DCT

3:18-cv-11213

Amgen Inc v. MSN Laboratories Private Ltd

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-11213, D.N.J., 03/05/2019
  • Venue Allegations: Venue is alleged on the basis that Defendant is a foreign corporation and that its wholly-owned U.S. subsidiary, which is involved in the development and marketing of generic drugs, has its principal place of business in New Jersey.
  • Core Dispute: Plaintiff alleges that Defendant’s Abbreviated New Drug Application (ANDA) to market generic versions of Plaintiff's OTEZLA® (apremilast) tablets infringes eight patents related to the apremilast compound, compositions, 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 psoriatic arthritis and plaque psoriasis.
  • Key Procedural History: This action arises under the Hatch-Waxman Act following Defendant's submission of ANDA No. 211887 with a Paragraph IV certification, challenging the patents-in-suit. Plaintiff's allegations are based on two separate notice letters from Defendant: a "First Notice Letter" dated May 22, 2018, addressing U.S. Patent No. 7,427,638, and a "Second Notice Letter" dated February 15, 2019, addressing the other seven patents-in-suit.

Case Timeline

Date Event
2002-03-20 Priority Date for ’940, ’638, ’302, ’101, ’536, ’243, ’330 Patents
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 OTEZLA® (apremilast)
2014-08-15 Priority Date for ’541 Patent
2015-04-28 U.S. Patent No. 9,018,243 Issued
2017-08-08 U.S. Patent No. 9,724,330 Issued
2018-05-22 Plaintiff receives First Notice Letter regarding ’638 Patent
2018-10-09 U.S. Patent No. 10,092,541 Issued
2019-02-15 Plaintiff receives Second Notice Letter regarding seven other patents
2019-03-05 Second Amended 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

The Invention Explained

  • Problem Addressed: The patent describes the role of tumor necrosis factor alpha (TNF-α) and phosphodiesterase 4 (PDE4) in a wide range of inflammatory, allergic, and autoimmune diseases, noting that compounds which inhibit these pathways are needed for therapeutic intervention (ʼ940 Patent, col. 1:20-2:4).
  • The Patented Solution: The invention is directed to the specific (+) enantiomer of a phenethylsulfone compound, known as apremilast. The patent discloses that isolating this specific stereoisomer from its racemic mixture results in a compound with increased potency and other therapeutic benefits for treating diseases associated with TNF-α and PDE4 inhibition (ʼ940 Patent, Abstract; col. 3:19-27). The invention covers methods of using this specific enantiomer to treat these diseases.
  • Technical Importance: By isolating a single, more potent enantiomer, the invention suggests a path to achieving therapeutic effects at potentially lower doses, which can reduce side effects compared to administering a racemic mixture containing a less active or inactive enantiomer.

Key Claims at a Glance

  • The complaint asserts claims reciting methods of administering the compound (Compl. ¶51). Independent claim 1 is representative.
  • The essential elements of independent claim 1 are:
    • 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.
  • The complaint does not explicitly reserve the right to assert dependent claims for this patent, but makes general allegations covering one or more claims.

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

The Invention Explained

  • Problem Addressed: Similar to the ’940 Patent, the ’638 Patent addresses inflammatory diseases and other conditions that can be treated by reducing levels of TNF-α or inhibiting PDE4 (ʼ638 Patent, col. 1:20-2:47).
  • The Patented Solution: This patent claims the pharmaceutical composition of the (+) enantiomer of apremilast itself, rather than just the method of using it. The invention provides for a composition comprising the stereomerically pure compound combined with a pharmaceutically acceptable carrier, which is suitable for administration to patients (ʼ638 Patent, Abstract; col. 13:30-43).
  • Technical Importance: Claiming the tangible pharmaceutical composition provides a different scope of protection than claiming the method of use, focusing on the drug product itself as sold and manufactured.

Key Claims at a Glance

  • The complaint asserts claims that recite the compound itself or a pharmaceutical composition or dosage form containing it (Compl. ¶73). Independent claim 1 is representative of a composition claim.
  • The essential elements of independent claim 1 are:
    • A pharmaceutical composition
    • comprising stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a pharmaceutically acceptable salt, solvate or hydrate, thereof; and
    • a pharmaceutically acceptable carrier, excipient or diluent.
  • The complaint makes general allegations covering one or more claims of the ’638 Patent.

