DCT

3:19-cv-18756

Chiesi USA Inc v. Aurobindo Pharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:19-cv-18756, D.N.J., 09/07/2021
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey based on Defendant Aurobindo USA having its principal place of business and a distribution center in the state, and Defendant Aurobindo Ltd. being an alien corporation subject to suit in any judicial district.
  • Core Dispute: Plaintiffs allege that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic clevidipine injectable emulsion constitutes an act of infringement of three U.S. patents listed in the FDA's Orange Book for the branded drug Cleviprex®.
  • Technical Context: The technology concerns pharmaceutical formulations of clevidipine, an intravenous antihypertensive drug, in an oil-in-water emulsion designed to be stable and resistant to microbial contamination.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 213280 with a Paragraph IV certification, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by their proposed generic product. Plaintiffs received a Notice Letter regarding the ANDA filing on or about August 23, 2019. This First Amended Complaint was filed to add allegations concerning the '490 patent, which issued on August 31, 2021.

Case Timeline

Date Event
2010-10-12 Earliest Priority Date for '676, '537, and '490 Patents
2014-02-25 U.S. Patent No. 8,658,676 Issues
2018-07-03 U.S. Patent No. 10,010,537 Issues
2019-08-23 Defendants send Paragraph IV Notice Letter to Plaintiffs
2021-08-31 U.S. Patent No. 11,103,490 Issues
2021-09-07 First Amended Complaint Filed

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

U.S. Patent No. 8,658,676 - “Clevidipine Emulsion Formulations Containing Antimicrobial Agents,” issued Feb. 25, 2014

The Invention Explained

  • Problem Addressed: The patent identifies that oil-in-water emulsion formulations, such as those used for the drug clevidipine, contain components like soybean oil and egg yolk phospholipids that can support microbial growth ('676 Patent, col. 1:39-41). This risk necessitates strict aseptic handling techniques and requires that opened vials be discarded after only four hours, creating a burden for healthcare providers and generating waste ('676 Patent, col. 1:41-49).
  • The Patented Solution: The invention adds an antimicrobial agent, specifically the chelating agent disodium edetate (EDTA), to the clevidipine emulsion formulation ('676 Patent, col. 3:9-12). This addition is designed to inhibit or retard the growth of microorganisms in the event of "accidental extrinsic contamination," thereby increasing the in-use safety and convenience of the product ('676 Patent, Abstract; col. 3:13-17).
  • Technical Importance: The invention provides a practical solution to the clinical challenge of microbial contamination in lipid-based intravenous drug products, potentially extending the safe in-use time of the drug beyond the standard four hours and reducing the associated clinical burden and cost ('676 Patent, col. 1:49-56).

Key Claims at a Glance

  • The complaint asserts claims 1-8 (Compl. ¶1).
  • Independent claim 1 recites:
    • A pharmaceutical formulation comprising
    • (a) an effective amount of clevidipine, or a pharmaceutically acceptable salt or ester,
    • (b) an antimicrobial agent, EDTA, present at about 0.001 to about 1.5% w/v,
    • (c) a lipid,
    • (d) an emulsifier,
    • (e) a tonicity modifier, and
    • (f) water
    • wherein the formulation is resistant to microbial growth.
  • The complaint asserts dependent claims which further specify the concentrations and identities of the formulation components.

U.S. Patent No. 10,010,537 - “Clevidipine Emulsion Formulations Containing Antimicrobial Agents,” issued Jul. 3, 2018

The Invention Explained

  • Problem Addressed: Like the '676 patent, this patent addresses the need for antimicrobial properties in clevidipine emulsions ('537 Patent, col. 1:39-49). It also implicitly addresses the challenge of maintaining the physical stability of the emulsion, which is the tendency of the oil and water components to remain mixed rather than separate over time ('537 Patent, col. 12:4-7).
  • The Patented Solution: The invention describes a clevidipine formulation that includes not only an antimicrobial agent (EDTA) but also a "co-emulsifier," such as oleic acid ('537 Patent, col. 2:20-22). The inclusion of the co-emulsifier is shown to substantially increase the formulation's zeta potential, a key indicator of electrostatic repulsion between oil droplets and thus a measure of the emulsion's physical stability, without negatively impacting the antimicrobial efficacy of the EDTA ('537 Patent, col. 12:50-57; Table 9).
  • Technical Importance: This technology aims to create a more robust pharmaceutical product by simultaneously solving for two distinct challenges: inhibiting microbial growth (a safety and handling issue) and enhancing long-term physical stability (a product quality and shelf-life issue).

