Details for Patent: 11,311,486

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Which drugs does patent 11,311,486 protect, and when does it expire?

Patent 11,311,486 protects EXPAREL and is included in one NDA.

This patent has thirteen patent family members in seven countries.

Summary for Patent: 11,311,486

Title:	Manufacturing of bupivacaine multivesicular liposomes
Abstract:	Embodiments of the present application relate to commercial manufacturing processes for making bupivacaine multivesicular liposomes (MVLs) using independently operating dual tangential flow filtration modules.
Inventor(s):	Jeffrey S. Hall, David J. Turnbull, John J. Grigsby, Jr., Soroush M. Ardekani, Paige N. Davis, Louie D. Garcia, Stephanie M. Kurz, Kathleen D. A. Los
Assignee:	Pacira Pharmaceuticals Inc
Application Number:	US17/536,478
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 11,311,486
Patent Claim Types: see list of patent claims	Use; Composition; Formulation; Dosage form;

US Patent 11,311,486: Scope, Claim Construction, Exparel Patent Landscape, and Generic Entry Risk

US Patent 11,311,486 protects a narrowly defined bupivacaine multivesicular liposome composition and related pain-treatment methods. The independent claims require a specific lipid architecture, lysine inside the aqueous chambers, unencapsulated bupivacaine in the surrounding medium, a defined bupivacaine concentration, and post-storage limits for erucic acid. The claims are directed to a stabilized formulation rather than to bupivacaine or liposomal delivery in the abstract.

The patent is commercially relevant to Exparel, Pacira Pharmaceuticals' liposomal bupivacaine product. Infringement risk depends on whether a competing product uses the claimed DEPC/DPPG/cholesterol/neutral-lipid system and satisfies the stability limitations after the specified storage periods.

What does US Patent 11,311,486 cover?

The patent has two principal claim groups:

1. Composition claims 1-13.
2. Method-of-treatment claims 14-34.

Claim 1 is the primary composition claim. Claim 14 is the primary treatment-method claim and incorporates the limitations of claim 3.

Core elements of independent claim 1

A product must contain all of the following elements:

Claim element	Required limitation
Active ingredient	Bupivacaine
Delivery system	Bupivacaine encapsulated in multivesicular liposomes, or MVLs
Internal structure	Multiple internal aqueous chambers separated by lipid membranes
Required membrane components	DEPC, DPPG, cholesterol, and at least one neutral lipid
Internal chamber excipient	Lysine
External phase	Aqueous medium containing unencapsulated bupivacaine
Total bupivacaine concentration	About 11.3 mg/mL to about 17.0 mg/mL
Three-month stability	Erucic acid concentration of about 53 micrograms/mL or less after storage at 25°C for three months

A competing formulation that omits any one of these required features may avoid literal infringement of claim 1. The most important limitations are the combined lipid composition, the presence of unencapsulated bupivacaine, the lysine requirement, and the erucic-acid stability threshold.

Claim 14 is narrower than a general liposomal-bupivacaine treatment claim

Claim 14 requires administration of the composition of claim 3. Therefore, the method claim incorporates the six-month erucic-acid limitation and the six-month pH limitation from claim 3 and claim 4.

A method using a different liposomal bupivacaine composition would not literally satisfy claim 14, even if it were used for the same type of postsurgical pain.

How narrow is the patent's composition claim?

The composition claim is technically narrow but commercially meaningful. It does not cover every liposomal bupivacaine formulation. It covers a formulation within a specific product-development window.

Required lipid system

The claim requires four lipid categories:

• DEPC, or 1,2-dierucoylphosphatidylcholine.
• DPPG, or 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol).
• Cholesterol.
• At least one neutral lipid.

Claim 5 specifies tricaprylin as the neutral lipid. A formulation using a different neutral lipid may fall outside claim 5 but could still infringe claim 1 if the other claim limitations are met.

Claim 8 narrows the DEPC-to-DPPG mass ratio to approximately 7:1 to 10:1. This ratio is not required by claim 1. A product outside that ratio may still infringe the broader composition claim.

