DCT

2:16-cv-02525

Amarin Pharma Inc v. Hikma Pharma USA Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:16-cv-02525, D. Nev., 10/31/2016
  • Venue Allegations: Venue is alleged to be proper in the District of Nevada based on Defendant Roxane Laboratories, Inc.'s incorporation in Nevada, as well as Defendants' regular and systematic business activities within the state, including the sale of generic pharmaceutical products.
  • Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) for a generic version of Plaintiff's VASCEPA® product constitutes an act of infringement of fourteen U.S. patents related to methods of treating hypertriglyceridemia and pharmaceutical compositions thereof.
  • Technical Context: The technology concerns pharmaceutical compositions of highly purified eicosapentaenoic acid (EPA) ethyl ester, used to treat severe hypertriglyceridemia, a condition characterized by abnormally high levels of triglycerides in the bloodstream and associated with cardiovascular risk.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 209457 to the U.S. Food and Drug Administration (FDA). The ANDA filing included a Paragraph IV certification, asserting that the patents-in-suit are invalid or will not be infringed by the proposed generic product.

Case Timeline

Date Event
2009-02-10 Priority Date for ’728, ’715, ’677, ’652, ’920, ’446, ’335, ’399, ’560, ’650, ’929, ’698, and ’372 Patents
2009-04-29 Priority Date for ’594 Patent
2012-07-26 FDA approves Plaintiff's VASCEPA® (NDA No. 202057)
2012-10-23 U.S. Patent No. 8,293,728 Issued
2012-11-27 U.S. Patent No. 8,318,715 Issued
2013-01-22 U.S. Patent No. 8,357,677 Issued
2013-02-05 U.S. Patent No. 8,367,652 Issued
2013-02-19 U.S. Patent No. 8,377,920 Issued
2013-03-19 U.S. Patent No. 8,399,446 Issued
2013-04-09 U.S. Patent No. 8,415,335 Issued
2013-04-23 U.S. Patent No. 8,426,399 Issued
2013-04-30 U.S. Patent No. 8,431,560 Issued
2013-05-14 U.S. Patent No. 8,440,650 Issued
2013-08-27 U.S. Patent No. 8,518,929 Issued
2013-09-03 U.S. Patent No. 8,524,698 Issued
2013-10-01 U.S. Patent No. 8,546,372 Issued
2013-12-31 U.S. Patent No. 8,617,594 Issued
2016-09-21 Defendants submit ANDA No. 209457 to FDA (on or before this date)
2016-10-31 Complaint Filed

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

U.S. Patent No. 8,293,728 - Methods of Treating Hypertriglyceridemia

Issued: October 23, 2012 (’728 Patent)

The Invention Explained

  • Problem Addressed: The patent addresses cardiovascular disease, which it identifies as a leading cause of death in the United States and Europe, noting that hypertriglyceridemia is a significant risk factor (Compl. Ex. B, ’728 Patent, col. 1:13-21).
  • The Patented Solution: The invention is a method of blood lipid therapy that involves administering a pharmaceutical composition containing highly purified eicosapentaenoic acid (EPA) ethyl ester (at least 96% by weight) with "substantially no" docosahexaenoic acid (DHA) ('728 Patent, col. 2:33-40). This high-purity, DHA-free formulation is described as effective in reducing triglycerides without the undesirable side effect of elevating LDL-C ("bad cholesterol"), an issue potentially associated with other omega-3 fatty acid compositions containing both EPA and DHA ('728 Patent, Abstract; col. 3:1-4).
  • Technical Importance: The claimed method suggests a way to achieve the therapeutic benefit of triglyceride reduction for patients with severe hypertriglyceridemia while avoiding a concomitant, and potentially harmful, increase in LDL-C levels ('728 Patent, col. 3:1-4; col. 14:4-6).

