulation must contain an emulsifier.
The formulation must contain water or a buffer.
The route must be intravenous.

A product would not literally satisfy claim 1 if it were:

An aqueous solution without a lipid phase.
A suspension rather than an emulsion.
An oral or transdermal formulation.
An emulsion containing a long-acting dihydropyridine.
An emulsion using a non-dihydropyridine antihypertensive.

The half-life limitation is functional and potentially fact-intensive. Infringement analysis would likely examine clinical pharmacokinetic data, the relevant salt or ester form, dosage, patient population, and the meaning of “half-life in plasma.” A product developer could not rely solely on the labeled half-life if the claimed compound or active metabolite exhibits different pharmacokinetics.

Which compounds are covered by claims 2 and 3?

Markush scope under claim 2

Claim 2 covers a defined 1,4-dihydropyridine structure with:

R1 and R2 independently selected from hydrogen, chloro, bromo, nitro, cyano, and trifluoromethyl.
R3 and R4 independently selected from straight or branched C1-C5 alkyl groups.
Specific exclusions for certain substituent combinations.

The claim includes pharmaceutically acceptable salts and stereoisomers. The exclusions narrow the Markush group and prevent coverage of particular compounds or substitution patterns identified in the claim.

The claim does not cover every dihydropyridine. A compound must satisfy the structural formula, the substituent definitions, the exclusions, and the short plasma half-life requirement incorporated from claim 1.

Express compounds under claim 3

Claim 3 identifies six compounds:

Acetoxymethyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Propionoxymethyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Butyroxymethyl methyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.
The (4S) isomer of the butyroxymethyl compound.
The (4R) isomer of the butyroxymethyl compound.
The isobutyroxymethyl analogue.

Clevidipine, the active ingredient in Cleviprex, is chemically associated with the butyroxymethyl 2,3-dichlorophenyl dihydropyridine disclosed in this claim set. The precise infringement analysis depends on the marketed active form, stereochemical composition, salt or ester identity, and how the product is characterized in regulatory and technical documents. [2]

What formulations are protected by claims 4 through 8?

Claims 4 through 8 narrow the core formulation by specifying quantitative or compositional features.

Active concentration

Claim 4 covers 0.001% to 20% by weight of the total emulsion. The range is wide. It captures both highly dilute injectable emulsions and substantially more concentrated formulations, provided the product remains suitable for intravenous administration and satisfies the other claim limitations.

Lipid phase

Claim 5 identifies triglycerides as a qualifying lipid phase. Claim 6 requires 1% to 35% lipid by total emulsion weight.

A triglyceride-based emulsion outside the 1%-35% range could avoid claim 6 while potentially remaining within claim 5 and claim 1. Conversely, an emulsion using a non-triglyceride lipid could potentially avoid claim 5 but remain within claim 1 if the lipid phase otherwise qualifies.

Emulsifier

Claim 7 specifies a phospholipid. Claim 8 requires the phospholipid emulsifier to be present at 0.01 to 2 times the weight of the lipid phase.

These dependent claims are useful in assessing design-around options. A formulation could potentially avoid claims 7 and 8 by using a different emulsifier system or a ratio outside the claimed range, but claim 1 would remain relevant if the alternative emulsifier still performs the claimed emulsification function.

What method-of-use protection does U.S. Patent 5,739,152 provide?

Claim 9 covers a method for short-term lowering of blood pressure during surgery and postoperatively. The method requires:

A patient requiring blood-pressure reduction.
A therapeutically active amount.
Intravenous administration.
A formulation satisfying claim 1.
Perioperative use during surgery or after surgery.

Claim 10 is broader in wording because it covers a formulation for short-term blood-pressure reduction in a patient in need. It does not expressly repeat the surgical and postoperative limitation found in claim 9.

The claims therefore target acute-care settings rather than chronic hypertension. Relevant clinical settings include controlled hypotension, perioperative hypertension, and rapid blood-pressure management in intensive-care environments.

When did U.S. Patent 5,739,152 expire?

U.S. Patent 5,739,152 issued April 14, 1998. Its ordinary patent term ran 20 years from the U.S. nonprovisional filing date and expired in 2015. Patent-term adjustment, patent-term extension, terminal disclaimers, and regulatory exclusivity must be evaluated separately from the basic expiration calculation. The patent is not a currently enforceable patent blocking ordinary commercial practice of the claimed formulation technology. [1]

The expiration of this patent does not eliminate later patents covering:

Clevidipine itself or related chemical forms.
Improved emulsion stability.
Packaging and container systems.
Manufacturing processes.
Specific concentrations or administration regimens.
Commercial formulations of Cleviprex.

What is the Orange Book status of Patent 5,739,152?

