United States Patent 8,658,676: Clevidipine Formulation Claims, Scope and Patent Landscape

US Patent 8,658,676 protects a specific clevidipine injectable emulsion architecture rather than clevidipine as a molecule. Its independent claim requires clevidipine, EDTA at a defined concentration, a lipid, an emulsifier, a tonicity modifier, water, and resistance to microbial growth. The most commercially relevant embodiment is an intravenous lipid emulsion containing clevidipine, soybean oil, phospholipids, glycerin, water, and low-level EDTA, consistent with the formulation used in Cleviprex.[1,2]

The patent creates meaningful formulation risk for a generic or follow-on product that copies the Cleviprex excipient system. It does not, on the claim text provided, cover every clevidipine formulation, every clevidipine method of use, or the clevidipine active ingredient independently.

What does US Patent 8,658,676 cover?

The patent covers a pharmaceutical formulation comprising six required technical components:

Required element	Claim requirement
Active ingredient	Effective amount of clevidipine, or a pharmaceutically acceptable salt or ester
Antimicrobial system	EDTA, described in claim 1 as the antimicrobial agent
EDTA concentration	About 0.001% to about 1.5% w/v in claim 1
Lipid phase	A lipid
Emulsifier	An emulsifier
Aqueous phase and isotonicity	A tonicity modifier and water
Performance limitation	The formulation must resist microbial growth

Claim 1 is a combination claim. A formulation must satisfy every required element to fall within its literal scope. A product containing clevidipine and EDTA but lacking the claimed lipid or emulsifier would not meet claim 1 as written.

The claim is directed to a sterile or substantially sterile pharmaceutical emulsion with improved resistance to microbial proliferation. The patent therefore addresses both composition and microbiological performance.

How do claims 1 through 8 narrow the patent scope?

Claims 2 through 8 add concentration, excipient, pH, or performance limitations.

Claim	Added limitation	Commercial significance
1	Core clevidipine formulation with EDTA, lipid, emulsifier, tonicity modifier, water, and microbial-growth resistance	Broadest composition claim
2	EDTA at about 0.001% to about 0.025% w/v	Targets low-level EDTA formulations, including the range associated with commercial clevidipine emulsions
3	Specified lipids, including soybean oil, safflower oil, olive oil, cottonseed oil, sunflower oil, sesame oil, peanut oil, corn oil, medium-chain triglycerides, triacetin, propylene glycol diesters, and monoglycerides	Captures common parenteral lipid systems
4	Specified emulsifiers, including egg-yolk phospholipids, soybean phospholipids, synthetic phosphatidyl cholines, purified phosphatidyl cholines, and hydrogenated phosphatidyl choline	Captures phospholipid-based injectable emulsions
5	Listed antioxidants, including sodium ascorbate, sulfites, BHA, BHT, propyl gallate, and tocopherol	Covers oxidative-stability additives
6	pH of about 6.0 to about 8.8	Encompasses the near-neutral pH range used for injectable formulations
7	Co-emulsifier, with EDTA limited through dependency on claim 2	Protects more complex emulsion systems
8	Less than a 10-fold increase in viable microbial colonies over 24 hours	Adds a quantitative microbiological performance test

Claim 2 is commercially important because it focuses the patent on the low EDTA concentration likely to be used in a marketed formulation. Its range is nested within claim 1. A formulation containing EDTA at 0.005% w/v, for example, would fall within both the numerical range of claim 1 and the narrower range of claim 2, assuming the remaining elements are present.

What is the scope of the EDTA limitation?

EDTA is the central differentiating element in the claims. The patent does not merely require a preservative generally. Claim 1 identifies EDTA and sets a broad concentration range of approximately 0.001% to 1.5% w/v. Claim 2 narrows the concentration to approximately 0.001% to 0.025% w/v.

The claims raise three construction issues:

Whether “about” permits modest variation around the stated numerical boundaries.
Whether the EDTA must perform an antimicrobial function or only be present in the claimed amount.
Whether a different chelating agent, such as a citrate or another aminopolycarboxylic acid, avoids the literal EDTA limitation.

A formulation using disodium edetate, calcium disodium edetate, or another pharmaceutically acceptable EDTA salt could create infringement risk depending on how “EDTA” is construed in the specification and prosecution history. A non-EDTA chelator would not literally satisfy the express EDTA limitation, although an equivalent-agent theory could be asserted in litigation.