Lysine limitation

Claim 1 requires lysine in the internal aqueous chambers of the MVLs. Claims 6, 20, and 27 narrow the formulation to an encapsulated lysine concentration of approximately 0.03 micrograms/mL.

The location of the lysine matters. Lysine merely present in the external aqueous medium may not satisfy the requirement that the plurality of internal chambers comprise lysine. Analytical evidence would likely be required to distinguish encapsulated from unencapsulated lysine.

Unencapsulated bupivacaine

Claim 1 requires bupivacaine in two locations:

1. Encapsulated within the MVLs.
2. Unencapsulated in the aqueous suspension medium.

This limitation distinguishes a formulation containing only encapsulated drug from a formulation with both immediate-release and sustained-release bupivacaine fractions.

A generic manufacturer could attempt to design around the claim by changing the free-drug fraction. That strategy would require careful analysis because the claim does not provide a numerical limit for unencapsulated bupivacaine.

What formulations are protected by US 11,311,486?

The dependent claims identify a commercially recognizable formulation profile.

Feature	Claim coverage
Bupivacaine concentration of approximately 13.3 mg/mL	Claim 7 and claims 21, 27-34 through dependency
Bupivacaine salt	Claim 10 and claims 24, 29-30
Bupivacaine phosphate	Claim 11 and claims 25, 30
Saline suspension medium	Claims 12-13 and claim 26
Tricaprylin neutral lipid	Claim 5 and claim 19
DEPC:DPPG ratio of approximately 7:1 to 10:1	Claim 8 and claim 22
Packed particle volume of approximately 32% to 44%	Claim 9 and claims 23, 28
Six-month erucic acid concentration of approximately 99 micrograms/mL or less	Claim 3 and dependent method claims
Six-month pH of approximately 6.5	Claim 4 and claims 18, 32-34
Ten-mL or 20-mL single-dose volume	Claim 17 and claims 34

The most commercially important embodiment is a 13.3 mg/mL bupivacaine formulation in a 10 mL or 20 mL presentation, with saline, bupivacaine phosphate, tricaprylin, lysine, the specified phospholipids, and the claimed storage performance.

What are the stability limitations in claims 1-4?

The stability limitations are central to the patent.

Erucic acid

DEPC contains erucic-acid-derived chains. The claims impose an upper limit on erucic acid after storage:

Storage condition	Claimed limit
25°C for three months	Approximately 53 micrograms/mL or less
25°C for six months	Approximately 99 micrograms/mL or less

The three-month limit appears in independent claim 1. The six-month limit appears in claim 3, which depends on claim 1.

These are product-by-process-like performance limitations. The claim does not merely require a starting formulation. It requires the formulation to meet a measured chemical condition after storage.

pH

The pH limitations are dependent limitations:

• Approximately 6.9 after three months at 25°C under claim 2.
• Approximately 6.5 after six months at 25°C under claim 4.

The relevant question in an infringement dispute would be how "about" is construed and which analytical method, sampling protocol, temperature control, and storage container are used.

A product that has the required composition but fails the claimed storage result may avoid literal infringement of the stability-limited claim. Conversely, a formulation cannot avoid the claim merely by using different release or stability language in its labeling if testing shows that the claimed property is present.

What methods of use are protected?

Claim 14 covers treating or ameliorating pain by administering the composition of claim 3. The dependent claims specify several use conditions.

Local infiltration

Claim 15 covers local infiltration at a surgical site to provide postsurgical local analgesia. Claims 32 and 33 further specify local infiltration and regional nerve-block use for the 13.3 mg/mL embodiment.

Regional analgesia

Claim 16 identifies:

• Interscalene brachial plexus nerve block.
• Femoral nerve block.

The claims do not cover every route of administration. A method using intravenous, epidural, intrathecal, or another route may not satisfy these dependent claims, although it could raise issues under broader claim 14 depending on the product and factual circumstances.