Key Claims at a Glance

  • The complaint does not specify which claims are asserted, alleging infringement of "one or more claims" (Compl. ¶36). Independent claim 1 is representative of the patent’s core method claims.
  • Independent Claim 1:
    • A method of reducing triglycerides in a subject having a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl who does not receive concurrent lipid altering therapy,
    • comprising: administering orally to the subject about 4 g per day of a pharmaceutical composition,
    • wherein the composition comprises at least about 96%, by weight of all fatty acids present, ethyl eicosapentaenoate, and substantially no docosahexaenoic acid or its esters,
    • for a period of 12 weeks to effect a reduction in triglycerides without substantially increasing LDL-C.
  • The complaint does not explicitly reserve the right to assert dependent claims.

U.S. Patent No. 8,318,715 - Methods of Treating Hypertriglyceridemia

Issued: November 27, 2012 (’715 Patent)

The Invention Explained

  • Problem Addressed: The '715 Patent addresses the same technical problem as the '728 Patent: treating hypertriglyceridemia as a risk factor for cardiovascular disease (Compl. Ex. C, ’715 Patent, col. 1:13-21).
  • The Patented Solution: The patented solution is a method of using a highly purified EPA composition, substantially free of DHA, to reduce both triglycerides and apolipoprotein B (Apo B), another component of lipoproteins linked to cardiovascular risk (’715 Patent, Abstract).
  • Technical Importance: The method provides a dual therapeutic benefit by lowering two distinct lipid-related risk factors, triglycerides and Apo B, without the potential negative effect of raising LDL-C levels (’715 Patent, col. 14:41-42).

Key Claims at a Glance

  • The complaint does not specify which claims are asserted, alleging infringement of "one or more claims" (Compl. ¶46). Independent claim 1 is representative.
  • Independent Claim 1:
    • A method of reducing triglycerides and apolipoprotein B in a subject having a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl who does not receive a concurrent lipid altering therapy,
    • comprising administering orally to the subject about 4 g per day of a pharmaceutical composition,
    • wherein the composition comprises at least about 96% by weight, ethyl eicosapentaenoate (ethyl-EPA) and substantially no docosahexaenoic acid (DHA) or its esters,
    • for a period of at least 12 weeks to effect reduction in triglycerides and apolipoprotein B.
  • The complaint does not explicitly reserve the right to assert dependent claims.

Multi-Patent Capsule: U.S. Patent No. 8,357,677 (’677 Patent) et al.

  • Patents: U.S. Patent Nos. 8,357,677; 8,367,652; 8,377,920; 8,399,446; 8,415,335; 8,426,399; 8,431,560; 8,440,650; 8,518,929; 8,524,698; and 8,546,372.
  • Technology Synopsis: These patents are all titled Methods of Treating Hypertriglyceridemia and belong to the same family as the '728 and '715 Patents. They claim methods of using a highly purified EPA composition, substantially free of DHA, to achieve various therapeutic outcomes in patients with severe hypertriglyceridemia, such as reducing specific lipid or lipoprotein markers without substantially raising LDL-C.
  • Asserted Claims: The complaint asserts infringement of "one or more claims" of each patent (Compl. ¶¶ 56, 66, 76, 86, 96, 106, 116, 126, 136, 146, 156).
  • Accused Features: The accused features are Defendants' proposed generic icosapent ethyl product and the methods of its use as described in ANDA No. 209457, which are alleged to be the same as the approved use for VASCEPA® (Compl. ¶¶ 54, 64, 74, 84, 94, 104, 114, 124, 134, 144, 154).