Key Claims at a Glance

  • The complaint asserts claims 1, 2, 7, and 8 (Compl. ¶1).
  • Independent claim 1 recites:
    • A pharmaceutical formulation comprising,
    • (a) clevidipine butyrate, present at about 0.01 to about 1% w/v,
    • (b) EDTA, present at about 0.001 to about 0.1% w/v,
    • (c) soybean oil, present at about 4 to about 30% w/v,
    • (d) purified egg yolk phospholipids, present at about 0.2 to about 2% w/v,
    • (e) glycerin, present at about 2 to about 3% w/v, and
    • (f) water up to 100%.
  • The complaint also asserts dependent claims which add a co-emulsifier (oleic acid) and specify a pH range.

U.S. Patent No. 11,103,490 - “Clevidipine Emulsion Formulations Containing Antimicrobial Agents,” issued Aug. 31, 2021

Technology Synopsis

This patent claims a clevidipine emulsion formulation that is resistant to microbial growth and also possesses a high degree of physical stability. The invention is defined by a specific combination of ingredients, including clevidipine, an antimicrobial agent (EDTA), a lipid, an emulsifier, a tonicity modifier, water, and a co-emulsifier (oleic acid), which results in a formulation with a specific, high-magnitude negative zeta potential of -36.1 mV, a quantitative marker of enhanced stability against phase separation ('490 Patent, Claim 7; col. 13:1-12).

Asserted Claims

The complaint asserts claim 6, which depends from independent claim 1 (Compl. ¶1).

Accused Features

The complaint alleges that Defendants' proposed generic clevidipine emulsion, as described in their ANDA, will infringe the claimed formulation (Compl. ¶¶ 79-82).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendants' proposed generic "Clevidipine injectable emulsion, 25 mg/ 50 mL and 50 mg/ 100 mL," for which they seek FDA approval via ANDA No. 213280 (the "ANDA Product") (Compl. ¶¶ 13, 18).

Functionality and Market Context

The ANDA Product is a generic version of Plaintiffs' Cleviprex® and is intended for intravenous administration "for the reduction of blood pressure when oral therapy is not feasible or not desirable" (Compl. ¶¶ 28, 35). The complaint alleges the ANDA Product is based on Cleviprex® as its reference listed drug and will have the same indication, usage, dosage, and administration (Compl. ¶¶ 33-34, 49). The act of infringement alleged is the submission of the ANDA itself, which seeks approval to market the generic drug prior to the expiration of the patents-in-suit (Compl. ¶¶ 55, 70). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain a detailed claim chart. The infringement theory is that the ANDA Product, to be approved as a generic equivalent of Cleviprex®, must necessarily be formulated in a way that meets the limitations of the asserted claims.

'676 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(a) an effective amount of clevidipine, or a pharmaceutically acceptable salt or ester The ANDA Product is a clevidipine injectable emulsion. ¶50 col. 3:51-66
(b) an antimicrobial agent, EDTA, present at about 0.001 to about 1.5% w/v The ANDA Product is alleged to contain the claimed ingredients, including EDTA, as part of a formulation that infringes the patent. ¶55 col. 5:21-44
(c) a lipid The ANDA Product is an oil-in-water emulsion alleged to be based on Cleviprex®, which contains soybean oil. ¶49, ¶50 col. 6:10-26
(d) an emulsifier The ANDA Product, as an emulsion, contains an emulsifier. ¶49, ¶50 col. 6:27-41
(e) a tonicity modifier The ANDA Product, as an injectable formulation, contains a tonicity modifier. ¶49, ¶50 col. 7:1-11
(f) water The ANDA Product is an aqueous injectable emulsion. ¶50 col. 7:12-18
wherein the formulation is resistant to microbial growth The ANDA Product is alleged to possess this functional property. ¶57 col. 8:1-10