Dose volume

Claim 17 requires a 10 mL or 20 mL volume for a single-dose administration. Claim 34 repeats this limitation for the 13.3 mg/mL embodiment.

These volume claims align with the commercial presentation of liposomal bupivacaine. The FDA-approved Exparel label identifies single-dose vial presentations containing 133 mg/10 mL and 266 mg/20 mL of bupivacaine, equivalent to 13.3 mg/mL.[2]

How does US 11,311,486 compare with earlier Exparel patents?

US 11,311,486 should be analyzed as part of a layered Exparel patent estate.

Patent layer	Typical subject matter	Competitive significance
MVL platform patents	Multivesicular liposomes and sustained-release local anesthetics	Broad technology foundation
Bupivacaine composition patents	Liposomal bupivacaine, lipid ratios, drug loading, and particle characteristics	Product-specific composition protection
Stability patents	Degradation products, pH, storage conditions, and excipient combinations	Later-expiring protection against formulation redesign
Method-of-use patents	Surgical infiltration and regional nerve-block applications	Potential method liability
Manufacturing patents	Loading, formation, sizing, purification, and sterile processing	Process and supply-chain barriers
Regulatory exclusivity	FDA approval protections and labeling controls	Separate from patent term

The claims supplied for US 11,311,486 are not broad platform claims. They are directed to a defined bupivacaine MVL formulation with stability characteristics. Their strategic function is likely to extend product protection beyond earlier foundational MVL patents and to make formulation substitution more difficult.

When does US 11,311,486 lose exclusivity?

The exact patent expiration date depends on the patent's earliest effective nonprovisional priority date, patent-term adjustment, terminal disclaimers, and any patent-term extension. Patent term is generally 20 years from the earliest effective U.S. nonprovisional filing date, subject to statutory adjustments.[3]

The patent's issue date alone does not establish its expiration date. A complete freedom-to-operate analysis must review:

• The front-page priority chain.
• Continuation and divisional relationships.
• Patent-term adjustment.
• Terminal disclaimer records.
• Any patent-term extension.
• Orange Book listing data, if applicable.

Patent expiry and FDA exclusivity are separate. A patent may remain enforceable after regulatory exclusivity expires, and regulatory exclusivity may end before the last relevant patent expires.

What is the Orange Book status of the patent?

The Orange Book status of US 11,311,486 must be determined from the FDA's current Approved Drug Products with Therapeutic Equivalence Evaluations database and the patent listing information submitted for the relevant Exparel product.[1]

The patent's claims are potentially listable as composition, formulation, or method-of-use claims if they meet the FDA's patent-listing standards. Listing does not establish validity or enforceability. It can, however, affect the timing of an abbreviated new drug application and trigger a Paragraph IV certification process.

The relevant product is Exparel, bupivacaine liposome injectable suspension, marketed by Pacira Pharmaceuticals, Inc. The FDA approved Exparel in 2011 for postsurgical analgesia by infiltration. The FDA later expanded its labeling for certain regional analgesia uses, including interscalene brachial plexus nerve block.[2]

What Paragraph IV challenges and generic entry risks exist?

A generic applicant seeking approval for a liposomal bupivacaine product could face several certification and litigation issues:

1. A Paragraph IV certification against any listed patent alleged to be invalid, unenforceable, or not infringed.
2. A Paragraph III certification if the applicant accepts a later patent expiration date.
3. A section viii statement to omit a patented method of use, if the proposed labeling can lawfully exclude that use.
4. Hatch-Waxman litigation and a possible 30-month stay after timely patent litigation.[4]

Product-specific risk

For a product resembling Exparel, US 11,311,486 presents risk across several measurable attributes:

• DEPC and DPPG identity.
• Cholesterol and neutral-lipid content.
• Tricaprylin use.
• Internal lysine concentration.
• Free bupivacaine content.
• Bupivacaine concentration.
• Packed particle volume.
• Erucic-acid degradation profile.
• Six-month pH.

