DCT

1:17-cv-00276

Apotex Inc v. Symplmed Pharma LLC

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-00276, D. Del., 03/15/2017
  • Venue Allegations: Venue is alleged to be proper in the District of Delaware based on Defendant Symplmed’s incorporation in Delaware and because both Defendants market and distribute products, including the branded drug at issue, within the district.
  • Core Dispute: Plaintiff, a generic drug manufacturer, seeks a declaratory judgment that its proposed generic version of the hypertension drug PRESTALIA® does not infringe, and/or that the patents covering the drug are invalid.
  • Technical Context: The technology concerns specific salt and crystalline forms of perindopril, an ACE inhibitor, designed to improve the drug's stability and manufacturability.
  • Key Procedural History: This is a Hatch-Waxman Act case. Defendants listed the patents-in-suit in the FDA’s Orange Book for their branded drug, PRESTALIA®. Plaintiff Apotex filed an Abbreviated New Drug Application (ANDA) with a "Paragraph IV certification," asserting non-infringement or invalidity of the listed patents. When Defendants did not file an infringement suit within the statutory 45-day window, Apotex initiated this declaratory judgment action to obtain legal certainty regarding its right to market its generic product.

Case Timeline

Date Event
2003-02-21 U.S. Patent No. 6,696,481 Priority Date
2004-02-24 U.S. Patent No. 6,696,481 Issue Date
2006-02-28 U.S. Patent No. 7,846,961 Priority Date
2010-12-07 U.S. Patent No. 7,846,961 Issue Date
2016-12-30 Symplmed receives Apotex's ANDA Notice Letter
2017-01-02 Servier receives Apotex's ANDA Notice Letter
2017-03-15 Complaint Filing Date

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

U.S. Patent No. 6,696,481 - "Salt of Perindopril and Pharmaceutical Compositions Containing It," Issued Feb. 24, 2004

The Invention Explained

  • Problem Addressed: The patent's background section describes the "intrinsic fragility" of the perindopril compound. It notes that previously studied forms, including the non-salt form and the marketed tert-butylamine salt, exhibit poor stability against heat and humidity, leading to rapid degradation. This instability necessitates "onerous" packaging and storage constraints and limits the product's shelf-life. (’481 Patent, col. 1:39-54).
  • The Patented Solution: The invention is the arginine salt of perindopril. The specification presents stability study data comparing the new arginine salt to the existing tert-butylamine salt, concluding that the arginine salt shows "extremely clearly the very great stability" with "practically no degradation" under conditions where the prior art salt degraded by approximately 33%. (’481 Patent, col. 2:55-61). This improved stability is presented as an "entirely unexpected" advantage. (’481 Patent, col. 2:58-63).
  • Technical Importance: A more stable salt form of a drug can allow for a longer shelf-life, less stringent storage requirements (e.g., refrigeration), and simplified packaging, which can reduce manufacturing and distribution costs. (’481 Patent, col. 2:63-68).

Key Claims at a Glance

  • The complaint seeks a declaration of non-infringement and invalidity as to any valid claim of the '481 patent (Compl. ¶¶44, 47). The independent claims are:
  • Claim 1: An arginine salt of perindopril and its hydrates.
  • Claim 2: A pharmaceutical composition comprising, as active ingredient, the arginine salt of perindopril and its hydrates, in combination with one or more pharmaceutically acceptable excipients.
  • Claim 5: A method for treating a living animal body afflicted with hypertension and heart failure comprising the step of administering...an amount of the pharmaceutical composition of claim 2...

U.S. Patent No. 7,846,961 - "α Crystalline Form of the Arginine Salt of Perindopril, a Process for Its Preparation and Pharmaceutical Compositions Containing It," Issued Dec. 7, 2010

The Invention Explained

  • Problem Addressed: While the '481 patent disclosed the arginine salt of perindopril, this patent addresses a subsequent challenge: obtaining the salt in a form with consistent and desirable physical properties. The patent notes that for pharmaceutical manufacturing, it is of "prime importance to obtain it with excellent stability... processability of the powder, ...filterability of the solid, [and] grindability," and that a "well-defined crystalline form allows those requirements to be met." (’961 Patent, col. 2:47-54).
  • The Patented Solution: The invention is a specific crystalline polymorph of the perindopril arginine salt, designated the "α-crystalline form." This form is not defined by its chemical composition alone, but by its unique physical structure, which is identified by a characteristic powder X-ray diffraction (XRPD) pattern with specific peaks at certain angles. (’961 Patent, col. 1:57-60; col. 2:1-6).
  • Technical Importance: Controlling the crystalline form (polymorphism) of an active pharmaceutical ingredient is critical for ensuring lot-to-lot consistency in drug product performance, including dissolution rate and bioavailability.

