DCT

3:18-cv-11358

Amgen Inc v. Amneal Pharma LLC

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-11358, D.N.J., 07/03/2018
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey as Defendant Amneal Pharmaceuticals LLC has its principal place of business in the district and has allegedly committed acts of infringement there.
  • Core Dispute: Plaintiff alleges that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to market generic versions of OTEZLA® (apremilast) tablets constitutes an act of infringement of six U.S. patents related to the apremilast compound, its crystalline forms, and methods of use.
  • Technical Context: The technology concerns apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) used for treating inflammatory conditions such as active psoriatic arthritis and moderate to severe plaque psoriasis.
  • Key Procedural History: This action was filed under the Hatch-Waxman Act following Plaintiff’s receipt of a Notice of Paragraph IV Certification from Defendant on May 31, 2018, which asserted that the patents-in-suit are invalid, unenforceable, or would not be infringed by the proposed generic products. The patents-in-suit are listed in the FDA’s Approved Drug Products With Therapeutic Equivalence Evaluations (the "Orange Book") in connection with Plaintiff's OTEZLA®, which was the first FDA-approved pharmaceutical product to contain apremilast.

Case Timeline

Date Event
2002-03-20 Earliest Priority Date for all Patents-in-Suit
2005-11-08 U.S. Patent No. 6,962,940 Issued
2008-09-23 U.S. Patent No. 7,427,638 Issued
2010-02-09 U.S. Patent No. 7,659,302 Issued
2011-02-22 U.S. Patent No. 7,893,101 Issued
2013-06-04 U.S. Patent No. 8,455,536 Issued
2014-03-21 FDA approves Celgene’s New Drug Application for OTEZLA® (apremilast)
2015-04-28 U.S. Patent No. 9,018,243 Issued
2018-05-31 Celgene receives Notice of Paragraph IV Certification from Amneal
2018-07-03 Complaint Filed

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

U.S. Patent No. 6,962,940 - "(+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione: Methods of Using and Compositions Thereof,"

  • Patent Identification: U.S. Patent No. 6962940, "(+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione: Methods of Using and Compositions Thereof," issued November 8, 2005.

The Invention Explained

  • Problem Addressed: The patent describes that enhanced or unregulated production of Tumor Necrosis Factor alpha (TNF-α) is implicated in a number of inflammatory, allergic, and autoimmune diseases (Compl. Ex. B, ’940 Patent, col. 1:40-48). The patent notes that compounds that specifically inhibit phosphodiesterase type 4 (PDE4) can reduce inflammation but that existing PDE4 inhibitors lacked selective action at acceptable therapeutic doses (Compl. Ex. B, ’940 Patent, col. 1:62-2:4).
  • The Patented Solution: The invention is directed to the stereomerically pure (+)-enantiomer of a specific substituted phenethylsulfone compound, known as apremilast, and methods of using it to treat disorders ameliorated by the inhibition of TNF-α or PDE4 (Compl. Ex. B, ’940 Patent, col. 3:6-18). The patent asserts that this specific (+)-enantiomer has increased potency and other benefits compared to the racemic mixture of both (+) and (-) enantiomers (Compl. Ex. B, ’940 Patent, col. 3:20-29).
  • Technical Importance: Isolating a single, more potent stereoisomer from a racemic mixture is a significant step in pharmaceutical development, as it can offer an improved therapeutic index by potentially increasing efficacy and reducing side effects associated with the less active isomer (Compl. Ex. B, ’940 Patent, col. 3:20-29).

Key Claims at a Glance

  • The complaint asserts method claims (Compl. ¶42, ¶53). Independent claim 1 is representative.
  • Essential elements of independent claim 1:
    • A method of treating diseases or disorders ameliorated by the inhibition of PDE4 in a patient.
    • The method comprises administering a therapeutically effective amount of stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a pharmaceutically acceptable prodrug, polymorph, salt, or solvate thereof.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 7,427,638 - "(+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione:, and Methods of Synthesis and Compositions Thereof,"

  • Patent Identification: U.S. Patent No. 7427638, "(+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione:, and Methods of Synthesis and Compositions Thereof," issued September 23, 2008.

The Invention Explained

  • Problem Addressed: The technical problem is identical to that described in the parent '940 Patent: the need for selective and potent PDE4 inhibitors to treat a range of inflammatory and autoimmune diseases (Compl. Ex. C, ’638 Patent, col. 1:22-2:4).
  • The Patented Solution: This patent, a divisional of the application that led to the '940 Patent, claims pharmaceutical compositions containing the stereomerically pure (+)-enantiomer of apremilast (Compl. Ex. C, ’638 Patent, col. 3:10-21). It explicitly claims the compound itself and formulations comprising the compound with a carrier or excipient, rather than only methods of its use (Compl. Ex. C, ’638 Patent, col. 32:25-31).
  • Technical Importance: Claiming a pharmaceutical composition provides a different scope of protection than a method claim, allowing for infringement claims based on the sale of the product itself, independent of how it is used or administered.