The high upper boundary in claim 1 gives the independent claim substantial numerical breadth. Claim 2 is narrower but likely more relevant to commercial products because parenteral formulations generally use much lower concentrations than 1.5% w/v.

What lipid systems are protected by US 8,658,676?

Claim 3 covers a broad group of pharmaceutically usable lipid materials. The list includes conventional vegetable oils and synthetic or semisynthetic triglyceride systems.

The practical scope is strongest for:

Soybean-oil emulsions
Medium-chain-triglyceride emulsions
Mixed soybean and medium-chain-triglyceride systems
Other parenteral oil phases stabilized with phospholipids

The claim uses “selected from the group consisting of” language. That generally limits the literal scope to the listed lipid categories and mixtures of two or more listed categories. A formulation using a materially different lipid not falling within the listed categories may avoid claim 3, but it could remain within claim 1 if it still contains “a lipid.”

Claim 1 is therefore broader than claim 3 with respect to the lipid identity. Claim 3 provides a more defined fallback position if a court narrows the generic “lipid” term in claim 1.

What emulsifiers are protected by the patent?

Claim 4 covers phospholipid emulsifiers used to stabilize oil-in-water injectable emulsions. The listed materials include:

Egg-yolk phospholipids
Soybean phospholipids
Synthetic phosphatidyl cholines
Purified phosphatidyl cholines
Hydrogenated phosphatidyl choline

This limitation is closely aligned with conventional intravenous emulsion technology. A product using soybean phospholipids or egg-yolk phospholipids would present a direct claim 4 issue if the other limitations are met.

A formulation stabilized solely with a non-listed surfactant may avoid claim 4, but it would still need to be assessed against claim 1, which does not restrict the emulsifier to the claim 4 list.

How does claim 8 affect infringement and validity analysis?

Claim 8 adds an objective microbiological performance limitation: less than a 10-fold, or 1-log, increase in viable microbial colonies over 24 hours.

This limitation can operate in two ways.

First, it narrows the claim. A formulation containing all listed ingredients but failing the 24-hour microbial-growth test may not meet claim 8.

Second, it creates testing and proof issues. The result may depend on:

The microbial species used
Initial inoculum level
Temperature
Sampling intervals
Container closure
Storage conditions
Test method and recovery medium
Whether the formulation is tested before or after dilution or administration

Claim 8 is less likely to be dispositive against claim 1 because claim 1 contains the broader functional phrase “resistant to microbial growth.” Claim 8 provides a quantitative definition of one protected performance level, but the independent claim may be argued to cover formulations that satisfy the broader resistance requirement without meeting the exact claim 8 protocol or result.

What formulations are most exposed to US 8,658,676?

The highest-risk formulation profile is:

Formulation characteristic	Risk under the supplied claims
Clevidipine in an injectable emulsion	High
EDTA at approximately 0.001% to 0.025% w/v	High
Soybean oil or another listed lipid	High
Egg-yolk or soybean phospholipid emulsifier	High
Glycerin as a tonicity modifier	High, if combined with the other elements
pH between 6.0 and 8.8	Supports claim 6
Antioxidant such as sodium ascorbate or tocopherol	Supports claim 5
Co-emulsifier such as glycerin, polysorbate, or poloxamer	Supports claim 7
Demonstrated less-than-1-log microbial increase over 24 hours	Supports claim 8

The commercial Cleviprex formulation is described as a clevidipine injectable emulsion containing soybean oil, glycerin, egg-yolk phospholipids, sodium hydroxide, water, and EDTA.[2] The overlap with the claim architecture is substantial, particularly for the active ingredient, lipid phase, emulsifier, tonicity component, aqueous phase, and EDTA.

What does US 8,658,676 not expressly cover?

The supplied claims do not expressly cover:

Clevidipine as a chemical compound without the formulation elements
Oral clevidipine products
Tablets, capsules, or transdermal dosage forms
A method of lowering blood pressure
A method of treating acute hypertension
A particular dose, infusion rate, or patient population
A specific container or vial
A manufacturing process for producing clevidipine
A specific particle-size distribution
A particular sterilization method
A formulation containing no EDTA
A formulation containing clevidipine in a non-lipid dosage form

The patent is therefore a formulation barrier, not a complete product monopoly.

How strong is the patent estate for a clevidipine generic?

The patent’s strongest features are the close relationship between the claimed excipient combination and the commercial injectable emulsion, plus the dependent claims covering standard parenteral formulation choices.