A generic sponsor could challenge one or more limitations through formulation design, analytical testing, or claim construction. The most practical design-around opportunities appear to be changing the lipid system, removing or relocating lysine, changing the concentration, or developing a formulation that fails the claimed storage thresholds while maintaining acceptable product quality.

Those changes may create separate FDA comparability and clinical risks. Liposomal products are complex drug products, and a formulation that avoids one patent claim may not be substitutable through a simple conventional generic pathway.

Which companies are most exposed?

Pacira is the principal commercial party associated with Exparel and the related liposomal bupivacaine estate. Potential challengers include manufacturers developing generic or alternative long-acting local anesthetic products.

Commercial exposure is concentrated in Exparel revenue because the patent covers attributes closely associated with the approved product presentation. The commercial risk is greater if:

• The patent is listed in the Orange Book.
• The patent has a later expiration than foundational Exparel patents.
• No competing product has secured FDA approval.
• A challenger must reproduce the same lipid and stability profile to obtain an equivalent product.

The patent does not, by itself, prevent all nonliposomal bupivacaine products or all sustained-release local anesthetics from entering the market.

How strong is the patent estate?

Strengths

The patent has several features that can increase practical value:

• It covers both composition and treatment methods.
• The composition claim combines structural, quantitative, and stability limitations.
• The claimed concentrations correspond to a commercial product profile.
• The claims address degradation and storage behavior, which can be difficult to design around without affecting product performance.
• Dependent claims create multiple fallback positions involving tricaprylin, bupivacaine phosphate, saline, particle volume, and dose volume.

Vulnerabilities

The same limitations may create validity and enforcement vulnerabilities:

• "About" ranges may create claim-construction disputes.
• Erucic-acid and pH limits require reproducible analytical methods.
• The storage conditions may raise questions about whether the claim defines an inherent property or a required product limitation.
• Prior art may disclose overlapping MVL compositions, local anesthetics, lysine, cholesterol, phospholipids, and stability testing.
• Method claims may be limited by the actual approved label and by proof of direct infringement.
• A challenger may argue lack of written description or enablement for the full range of compositions covered by claim 1.

The patent is strongest against a product that intentionally replicates the Exparel formulation profile. It is weaker against a materially different long-acting local anesthetic platform.

What manufacturing and IP barriers affect competition?

Manufacturing a bupivacaine MVL product requires more than combining bupivacaine with lipids. Relevant technical barriers include:

• Formation of multiple aqueous chambers.
• Control of particle size and packed particle volume.
• Reproducible drug loading.
• Control of free versus encapsulated bupivacaine.
• Sterile processing and aseptic filling.
• Control of lipid oxidation and hydrolysis.
• Management of erucic-acid-related degradation.
• Maintenance of pH during storage.
• Batch-to-batch control of lysine distribution.

These manufacturing characteristics may be protected by separate process patents or confidential know-how. A competitor that avoids US 11,311,486 may still confront other Pacira patents, manufacturing trade secrets, FDA comparability requirements, and clinical-performance barriers.

What is the likely generic launch scenario?

A credible generic launch would likely follow one of three paths:

Scenario	Product strategy	Risk profile
Direct formulation challenge	Reproduce the commercial MVL profile and challenge the patent	Highest infringement and litigation risk
Formulation design-around	Change lipids, lysine, concentration, or stability profile	Lower patent risk, higher development and regulatory risk
Label carve-out	Omit patented regional or surgical uses where permitted	Reduces method-claim risk but does not address composition claims
Post-expiry launch	Accept patent expiry and launch later	Lowest litigation risk, delayed revenue opportunity

A direct generic equivalent would face the highest exposure because the claimed parameters map closely to the commercial formulation. A design-around product may avoid this patent but could require substantial clinical, analytical, and regulatory work.