Key Claims at a Glance

  • The complaint asserts composition claims (Compl. ¶64, ¶76). Independent claim 1 is representative.
  • Essential elements of independent claim 1:
    • A pharmaceutical composition.
    • Comprising stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a salt, solvate, or hydrate thereof.
    • And a pharmaceutically acceptable carrier, excipient or diluent.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent.

U.S. Patent No. 7,659,302 - "Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione,"

  • Patent Identification: U.S. Patent No. 7659302, "Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione," issued February 9, 2010.
  • Technology Synopsis: This patent covers methods of using the stereomerically pure (+)-enantiomer of apremilast to treat inflammatory diseases by inhibiting PDE4 (Compl. Ex. D, ’302 Patent, Abstract). The technology is substantially similar to that of the ’940 Patent.
  • Asserted Claims: The complaint asserts method claims reciting the administration of (+)-apremilast (Compl. ¶88, ¶99).
  • Accused Features: The accused features are Defendant's proposed generic apremilast tablets and the instructions for their administration, which allegedly direct infringement of the patented methods (Compl. ¶89, ¶102).

U.S. Patent No. 7,893,101 - "Solid Forms Comprising (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione, Compositions Thereof, and Uses Thereof,"

  • Patent Identification: U.S. Patent No. 7893101, "Solid Forms Comprising (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione, Compositions Thereof, and Uses Thereof," issued February 22, 2011.
  • Technology Synopsis: This patent is directed to specific crystalline forms (polymorphs) of (+)-apremilast (Compl. Ex. E, ’101 Patent, Abstract). The claims define these solid forms by characteristic peaks in an X-ray powder diffraction (XRPD) pattern, a standard technique for identifying crystalline structures (Compl. Ex. E, ’101 Patent, col. 59:1-4).
  • Asserted Claims: The complaint asserts claims that recite a specific crystalline form of (+)-apremilast defined by an XRPD pattern (Compl. ¶110, ¶120).
  • Accused Features: The complaint alleges that Defendant's proposed generic product contains a form of (+)-apremilast having the specific, claimed XRPD pattern (Compl. ¶111, ¶121).

U.S. Patent No. 8,455,536 - "Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione,"

  • Patent Identification: U.S. Patent No. 8455536, "Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione," issued June 4, 2013.
  • Technology Synopsis: This patent covers methods of using the stereomerically pure (+)-enantiomer of apremilast to treat various inflammatory conditions by inhibiting PDE4 (Compl. Ex. F, ’536 Patent, Abstract). The technology is substantially similar to that of the ’940 and ’302 Patents.
  • Asserted Claims: The complaint asserts method claims reciting the administration of (+)-apremilast (Compl. ¶131, ¶142).
  • Accused Features: The accused features are Defendant's proposed generic apremilast tablets and the instructions for their administration, which allegedly direct infringement of the patented methods (Compl. ¶132, ¶145).

U.S. Patent No. 9,018,243 - "Solid Forms Comprising (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione,"

  • Patent Identification: U.S. Patent No. 9018243, "Solid Forms Comprising (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione," issued April 28, 2015.
  • Technology Synopsis: This patent, like the ’101 Patent, is directed to specific crystalline forms of (+)-apremilast, defined by characteristic XRPD peaks (Compl. Ex. G, ’243 Patent, Abstract). The complaint states the claims recite methods of administering such a form (Compl. ¶153).
  • Asserted Claims: The complaint asserts claims reciting methods of administering a specific crystalline form of (+)-apremilast defined by an XRPD pattern (Compl. ¶153, ¶163).
  • Accused Features: The complaint alleges that Defendant's proposed product contains a form of (+)-apremilast having the claimed XRPD pattern and that its label will instruct users to administer it, thereby infringing the patented methods (Compl. ¶154, ¶166).

III. The Accused Instrumentality

Product Identification

  • Defendant's apremilast tablets in 10 mg, 20 mg, and 30 mg dosage strengths, for which Defendant seeks FDA approval via ANDA No. 211782 (Compl. p. 2, ¶30).

Functionality and Market Context

  • The accused products are purported generic versions of Plaintiff's OTEZLA® tablets, containing the same active pharmaceutical ingredient, apremilast (Compl. p. 2, ¶30, ¶43). The complaint alleges that the proposed product label for the accused products will contain instructions for use that are substantially similar to those in the prescribing information for OTEZLA® (Compl. ¶45; Ex. A). The OTEZLA® label, attached as Exhibit A to the complaint, provides a detailed dosage titration schedule for initiating therapy to treat psoriatic arthritis and psoriasis (Compl. Ex. A, p. 44, Table 1). The complaint further alleges that the accused products contain specific crystalline forms of apremilast covered by the ’101 and ’243 patents (Compl. ¶111, ¶154).
  • The complaint alleges that Defendant seeks to engage in the commercial manufacture and sale of its generic products prior to the expiration of the patents-in-suit (Compl. ¶29).