Multi-Patent Capsule: U.S. Patent No. 8,617,594 (’594 Patent)

  • Patent Identification: U.S. Patent No. 8,617,594, Stable Pharmaceutical Composition and Methods of Using Same, issued December 31, 2013.
  • Technology Synopsis: This patent describes a pharmaceutical composition comprising highly purified EPA in a capsule shell. The claimed invention focuses on the formulation itself, particularly the characteristics of the capsule shell, which is described as comprising a film-forming material and specific plasticizers in a ratio designed to ensure stability of the highly susceptible EPA active ingredient.
  • Asserted Claims: The complaint asserts infringement of "one or more claims" of the patent (Compl. ¶166).
  • Accused Features: The accused feature is the proposed generic icosapent ethyl product itself as described in ANDA No. 209457, including its composition and formulation (Compl. ¶164).

III. The Accused Instrumentality

Product Identification

The accused product is Defendants' proposed generic version of VASCEPA®, described as "1g icosapent ethyl capsules" submitted for FDA approval under ANDA No. 209457 (Compl. ¶27).

Functionality and Market Context

The complaint alleges that the proposed generic product is "purportedly bioequivalent to VASCEPA®" and that its proposed labeling sets forth the same indication: "to reduce triglyceride levels in adult patients with severe hypertriglyceridemia" (Compl. ¶¶ 27-28). The filing of the ANDA is alleged to be an act of infringement under 35 U.S.C. § 271(e)(2)(A), as it seeks FDA approval to market a generic product for a patented use before the expiration of the patents-in-suit (Compl. ¶30).
No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint does not provide claim charts or detailed infringement contentions. The analysis below is based on the complaint's allegations of bioequivalence and identical intended use.

’728 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of reducing triglycerides... Defendants' proposed label allegedly instructs use of the generic product for the same indication as VASCEPA®: to reduce triglyceride levels. ¶28 col. 2:26-27
...in a subject having a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl... The proposed label is allegedly for use in patients with severe hypertriglyceridemia, which corresponds to the claimed patient population. ¶28 col. 13:61-65
...who does not receive concurrent lipid altering therapy... The complaint's infringement theory is based on administration by physicians, which could occur in patients not on other lipid-altering therapies. ¶36 col. 14:4-6
...administering orally to the subject about 4 g per day of a pharmaceutical composition... The proposed product is an oral capsule allegedly bioequivalent to VASCEPA®, which is prescribed at 4 g/day. ¶27, 28 col. 14:64-65
...wherein the composition comprises at least about 96%, by weight...ethyl eicosapentaenoate, and substantially no docosahexaenoic acid or its esters... Defendants' ANDA product is for 1g icosapent ethyl capsules, the active ingredient of VASCEPA®, which is a >96% pure ethyl-EPA formulation. ¶27 col. 9:48-50; col. 10:36-37
...for a period of 12 weeks to effect a reduction in triglycerides without substantially increasing LDL-C. Administration of the generic product as allegedly instructed by the proposed label is alleged to result in the claimed therapeutic outcome. ¶36 col. 14:4-6

’715 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of reducing triglycerides and apolipoprotein B... Defendants' proposed label allegedly instructs use of the generic product for the same indication as VASCEPA®, which is alleged to reduce triglycerides and apolipoprotein B. ¶28, 46 col. 2:26-27
...in a subject having a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl... The proposed label is allegedly for use in patients with severe hypertriglyceridemia, which corresponds to the claimed patient population. ¶28 col. 13:61-65
...administering orally to the subject about 4 g per day of a pharmaceutical composition... The proposed product is an oral capsule allegedly bioequivalent to VASCEPA®, which is prescribed at 4 g/day. ¶27, 46 col. 14:64-65
...wherein the composition comprises at least about 96% by weight, ethyl eicosapentaenoate (ethyl-EPA) and substantially no docosahexaenoic acid (DHA) or its esters... Defendants' ANDA product is for 1g icosapent ethyl capsules, the active ingredient of VASCEPA®, which is a >96% pure ethyl-EPA formulation. ¶27 col. 9:48-50; col. 10:36-37

Identified Points of Contention

  • Scope Questions: A central issue may be the construction of "substantially no docosahexaenoic acid or its esters." The parties may dispute the quantity of DHA that this term permits. A second key scope question may concern the negative limitation "without substantially increasing LDL-C" in the '728 Patent, as its definition and the evidence required to prove its presence (or absence) could be a point of contention.
  • Technical Questions: For the method-of-use patents, a key question for the court will be whether Defendants' proposed product label will induce infringement by physicians. This raises the evidentiary question of what the label instructs or encourages, and whether performing those instructions necessarily results in practicing every step of the claimed method, including the recited clinical outcomes.

