DCT

2:22-cv-00718

Pacira Pharma Inc v. eVenus Pharma Laboratories Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:22-cv-00718, D.N.J., 02/10/2022
  • Venue Allegations: Venue is alleged to be proper as to eVenus due to its incorporation and established place of business in New Jersey. Venue as to Jiangsu Hengrui is asserted based on its status as a foreign company and its alleged consent to jurisdiction in prior litigation.
  • Core Dispute: Plaintiff alleges that Defendants’ submission of an Abbreviated New Drug Application (ANDA) for a generic version of the anesthetic EXPAREL® constitutes an act of infringement of patents covering the drug's composition and manufacturing process.
  • Technical Context: The technology relates to multivesicular liposomes (MVLs), a drug delivery system that encapsulates an active pharmaceutical ingredient (bupivacaine) to enable its gradual, extended release for post-surgical pain management.
  • Key Procedural History: This action was filed under the Hatch-Waxman Act following Defendants' notice letters and Paragraph IV certification asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed. The complaint notes a prior, pending lawsuit between the parties involving one of the same patents.

Case Timeline

Date Event
2011-10-28 FDA approves commercial marketing of EXPAREL®
2021-01-22 Earliest priority date for '495 and '336 Patents
2021-06-15 U.S. Patent No. 11,033,495 issues
2021-09-30 Defendants send first notice letter to Plaintiff regarding ANDA submission
2021-11-23 U.S. Patent No. 11,179,336 issues
2021-12-28 Defendants send second notice letter to Plaintiff
2022-02-10 Complaint filed

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 11,033,495 - "Manufacturing of Bupivacaine Multivesicular Liposomes"

  • Issued: June 15, 2021

The Invention Explained

  • Problem Addressed: The patent describes an "urgent need for new and improved large scale productions of Exparel® to meet the substantial and growing market demand" ('495 Patent, col. 1:31-37).
  • The Patented Solution: The invention is a commercial-scale manufacturing process for creating bupivacaine-encapsulated multivesicular liposomes (MVLs). The process involves forming a double emulsion (water-in-oil-in-water) and then using a specialized tangential flow filtration system, which may include independently operating modules, to remove the solvent, wash, and concentrate the resulting MVL suspension under aseptic conditions ('495 Patent, Abstract; Fig. 1A-1B). This process is designed to produce a more stable final product with fewer lipid degradation byproducts ('495 Patent, col. 4:35-42).
  • Technical Importance: The described process aims to enable higher-volume, more efficient, and more consistent manufacturing of a complex, extended-release drug formulation, which is critical for meeting commercial demand ('495 Patent, col. 4:30-34).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims (Compl. ¶56). Independent claim 1 is a representative process claim.
  • Essential elements of claim 1 include:
    • (a) Mixing a first aqueous solution (phosphoric acid) with a volatile water-immiscible solvent solution (containing bupivacaine and lipids) to form a water-in-oil first emulsion.
    • (b) Mixing the first emulsion with a second aqueous solution (containing lysine and dextrose) to form a water-in-oil-in-water second emulsion.
    • (c) Removing the volatile solvent to form a first aqueous suspension of MVLs.
    • (d) Reducing the volume of the suspension by microfiltration.
    • (e) Exchanging the aqueous supernatant with a saline solution by diafiltration.
    • (f) Further reducing the volume by microfiltration to achieve a target bupivacaine concentration.
  • The complaint does not explicitly reserve the right to assert dependent claims, but the broad allegation of infringing "one or more claims" suggests this possibility (Compl. ¶56).

U.S. Patent No. 11,179,336 - "Manufacturing of Bupivacaine Multivesicular Liposomes"

  • Issued: November 23, 2021

The Invention Explained

  • Problem Addressed: As a continuation of the application leading to the '495 patent, this patent addresses the same underlying need for improved, large-scale production of bupivacaine MVLs ('336 Patent, col. 1:30-36). It particularly focuses on achieving a final product with specific, desirable stability characteristics.
  • The Patented Solution: The invention is a composition of bupivacaine MVLs characterized by specific properties that result from an improved manufacturing process. These properties include a defined internal pH, a specific concentration of encapsulated lysine, and a limited concentration of erucic acid (a lipid degradation byproduct) after storage for a defined period ('336 Patent, Abstract; col. 2:50-col. 3:10). The patent teaches that these characteristics lead to a more stable drug product ('336 Patent, col. 13:50-60).
  • Technical Importance: By claiming specific compositional and stability-indicating features, the patent aims to protect not just a process, but the resulting drug product itself, which possesses improved stability and a distinct chemical fingerprint ('336 Patent, col. 18:50-60).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims (Compl. ¶90). Independent claim 1 is a representative composition claim.
  • Essential elements of claim 1 include:
    • A composition of bupivacaine encapsulated MVLs.
    • The MVLs contain internal aqueous chambers separated by lipid membranes comprising specific lipids (DEPC and DPPG).
    • The internal aqueous chambers also comprise lysine.
    • The plurality of internal aqueous chambers has a pH of "about 5.5".
    • The composition has a bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL.
    • The erucic acid concentration is about 23 µg/mL or less after storage at 25° C. for one month.
    • The composition has a shelf life of up to 2 years when stored at 2-8° C.
  • The complaint's broad infringement allegation suggests the possibility that dependent claims may also be asserted (Compl. ¶90).

