US Patent 8,182,835: Claim Scope, Expiration, Orange Book Status, and Exparel Patent Landscape

US Patent 8,182,835 protected a bupivacaine phosphate formulation using multivesicular liposomes, particularly formulations made with phosphoric acid, dierucoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, and a neutral lipid such as tricaprylin. Its method claims covered single-dose regional anesthesia and post-operative pain treatment lasting at least 12 hours. The patent issued May 22, 2012, and its standard US patent term expired in December 2022. It is therefore no longer an enforceable barrier to generic manufacture or launch.

The patent remains commercially important because it is part of the foundational intellectual-property estate associated with Exparel, Pacira BioSciences' liposomal bupivacaine product. Later continuation and formulation patents, rather than US 8,182,835 itself, determine current patent risk.

What does US Patent 8,182,835 protect?

The patent protects three related subject areas:

A multivesicular liposome formulation containing bupivacaine phosphate.
A pharmaceutical composition containing specified lipid components.
Single-dose methods for regional anesthesia and post-operative or post-trauma pain.

The independent claims are claims 1, 5, 14, and 18.

Claim group	Protected subject	Principal limitations
Claim 1	Multivesicular liposome formulation made by a process	Phosphoric acid; amphipathic lipid; neutral lipid without hydrophilic head group; water-in-oil emulsion; solvent spherules; solvent removal
Claim 5	Pharmaceutical composition made by a process	Bupivacaine phosphate; phosphoric acid; amphipathic and neutral lipids; optional cholesterol or plant sterol
Claim 14	Regional-anesthesia method	Single dose; bupivacaine phosphate in multivesicular liposomes; intracutaneous, subcutaneous, or nerve-block administration
Claim 18	Pain-treatment method	Single dose; post-operative or post-trauma pain; bupivacaine phosphate in multivesicular liposomes
Claims 2-4, 6-13	Dependent formulation claims	Specific phospholipids, neutral lipids, and cholesterol
Claims 15-17, 19-21	Dependent method claims	Administration route, 12-hour duration, and 20-300 mg dose range

The claims use the transitional term "comprising." That language generally permits additional ingredients or process steps unless the added element changes the claimed formulation or defeats a required limitation.

How narrow are the formulation claims?

The formulation claims are narrower than a claim to all liposomal bupivacaine products.

Phosphoric acid is a central limitation

Claims 1 and 5 require phosphoric acid in the first aqueous component. The claim is not directed broadly to any acid capable of solubilizing bupivacaine. It expressly identifies phosphoric acid.

A product made with hydrochloric acid, citric acid, lactic acid, or another acid would not literally satisfy this limitation, although other patents or legal theories could apply.

The lipid system is structurally specific

The claims require:

At least one amphipathic lipid; and
At least one neutral lipid lacking a hydrophilic head group.

The specification identifies dierucoylphosphatidylcholine, commonly abbreviated DEPC, and dipalmitoylphosphatidylglycerol, or DPPG, as principal amphipathic lipids. Tricaprylin is the principal neutral lipid identified in the asserted dependent claims.

Claim 11 lists a group of neutral lipids:

Triolein
Tripalmitolein
Trimyristolein
Trilinolein
Tributyrin
Tricaproin
Tricaprylin
Tricaprin

Claim 12 narrows that group to tricaprylin. Claim 13 adds cholesterol.

Multivesicular architecture matters

The claimed product is not merely a liposome containing bupivacaine. It must be a multivesicular liposome, generally understood as a vesicular structure containing multiple internal aqueous compartments separated by lipid membranes.

A conventional unilamellar liposome, polymeric depot, microsphere, emulsion, or nonvesicular suspension would fall outside the literal formulation scope unless it also met the multivesicular-liposome limitations.

What process is required by claims 1 and 5?

Claims 1 and 5 are product-by-process claims. They define the formulation by reference to how it is made.

The required process contains five stages:

A first aqueous component is prepared with phosphoric acid in an amount sufficient to solubilize bupivacaine or a bupivacaine salt.
A lipid component is prepared using an organic solvent, amphipathic lipid, and neutral lipid lacking a hydrophilic head group.
The aqueous and lipid components are mixed to form a water-in-oil emulsion.
The emulsion is mixed with a second aqueous component to form solvent spherules.
Organic solvent is removed to create multivesicular liposomes.

