Amarin Pharma Inc v. Apotex Inc

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: Amarin Pharma, Inc. (Delaware) and Amarin Pharmaceuticals Ireland Limited (Ireland)
  • Defendant: Apotex, Inc. (Canada) and Apotex Corporation (Delaware)
  • Plaintiff's Counsel: ROBINSON, WETTRE & MILLER LLC; Covington & Burling LLP
• Case Identification: 3:14-cv-02550, D.N.J., 04/21/2014
• Venue Allegations: Venue is alleged based on Defendants' purposeful availment of the jurisdiction of the District of New Jersey, including through prior litigation in the district and plans to develop, market, and sell the accused generic drug product within the state.
• Core Dispute: Plaintiff alleges that Defendant's filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's VASCEPA® (icosapent ethyl) constitutes an act of infringement of sixteen U.S. patents related to pharmaceutical compositions and methods for treating severe hypertriglyceridemia.
• Technical Context: The technology concerns pharmaceutical-grade compositions of highly purified eicosapentaenoic acid (EPA), an omega-3 fatty acid, used to reduce very high triglyceride levels in adult patients.
• Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendant's submission of ANDA No. 205753 to the U.S. Food and Drug Administration (FDA) with a Paragraph IV certification, alleging that Plaintiff's Orange Book-listed patents are invalid and/or will not be infringed by the proposed generic product.

Case Timeline

Date	Event
2009-02-10	Priority Date for U.S. Patent No. 8,293,728, U.S. Patent No. 8,318,715, U.S. Patent No. 8,357,677, U.S. Patent No. 8,367,652, U.S. Patent No. 8,377,920, U.S. Patent No. 8,399,446, U.S. Patent No. 8,415,335, U.S. Patent No. 8,426,399, U.S. Patent No. 8,431,560, U.S. Patent No. 8,440,650, U.S. Patent No. 8,501,225, U.S. Patent No. 8,518,929, U.S. Patent No. 8,524,698, U.S. Patent No. 8,546,372, U.S. Patent No. 8,551,521, and U.S. Patent No. 8,617,594 Patents
2012-07-26	FDA first approves NDA No. 202057 for VASCEPA®
2012-10-23	U.S. Patent No. 8,293,728 ('728 Patent) is issued
2012-11-27	U.S. Patent No. 8,318,715 ('715 Patent) is issued
2013-01-22	U.S. Patent No. 8,357,677 ('677 Patent) is issued
2013-02-05	U.S. Patent No. 8,367,652 ('652 Patent) is issued
2013-02-19	U.S. Patent No. 8,377,920 ('920 Patent) is issued
2013-03-19	U.S. Patent No. 8,399,446 ('446 Patent) is issued
2013-04-09	U.S. Patent No. 8,415,335 ('335 Patent) is issued
2013-04-23	U.S. Patent No. 8,426,399 ('399 Patent) is issued
2013-04-30	U.S. Patent No. 8,431,560 ('560 Patent) is issued
2013-05-14	U.S. Patent No. 8,440,650 ('650 Patent) is issued
2013-08-06	U.S. Patent No. 8,501,225 ('225 Patent) is issued
2013-08-27	U.S. Patent No. 8,518,929 ('929 Patent) is issued
2013-09-03	U.S. Patent No. 8,524,698 ('698 Patent) is issued
2013-10-01	U.S. Patent No. 8,546,372 ('372 Patent) is issued
2013-10-08	U.S. Patent No. 8,551,521 ('521 Patent) is issued
2013-12-31	U.S. Patent No. 8,617,594 ('594 Patent) is issued
2014-03-07	Apotex submits ANDA No. 205753 and sends Notice Letter to Amarin
2014-03-10	Amarin receives Apotex's Notice Letter
2014-04-21	Complaint for Patent Infringement is filed

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

U.S. Patent No. [8,293,728](https://ai-lab.exparte.com/patent/8293728) - "Methods of Treating Hypertriglyceridemia"