Its principal vulnerabilities are claim breadth and functional limitations.

Potential validity pressure points

A challenger could examine:

Prior art disclosing clevidipine emulsions with lipid and phospholipid excipients
Prior art using EDTA to suppress microbial growth in injectable emulsions
Written-description support for the full EDTA range up to 1.5% w/v
Enablement across the large range of lipids, emulsifiers, antioxidants, co-emulsifiers, and pH values
Definiteness of “about”
Definiteness of “resistant to microbial growth”
Whether claim 8 identifies a sufficiently reproducible test condition
Whether the claimed formulation is an obvious combination of known clevidipine and emulsion technologies

The narrower claims may be more defensible than claim 1 if the specification contains experimental evidence showing that low-level EDTA produces the claimed microbial performance in clevidipine emulsions.

What is the Orange Book relevance of this patent?

A formulation patent can be listed in the FDA Orange Book if it claims an approved drug product, an approved formulation, or an approved method of use under the applicable FDA listing rules.[3] If US 8,658,676 is listed against clevidipine injection, an ANDA applicant may need to address it through a Paragraph IV certification unless the applicant seeks approval after patent expiration or submits a different certification.

The regulatory consequences are:

ANDA action	Potential consequence
Paragraph IV certification	Notice to the patent owner and NDA holder
Patent-owner infringement suit within 45 days	Potential 30-month stay of ANDA approval under Hatch-Waxman
Section viii statement	Available only if the listed patent claims a method of use that the ANDA omits
Formulation patent challenge	Generally requires Paragraph IV if the proposed product practices the claimed formulation
Non-infringement design-around	May support a Paragraph IV position or reduce litigation exposure

A formulation patent cannot ordinarily be avoided through a section viii statement when the patent claims the composition of the drug product itself.

What generic launch scenarios exist?

Scenario 1: Copy of the commercial emulsion

A generic using clevidipine, soybean oil, phospholipids, glycerin, water, and low-level EDTA would face the highest infringement exposure. The applicant would likely need a Paragraph IV strategy if the patent remains listed and unexpired.

Scenario 2: EDTA-free formulation

Removing EDTA may avoid the literal EDTA limitation. The formulation would still require review against other clevidipine formulation patents and any separate patents covering emulsion structure, stability, particle size, or manufacturing.

Scenario 3: Alternative antimicrobial or chelating system

Replacing EDTA with another antimicrobial or chelator may reduce literal infringement risk. The risk depends on whether the patent specification and prosecution history support an equivalent-agent theory.

Scenario 4: Non-lipid clevidipine formulation

A non-lipid dosage form could avoid the lipid and emulsion architecture, but it would need to remain pharmaceutically suitable for intravenous administration. It may also face separate formulation, delivery, and stability barriers.

Scenario 5: Delayed launch after expiration

A generic may accept a post-expiration launch date, avoiding Paragraph IV litigation over the patent but sacrificing earlier market entry.

Does this patent create biosimilar risk?

No. Clevidipine is a small-molecule drug, not a biologic. The relevant competitive pathway is an ANDA for a generic injectable, not a biosimilar application under the Public Health Service Act.

The principal regulatory and commercial issues are pharmaceutical equivalence, bioequivalence or applicable injectable-product requirements, quality controls, sterile manufacturing, emulsion characterization, and patent certification.

What manufacturing and IP barriers remain after this patent?

Even if a competitor avoids US 8,658,676, injectable emulsion development presents technical barriers:

Control of droplet-size distribution
Physical stability and avoidance of coalescence
Oxidative stability of the lipid phase
Sterility assurance
Container-closure compatibility
Control of phospholipid composition
Reproducible clevidipine loading
Prevention of precipitation during storage and dilution
Consistency of microbial-resistance testing
Scale-up of high-pressure homogenization or related emulsion processes

These technical features may be protected by separate patents or trade secrets. A complete freedom-to-operate review must therefore include the patent family for US 8,658,676, related continuations and divisionals, earlier clevidipine composition patents, later formulation patents, and manufacturing-process patents.

What is the geographic coverage of US 8,658,676?

US 8,658,676 is enforceable only in the United States. Parallel protection, if any, must be assessed in separate national or regional patent rights, including:

European Patent Office members
Canada
Japan
Australia
China
Other markets where clevidipine injection is marketed or developed

A US claim chart does not establish infringement in another jurisdiction. Claim language, prosecution history, patent term, regulatory linkage, and remedies differ by country.