The process limitations create a material design-around opportunity. A competing product made through a different manufacturing route may avoid literal infringement of claims 1 and 5 even if its final composition is chemically similar. The scope of product-by-process claims can depend on claim construction and the applicable infringement analysis. In US patent litigation, an accused product generally must possess the claimed product characteristics, while the process language can also be material to the infringement inquiry. See Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282 (Fed. Cir. 2009).

What do the method-of-use claims cover?

Claims 14 and 18 are broader in commercial application than the process claims because they focus on administration and treatment.

Regional anesthesia

Claim 14 covers administering a single dose of multivesicular liposomal bupivacaine phosphate to provide regional anesthesia. Claim 15 identifies intracutaneous, subcutaneous, and nerve-block administration. Claim 16 narrows nerve block to local or regional nerve block. Claim 17 requires regional anesthesia lasting at least 12 hours.

Post-operative and post-trauma pain

Claim 18 covers single-dose treatment of post-operative or post-trauma pain. Claim 19 requires pain relief lasting at least 12 hours. Claims 20 and 21 add dose limitations:

Claim	Dose limitation
Claim 20	At least 20 mg of bupivacaine in phosphate salt form
Claim 21	About 20 mg to about 300 mg

The method claims require more than the presence of bupivacaine liposomes. Infringement would require performance of the claimed treatment method, including the relevant patient condition, single-dose administration, and the claimed anesthesia or pain-relief result where applicable.

When did US Patent 8,182,835 expire?

Event	Date
Patent issued	May 22, 2012
Standard patent-term endpoint	December 2022
Current status	Expired
Current enforceability	No enforceable patent rights under this patent

The expiration date is based on the patent's underlying filing and priority record and any applicable patent-term adjustment or terminal-disclaimer treatment shown in the USPTO record. The patent's expiration ended the ability to assert its claims against a generic manufacturer or competing liposomal bupivacaine product.

The patent did not receive the type of long-term patent-term extension associated with an unexpired primary patent covering a new active ingredient. Bupivacaine was an established active pharmaceutical ingredient before Exparel approval.

What is the Orange Book status of US Patent 8,182,835?

US 8,182,835 was listed in the FDA Orange Book for Exparel, bupivacaine liposome injectable suspension, NDA 022496. The listing connected the product with formulation and method-of-use patent protection during the period before expiration.

The FDA Orange Book does not itself determine infringement or validity. It records patent information submitted by the NDA holder under the Hatch-Waxman framework. A generic applicant seeking approval before patent expiration could have addressed the listing through:

Paragraph III certification, agreeing not to market until expiration;
Paragraph IV certification, asserting that the patent was invalid, unenforceable, or not infringed; or
A section viii statement carving out a patented method of use.

Because US 8,182,835 expired in December 2022, it no longer creates a Paragraph IV-based launch delay for a current abbreviated new drug application. Any historical 30-month stay associated with litigation over this patent would also have ended with patent expiration or earlier resolution.

What FDA exclusivity protected Exparel?

Exparel was approved by FDA in August 2011 under NDA 022496 for administration into the surgical site to produce postsurgical analgesia. FDA later expanded the product's labeling to include use for certain nerve blocks, including interscalene brachial plexus nerve block in adults undergoing shoulder surgery. [1]

The product's regulatory exclusivity was separate from US 8,182,835:

Protection	Relevance
New chemical entity exclusivity	Generally unavailable because bupivacaine was not a new active ingredient
Three-year clinical-investigation exclusivity	Potentially relevant to the original approval or later supplement if statutory requirements were met
Patent protection	Provided by US 8,182,835 and later patents
Orphan-drug exclusivity	Not the principal basis of Exparel's US protection
Pediatric exclusivity	Must be assessed from FDA records for any applicable period

Regulatory exclusivity does not revive an expired patent and does not block approval indefinitely. Current generic entry risk depends mainly on later Orange Book-listed patents, FDA review status, and litigation settlements.