• Issued: October 23, 2012 Compl. ¶36

The Invention Explained

• Problem Addressed: The patent background identifies cardiovascular disease as a leading cause of death and notes a need for improved treatments Compl. Ex. B, '728 Patent, col. 1:12-21
• The Patented Solution: The patent describes a method of blood lipid therapy that involves administering a pharmaceutical composition containing highly purified eicosapentaenoic acid (EPA), or a derivative thereof, to a subject Compl. Ex. B, '728 Patent, abstract The composition is characterized by containing at least 96% EPA ethyl ester by weight and being substantially free of docosahexaenoic acid (DHA), another common omega-3 fatty acid Compl. Ex. B, '728 Patent, col. 13:30-53 This formulation is intended to reduce triglyceride levels in patients with severe hypertriglyceridemia without causing a clinically significant increase in low-density lipoprotein cholesterol (LDL-C), a potential side effect observed with other omega-3 therapies that contain both EPA and DHA Compl. Ex. B, '728 Patent, col. 14:1-4
• Technical Importance: The claimed method provides a therapeutic option that isolates the triglyceride-lowering effects of EPA while avoiding the potential LDL-C-raising effects of DHA, which is significant for managing cardiovascular risk in this patient population Compl. Ex. B, '728 Patent, col. 14:1-4

Key Claims at a Glance

• The complaint asserts one or more claims of the '728 Patent Compl. ¶39 Independent claim 1 is representative of the asserted method patents.
• Claim 1 includes the following essential elements:
  • A method of reducing triglycerides in a subject with a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl who does not receive concurrent lipid altering therapy.
  • Orally administering about 4 g per day of a pharmaceutical composition for a period of 12 weeks.
  • The composition comprises at least about 96% by weight ethyl eicosapentaenoate.
  • The composition contains substantially no docosahexaenoic acid or its esters.
  • The administration effects a reduction in triglycerides without substantially increasing LDL-C compared to a specified control group.
• The complaint states that infringement is of one or more claims, either literally or under the doctrine of equivalents Compl. ¶39

U.S. Patent No. [8,318,715](https://ai-lab.exparte.com/patent/8318715) - "Methods of Treating Hypertriglyceridemia"

• Issued: November 27, 2012 Compl. ¶46

The Invention Explained

• Problem Addressed: The patent addresses the need for improved treatments for cardiovascular-related diseases such as hypertriglyceridemia Compl. Ex. C, '715 Patent, col. 1:12-21
• The Patented Solution: The patent discloses a method of reducing both triglycerides and apolipoprotein B by administering a pharmaceutical composition that consists of at least 96% by weight ethyl eicosapentaenoate (EPA-E) and is substantially free of docosahexaenoic acid (DHA) Compl. Ex. C, '715 Patent, col. 13:5-50 Apolipoprotein B is a primary component of LDL-C, and its reduction is a therapeutic goal in managing cardiovascular risk.
• Technical Importance: This invention targets not only the reduction of triglycerides but also the reduction of apolipoprotein B, providing a dual mechanism for lipid management in patients with severe hypertriglyceridemia, again without the potential counter-effect of raising LDL-C associated with DHA Compl. Ex. C, '715 Patent, col. 13:41-47

Key Claims at a Glance

• The complaint asserts one or more claims of the '715 Patent Compl. ¶49 Independent claim 1 is representative.
• Claim 1 includes the following essential elements:
  • A method of reducing triglycerides and apolipoprotein B in a subject with a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl.
  • Orally administering about 4 g per day of a pharmaceutical composition for at least 12 weeks.
  • The composition comprises at least about 96% by weight ethyl eicosapentaenoate.
  • The composition contains substantially no docosahexaenoic acid or its esters.
  • The administration effects a reduction in triglycerides and apolipoprotein B compared to baseline levels.
• The complaint states that infringement is of one or more claims, either literally or under the doctrine of equivalents Compl. ¶49

Multi-Patent Capsule: U.S. Patent No. [8,357,677](https://ai-lab.exparte.com/patent/8357677)

• Patent Identification: U.S. Patent No. 8,357,677, "Methods of Treating Hypertriglyceridemia," issued January 22, 2013 Compl. ¶56
• Technology Synopsis: The patent describes methods of reducing triglyceride levels in a subject on statin therapy by administering a pharmaceutical composition of highly purified EPA that is substantially free of DHA Compl. Ex. D, '677 Patent, abstract This addresses the clinical scenario of patients whose triglycerides remain high despite statin treatment.
• Asserted Claims: One or more claims Compl. ¶59
• Accused Features: The administration of Defendant's generic icosapent ethyl product to patients with severe hypertriglyceridemia is alleged to infringe Compl. ¶59