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

  • Technology Synopsis: This patent covers methods of treating diseases ameliorated by PDE4 inhibition by administering stereomerically pure apremilast. It specifically claims methods of treating conditions such as psoriasis and inflammatory arthritis.
  • Asserted Claims: The complaint alleges infringement of claims reciting methods of administering the compound (Compl. ¶97).
  • Accused Features: The accused features are the future manufacture, use, sale, and importation of Defendant's ANDA products, which contain apremilast and will allegedly be labeled for indications that infringe the claimed methods (Compl. ¶99, 100).

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

  • Technology Synopsis: This patent is directed to specific crystalline (polymorphic) forms of apremilast. Different solid forms of a drug can have different properties affecting stability, dissolution, and manufacturability. This patent claims specific forms identified by their X-ray powder diffraction (XRPD) patterns.
  • Asserted Claims: The complaint alleges infringement of claims reciting a form of apremilast with a specific X-ray powder diffraction pattern (Compl. ¶119).
  • Accused Features: Defendant's ANDA products are alleged to contain a form of apremilast that has the claimed XRPD pattern (Compl. ¶120).

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

  • Technology Synopsis: This patent claims methods of treating specific diseases, including psoriasis and Behcet's Disease, by orally administering apremilast in particular dosage amounts and forms.
  • Asserted Claims: The complaint alleges infringement of claims reciting methods of administering the compound (Compl. ¶140).
  • Accused Features: Defendant's ANDA products, when used according to their proposed label, are alleged to infringe the claimed methods of administration for treating specified diseases (Compl. ¶143).

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

  • Technology Synopsis: Like the '101 Patent, this patent is directed to specific solid crystalline forms of apremilast, characterized by physical data such as XRPD patterns. It provides protection for distinct polymorphic forms of the drug substance.
  • Asserted Claims: The complaint alleges infringement of claims reciting methods of administering a form of apremilast having a specified X-ray powder diffraction pattern (Compl. ¶162).
  • Accused Features: Defendant's ANDA products are alleged to contain a crystalline form of apremilast that meets the claimed structural characteristics (Compl. ¶163).

U.S. Patent No. 9,724,330 - Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione

  • Technology Synopsis: This patent covers further methods of using stereomerically pure apremilast to treat various inflammatory and autoimmune diseases. It appears to be a continuation of earlier patents in the family, covering similar methods of use.
  • Asserted Claims: The complaint alleges infringement of claims reciting methods of administering the compound (Compl. ¶183).
  • Accused Features: The accused features are the intended uses of Defendant's ANDA products, which are alleged to align with the methods of treatment claimed in the patent (Compl. ¶186).

U.S. Patent No. 10,092,541 - Methods for the Treatment of Diseases Ameliorated by PDE4 Inhibition Using Dosage Titration of Apremilast

  • Technology Synopsis: This patent is directed specifically to a method of administering apremilast using a dose titration schedule. This involves starting the patient on a low dose and gradually increasing it over several days to the maintenance dose, a technique often used to improve tolerability and reduce gastrointestinal side effects.
  • Asserted Claims: The complaint alleges infringement of claims reciting methods of administering the compound according to a specific titration schedule (Compl. ¶205).
  • Accused Features: Defendant's proposed product label is alleged to instruct for a dosage titration schedule that infringes the claimed methods. The OTEZLA® prescribing information, provided as Exhibit A, contains a table outlining this specific titration schedule (Compl. ¶208; Compl. Ex. A, p. 52).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentalities are Defendant MSN’s proposed generic apremilast tablets in 10 mg, 20 mg, and 30 mg dosage forms, for which MSN seeks FDA approval via ANDA No. 211887 (Compl. ¶¶ 1, 33).

Functionality and Market Context

  • The complaint alleges that MSN's ANDA Products contain apremilast as the active pharmaceutical ingredient and are intended to be generic copies of Celgene’s OTEZLA® product (Compl. ¶¶ 1, 33). The complaint further alleges that upon approval, MSN's products will be marketed with a product label and insert that are substantially similar to the prescribing information for OTEZLA®, instructing physicians and patients to use the product for FDA-approved indications such as psoriatic arthritis and psoriasis (Compl. ¶¶ 54, 77). The OTEZLA® label, attached as Exhibit A to the complaint, includes a specific "Dosage Titration Schedule" for initiating therapy (Compl. Ex. A, p. 52).

