DCT

3:18-cv-11215

Amgen Inc v. Teva Pharma USA Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-11215, D.N.J., 06/28/2018
  • Venue Allegations: Venue is alleged in the District of New Jersey based on Defendant Actavis LLC’s principal place of business being in New Jersey, and Defendant Teva Pharmaceuticals USA, Inc.’s regular and established places of business in the state.
  • Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the FDA, seeking approval to market generic versions of Plaintiff's OTEZLA® (apremilast) tablets, constitutes an act of infringement of nine U.S. patents.
  • Technical Context: The technology relates to the pharmaceutical compound apremilast, a phosphodiesterase 4 (PDE4) inhibitor, and its use in treating inflammatory and autoimmune conditions such as psoriatic arthritis and plaque psoriasis.
  • Key Procedural History: The action arises under the Hatch-Waxman Act following Defendants' submission of ANDA No. 211897 with a Paragraph IV certification, alleging that the patents-in-suit are invalid, unenforceable, or would not be infringed. The patents are listed in the FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations" (the "Orange Book") in connection with OTEZLA®. Plaintiff filed this complaint within the 45-day statutory window after receiving Defendants' notice letter, triggering an automatic 30-month stay of FDA approval for the ANDA.

Case Timeline

Date Event
2002-03-20 Priority Date for ’940, ’516, ’638, ’302, ’101, ’536, ’717, ’243 Patents
2005-11-08 U.S. Patent No. 6,962,940 Issued
2007-04-24 U.S. Patent No. 7,208,516 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
2013-03-14 Priority Date for ’854 Patent
2014-03-21 FDA Approved OTEZLA® (apremilast)
2014-08-12 U.S. Patent No. 8,802,717 Issued
2015-04-28 U.S. Patent No. 9,018,243 Issued
2018-01-23 U.S. Patent No. 9,872,854 Issued
2018-05-24 Celgene Received Notice Letter from Defendants
2018-06-28 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," issued November 8, 2005

The Invention Explained

  • Problem Addressed: The patent's background section describes the role of Tumor Necrosis Factor alpha (TNF-α) and phosphodiesterase type IV (PDE4) in mediating a range of inflammatory, autoimmune, and cancerous diseases. It notes that while PDE4 inhibitors were known to be effective anti-inflammatory agents, existing compounds lacked the necessary selectivity to be used at therapeutically effective doses without significant side effects (ʼ940 Patent, col. 1:16-col. 2:67).
  • The Patented Solution: The invention claims to solve this problem by isolating a specific, stereomerically pure enantiomer of a phenethylsulfone compound, identified as apremilast. This specific "(+)" isomer is described as a potent inhibitor of both TNF-α and PDE4, with the patent asserting that this stereoisomer possesses greater potency and other benefits compared to the racemic (mixed-isomer) version of the compound ('940 Patent, Abstract; col. 3:20-27). The detailed description and Figure 1 illustrate a multi-stage process for synthesizing this specific enantiomer ('940 Patent, col. 21:10-col. 22:48; FIG. 1).
  • Technical Importance: By identifying and claiming a single, more active stereoisomer, the invention offered a path to a more potent therapeutic with a potentially improved safety profile, a crucial step in developing a viable oral treatment for chronic inflammatory diseases ('940 Patent, col. 3:20-27).

Key Claims at a Glance

  • The complaint asserts "one or more claims" of the patent (Compl. ¶59). Independent claim 1 is representative of the patent's method-of-use claims.
  • Independent Claim 1:
    • A method of treating diseases or disorders ameliorated by the inhibition of PDE4 in a patient
    • which comprises administering to a patient in need of such treatment
    • 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.

U.S. Patent No. 7,208,516, "Methods of the Treatment of Psoriatic Arthritis Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione," issued April 24, 2007

The Invention Explained

  • Problem Addressed: The patent background describes psoriatic arthritis as a chronic inflammatory condition affecting the skin and joints, for which there is a "significant need for safe and effective methods of treating, preventing and managing" the disease, particularly for patients refractory to conventional therapies ('516 Patent, col. 2:25-40).
  • The Patented Solution: The patent claims a specific method for treating psoriatic arthritis by administering apremilast, the same stereomerically pure compound from the ’940 Patent. This patent refines the broader teachings of the parent '940 patent by focusing on a specific disease indication and provides clinical data supporting its efficacy for this use ('516 Patent, Abstract; col. 6:42-col. 7:42). The patent's figures present clinical data showing apremilast's effect on epidermal thickness, Psoriasis Area and Severity Index (PASI), and Body Surface Area (BSA) in patients ('516 Patent, FIGS. 1-3).
  • Technical Importance: This patent provided specific support for the use of apremilast in treating psoriatic arthritis, a distinct clinical indication, thereby carving out a focused and protected use for the compound beyond the broader inflammatory disease categories ('516 Patent, col. 2:41-52).

Key Claims at a Glance

  • The complaint asserts "one or more claims" of the patent (Compl. ¶80). Independent claim 1 is representative.
  • Independent Claim 1:
    • A method of treating psoriatic arthritis
    • which comprises administering to a patient in need of such treatment
    • a therapeutically effective amount of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a pharmaceutically acceptable salt or solvate thereof
    • substantially free of its (-) enantiomer.