The patent has been associated with the Cleviprex regulatory patent estate. The Orange Book is a product-specific listing system, and listing status should be separated from enforceability. An expired patent may remain visible in historical or current FDA records even though it no longer creates a live exclusionary right. [3]

Cleviprex is an approved small-molecule injectable emulsion, not a biologic. Generic applicants would use the Abbreviated New Drug Application pathway rather than the biosimilar pathway under section 351(k) of the Public Health Service Act.

The relevant regulatory issues include:

Whether the reference listed drug is Cleviprex injectable emulsion.
Whether a proposed generic has the same active ingredient, dosage form, strength, route, and conditions of use.
Whether the applicant must address listed patents through Paragraph IV certification.
Whether later-listed patents remain unexpired at the time of ANDA filing.
Whether the FDA considers the proposed product therapeutically equivalent and pharmaceutically equivalent.

Which patents are associated with the Cleviprex and clevidipine estate?

Public Orange Book and patent records associate the Cleviprex product with several U.S. patents beyond U.S. 5,739,152. Frequently cited members include the following:

U.S. patent	Relevance to the clevidipine estate	Commercial significance
5,739,152	Intravenous emulsion containing a short-acting dihydropyridine	Core formulation patent; expired
6,350,869	Related clevidipine/dihydropyridine patent rights	Potential chemical or product protection
7,598,343	Later clevidipine formulation or product protection	May address commercial formulation characteristics
8,969,616	Later patent associated with the marketed product estate	May affect later generic entry analysis

The claim scope and expiration dates of the later patents must be reviewed independently. A patent number appearing in an Orange Book record does not establish that every claim covers every proposed generic formulation. It also does not establish that the patent remains enforceable, because expiration, terminal disclaimers, maintenance-fee status, and litigation outcomes must be checked at the claim level. [3]

Are there Paragraph IV challenges to Cleviprex?

A Paragraph IV challenge would assert that a listed patent is invalid, unenforceable, or not infringed. Because U.S. Patent 5,739,152 expired in 2015, it no longer provides a meaningful Paragraph IV barrier by itself.

The commercially important question is whether a generic applicant must address later unexpired patents associated with Cleviprex. A Paragraph IV notice concerning a later patent could trigger:

A 45-day period for the patent holder to sue.
A potential 30-month FDA approval stay under the Hatch-Waxman framework.
Patent litigation over formulation equivalence, infringement, validity, or enforceability.
A possible settlement with a negotiated launch date.

A Paragraph IV certification does not itself establish market entry. The outcome depends on the asserted patents, litigation timing, settlement terms, and FDA approval status. [4]

What generic entry risks exist for clevidipine injectable emulsion?

Generic entry risk is higher for the expired core emulsion patent but remains dependent on later patent and regulatory barriers.

Main technical barriers

A generic applicant must reproduce or adequately characterize a sterile injectable lipid emulsion with:

Consistent droplet-size distribution.
Acceptable physical and chemical stability.
Low levels of degradation products.
Sterility and endotoxin control.
Compatible container and closure systems.
Reliable dose uniformity.
Acceptable intravenous administration characteristics.

These are manufacturing and regulatory barriers, not necessarily enforceable patent barriers.

Main patent barriers

Potential patent issues include:

Later formulation patents.
Concentration-specific claims.
Container or packaging claims.
Manufacturing-process claims.
Method-of-use claims.
Patents covering a specific clevidipine composition or stereochemical form.

A formulation that avoids claim 1 of U.S. 5,739,152 could still infringe a later patent. Conversely, a formulation that resembles Cleviprex commercially could avoid an expired patent while facing non-patent technical hurdles.

How does the patent estate compare with competing intravenous antihypertensives?

Clevidipine competes with intravenous agents such as nicardipine, nitroprusside, nitroglycerin, esmolol, and labetalol. Its patent profile differs because clevidipine is delivered as a lipid emulsion rather than a conventional aqueous injectable solution.

Product	Active ingredient	Delivery characteristics	Patent risk profile
Cleviprex	Clevidipine butyrate	Injectable lipid emulsion	Formulation, chemical, and product-specific patents
Cardene IV	Nicardipine hydrochloride	Intravenous solution	Older chemical and formulation estate
Nitropress	Sodium nitroprusside	Intravenous solution	Older compound and use rights
Brevibloc	Esmolol hydrochloride	Intravenous solution	Chemical and formulation rights generally older
Trandate IV	Labetalol hydrochloride	Intravenous solution	Older compound and method rights

Cleviprex has a more specialized formulation profile. The emulsion manufacturing process, droplet control, and stability program can make market entry more difficult than entry for a conventional aqueous solution even when the principal formulation patent has expired.