What patent litigation and settlement issues matter?

For an ANDA applicant, the key litigation questions are:

Whether the patent was listed for the approved clevidipine product.
Whether the patent was unexpired when the ANDA was filed.
Whether the proposed formulation satisfies every limitation of claim 1 or a dependent claim.
Whether the applicant has a credible non-infringement or invalidity position.
Whether the NDA holder files suit within the 45-day Hatch-Waxman period.
Whether a settlement imposes a launch date, supply restriction, license, or other commercial limitation.
Whether later-listed continuation patents create a second litigation wave.

No settlement terms or current litigation outcome are established by the claim text alone. Those issues must be determined from court dockets, FDA Orange Book records, ANDA notices, and SEC disclosures.

Key Takeaways

US 8,658,676 is a clevidipine formulation patent focused on an antimicrobial lipid emulsion containing EDTA.
Claim 1 requires clevidipine, EDTA, a lipid, an emulsifier, a tonicity modifier, water, and microbial-growth resistance.
Claim 2 targets low EDTA concentrations of approximately 0.001% to 0.025% w/v.
Claims 3 and 4 cover common soybean-oil and phospholipid emulsion systems.
Claims 5 through 7 add antioxidants, pH, and co-emulsifiers.
Claim 8 adds a quantitative microbial-growth limitation.
The patent is most relevant to generic intravenous clevidipine products that copy the Cleviprex formulation architecture.
EDTA-free, non-lipid, or materially different emulsion designs may reduce literal infringement risk.
Clevidipine is a small molecule, so generic ANDA and Paragraph IV issues apply; biosimilar analysis does not.
A complete commercial assessment requires review of the patent family, Orange Book listing, current patent term, related patents, litigation dockets, and any settlement agreements.

FAQs About US Patent 8,658,676

Does US 8,658,676 cover clevidipine itself?

No. The supplied claims cover a pharmaceutical formulation containing clevidipine and specified excipient and performance elements. They do not claim clevidipine as a standalone chemical compound.

Can a generic avoid the patent by changing the lipid?

Possibly. Changing the lipid may avoid claim 3 if the substitute is outside the listed group. It may not avoid claim 1, which broadly requires only “a lipid,” subject to the remaining claim elements.

Is EDTA-free clevidipine automatically outside the patent?

An EDTA-free formulation would not literally satisfy the express EDTA limitation in claim 1. It could still implicate other clevidipine formulation patents or an equivalent-agent theory, depending on the facts.

Does claim 8 require a specific microbial test?

Claim 8 requires the stated less-than-1-log increase over 24 hours, but the supplied claim text does not identify all testing conditions. The specification and prosecution history would be important in determining how the limitation is measured.

Is the patent relevant to a clevidipine tablet?

Generally no, based on the supplied claims. The claims are directed to a water-containing lipid formulation with an emulsifier and parenteral-type excipient system, not an oral solid dosage form.

References

U.S. Patent No. 8,658,676, claims 1-8. United States Patent and Trademark Office, 2014.
U.S. Food and Drug Administration. (n.d.). Cleviprex (clevidipine butyrate) injectable emulsion prescribing information.
U.S. Food and Drug Administration. (n.d.). Approved drug products with therapeutic equivalence evaluations. Orange Book.

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Chiesi	CLEVIPREX	clevidipine	EMULSION;INTRAVENOUS	022156-001	Aug 1, 2008		RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial	Y				⤷ Start Trial
Chiesi	CLEVIPREX	clevidipine	EMULSION;INTRAVENOUS	022156-002	Aug 1, 2008		RX	Yes	Yes	⤷ Start Trial	⤷ Start Trial	Y				⤷ Start Trial
Chiesi	CLEVIPREX	clevidipine	EMULSION;INTRAVENOUS	022156-003	Nov 8, 2013		DISCN	Yes	No	⤷ Start Trial	⤷ Start Trial	Y				⤷ Start Trial
>Applicant	>Tradename	>Generic Name	>Dosage	>NDA	>Approval Date	>TE	>Type	>RLD	>RS	>Patent No.	>Patent Expiration	>Product	>Substance	>Delist Req.	>Patented / Exclusive Use	>Submissiondate

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Australia	2011313852	⤷ Start Trial
Brazil	112013008601	⤷ Start Trial
Canada	2814495	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,658,676

Which drugs does patent 8,658,676 protect, and when does it expire?

Summary for Patent: 8,658,676