Key Claims at a Glance

  • The complaint seeks a declaration of non-infringement as to any valid claim of the '961 patent (Compl. ¶41). The independent claims are:
  • Claim 1: An α-crystalline form of the L-arginine salt of perindopril... exhibiting essentially the following powder X-ray diffraction peaks...: 4.5, 7.9 and 13.5.
  • Claim 4: A process for the preparation of the α-crystalline form...
  • Claim 6: A pharmaceutical composition comprising as active ingredient the compound of claim 1...
  • Claim 9: A method for treating arterial hypertension and heart failure, comprising the step of administering... a therapeutically effective amount of the compound of claim 1.

III. The Accused Instrumentality

Product Identification

  • "Apotex's Proposed ANDA Products," which are described as "amlodipine besylate; perindopril arginine oral tablets" in various dosages (Compl. ¶27).

Functionality and Market Context

  • The products are proposed generic versions of the branded drug PRESTALIA® and are described as being "bioequivalent" to it (Compl. ¶27). They are intended to provide a lower-cost alternative for the treatment of hypertension and enter the market upon receiving FDA approval (Compl. ¶38). The complaint does not contain technical details about the product's manufacturing process or specific physical form beyond identifying the active pharmaceutical ingredient as perindopril arginine (Compl. ¶27).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

The complaint is for declaratory judgment of non-infringement and does not contain affirmative infringement allegations or claim charts. It makes conclusory assertions that Apotex's products do not and will not infringe any valid claims of the '481 and '961 patents (Compl. ¶¶41, 44). The substantive dispute over infringement will depend on evidence developed during litigation regarding the precise nature of Apotex's product.

Identified Points of Contention

  • ’481 Patent: The primary infringement question for the '481 patent will be whether Apotex's product contains the "arginine salt of perindopril" as claimed. The complaint identifies the active ingredient as "perindopril arginine" (Compl. ¶27), suggesting a direct overlap. Therefore, the dispute may focus more on the validity of the '481 patent claims rather than non-infringement.
  • ’961 Patent: The central infringement question will be a factual one: does the perindopril arginine in Apotex's proposed product exist in the specific "α-crystalline form" claimed in the '961 patent? Apotex may argue for non-infringement by demonstrating that its active ingredient is in an amorphous state or a different, non-infringing crystalline polymorph. The resolution will depend on expert analysis of Apotex's product using techniques like XRPD.

V. Key Claim Terms for Construction

  • ’961 Patent: "α-crystalline form" / "exhibiting essentially the following powder X-ray diffraction peaks"
    • The Terms: ""α-crystalline form"" and ""exhibiting essentially the following powder X-ray diffraction peaks"" (from Claim 1).
    • Context and Importance: These terms are the primary limitations distinguishing the '961 patent from the earlier '481 patent. The scope of "essentially" will be critical, as it determines how closely Apotex's product must match the patented XRPD pattern to be found infringing. Practitioners may focus on this term because Apotex's non-infringement defense likely hinges on its product's XRPD pattern falling outside the scope of "essentially" matching the claimed peaks.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The use of the word "essentially" suggests the claim does not require a perfect, identical match to the specified peaks, potentially covering patterns with minor shifts in peak position or relative intensity due to experimental variables (’961 Patent, col. 4:38). Claim 1 itself only recites three peaks, suggesting that matching these three may be sufficient (’961 Patent, col. 4:42).
      • Evidence for a Narrower Interpretation: The specification provides a detailed table with nineteen characteristic peaks for the α-form, including their relative intensities (’961 Patent, col. 2:15-32). Defendants may argue that "α-crystalline form" is defined by this more complete pattern and that "essentially" only allows for minor instrumental variations, not the absence of key characteristic peaks beyond the three recited in Claim 1.

VI. Other Allegations

  • Indirect Infringement: The complaint requests a declaration of non-infringement for both direct and indirect infringement (Compl., Prayer for Relief ¶¶A, B). However, as a declaratory judgment action, it pleads no specific facts regarding inducement or contributory infringement, as its purpose is to negate such claims.
  • Willful Infringement: Willful infringement is not alleged in the complaint.

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

The resolution of this case will likely depend on the answers to two central questions, one factual and one legal:

  1. A dispositive factual issue will be one of physical structure: Does the perindopril arginine active ingredient in Apotex’s proposed generic product exist in the specific "α-crystalline form" claimed by the ’961 patent, or does it utilize an alternative form (e.g., amorphous, a different polymorph) to avoid infringement?

  2. A key legal question will concern claim construction and scope: How should the term "essentially" in the claims of the '961 patent be construed? The court's interpretation will define the boundary for infringement, determining how much deviation from the recited X-ray diffraction pattern is permissible before a competing product is deemed non-infringing.

  3. A likely focus of the invalidity challenge will be on obviousness: Was the invention of the specific α-crystalline polymorph in the '961 patent a non-obvious development over the prior disclosure of the chemically stable arginine salt in the '481 patent, when considered in light of standard techniques for polymorph screening in the pharmaceutical industry?