IV. Analysis of Infringement Allegations

'940 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating diseases or disorders ameliorated by the inhibition of PDE4 in a patient Defendant's ANDA seeks approval to market its product for treating psoriatic arthritis and plaque psoriasis, which are inflammatory diseases ameliorated by PDE4 inhibition, and its proposed label will instruct such use (Compl. Ex. A, sec. 1.1, 1.2). ¶17, ¶45 col. 2:13-24
which comprises administering to a patient in need of such treatment a therapeutically effective amount The accused product will be provided in 10 mg, 20 mg, and 30 mg tablets, which are therapeutically effective amounts, and the proposed label will instruct administration according to a specific dosage titration schedule (Compl. Ex. A, p. 44, Table 1). ¶30, ¶45 col. 14:1-12
of stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a... salt, or solvate thereof. The complaint alleges on information and belief that the active pharmaceutical ingredient in Defendant's ANDA products is the claimed stereomerically pure (+)-enantiomer of the specified compound. ¶43, ¶54 col. 3:20-24

'638 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition The accused ANDA products are tablets, which are pharmaceutical compositions. ¶66, ¶78 col. 3:10-18
comprising stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione... The complaint alleges on information and belief that the accused ANDA products contain the claimed stereomerically pure (+)-enantiomer of the specified compound as the active ingredient. ¶65, ¶77 col. 3:48-53
and a pharmaceutically acceptable carrier, excipient or diluent. As tablets, the accused products necessarily include pharmaceutically acceptable excipients and carriers to form the solid dosage unit. ¶66 col. 15:3-12

Identified Points of Contention

  • Scope Questions: A potential issue for the method claims ('940, '302, '536, '243) may be whether the specific indications for which Amneal seeks FDA approval fall squarely within the scope of the claimed methods of "treating" the recited disorders. A central question for the solid form patents ('101, '243) will be one of definitional scope: does the term "X-ray powder diffraction pattern comprising... peaks" require only the presence of the listed peaks, or does it implicitly exclude the presence of other significant peaks?
  • Technical Questions: A key technical question for the '101 and '243 patents is factual: does the crystalline form of apremilast in Amneal’s product actually produce an XRPD pattern with the peaks recited in the claims? This will likely be a central point of dispute requiring expert analysis and testing of Amneal's product. The complaint notes that Amneal does not allege non-infringement of the '940 and '638 patents, which suggests that for those patents, the dispute may focus on validity rather than on the technical question of whether the accused product meets the claim limitations (Compl. ¶48, ¶71).

V. Key Claim Terms for Construction

  • The Term: "stereomerically pure"
  • Context and Importance: This term appears in the independent claims of both the '940 and '638 patents and is foundational to the entire patent portfolio. Its construction is critical because it defines the required level of purity of the (+) enantiomer relative to the (-) enantiomer for an accused product to infringe.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The '940 patent specification provides an explicit definition: "a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound," further clarifying that a "typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer... and less than about 20% by weight of other stereoisomers" (Compl. Ex. B, ’940 Patent, col. 6:14-25). Plaintiff may argue this express definition should control.
    • Evidence for a Narrower Interpretation: The specification immediately follows the broad definition with progressively narrower preferred embodiments: "more preferably greater than about 90%... even more preferably greater than about 95%... and most preferably greater than about 97% by weight of one stereoisomer" (Compl. Ex. B, ’940 Patent, col. 6:25-34). Defendant may argue that these preferences, or language in the prosecution history, serve to narrow the scope of the term as understood by a person of ordinary skill in the art.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement for all asserted method patents ('940, '302, '536, and '243). The basis for these allegations is that Defendant, with knowledge of the patents, will market and sell its generic products with a label and product insert that will instruct physicians and patients to administer the drug in a manner that directly infringes the claims (Compl. ¶45, ¶91, ¶134, ¶156).
  • Willful Infringement: The complaint does not use the word "willful," but for each patent it alleges that Defendant's conduct renders the case "exceptional" under 35 U.S.C. § 285, which is the statutory basis for awarding attorneys' fees, often in cases of willful infringement (Compl. ¶49, ¶72, ¶95, ¶116, ¶138, ¶159). The basis for this allegation is Defendant's alleged pre-suit knowledge of the patents-in-suit via their listing in the FDA's Orange Book, followed by the submission of the ANDA with a Paragraph IV certification (Compl. ¶46, ¶69).

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

  • A core issue will be one of validity: as the complaint states that Amneal does not contest infringement of at least the '940 and '638 patents, the dispute for those patents will likely center on whether Amneal can prove by clear and convincing evidence that the asserted claims are invalid, for reasons such as obviousness over the prior art.
  • A key evidentiary question will be one of structural identity: for the polymorph patents ('101 and '243), does the specific crystalline form of apremilast in Amneal's proposed generic product exhibit the X-ray powder diffraction pattern defined by the patent claims, or is there a structural mismatch that avoids infringement?
  • A central question for the method-of-use patents will be one of inducement: what is the exact language of Amneal's proposed product label, and does it provide sufficient instruction and encouragement to physicians to prescribe, and patients to use, the drug for the claimed indications such that it induces infringement of the patented methods?