Which later patents are relevant to the Exparel estate?

US 8,182,835 is part of a broader Pacira liposomal-bupivacaine patent family. Publicly identified Exparel-related US patents have included the following:

Patent	General relevance	Status significance
US 8,182,835	Bupivacaine phosphate multivesicular liposomes and uses	Expired in December 2022
US 8,980,289	Related multivesicular-liposome formulation technology	Must be checked independently for term and listing
US 9,572,796	Related bupivacaine liposome formulation and use claims	Later family protection
US 10,350,223	Formulation or manufacturing-related continuation protection	Later family protection
US 11,033,495	Later continuation patent associated with liposomal bupivacaine	Potential post-2022 relevance
US 11,147,878	Later continuation or formulation protection	Potential post-2022 relevance

Continuation patents can contain materially different claims from the parent patent. A continuation may preserve protection for a narrower lipid ratio, particle property, manufacturing parameter, stability requirement, dosage form, or method of administration even after the parent patent expires.

The commercial analysis should therefore separate:

The expired parent claims;
Unexpired patents listed for Exparel;
Patents not listed in the Orange Book but potentially relevant to manufacturing or composition;
Patent applications that have not yet issued;
Patents subject to terminal disclaimers tied to earlier family members.

What generic entry risks exist after expiration?

The expired patent removes one major barrier but does not eliminate all entry risk.

Formulation risk

A generic bupivacaine liposome product may need to demonstrate pharmaceutical equivalence to Exparel, including dosage form, route, strength, and relevant quality attributes. Multivesicular-liposome structure can create complex equivalence issues involving:

Particle-size distribution
Internal aqueous compartments
Encapsulation efficiency
Free versus encapsulated bupivacaine
Release profile
Lipid composition
Sterility and stability
In-vitro and in-vivo performance

These FDA requirements are regulatory barriers rather than patent rights.

Manufacturing risk

The disclosed double-emulsion and solvent-removal process can create scale-up and reproducibility challenges. Important process variables include emulsion formation, solvent extraction, lipid purity, shear conditions, temperature, residual solvent, and batch uniformity.

A competitor may avoid claims 1 and 5 by using a materially different process. It must still establish that the resulting product meets FDA quality and equivalence requirements.

Method-of-use risk

Claims 14 and 18 cover clinical use rather than manufacturing. A generic applicant may seek a label carve-out for patented uses under section viii of the Hatch-Waxman Act. That approach depends on the remaining patent claims and whether the proposed label can omit the patented indication without encouraging the patented use.

Which companies have challenged Exparel patents?

Pacira has faced generic competition involving companies that sought to develop or obtain approval for bupivacaine liposome products, including major generic manufacturers such as Fresenius Kabi, Sandoz, and Sun Pharmaceutical companies. The relevant disputes have involved the broader Exparel patent estate rather than only US 8,182,835.

The expired status of US 8,182,835 means that current disputes cannot rely on this patent as an enforceable exclusion right. Litigation exposure must be evaluated patent by patent, including:

The asserted patent numbers;
The filing date of each ANDA lawsuit;
Whether a 30-month stay applied;
Any preliminary injunction;
Any settlement or license;
The agreed generic launch date;
Whether the patent was dismissed, invalidated, or expired during the case.

A Paragraph IV challenge to an unexpired continuation can remain commercially significant even when the original 8,182,835 patent is no longer enforceable.

How strong is the patent estate for bupivacaine multivesicular liposomes?

US 8,182,835 had meaningful historical strength because its claims combined a defined active ingredient, salt form, lipid architecture, and manufacturing process. Its strongest technical features were:

Multivesicular rather than conventional liposomal structure;
Bupivacaine phosphate encapsulation;
Phosphoric-acid solubilization;
Specific amphipathic lipids;
Neutral lipids such as tricaprylin;
Single-dose, extended-duration anesthesia.

Its present legal strength is zero because the patent has expired. The remaining estate's strength depends on whether later patents claim genuinely distinct and difficult-to-design-around features or merely repeat the expired formulation concept in narrower language.

How does US 8,182,835 compare with conventional bupivacaine products?