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,” issued September 23, 2008

  • Technology Synopsis: This patent claims the stereomerically pure compound apremilast itself, as well as pharmaceutical compositions and single-unit dosage forms containing it. It also discloses methods for synthesizing the compound.
  • Asserted Claims: Independent claims 1 and 13 are representative of the asserted composition of matter claims.
  • Accused Features: The complaint alleges that Defendants' ANDA products are pharmaceutical compositions and single-unit dosage forms containing apremilast (Compl. ¶¶100, 101).

U.S. Patent No. 7,659,302, “Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione,” issued February 9, 2010

  • Technology Synopsis: This patent claims methods of using apremilast to treat a range of inflammatory conditions, including psoriasis and various forms of arthritis. It builds upon the earlier method-of-use patents.
  • Asserted Claims: Independent claims 1 and 10 are representative of the asserted method claims.
  • Accused Features: The complaint alleges that the proposed label for Defendants' products will instruct users to administer the drug to treat psoriatic arthritis and psoriasis, thereby infringing these method claims (Compl. ¶¶122, 125).

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,” issued February 22, 2011

  • Technology Synopsis: This patent claims specific crystalline forms (polymorphs) of apremilast, characterized by data such as X-ray powder diffraction (XRPD) patterns. Different solid forms of a drug can affect its stability, solubility, and manufacturing, making specific, stable forms independently patentable.
  • Asserted Claims: Independent claim 1 is representative of claims to a specific crystalline form (Form B).
  • Accused Features: The complaint alleges on information and belief that Defendants' ANDA products contain a form of apremilast that has an X-ray powder diffraction pattern meeting the claim limitations (Compl. ¶¶143, 144).

U.S. Patent No. 8,455,536, “Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione,” issued June 4, 2013

  • Technology Synopsis: This patent claims specific dosing regimens for treating psoriasis and psoriatic arthritis, including escalating doses for an initial treatment period.
  • Asserted Claims: Independent claims 1, 17, 37, and 56 are representative of the asserted dosing regimen claims.
  • Accused Features: The complaint alleges that the proposed product label for Defendants' products will instruct users to follow dosing schedules that infringe these method claims (Compl. ¶¶164, 167; Compl. Ex. A, p. 59).

U.S. Patent No. 8,802,717, “Methods of Treating Arthritic Conditions Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione,” issued August 12, 2014

  • Technology Synopsis: This patent claims methods of treating various arthritic conditions, including rheumatoid spondylitis, by administering apremilast.
  • Asserted Claims: Independent claim 1 is representative of the asserted method claims.
  • Accused Features: The complaint alleges that the intended uses for Defendants' generic apremilast, including psoriatic arthritis, fall within the scope of the claimed methods (Compl. ¶¶185, 186).

U.S. Patent No. 9,018,243, “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, claims specific crystalline forms of apremilast identified by distinct physical and chemical properties.
  • Asserted Claims: Independent claim 1 is representative of claims to a specific crystalline form (Form B).
  • Accused Features: The complaint alleges that Defendants' ANDA products contain a form of apremilast having the characteristics of the claimed crystalline solid form (Compl. ¶¶206, 207).

U.S. Patent No. 9,872,854, “Methods For the Treatment of Psoriatic Arthritis Using Apremilast,” issued January 23, 2018

  • Technology Synopsis: This patent claims a specific dosing regimen for apremilast, particularly an initial escalating dose schedule for treating psoriatic arthritis.
  • Asserted Claims: Independent claim 1 is representative of the asserted dosing schedule claim.
  • Accused Features: The complaint alleges the proposed label for Defendants' product will instruct users to follow the patented dosing schedule, which includes an initial titration period (Compl. ¶¶227, 230; Compl. Ex. A, p. 59). The OTEZLA® prescribing information, attached as Exhibit A to the complaint, includes a table detailing this 5-day titration schedule (Compl. Ex. A, p. 59, Table 1).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentalities are the generic apremilast 10 mg, 20 mg, and 30 mg tablets for which Defendants seek FDA approval under ANDA No. 211897 (Compl. ¶1).
  • Functionality and Market Context: The products are intended to be generic bioequivalents to Celgene's OTEZLA® tablets (Compl. ¶44). The complaint alleges these products contain (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione (apremilast) as the active pharmaceutical ingredient (Compl. ¶45). The act of infringement alleged is the filing of the ANDA itself under 35 U.S.C. § 271(e)(2)(A), which seeks approval to market these tablets for the treatment of psoriatic arthritis and psoriasis prior to the expiration of the patents-in-suit (Compl. ¶¶1, 56). The commercialization of these products would directly compete with Celgene's OTEZLA® (Compl. ¶25).