V. Key Claim Terms for Construction

  • The Term: "substantially no docosahexaenoic acid or its esters" (from Claim 1 of the '728 and '715 Patents).

  • Context and Importance: The asserted patents distinguish the invention from prior art omega-3 compositions by claiming high-purity EPA with very little or no DHA. The definition of "substantially no" is therefore critical to determining the scope of the claims and whether Defendants' product, which may contain trace amounts of DHA, infringes. Practitioners may focus on this term because its ambiguity could be central to non-infringement arguments.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The term "substantially" is not explicitly defined with a numerical value in the specification, which may support an interpretation that it allows for some measurable, albeit low, amount of DHA ('728 Patent, col. 10:36-38).
    • Evidence for a Narrower Interpretation: The specification repeatedly emphasizes the purity of the EPA and the absence of DHA, stating in one embodiment that the composition contains "no docosahexaenoic acid or derivative thereof" ('728 Patent, col. 2:32-33). This language could be used to argue that "substantially no" means an amount that is undetectable or functionally irrelevant.

  • The Term: "without substantially increasing LDL-C" (from Claim 1 of the '728 Patent).

  • Context and Importance: This term defines a clinical outcome and functions as a negative limitation. It is a key feature used to differentiate the claimed method from other lipid therapies that may lower triglycerides but raise LDL-C. The construction of what constitutes a "substantial" increase in LDL-C will be critical to the infringement analysis.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The term "substantially" is a term of degree and is not given a precise numerical definition (e.g., a specific percentage increase). This may support a construction that it encompasses a range of clinically insignificant LDL-C increases.
    • Evidence for a Narrower Interpretation: The patent's clinical trial example section may provide data showing a specific, very small or non-existent mean LDL-C increase in the treatment group, which could be used to argue for a narrow, quantitative definition of what is "not a substantial increase" ('728 Patent, col. 14:4-6, referencing the outcome of the described study).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement under 35 U.S.C. § 271(b) for all asserted patents. The basis for inducement is the allegation that Defendants' "sales, marketing, and distribution of their ANDA Product," including the proposed product labeling, will instruct and encourage physicians and patients to administer the generic product in a manner that directly infringes the patented methods (Compl. ¶¶ 36, 46). Knowledge is alleged based on Defendants' Paragraph IV certification and the associated notice letter sent to Amarin (Compl. ¶¶ 29, 39).
  • Willful Infringement: The complaint does not include an explicit allegation of willful infringement. However, it alleges that the case is "an exceptional one" and seeks an award of attorneys' fees pursuant to 35 U.S.C. § 285 (Compl. ¶31).

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

This case will likely focus on several key questions that are common in ANDA litigation concerning method-of-use and composition patents.

  • A central issue will be one of claim construction: how will the court define the terms of degree "substantially no [DHA]" and "without substantially increasing [LDL-C]"? The resolution of these terms will determine the scope of the claims and may be dispositive of infringement.
  • A key evidentiary question will be one of induced infringement: does the proposed label for Defendants' generic product instruct or encourage physicians to perform all the steps of the claimed methods? Proving that a label induces a method claim that includes a negative clinical outcome will present a distinct evidentiary challenge.
  • For the '594 patent, a primary question will be one of formulation equivalence: does the composition of Defendants' proposed generic product, including its capsule shell and excipients, fall within the scope of the claims directed to a "stable pharmaceutical composition"? This will require a detailed technical comparison of the respective formulations.