DCT

3:18-cv-11026

Amgen Inc v. Sandoz Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-11026, D.N.J., 06/26/2018
  • Venue Allegations: Venue is alleged to be proper in the District of New Jersey because Defendant Sandoz has a principal place of business in New Jersey and has committed acts of infringement there.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's OTEZLA® (apremilast) tablets constitutes an act of infringement of nine U.S. patents.
  • Technical Context: The technology concerns apremilast, a small-molecule inhibitor of phosphodiesterase 4 (PDE4) used for treating inflammatory conditions such as psoriatic arthritis and psoriasis.
  • Key Procedural History: This litigation was initiated under the Hatch-Waxman Act following Plaintiff’s receipt of a Paragraph IV Notice Letter from Defendant, dated May 29, 2018, which stated Defendant’s intent to market a generic version of OTEZLA® before the expiration of the patents-in-suit. The Notice Letter asserted that the patents-in-suit are invalid, unenforceable, or would not be infringed by the generic product.

Case Timeline

Date Event
2002-03-20 Earliest 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
2013-03-14 Earliest Priority Date for ’854 Patent
2013-06-04 U.S. Patent No. 8,455,536 Issued
2014-03-21 FDA approves 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
2018-05-29 Celgene receives Paragraph IV Notice Letter from Sandoz
2018-06-26 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 (’940 Patent)

The Invention Explained

  • Problem Addressed: The patent background describes that enhanced or unregulated production of the cytokine Tumor Necrosis Factor alpha (TNF-α) is implicated in a number of inflammatory, autoimmune, and other diseases (Compl. Ex. B, ’940 Patent, col. 1:21-41). The patent also notes that inhibiting an enzyme family known as phosphodiesterase type IV (PDE4) can be effective in inhibiting inflammatory mediator release, but that existing PDE4 inhibitors lacked selective action at acceptable therapeutic doses (Compl. Ex. B, ’940 Patent, col. 2:40-57).
  • The Patented Solution: The invention provides a stereomerically pure compound, specifically the (+) enantiomer of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, known as apremilast. This specific stereoisomer is disclosed as having increased potency for inhibiting TNF-α and PDE4 compared to its racemate, making it a more effective therapeutic for treating these conditions (Compl. Ex. B, ’940 Patent, col. 3:20-31). The synthesis of the compound is illustrated in the patent’s Figure 1 (Compl. Ex. B, ’940 Patent, FIG. 1).
  • Technical Importance: The invention provides a specific, potent, and orally administered small-molecule inhibitor for treating a wide range of inflammatory diseases, offering a potential alternative to biologic drugs or less selective compounds (Compl. Ex. B, ’940 Patent, col. 2:13-33).

Key Claims at a Glance

  • The complaint asserts infringement of "one or more claims" (Compl. ¶47). Independent claim 1 is representative of the patent's method of use claims.
  • 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 (’516 Patent)

The Invention Explained

  • Problem Addressed: The patent background describes psoriatic arthritis as a chronic inflammatory condition 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 treatments (Compl. Ex. C, ’516 Patent, col. 2:25-31).
  • The Patented Solution: The patent claims methods for treating, preventing, or managing psoriatic arthritis by administering the specific apremilast compound described in the ’940 Patent. The solution focuses on the specific application of this compound to a particular arthritic condition, leveraging the compound's known anti-inflammatory properties (Compl. Ex. C, ’516 Patent, col. 3:5-15).
  • Technical Importance: This invention established a specific, patented use for apremilast in treating psoriatic arthritis, a distinct and recognized inflammatory disease (Compl. Ex. C, ’516 Patent, col. 2:32-35).

Key Claims at a Glance

  • The complaint asserts infringement of "one or more claims" (Compl. ¶69). Independent claim 1 is representative.
  • 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.

Multi-Patent Capsule: U.S. Patent No. 7,427,638 (’638 Patent)

  • Patent Identification: "(+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione, and Methods of Synthesis and Compositions Thereof," issued September 23, 2008 (Compl. ¶25).
  • Technology Synopsis: This patent claims the apremilast compound itself, as well as pharmaceutical compositions and single unit dosage forms comprising the compound. It provides another layer of protection covering the drug product, distinct from methods of use (Compl. ¶89).
  • Asserted Claims: "One or more claims" are asserted (Compl. ¶92). Claim 13 is a representative independent claim covering the compound itself.
  • Accused Features: Sandoz's ANDA Products, which are alleged to be pharmaceutical compositions containing apremilast (Compl. ¶¶ 90-91).

