DCT

2:19-cv-09759

Allergan Sales LLC v. Micro Labs Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:19-cv-09759, D.N.J., 04/12/2019
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Micro Labs USA, Inc. is a New Jersey corporation, and Defendant Micro Labs Ltd. is an Indian corporation subject to personal jurisdiction in the district.
  • Core Dispute: Plaintiffs allege that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the antidepressant drug Fetzima® constitutes an act of infringement of three U.S. patents.
  • Technical Context: The technology relates to pharmaceutical formulations and crystalline forms of levomilnacipran, an active ingredient used for treating major depressive disorder.
  • Key Procedural History: This action was triggered by Defendant Micro Labs Ltd.'s submission of ANDA No. 210779 to the U.S. Food and Drug Administration, which contained a Paragraph IV certification challenging the asserted patents. Plaintiffs state they were notified via a letter dated February 27, 2019. The complaint notes that patent term adjustments have been granted for a patent term extension is pending for the third.

Case Timeline

Date Event
2003-02-14 ’879 Patent Priority Date
2009-11-06 ’598 Patent Priority Date
2009-11-06 ’937 Patent Priority Date
2012-12-25 ’879 Patent Issued (Reissue)
2013-07-09 ’598 Patent Issued
2013-07-25 FDA approved NDA No. 204168 for Fetzima®
2014-10-21 ’937 Patent Issued
2019-02-27 Defendant sent Paragraph IV notice letter to Plaintiffs
2019-04-12 Complaint Filed

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

U.S. Patent No. 8,481,598 - "Stable Dosage Forms of Levomilnacipran"

  • Patent Identification: U.S. Patent No. 8,481,598, "Stable Dosage Forms of Levomilnacipran," issued July 9, 2013.

The Invention Explained

  • Problem Addressed: The patent's background section describes difficulties in preparing stable dosage forms of the drug levomilnacipran, noting the active ingredient's sensitivity to certain reaction conditions and its reactivity with common pharmaceutical excipients, which can lead to impurities and degradation (’598 Patent, col. 1:33-40).
  • The Patented Solution: The invention provides novel, stable formulations of levomilnacipran that exhibit improved purity and a desirable pharmacokinetic profile for treating conditions like depression (’598 Patent, col. 1:41-54). A key aspect of the preparation process involves using dehydrated alcohol as a solvent to minimize the formation of a specific degradation product, (1S,5R) 1-phenyl-3-azabicyclo[3-1-0]hexane-2-one, thereby enhancing the stability of the final dosage form (’598 Patent, col. 9:5-24).
  • Technical Importance: Developing a stable, extended-release oral dosage form for an antidepressant allows for once-daily dosing, which can improve patient compliance and provide more consistent therapeutic plasma concentrations, potentially reducing side effects (’598 Patent, col. 1:41-47).

Key Claims at a Glance

  • The complaint alleges infringement of one or more unspecified claims (Compl. ¶24). Independent claim 1 is a representative method of treatment claim.
  • Essential elements of independent claim 1 include:
    • A method for treating major depressive disorder in a patient
    • administering to the patient about 120 mg/day of levomilnacipran or a salt thereof
    • in one or more sustained release oral dosage forms
    • providing an average maximum plasma concentration (Cmax) between about 50 ng/mL and about 350 ng/mL
    • providing an AUC0-∞ between about 1000 ng-hr/mL and about 9000 ng-hr/mL
    • providing a Tmax of at least 3 hours to the patient

U.S. Patent No. 8,865,937 - "Crystalline Forms of (1S, 2R)-2-(Amino methyl)-N, N-Diethyl-1-Phenyl Cyclopropane Carboxamide"

  • Patent Identification: U.S. Patent No. 8,865,937, "Crystalline Forms of (1S, 2R)-2-(Amino methyl)-N, N-Diethyl-1-Phenyl Cyclopropane Carboxamide," issued October 21, 2014.

The Invention Explained

  • Problem Addressed: The patent addresses the fact that a single pharmaceutical compound can exist in different solid-state physical forms, known as polymorphs or crystalline forms. These different forms can have distinct physical properties, such as stability, dissolution rate, and flowability, which can significantly impact the manufacturing process and the drug's therapeutic performance (’937 Patent, col. 1:41-55).
  • The Patented Solution: The invention discloses and claims new, specific crystalline forms of levomilnacipran hydrochloride. These forms are identified and defined by their unique X-ray powder diffraction (XRPD) patterns, which serve as a structural fingerprint for each distinct crystalline arrangement (’937 Patent, col. 2:25-33; col. 4:15-24).
  • Technical Importance: Identifying and controlling the specific crystalline form of an active pharmaceutical ingredient is critical for ensuring batch-to-batch consistency in drug product manufacturing, bioavailability, and stability over the product's shelf life (’937 Patent, col. 2:5-13).