Multi-Patent Capsule: U.S. Patent No. [8,367,652](https://ai-lab.exparte.com/patent/8367652)

• Patent Identification: U.S. Patent No. 8,367,652, "Methods of Treating Hypertriglyceridemia," issued February 5, 2013 Compl. ¶66
• Technology Synopsis: The patent describes a method of reducing triglyceride levels by administering about 4 g per day of a pharmaceutical composition comprising at least 96% ethyl eicosapentaenoate and substantially no DHA Compl. Ex. E, '652 Patent, abstract
• Asserted Claims: One or more claims Compl. ¶69
• Accused Features: The administration of Defendant's generic icosapent ethyl product to patients with severe hypertriglyceridemia is alleged to infringe Compl. ¶69

The complaint asserts twelve additional patents: U.S. Patent No. 8,377,920, U.S. Patent No. 8,399,446, U.S. Patent No. 8,415,335, U.S. Patent No. 8,426,399, U.S. Patent No. 8,431,560, U.S. Patent No. 8,440,650, U.S. Patent No. 8,501,225, U.S. Patent No. 8,518,929, U.S. Patent No. 8,524,698, U.S. Patent No. 8,546,372, U.S. Patent No. 8,551,521, and U.S. Patent No. 8,617,594. The allegations for each are substantially similar, accusing the same generic product of infringing method-of-use or composition claims related to highly purified EPA for treating hypertriglyceridemia Compl. ¶¶75-194

III. The Accused Instrumentality

Product Identification

• The accused instrumentality is the generic drug product for which *Amarin Pharma Inc v. Apotex Inc* and Apotex Corporation seek FDA approval under ANDA No. 205753 Compl. ¶1 Compl. ¶30

Functionality and Market Context

• The accused product is described as "1g icosapent ethyl capsules purportedly bioequivalent to VASCEPA®" Compl. ¶30 The complaint alleges that the proposed labeling for the generic product includes the same indication as VASCEPA®: "to reduce triglyceride levels in adult patients with severe hypertriglyceridemia" Compl. ¶31 The filing of the ANDA is alleged to be for the purpose of engaging in the commercial manufacture and sale of a generic version of VASCEPA® before the expiration of Plaintiff's patents Compl. ¶33
• No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint alleges that by filing ANDA No. 205753, Defendants have committed an act of infringement under 35 U.S.C. § 271(e)(2)(A) Compl. ¶43 Compl. ¶53 It further alleges that the future commercial manufacture, use, or sale of the approved generic product would constitute direct infringement of the asserted claims Compl. ¶39, and that Defendants would actively induce infringement by health care providers and patients through the product's labeling and instructions Compl. ¶40

'728 Patent Infringement Allegations

Claim Element (from Independent Claim 1)	Alleged Infringing Functionality	Complaint Citation	Patent Citation
A method of reducing triglycerides in a subject having a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl...	The proposed labeling for the accused generic product is alleged to be for use in adult patients with severe hypertriglyceridemia, which corresponds to the claimed patient population Compl. ¶39	¶39	col. 13:59-62
...who does not receive concurrent lipid altering therapy...	The claim is directed to a method where no other lipid-altering therapies are used. The complaint's allegations of inducement via the product label would apply to this patient subgroup Compl. ¶39	¶39	col. 20:53-56
...administering orally to the subject about 4 g per day of a pharmaceutical composition...	Administration of the accused product is alleged to constitute infringement. The proposed label, mirroring VASCEPA®'s, is expected to instruct a 4 g/day dosage Compl. ¶39 Compl. Ex. A	¶39	col. 13:55-58
...comprising at least about 96%, by weight of all fatty acids present, ethyl eicosapentaenoate, and substantially no docosahexaenoic acid or its esters...	The accused product is alleged to be a bioequivalent version of VASCEPA®, which is a highly-purified EPA composition. The complaint's theory suggests bioequivalence necessitates meeting the claimed purity limitations Compl. ¶30	¶30	col. 13:30-36
...to effect a reduction in triglycerides without substantially increasing LDL-C...	The complaint alleges the accused product will be administered to achieve the patented therapeutic outcome, as instructed by its label Compl. ¶39	¶39	col. 14:1-4