Key Takeaways

• US 11,311,486 is a narrow, product-focused patent covering a bupivacaine MVL formulation.
• Claim 1 requires DEPC, DPPG, cholesterol, a neutral lipid, internal lysine, encapsulated and unencapsulated bupivacaine, a defined concentration range, and a three-month erucic-acid limit.
• Claims 3 and 4 add six-month erucic-acid and pH requirements.
• The most commercially relevant embodiment is a 13.3 mg/mL formulation in a 10 mL or 20 mL presentation.
• Claims 14-34 extend protection to specified postsurgical analgesia methods, including local infiltration and selected nerve blocks.
• A generic product that reproduces the Exparel formulation profile faces substantial infringement risk.
• The patent does not cover every liposomal bupivacaine product or every sustained-release local anesthetic.
• Exact expiration and Orange Book status require review of the current USPTO patent record and FDA Orange Book listing for the relevant Exparel product.

FAQs

Does US 11,311,486 cover ordinary bupivacaine hydrochloride injection?

No. The claims require bupivacaine encapsulated in multivesicular liposomes with specified lipid, lysine, concentration, and stability characteristics.

Can a product avoid the patent by eliminating unencapsulated bupivacaine?

Potentially, because claim 1 expressly requires unencapsulated bupivacaine in the aqueous medium. The product would still require analysis against other patents and regulatory requirements.

Does the patent cover tricaprylin-free formulations?

Claim 1 can cover a formulation with another neutral lipid because it requires at least one neutral lipid. Claim 5 specifically requires tricaprylin. Removing tricaprylin may avoid claim 5 but not necessarily claim 1.

Are femoral nerve-block uses necessarily covered by the FDA label?

Not necessarily. Patent claim scope and FDA-approved labeling are different. The patent claims recite femoral nerve block, while regulatory approval depends on the approved Exparel labeling in force at the relevant time.

Is a Paragraph IV challenge required for every generic bupivacaine liposome product?

No. The certification required depends on the patents listed for the reference product, the proposed product, and the applicant's legal position on each listed patent. A product may use Paragraph III or section viii pathways in appropriate circumstances.

References

1. U.S. Food and Drug Administration. (2024). Approved drug products with therapeutic equivalence evaluations, 44th ed. Orange Book.
2. U.S. Food and Drug Administration. (2023). Exparel (bupivacaine liposome injectable suspension) prescribing information. Pacira Pharmaceuticals, Inc.
3. United States Patent and Trademark Office. (2024). Patent term adjustment and patent term extension guidance.
4. Drug Price Competition and Patent Term Restoration Act, 21 U.S.C. § 355(j).
5. United States Patent No. 11,311,486. (2022). Bupivacaine multivesicular liposome composition and related methods. United States Patent and Trademark Office.

Drugs Protected by US Patent 11,311,486

Applicant	Tradename	Generic Name	Dosage	NDA	Approval Date	TE	Type	RLD	RS	Patent No.	Patent Expiration	Product	Substance	Delist Req.	Patented / Exclusive Use	Submissiondate
Pacira Pharms Inc	EXPAREL	bupivacaine	INJECTABLE, LIPOSOMAL;INJECTION	022496-001	Oct 28, 2011		RX	Yes	Yes			Y			METHOD OF TREATING PAIN, FOR EXAMPLE, TREATING POSTSURGICAL PAIN VIA INFILTRATION FOR LOCAL ANALGESIA OR VIA INTERSCALENE BRACHIAL PLEXUS NERVE BLOCK FOR REGIONAL ANALGESIA
Pacira Pharms Inc	EXPAREL	bupivacaine	INJECTABLE, LIPOSOMAL;INJECTION	022496-002	Oct 28, 2011		RX	Yes	Yes			Y			METHOD OF TREATING PAIN, FOR EXAMPLE, TREATING POSTSURGICAL PAIN VIA INFILTRATION FOR LOCAL ANALGESIA OR VIA INTERSCALENE BRACHIAL PLEXUS NERVE BLOCK FOR REGIONAL ANALGESIA

International Family Members for US Patent 11,311,486

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
China	114209654
Denmark	4032528
European Patent Office	4032528
European Patent Office	4740937
Spain	3073947
Finland	4032528
United Kingdom	202200778