Multi-Patent Capsule: U.S. Patent No. 7,659,302 (’302 Patent)

  • Patent Identification: "Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione," issued February 9, 2010 (Compl. ¶26).
  • Technology Synopsis: This patent claims methods of treating various inflammatory and autoimmune diseases, including psoriasis and Crohn's disease, by administering apremilast. This broadens the "method of use" coverage beyond the specific indications of the earlier patents (Compl. ¶113).
  • Asserted Claims: "One or more claims" are asserted (Compl. ¶115). Claim 1 is a representative independent claim.
  • Accused Features: The intended use of Sandoz’s ANDA Products as instructed by the proposed label, which is expected to align with the approved uses for OTEZLA® (Compl. ¶¶ 114, 116).

Multi-Patent Capsule: U.S. Patent No. 7,893,101 (’101 Patent)

  • Patent Identification: "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 (Compl. ¶27).
  • Technology Synopsis: This patent is directed to specific crystalline forms (polymorphs) of apremilast, identified by their X-ray powder diffraction (XRPD) patterns. This type of patent protects the specific physical structure of the active pharmaceutical ingredient, which can be critical for stability and bioavailability (Compl. ¶135).
  • Asserted Claims: "One or more claims" are asserted (Compl. ¶137). Claim 1 is a representative independent claim.
  • Accused Features: The specific crystalline form of apremilast contained within Sandoz’s ANDA Products (Compl. ¶136).

Multi-Patent Capsule: U.S. Patent No. 8,455,536 (’536 Patent)

  • Patent Identification: "Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione," issued June 4, 2013 (Compl. ¶28).
  • Technology Synopsis: Similar to the ’302 Patent, this patent claims methods of using apremilast to treat a range of inflammatory diseases, including psoriasis. It further solidifies the intellectual property around the approved uses of the drug (Compl. ¶157).
  • Asserted Claims: "One or more claims" are asserted (Compl. ¶159). Claim 1 is a representative independent claim.
  • Accused Features: The intended use of Sandoz’s ANDA Products according to its proposed labeling (Compl. ¶¶ 158, 160).

Multi-Patent Capsule: U.S. Patent No. 8,802,717 (’717 Patent)

  • Patent Identification: "Methods of Treating Arthritic Conditions Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione," issued August 12, 2014 (Compl. ¶29).
  • Technology Synopsis: This patent provides additional claims covering methods of treating arthritic conditions, including psoriatic arthritis, by administering apremilast. This patent strengthens the protection around a key approved indication for OTEZLA® (Compl. ¶179).
  • Asserted Claims: "One or more claims" are asserted (Compl. ¶181). Claim 1 is a representative independent claim.
  • Accused Features: The intended use of Sandoz’s ANDA Products for treating psoriatic arthritis as instructed on its proposed label (Compl. ¶¶ 180, 182).

Multi-Patent Capsule: U.S. Patent No. 9,018,243 (’243 Patent)

  • Patent Identification: "Solid Forms Comprising (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione," issued April 28, 2015 (Compl. ¶30).
  • Technology Synopsis: This patent, like the '101 Patent, claims specific crystalline forms of apremilast. It provides further patent protection on the particular solid-state chemistry of the active pharmaceutical ingredient used in OTEZLA® (Compl. ¶201).
  • Asserted Claims: "One or more claims" are asserted (Compl. ¶203). Claim 1 is a representative independent claim.
  • Accused Features: The specific crystalline form of apremilast used in Sandoz’s ANDA Products (Compl. ¶202).

Multi-Patent Capsule: U.S. Patent No. 9,872,854 (’854 Patent)

  • Patent Identification: "Methods For the Treatment of Psoriatic Arthritis Using Apremilast," issued January 23, 2018 (Compl. ¶31).
  • Technology Synopsis: This patent claims specific dosing regimens for treating psoriatic arthritis with apremilast, including an initial dose-escalation schedule. This protects not just the use of the drug for an indication, but the specific, clinically validated way in which it is administered to patients (Compl. ¶223; Compl. Ex. J, ’854 Patent, cl. 1).
  • Asserted Claims: "One or more claims" are asserted (Compl. ¶225). Claim 1 is a representative independent claim.
  • Accused Features: The instructions for use in Sandoz's proposed product labeling, which are expected to include the FDA-approved dose titration schedule for OTEZLA® (Compl. ¶¶ 224, 226).