'537 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
(a) clevidipine butyrate, present at about 0.01 to about 1% w/v The ANDA Product is a clevidipine injectable emulsion with a concentration of 0.5 mg/mL (0.05% w/v), which is within the claimed range. ¶65 col. 5:51-67
(b) EDTA, present at about 0.001 to about 0.1% w/v The ANDA Product is alleged to contain EDTA within the claimed concentration range. ¶70 col. 6:42-59
(c) soybean oil, present at about 4 to about 30% w/v The ANDA Product is alleged to be based on Cleviprex®, which contains 20% w/v soybean oil, a value within the claimed range. ¶64 col. 6:10-26
(d) purified egg yolk phospholipids, present at about 0.2 to about 2% w/v The ANDA Product is alleged to be based on Cleviprex®, which contains 1.2% w/v phospholipids, a value within the claimed range. ¶64 col. 6:27-41
(e) glycerin, present at about 2 to about 3% w/v The ANDA Product is alleged to be based on Cleviprex®, which contains 2.25% w/v glycerin, a value within the claimed range. ¶64 col. 7:1-11
(f) water up to 100% The ANDA Product is an aqueous injectable emulsion. ¶65 col. 7:12-18
  • Identified Points of Contention:
    • Factual Questions: The central factual dispute will be the precise formulation specified in Aurobindo's confidential ANDA filing. The complaint alleges infringement but does not provide the ANDA's list of ingredients and concentrations. A primary question is whether the ANDA Product contains EDTA and/or oleic acid in the amounts required by the asserted claims.
    • Technical Questions: A key issue for the court may be whether Aurobindo's formulation, even if slightly different from the Cleviprex® formulation, inherently possesses the functional properties claimed, such as being "resistant to microbial growth" ('676 Patent) or having the specific zeta potential recited in the '490 Patent.

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail to identify specific claim construction disputes. However, based on the technology and the nature of ANDA litigation, certain terms may become central to the case.

  • The Term: "resistant to microbial growth" ('676 Patent, Claim 1)
  • Context and Importance: This functional limitation is a cornerstone of the '676 Patent. Practitioners may focus on this term because its definition will determine the standard of proof for infringement. Aurobindo could argue its product does not meet the specific level of "resistance" taught and claimed in the patent, even if it exhibits some antimicrobial properties.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patent's background describes the general problem of microbial growth in emulsions, which may support a broader reading that any formulation solving this general problem infringes ('676 Patent, col. 1:39-49).
    • Evidence for a Narrower Interpretation: The specification provides a specific, quantitative test for measuring resistance: "less than 10-fold (1 log) increase in viable colonies over a 24-hour period" ('676 Patent, col. 9:28-32). A party could argue that this definition from the detailed description limits the scope of the claim term.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon approval and commercialization, Defendants will induce and contribute to infringement by third parties (e.g., physicians and hospitals) (Compl. ¶¶ 58, 73, 83). The basis for these allegations is that Defendants' product labeling will instruct users to administer the ANDA Product for its patented use, and that the product lacks substantial non-infringing uses (Compl. ¶¶ 33-35).
  • Willful Infringement: While the term "willful" is not used in the infringement counts themselves, the prayer for relief for each patent seeks a judgment that infringement is willful and an award of enhanced damages (Compl. Prayer for Relief ¶¶ G, N, U). The basis for willfulness appears to be Defendants' filing of an ANDA with a Paragraph IV certification with knowledge of the patents-in-suit from their listing in the FDA's Orange Book (Compl. ¶¶ 29, 31).

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

  • A core question will be one of factual evidence: what is the precise formulation disclosed in Aurobindo's confidential ANDA? The presence or absence of key excipients like EDTA and oleic acid at the claimed concentrations will be determinative for literal infringement and is a fact that will only be revealed through discovery.
  • A key legal question will be one of claim scope: how will the court construe the functional limitation "resistant to microbial growth"? The case may turn on whether this term is limited to the specific quantitative performance metrics disclosed in the patent's examples or if it encompasses any formulation that demonstrates a meaningful retardation of microbial growth.
  • A central infringement question will be one of inherency: if Aurobindo's formulation is not identical to that disclosed in the patents, does it nonetheless inherently possess the claimed functional properties, such as a specific zeta potential ('490 Patent), by virtue of being a bioequivalent emulsion? This will require expert testimony on the physical chemistry of the formulations.