III. The Accused Instrumentality

Product Identification

  • The "eVenus 10 mL ANDA Product" and the "eVenus 20 mL ANDA Product" (collectively "eVenus ANDA Products") (Compl. ¶9).

Functionality and Market Context

  • The eVenus ANDA Products are purported generic versions of EXPAREL®, an injectable suspension of bupivacaine in multivesicular liposomes (Compl. ¶¶1, 9). The complaint alleges that the products are intended to be used as a single-dose local anesthetic for post-surgical pain management (Compl. ¶42). The active ingredient is bupivacaine (Compl. ¶50), and the submission is based on a Drug Master File from Defendant Jiangsu Hengrui (Compl. ¶51).
  • As a generic version of EXPAREL®, the eVenus ANDA Products seek to compete directly with a "first-of-its-kind" anesthetic that the complaint characterizes as a "significant advance in the field of anesthesiology" (Compl. ¶42).
  • No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide a detailed claim chart or sufficient technical detail about the accused products for a limitation-by-limitation analysis. The infringement theory is based on the statutory act of filing an ANDA under the Hatch-Waxman Act, which requires the generic product to be bioequivalent to the reference listed drug, EXPAREL®. The complaint alleges that the manufacture and sale of the eVenus ANDA Products as described in the ANDA will necessarily infringe the asserted patents (Compl. ¶¶60, 94). The following tables summarize this infringement theory.

'495 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(a) mixing a first aqueous solution...with a volatile water-immiscible solvent solution...to form a water-in-oil first emulsion... The complaint alleges that the manufacture of the eVenus ANDA Product is covered by one or more claims of the '495 patent, implying this step is performed. ¶56 col. 23:1-4
(b) mixing the water-in-oil first emulsion with a second aqueous solution...to form a water-in-oil-in-water second emulsion... The complaint's theory is that to create a bioequivalent generic of EXPAREL®, Defendants' manufacturing process will meet the claimed limitations. ¶60 col. 23:5-7
(c) removing the volatile water-immiscible solvent...to form a first aqueous suspension of bupivacaine encapsulated MVLs... The complaint alleges that the process used for the eVenus ANDA Product, if approved, would infringe the claims of the '495 patent. ¶56, ¶60 col. 23:8-10
(d) reducing the first volume of the first aqueous suspension...by microfiltration... The complaint alleges infringement based on the ANDA submission, which describes the process for making the accused product. ¶57 col. 23:11-14
(e) exchanging the aqueous supernatant...with a saline solution by diafiltration... The complaint asserts that the manufacture of the eVenus ANDA product will infringe one or more claims of the '495 patent. ¶56, ¶60 col. 23:15-18
(f) further reducing the third volume...by microfiltration to provide a final aqueous suspension... The complaint's theory relies on the premise that the ANDA-defined process must align with the patented method to achieve the same drug product. ¶57, ¶60 col. 23:18-22
  • Identified Points of Contention:
    • Technical Questions: A primary question will be whether the specific manufacturing steps, equipment, and parameters (e.g., mixing speeds, filtration methods) detailed in the confidential ANDA are the same as, or equivalent to, those claimed in the '495 Patent. The complaint's allegations are based on information and belief, and the actual process in the ANDA will be the central factual dispute.
      '336 Patent Infringement Allegations
Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A composition of bupivacaine encapsulated multivesicular liposomes (MVLs)... The eVenus ANDA Products are alleged to be purported generic versions of EXPAREL®, a bupivacaine MVL product. ¶9, ¶90 col. 22:46-47
...the lipid membranes comprise 1, 2-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), and at least one neutral lipid... The complaint's infringement theory rests on the ANDA product being bioequivalent to EXPAREL®, which is covered by the '336 patent, implying the same lipid composition. ¶90, ¶94 col. 22:50-55
...the plurality of internal aqueous chambers of the MVLs also comprise lysine... The complaint alleges the eVenus ANDA product is covered by the '336 patent, which requires the presence of lysine in the internal chambers. ¶90, ¶94 col. 22:56-57
...the plurality of internal aqueous chambers of the MVLs has a pH of about 5.5... A key factual dispute will be whether the accused product's internal pH, as specified in the ANDA, falls within the scope of "about 5.5." ¶90, ¶94 col. 22:58-59
...wherein erucic acid concentration in the composition is about 23 µg/mL or less after the composition is stored at 25° C. for one month... The infringement analysis will question whether the stability profile of the eVenus ANDA product meets this claimed limitation. ¶90, ¶94 col. 22:64-67
  • Identified Points of Contention:
    • Scope Questions: The term "about 5.5" regarding the internal pH is a classic point of contention. The court will need to determine the permissible range of this term, which could be dispositive for infringement.
    • Technical Questions: A central evidentiary question will be whether the defendants' generic product, when manufactured according to the ANDA, actually exhibits the claimed stability profile (i.e., the erucic acid concentration limit). This product-by-process limitation links the final composition to its method of manufacture and its stability over time.