Attribute	Conventional bupivacaine injection	Exparel-type multivesicular liposome
Active ingredient	Bupivacaine, generally hydrochloride salt	Bupivacaine encapsulated in multivesicular liposomes
Release	Immediate or relatively short acting	Extended release
Dosage form	Solution	Liposome injectable suspension
Manufacturing	Aqueous solution manufacture	Lipid emulsion and solvent-removal process
Patent dependence	Older bupivacaine patents expired	Later formulation and manufacturing patents
Generic pathway	Conventional ANDA pathway	Complex product-specific equivalence issues
Claimed duration in US 8,182,835	Not applicable	At least 12 hours in dependent method claims

Key Takeaways

US Patent 8,182,835 covered bupivacaine phosphate in multivesicular liposomes.
The formulation claims required phosphoric acid, an amphipathic lipid, and a neutral lipid lacking a hydrophilic head group.
DEPC, DPPG, tricaprylin, and cholesterol were central dependent-claim features.
Claims 1 and 5 were product-by-process claims requiring a water-in-oil emulsion, solvent spherules, and organic-solvent removal.
Claims 14 and 18 covered single-dose regional anesthesia and treatment of post-operative or post-trauma pain.
Claims 17 and 19 required at least 12 hours of anesthesia or pain relief.
Claims 20 and 21 covered doses of at least 20 mg and approximately 20-300 mg.
The patent issued May 22, 2012, and expired in December 2022.
It no longer blocks generic entry or supports a current infringement action.
Later Pacira patents and Orange Book listings, not US 8,182,835, control current Exparel patent risk.
Regulatory equivalence, multivesicular-liposome characterization, manufacturing scale-up, and remaining continuation patents are the principal post-expiration barriers.

FAQs About US Patent 8,182,835 and Exparel

Can a generic bupivacaine liposome product infringe US 8,182,835 today?

No. The patent expired in December 2022. A product could have raised infringement issues before expiration, but the patent no longer creates an enforceable exclusion right.

Does US 8,182,835 cover all liposomal bupivacaine formulations?

No. Its claims require multivesicular liposomes and specified chemical and process limitations, including phosphoric acid and defined lipid components.

Does the patent cover Exparel's current nerve-block indication?

Historically, the method claims were broad enough to encompass regional nerve-block administration if the claimed composition, single-dose administration, and duration limitations were satisfied. The patent is now expired.

Can an ANDA applicant avoid the patent by using hydrochloride instead of phosphate?

For literal infringement of claims requiring bupivacaine phosphate, using a different salt could avoid that limitation. The applicant would still need to assess other unexpired patents and FDA equivalence requirements.

Are Exparel's later patents automatically invalid because US 8,182,835 expired?

No. Continuation and related patents are assessed independently. Their validity, scope, patent term, terminal disclaimers, and Orange Book status must be analyzed separately.

References

U.S. Food and Drug Administration. (2011). Exparel (bupivacaine liposome injectable suspension) approval letter and prescribing information. FDA.
U.S. Food and Drug Administration. (2025). Approved drug products with therapeutic equivalence evaluations, Orange Book. FDA.
U.S. Patent and Trademark Office. (2012). U.S. Patent No. 8,182,835, Bupivacaine multivesicular liposomes. USPTO.
U.S. Patent and Trademark Office. (2025). Patent Center and Patent Examination Data System records for U.S. Patent No. 8,182,835 and related continuation patents. USPTO.
Abbott Laboratories v. Sandoz, Inc., 566 F.3d 1282 (Fed. Cir. 2009).
Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(j).

Country	Patent Number	Estimated Expiration	Supplementary Protection Certificate	SPC Country	SPC Expiration
Austria	463238	⤷ Start Trial
Austria	535232	⤷ Start Trial
Australia	735588	⤷ Start Trial
Australia	9494298	⤷ Start Trial
Canada	2304096	⤷ Start Trial
Cyprus	1110135	⤷ Start Trial
Germany	69841598	⤷ Start Trial
>Country	>Patent Number	>Estimated Expiration	>Supplementary Protection Certificate	>SPC Country	>SPC Expiration

Details for Patent: 8,182,835

Summary for Patent: 8,182,835