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 which comprises administering...a therapeutically effective amount... Defendant's proposed product label will allegedly instruct healthcare professionals and patients to administer the generic apremilast product to treat approved indications such as psoriatic arthritis and psoriasis, which are diseases ameliorated by PDE4 inhibition. ¶51, 54 col. 7:1-9
of stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione... Defendant's ANDA products are alleged to contain the specified (+)-enantiomer of apremilast as the active pharmaceutical ingredient. ¶52 col. 3:19-27

’638 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A pharmaceutical composition comprising stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione... Defendant's ANDA products are alleged to be pharmaceutical compositions that contain the specified (+)-enantiomer of apremilast as the active ingredient. ¶74, 75 col. 13:50-55
and a pharmaceutically acceptable carrier, excipient or diluent. Defendant's ANDA products are formulated as tablets, which necessarily include pharmaceutically acceptable carriers, excipients, and/or diluents to form a solid dosage form. ¶75 col. 13:40-43

Identified Points of Contention

  • Scope Questions: A central point of contention for all asserted patents may be the scope of the term "stereomerically pure". The patents define this term as comprising greater than about 80%, 90%, 95%, or 97% of the (+) isomer ('940 Patent, col. 5:15-33). The precise level of isomeric purity in Defendant's ANDA product compared to the scope of this claim term will likely be a key issue.
  • Technical Questions: For the method of use patents (e.g., ’940 and ’541 Patents), a key question will be evidentiary: does the proposed label for MSN's ANDA Products induce infringement by instructing users to follow the patented methods? The complaint points to the Dosage Titration Schedule in the OTEZLA® label as evidence of this for the '541 Patent (Compl. Ex. A, p. 52). For the solid form patents (e.g., ’101 and ’243 Patents), the dispute will likely turn on technical evidence, such as comparative X-ray powder diffraction analyses, to determine if Defendant's product has the claimed crystalline structure.

V. Key Claim Terms for Construction

  • The Term: "stereomerically pure"
  • Context and Importance: This term is foundational to nearly all asserted patents, as the core invention is the isolation and use of the (+) enantiomer. The infringement analysis will depend heavily on whether Defendant’s apremilast API meets the level of purity required by this term, as construed by the court. Practitioners may focus on this term because even small percentages of the (-) isomer in Defendant's product could form the basis of a non-infringement argument.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides a cascading definition, initially stating that a "typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer" ('940 Patent, col. 5:18-22). This could support an argument that any purity level above 80% falls within the scope of the claim.
    • Evidence for a Narrower Interpretation: The same passage continues by describing "more preferably greater than about 90%," "even more preferably greater than about 95%," and "most preferably greater than about 97%" ('940 Patent, col. 5:22-33). A defendant may argue this language suggests that a person of ordinary skill in the art would understand "stereomerically pure" in this context to require a higher level of purity, such as greater than 95% or 97%, to achieve the benefits of the invention.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement for all method claims. The basis for inducement is the allegation that Defendant's product label and insert for its ANDA Products will be substantially similar to that of OTEZLA® and will instruct physicians and patients to administer the drug for the patented indications and using the patented methods, including the specific dosage titration schedule (Compl. ¶¶ 54, 100, 208).
  • Willful Infringement: The complaint does not contain a separate count for willful infringement but alleges facts that may support such a claim. It asserts that Defendant had actual and constructive notice of the patents-in-suit prior to filing its ANDA, and that Defendant's certification of invalidity, unenforceability, and/or non-infringement lacked an adequate justification, rendering the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶¶ 55, 58, 78, 81).

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

  • A core issue will be one of definitional scope: how will the term "stereomerically pure" be construed? The dispute will likely focus on the required percentage of the (+) enantiomer, and whether Defendant’s product, which may contain some level of the (-) isomer, meets that threshold.
  • A second key question will be technical and evidentiary: For the patents claiming specific crystalline forms ('101 and '243 Patents), can Plaintiff produce evidence, such as XRPD data, showing that Defendant's product is made with the claimed polymorph? For the patent claiming a specific dosage titration method ('541 Patent), does Defendant's proposed label instruct users to follow the claimed multi-day dose-escalation schedule, thereby inducing infringement?
  • A final issue may be one of patentability over the prior art: Given the large number of patents covering various aspects of the same drug (the compound, compositions, different crystalline forms, and various methods of use), Defendant will likely challenge the validity of the later-issued patents as being obvious in light of the earlier patents and other prior art.