Were there licensing deals involving clevidipine?

Clevidipine was developed and commercialized through arrangements involving AstraZeneca and The Medicines Company. The Medicines Company commercialized Cleviprex in the United States under rights obtained from AstraZeneca. The commercial agreement illustrates the separation between patent ownership, development rights, regulatory sponsorship, and commercialization rights. [5]

Public summaries do not establish the full economic terms of every underlying agreement. The relevant diligence questions are:

Which entity owned each patent at filing and issuance?
Which entity held U.S. commercialization rights?
Were patent prosecution and enforcement rights assigned or licensed?
Did the agreement include milestone payments, royalties, or termination rights?
Did later patents arise from the licensee’s development work?

How strong is the patent estate for U.S. Patent 5,739,152?

The patent was commercially important when unexpired because claim 1 captured the central formulation concept: a short-acting dihydropyridine delivered intravenously in a lipid emulsion.

Its present legal strength is limited by expiration. The patent can still matter historically in:

Patent litigation records.
Prior-art analysis.
Obviousness and written-description assessments of later patents.
Freedom-to-operate reviews concerning abandoned or reformulated products.
Interpretation of the technical development path for clevidipine emulsions.

The strongest historical claims were claims 1, 3, and 7. Claim 1 established the broad combination. Claim 3 tied the formulation to specific compounds, including clevidipine-related structures. Claims 7 and 8 narrowed the emulsifier identity and ratio. Claims 4 through 6 provided concentration and lipid limitations that could support narrower infringement theories.

Key Takeaways

U.S. Patent 5,739,152 covers intravenous lipid emulsions containing short-acting dihydropyridines.
Claim 1 is the central formulation claim.
Claims 2 and 3 cover defined dihydropyridine structures and specifically identified compounds related to clevidipine.
Claims 4 through 8 address concentration, triglyceride content, phospholipid emulsifiers, and emulsifier-to-lipid ratios.
Claim 9 covers perioperative intravenous blood-pressure reduction.
Claim 10 covers the formulation for short-term blood-pressure reduction.
The patent issued in 1998 and expired in 2015 under its ordinary patent term.
The patent is no longer a standalone barrier to generic clevidipine entry.
Later patents associated with Cleviprex, together with FDA requirements and emulsion-manufacturing controls, remain relevant.
Clevidipine is a small molecule and is subject to ANDA and Paragraph IV analysis, not biosimilar approval.
Patent expiration does not eliminate regulatory, formulation, manufacturing, or commercial-entry risk.

FAQs About U.S. Patent 5,739,152 and Clevidipine

Does U.S. Patent 5,739,152 cover all intravenous dihydropyridines?

No. It requires a short-acting dihydropyridine with a plasma half-life below 30 minutes and an emulsion containing a lipid phase, emulsifier, and water or buffer.

Does the patent cover an aqueous clevidipine solution?

Not necessarily. Claim 1 requires an emulsion and a lipid phase. A purely aqueous solution would not literally satisfy those limitations, although other patents or infringement theories could remain relevant.

Is clevidipine a biologic requiring biosimilar approval?

No. Clevidipine is a small-molecule active pharmaceutical ingredient. A generic version would ordinarily proceed through the ANDA pathway.

Can a generic launch after expiration of Patent 5,739,152?

Expiration removes this patent as a blocking right, but launch timing can still depend on later patents, Paragraph IV litigation, FDA approval, regulatory exclusivity, and manufacturing readiness.

Does claim 9 cover chronic hypertension treatment?

The express language of claim 9 is directed to short-term blood-pressure lowering during surgery and postoperatively. Chronic outpatient hypertension treatment is outside the ordinary focus of that claim.

References

United States Patent and Trademark Office. (1998). U.S. Patent No. 5,739,152, Pharmaceutical emulsion.
U.S. Food and Drug Administration. (2008). Cleviprex (clevidipine butyrate) injectable emulsion prescribing information.
U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations: Orange Book.
U.S. Food and Drug Administration. (2024). Abbreviated new drug application submissions: Patent certification and 30-month stay provisions.
The Medicines Company. (2008). Cleviprex approval and commercial product information.

Foriegn Application Priority Data
Foreign Country	Foreign Patent Number	Foreign Patent Date
Sweden	9303744	Nov 12, 1993

PCT Information
PCT Filed	November 03, 1994	PCT Application Number:	PCT/SE94/01032
PCT Publication Date:	May 18, 1995	PCT Publication Number:	WO95/13066

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	213158	⤷ Start Trial
Australia	1037195	⤷ Start Trial
Australia	678650	⤷ Start Trial
Canada	2176360	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 5,739,152

Summary for Patent: 5,739,152