Key Claims at a Glance

  • The complaint alleges infringement of one or more unspecified claims (Compl. ¶37). Independent claim 1 is a representative composition of matter claim.
  • Essential elements of independent claim 1 include:
    • A crystalline form of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide hydrochloride
    • having an X-ray powder diffraction pattern comprising characteristic peaks at 12.0±0.2 degrees 2θ, 20.1±0.2 degrees 2θ and 22.5±0.2 degrees 2θ

U.S. Reissued Patent No. RE43,879 - "Use of the Dextrogyral Enantiomer of Milnacipran for the Preparation of a Drug"

  • Patent Identification: U.S. Reissued Patent No. RE43,879, "Use of the Dextrogyral Enantiomer of Milnacipran for the Preparation of a Drug," issued December 25, 2012.

Technology Synopsis

The patent addresses the problem that milnacipran, which exists as a 50/50 mixture of two mirror-image isomers (enantiomers), can cause cardiovascular side effects (’879 Patent, col. 3:1-11). The invention is based on the discovery that the therapeutic antidepressant effect resides primarily in the dextrogyral (d-) enantiomer (levomilnacipran), while the other enantiomer may contribute more significantly to adverse effects. The patented solution is the use of levomilnacipran in a "substantially pure" form to treat depression while limiting cardiovascular and other toxicities associated with the racemic mixture (’879 Patent, col. 4:1-12; col. 7:5-17).

Asserted Claims

The complaint alleges infringement of one or more unspecified claims (Compl. ¶47). Independent claim 1 is a representative method of treatment claim.

Accused Features

The complaint alleges that Micro's generic product, which by definition contains levomilnacipran as its active ingredient and is intended for treating depression, will infringe the patent's method claims (Compl. ¶43, ¶46).

III. The Accused Instrumentality

Product Identification

The accused products are Micro's proposed generic "levomilnacipran hydrochloride extended release capsules in 20 mg, 40 mg, 80 mg, and 120 mg dosage strengths," for which Micro has filed ANDA No. 210779 with the FDA (Compl. ¶20).

Functionality and Market Context

The accused products are intended to be generic equivalents of Plaintiffs' Fetzima® product, an extended-release capsule for the treatment of major depressive disorder (MDD) (Compl. ¶18, ¶23). As a generic drug under an ANDA, the product is designed to have the same active ingredient, strength, dosage form, and route of administration as Fetzima® and to be bioequivalent (Compl. ¶20, ¶23). The complaint alleges that Micro seeks to commercially manufacture, use, and sell these products in the United States before the expiration of the patents-in-suit (Compl. ¶20, ¶33, ¶43). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not contain a claim chart or provide a detailed factual basis for its infringement allegations, instead asserting that Micro's submission of its ANDA constitutes infringement under 35 U.S.C. § 271(e)(2) (Compl. ¶24, ¶37). The infringement theory is predicated on the requirement that a generic product under an ANDA must be the same as, and bioequivalent to, the brand-name drug it references.

’598 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method for treating major depressive disorder...comprising administering...about 120 mg/day of levomilnacipran...in one or more sustained release oral dosage forms Micro’s ANDA seeks approval to market sustained release capsules of levomilnacipran for treating MDD, including a 120 mg dosage strength. ¶20, ¶23 col. 31:30-34
providing an average maximum plasma concentration (Cmax) between about 50 ng/mL and about 350 ng/mL As a bioequivalent product, Micro's generic is alleged to provide a Cmax profile that falls within the claimed range upon administration. ¶24 col. 31:41-43
providing an AUC0-∞ between about 1000 ng-hr/mL and about 9000 ng-hr/mL As a bioequivalent product, Micro's generic is alleged to provide an AUC profile that falls within the claimed range upon administration. ¶24 col. 32:1-3
providing a Tmax of at least 3 hours As a bioequivalent product, Micro's generic is alleged to provide a Tmax that meets the claimed limitation upon administration. ¶24 col. 32:3-4

’937 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A crystalline form of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide hydrochloride Micro’s ANDA product contains levomilnacipran hydrochloride as its active pharmaceutical ingredient. ¶20 col. 36:38-41
having an X-ray powder diffraction pattern comprising characteristic peaks at 12.0±0.2 degrees 2θ, 20.1±0.2 degrees 2θ and 22.5±0.2 degrees 2θ Micro's ANDA product is alleged to contain the active ingredient in the specific crystalline form defined by the claimed XRPD peaks. ¶37 col. 36:41-45