V. Key Claim Terms for Construction

"commercial scale process" ('495 Patent, claim 1)

  • Context and Importance: This term appears in the preamble of the process claim. While preambles are not always limiting, in this case, the patent's stated purpose is to provide an improved "large scale" manufacturing process. Practitioners may focus on this term because Defendants could argue their process, as described in the ANDA, does not qualify as "commercial scale" in the manner envisioned by the patent, potentially avoiding infringement.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification does not provide an explicit numerical definition for "commercial scale," which may support a broader interpretation based on its plain and ordinary meaning in the pharmaceutical industry.
    • Evidence for a Narrower Interpretation: The specification describes embodiments producing final volumes of "about 150 L to about 250 L" ('495 Patent, col. 15:45-48). A defendant may argue that this context limits the term to processes of a similar magnitude.

"pH of about 5.5" ('336 Patent, claim 1)

  • Context and Importance: This limitation defines a core chemical property of the claimed composition's internal environment. The construction of "about" is critical; a narrow range could allow the accused product to fall outside the claim scope, while a broader range would favor the patentee. Practitioners will focus on this term because it is a precise, measurable parameter that will be a key point of comparison between the patent and the accused product.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The use of the word "about" itself suggests the patentee did not intend to be limited to the exact value of 5.5. The specification discusses the general importance of pH for stability, which might support interpreting "about 5.5" as encompassing a functionally equivalent pH range that achieves similar stability ('336 Patent, col. 16:50-53).
    • Evidence for a Narrower Interpretation: Table 2B in the patent discloses specific measured internal pH values for three batches, all of which round to 5.5 (5.49, 5.51, 5.50) ('336 Patent, col. 22, Table 2B). A defendant could argue these examples define the full scope of "about 5.5" and that any significant deviation is outside the claim.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges active inducement of infringement against both patents. The basis for this allegation is that the defendants' proposed product labeling for the eVenus ANDA Products will instruct healthcare professionals and other end-users on how to administer the drug, and following these instructions will allegedly constitute direct infringement (Compl. ¶¶ 62, 96-97).
  • Willful Infringement: Willfulness is alleged based on the defendants' knowledge of the '495 and '336 patents. The complaint contends this knowledge is evidenced by the defendants having sent Paragraph IV certification notice letters to Pacira, and that they proceeded with their intent to market a generic product without a reasonable basis for believing they would not be liable for infringement (Compl. ¶¶ 68, 102).

VII. Analyst’s Conclusion: Key Questions for the Case

The resolution of this Hatch-Waxman litigation will likely depend on the court's determination of several central issues that bridge technical evidence and legal interpretation.

  • A core issue will be one of process identity: Does the confidential manufacturing process described in the Defendants' ANDA contain the same, or legally equivalent, sequence of emulsification, solvent removal, and filtration steps as recited in the process claims of the '495 patent?
  • A second key issue will be one of compositional scope: Can the term "pH of about 5.5," as claimed in the '336 patent, be construed to read on the specific internal pH of the Defendants' generic product? This will involve a classic claim construction dispute over the breadth of "about" in light of the patent's examples and stated purpose.
  • Finally, a critical evidentiary question will be one of product-by-process proof: Does the accused generic product, when made by the ANDA process, actually meet the stability-defined limitation of the '336 patent, specifically the maximum allowable erucic acid concentration after one month of storage?