IV. Analysis of Infringement Allegations

U.S. Patent No. 6,962,940 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... Defendants seek approval to market their products for treating psoriatic arthritis and psoriasis, which the complaint alleges are diseases ameliorated by PDE4 inhibition. The proposed product label is alleged to instruct these uses. ¶¶57, 60 col. 7:46-48
which comprises administering to a patient in need... a therapeutically effective amount of stereomerically pure (+)-2-[1-(3-Ethoxy-4...]-1,3-dione... The complaint alleges that Defendants' ANDA Products contain the specified stereomerically pure compound as the active pharmaceutical ingredient and that the proposed label will instruct administration in therapeutically effective amounts. ¶58 col. 3:20-27

U.S. Patent No. 7,208,516 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating psoriatic arthritis... Defendants seek approval to market their products specifically for the treatment of psoriatic arthritis. The proposed product label is alleged to contain instructions for this indication. ¶¶78, 81 col. 2:41-45
which comprises administering... a therapeutically effective amount of (+)-2-[1-(3-ethoxy-4...]-1,3-dione... substantially free of its (-) enantiomer. The complaint alleges that Defendants' ANDA Products contain the specified active ingredient, apremilast, which is the (+) enantiomer. The proposed product is designed to be a generic equivalent to OTEZLA®, which is substantially free of the (-) enantiomer. ¶79 col. 4:20-30

Identified Points of Contention

  • Scope Questions: In the context of a Hatch-Waxman action where the generic product is designed to be bioequivalent, non-infringement arguments are less common than validity challenges. However, a potential point of contention could be the scope of terms like "stereomerically pure" and "substantially free of its (-) enantiomer." The case may raise the question of whether Defendants' specific formulation and isomeric purity level falls within the patent's definition of these terms.
  • Technical Questions: The primary technical questions will likely be raised by Defendants in challenging the validity of the patents. These may include whether the claimed invention was obvious in light of prior art related to PDE4 inhibitors and anti-inflammatory compounds, or whether the patent specifications provide adequate written description and enablement for the full scope of the claims. The complaint does not detail Defendants' invalidity contentions beyond stating they were made in the Paragraph IV notice letter (Compl. ¶48).

V. Key Claim Terms for Construction

The Term: "stereomerically pure" ('940 Patent) and "substantially free of its (-) enantiomer" ('516 Patent).

  • Context and Importance: These terms are central to defining the claimed active ingredient. The patents distinguish the invention from the prior art racemic mixture. The dispute will likely depend on the level of isomeric purity required to meet these limitations, and whether Defendants' product meets that threshold.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification of the ’940 Patent provides a definition for "stereomerically pure" that "comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers" (’940 Patent, col. 6:11-17). This language may support a broader construction that encompasses any product meeting this 80/20 ratio.
    • Evidence for a Narrower Interpretation: The same section of the ’940 Patent specification provides increasingly narrow preferred embodiments: "more preferably greater than about 90%," "even more preferably greater than about 95%," and "most preferably greater than about 97%" (’940 Patent, col. 6:17-27). A party may argue that these narrower definitions, particularly the "most preferred" embodiment, should inform or limit the claim's scope to higher purity levels.

The Term: "therapeutically effective amount" ('940 and '516 Patents).

  • Context and Importance: This term is crucial for the method claims, as infringement requires administration of an effective dose. In an ANDA case, this links to the proposed label's dosage instructions.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The patents' specifications disclose broad daily dose ranges, such as from "about 1 mg to about 1000 mg per day" (’940 Patent, col. 13:66-67). This may support a construction covering a wide range of potential dosages.
    • Evidence for a Narrower Interpretation: The patents also disclose more specific daily dose ranges (e.g., "between about 10 mg and about 200 mg per day") and specific single dosage forms (’940 Patent, col. 14:1-6). The ’516 patent further includes data from clinical studies using specific doses, which a party may argue limits the scope of an "effective amount" to those dosages proven to be effective for the claimed indication ('516 Patent, col. 6:42-67).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement under 35 U.S.C. § 271(b). The factual basis is the allegation that Defendants, upon receiving FDA approval, will market and sell their generic products with a product label and insert that instruct physicians and patients to use the drug in a manner that directly infringes the asserted method claims (Compl. ¶¶60, 81).
  • Willful Infringement: The complaint alleges that Defendants had actual and constructive notice of the patents-in-suit prior to filing their ANDA. This pre-suit knowledge is the basis for the allegation that the infringement is willful and for the request that the case be found "exceptional" under 35 U.S.C. § 285, which would entitle Plaintiff to attorneys' fees (Compl. ¶¶61, 63, 82, 84).

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

  • A central issue will be one of patent validity: can Defendants prove by clear and convincing evidence that the asserted claims—covering the specific (+)-enantiomer of apremilast, its methods of use, specific crystalline forms, and dosing regimens—are invalid as obvious or lacking adequate written description over the prior art concerning PDE4 inhibitors and inflammatory disease treatments?
  • A key question of infringement may turn on the precise characteristics of Defendants' ANDA product: does the specific crystalline form and isomeric purity of the active ingredient in Defendants' proposed tablets fall within the scope of the claims directed to specific polymorphs and the term "substantially free of its (-) enantiomer"?
  • A core question for the method claims will be one of induced infringement: does the proposed product label for Defendants' generic apremilast sufficiently instruct and encourage the performance of each step of the patented treatment and dosing methods, establishing the requisite intent for inducement?