Identified Points of Contention

  • Scope Questions: For the ’598 Patent, a central dispute may arise over the term "about" as it modifies the numerical boundaries of the pharmacokinetic parameters. The interpretation of this term could determine whether Micro's product, which may be bioequivalent without being identical in its PK profile, falls within the literal scope of the claims.
  • Technical Questions: For the ’937 Patent, the primary technical question is factual: does the levomilnacipran hydrochloride in Micro's proposed product actually exist in the crystalline form defined by the asserted claims? This will likely require expert analysis and comparison of the XRPD patterns of Micro's API against the patent's claims. For the ’598 Patent, the question is whether the data in Micro's ANDA demonstrates that its product will, in fact, achieve the Cmax, AUC, and Tmax recited in the claims when administered to patients as instructed on its proposed label.

V. Key Claim Terms for Construction

The Term: "about" (from '598 Patent, Claim 1)

Context and Importance

This term appears throughout claim 1 of the ’598 Patent, qualifying the dosage and all pharmacokinetic parameters (e.g., "about 120 mg/day," "about 50 ng/mL"). The construction of "about" is critical because it defines the permissible range of deviation from the stated numerical values. Practitioners may focus on this term because if Micro's product demonstrates a PK profile close to, but not exactly matching, the recited numbers, the scope of "about" could be dispositive on the issue of literal infringement.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The specification explicitly defines the term, stating "'about' can mean within 1 or more than 1 standard deviations... Alternatively, 'about' can mean a range of up to 20%... of a given value" (’598 Patent, col. 14:60-65). This language may support a construction that encompasses significant numerical variability.
  • Evidence for a Narrower Interpretation: The same passage also offers a more restrictive alternative: "...preferably up to 10%, more preferably up to 5%, and more preferably still up to 1% of a given value" (’598 Patent, col. 14:65-col. 15:1). This language may support a narrower construction that limits the term's scope to a smaller degree of deviation from the recited values.

The Term: "characteristic peaks" (from '937 Patent, Claim 1)

Context and Importance

This term is used to define the claimed crystalline structure via its XRPD pattern. The definition of which peaks are "characteristic" is central to determining infringement, as an accused product's XRPD pattern may show some, but not all, of the peaks listed in the patent, or may show them with different relative intensities.

Intrinsic Evidence for Interpretation

  • Evidence for a Broader Interpretation: The patent states that the phrase "one or more peaks" should be understood to be inclusive of crystalline forms that have an XRD peak at "only one of the peak values recited" (’937 Patent, col. 4:20-25). This suggests that not all peaks listed in a dependent claim, for instance, are necessarily required to be present to find that a form is "characteristic."
  • Evidence for a Narrower Interpretation: The specification presents exemplary XRPD data in tables where numerous peaks are listed for a given form (’937 Patent, col. 4, Table 2). A defendant may argue that "characteristic peaks" should be construed to mean the full set of peaks that collectively define the unique crystal structure, or at least the most prominent and consistently appearing peaks, as is common in crystallographic practice.

VI. Other Allegations

Indirect Infringement

The complaint alleges both induced and contributory infringement for all three patents. It asserts that Micro knows of the patents and intends for physicians and patients to use its generic product according to the proposed label, which will directly infringe method claims (Compl. ¶26, ¶49). The complaint also alleges that levomilnacipran is not a staple article of commerce suitable for substantial noninfringing use, forming the basis for contributory infringement (Compl. ¶27, ¶50).

Willful Infringement

The complaint does not contain an explicit allegation of willful infringement or a request for enhanced damages under 35 U.S.C. § 284. It does, however, plead that Micro has knowledge of the patents-in-suit, which is a prerequisite for willfulness (Compl. ¶25, ¶48).

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

  • A core issue will be one of physical identity: Does the active pharmaceutical ingredient in Micro’s proposed generic product possess the specific crystalline structure, as defined by the "characteristic peaks" in the asserted claims of the ’937 patent? This is a central, fact-intensive question that will likely be resolved through competing expert analyses of the materials.
  • A key evidentiary question will be one of pharmacokinetic performance: Does the data submitted in Micro's ANDA establish that its product, when used as directed, will result in a patient plasma profile that meets the specific Cmax, AUC, and Tmax limitations of the ’598 patent's method claims? The outcome will depend on a direct comparison of Micro's clinical data with the claim language.
  • The case may also turn on a question of definitional scope: How broadly will the court construe the term "about" as used to define the numerical ranges in the ’598 patent's claims? The court's interpretation will set the boundaries for literal infringement and could be dispositive if the accused product's performance lies near the edges of the recited ranges.