'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 in a subject having a fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl.	The proposed labeling for the accused generic product is alleged to be for use in patients with severe hypertriglyceridemia, which would achieve the claimed therapeutic outcome Compl. ¶49	¶49	col. 13:5-8
...administering orally to the subject about 4 g per day of a pharmaceutical composition...for a period of at least 12 weeks.	Administration of the accused product is alleged to constitute infringement. The proposed label is expected to instruct a 4 g/day dosage Compl. ¶49 Compl. Ex. A	¶49	col. 13:41-47
...comprising at least about 96%, by weight...ethyl eicosapentaenoate, and substantially no docosahexaenoic acid or its esters...	The accused product is alleged to be a bioequivalent version of VASCEPA®, suggesting its composition must meet the claimed purity limitations Compl. ¶30 Compl. ¶47	¶47	col. 13:10-17

• Identified Points of Contention:
  • Scope Questions: A likely point of dispute will be the construction of "substantially no docosahexaenoic acid." The precise quantitative limit of this term will be critical for determining both infringement and validity, as it distinguishes the claimed invention from prior art omega-3 compositions that may have contained both EPA and DHA.
  • Technical Questions: A central factual question for the litigation will be the actual chemical composition of the drug substance in Defendant's ANDA product. Does it, in fact, contain "at least about 96%" ethyl eicosapentaenoate and meet the "substantially no" DHA limitation? The complaint alleges infringement on the basis of the ANDA filing and bioequivalence, but discovery will be required to establish the specific characteristics of the accused product.

V. Key Claim Terms for Construction

• The Term: "substantially no docosahexaenoic acid or its esters"
• Context and Importance: This negative limitation is central to distinguishing the claimed methods and compositions from prior art fish oil products, which typically contained a mixture of EPA and DHA. The definition of this term is therefore critical to both the infringement and validity analyses. Practitioners may focus on this term because it represents the core technical advance alleged by the patentee.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification provides some flexibility, stating, "In one embodiment, the composition contains not more than about 10%, by weight, docosahexaenoic acid (DHA) or derivative thereof" before later stating that in "another embodiment" it contains "substantially no" DHA Compl. Ex. B, '728 Patent, col. 9:60-65 Plaintiff may argue this context supports a definition that is not absolute zero but is below a certain functional or analytical threshold.
  • Evidence for a Narrower Interpretation: The specification also discloses an embodiment where the "composition contains no docosahexaenoic acid and/or derivative thereof" Compl. Ex. B, '728 Patent, col. 10:35-37 A defendant could cite this language to argue that "substantially no" should be construed to mean an amount that is as close to zero as analytically possible, potentially distinguishing it from their own product if it contains any detectable level of DHA.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that upon approval, Apotex will actively induce infringement under 35 U.S.C. § 271(b) Compl. ¶40 Compl. ¶50 The basis for this allegation is that Apotex's product labeling will necessarily instruct physicians and patients to perform the patented method-administering the drug to reduce triglycerides in the specified patient population-thereby inducing direct infringement by those end-users Compl. ¶39 Compl. ¶49
• Willful Infringement: The complaint does not explicitly use the term "willful infringement." However, it alleges that the infringement will occur with Apotex's "intent, knowledge, and encouragement" and with "knowledge that it is in contravention of Plaintiffs' rights" Compl. ¶39 Compl. ¶49 It also pleads that the case is "exceptional" under 35 U.S.C. § 285, seeking an award of attorneys' fees Compl. ¶34 These allegations are based on Apotex's pre-suit knowledge of the patents-in-suit, as evidenced by its Paragraph IV certification and the notice letter sent to Amarin Compl. ¶32

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

• A core issue will be one of compositional identity: What is the precise chemical profile of the Apotex generic product? The case will likely depend on factual evidence establishing whether the accused product's level of ethyl-EPA meets the "at least about 96%" purity threshold and whether its DHA content falls within the court's construction of "substantially no" DHA.
• A second key issue will be one of claim validity and scope: Can the asserted claims, particularly the negative limitation "substantially no docosahexaenoic acid," be interpreted in a way that is both broad enough to cover the accused product and narrow enough to be valid over prior art omega-3 fatty acid formulations that may have contained varying levels of EPA and DHA?