III. The Accused Instrumentality

Product Identification

  • Defendant Sandoz’s "Infringing ANDA Products," which are generic versions of Celgene’s OTEZLA® (apremilast) tablets in 10 mg, 20 mg, and 30 mg strengths (Compl. ¶1).

Functionality and Market Context

  • The complaint alleges that Sandoz filed ANDA No. 211658 with the FDA seeking approval to market generic apremilast tablets prior to the expiration of the patents-in-suit (Compl. ¶1, ¶32). Apremilast is the active pharmaceutical ingredient in Celgene’s OTEZLA®, which is approved to treat psoriatic arthritis and plaque psoriasis (Compl. ¶17). The act of filing the ANDA with a "Paragraph IV Certification" is the statutory act of infringement under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶44, ¶66).
  • The infringement allegations for the method patents are based on the intended use of the Sandoz product, which will allegedly be directed by a product label and insert "substantially similar to the instructions found in the prescribing information for OTEZLA®" (Compl. ¶48). The prescribing information for OTEZLA®, attached as Exhibit A to the complaint, includes a specific "Dosage Titration Schedule" to be followed for the first five days of treatment to reduce gastrointestinal symptoms (Compl. Ex. A, p. 57, Table 1). This table provides a visual representation of the patented dosing method.

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 in a patient which comprises administering to a patient in need of such treatment a therapeutically effective amount Sandoz's ANDA seeks approval to market its apremilast products for treating conditions such as psoriasis, which are ameliorated by PDE4 inhibition, and its proposed label will instruct such use. ¶45; ¶48 col. 7:42-51
of stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a pharmaceutically acceptable...salt, or solvate thereof. Sandoz’s Infringing ANDA Products are alleged to contain (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione (apremilast) as the active pharmaceutical ingredient. ¶46 col. 3:20-25

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, which comprises administering to a patient in need of such treatment a therapeutically effective amount Sandoz's ANDA seeks approval to market its apremilast products for treating psoriatic arthritis, and its proposed label will instruct such use. ¶67; ¶70 col. 3:5-15
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. Sandoz’s Infringing ANDA Products are alleged to contain the specified (+) enantiomer of the compound as the active ingredient. ¶68 col. 3:16-25
  • Identified Points of Contention:
    • Legal Question: The central dispute in a Hatch-Waxman case is precipitated by the defendant's certification that the patents are invalid, unenforceable, or will not be infringed (Compl. ¶36). While the complaint pleads infringement under the statutory framework of § 271(e)(2), the substantive legal battle will likely focus on Sandoz’s defenses. A primary question for the court will be whether Sandoz can meet its burden of proving the invalidity or unenforceability of the asserted claims.
    • Technical Question: For patents claiming specific crystalline forms, such as the ’101 and ’243 Patents, a key technical question may arise: does the active ingredient in Sandoz's ANDA product exist in one of the patented crystalline forms claimed by Celgene? The infringement analysis for these patents will depend on scientific evidence, such as XRPD data, comparing the solid form of apremilast in the Sandoz product to the forms defined in the patent claims. The complaint does not provide sufficient detail for analysis of this specific element.

V. Key Claim Terms for Construction

  • The Term: "therapeutically effective amount" (asserted in claims of the ’940 and ’516 Patents)

    • Context and Importance: This term is central to nearly all asserted method claims. Its construction will define the dosage required to infringe. Practitioners may focus on this term because its definition could influence both infringement (whether the dose in the accused product's label is "effective") and validity (whether the patent adequately describes what constitutes an "effective" amount).
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification states that the dose "will vary... with the nature and severity of the disease," and that the daily dose range can be from "about 1 mg to about 1000 mg per day" (Compl. Ex. B, ’940 Patent, col. 14:3-13). This suggests a broad, patient-dependent definition.
      • Evidence for a Narrower Interpretation: The specification also provides more specific dosage ranges, such as "from about 5 mg to about 500 mg per day" and specific dosage forms of 5, 10, or 25 mg (Compl. Ex. B, ’940 Patent, col. 14:14-20). This may support a construction tied to these more concrete examples.

  • The Term: "stereomerically pure" (asserted in claims of the ’940 and ’516 Patents)

    • Context and Importance: The patents distinguish the claimed (+) enantiomer from its racemate. The definition of "stereomerically pure" is critical to determining the scope of the claims and whether an accused product containing any amount of the (-) isomer can infringe.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The patents do not require 100% purity. The term "stereomerically pure" is defined as a composition that comprises "greater than about 80% by weight of one stereoisomer" (Compl. Ex. B, ’940 Patent, col. 6:15-22). This language supports a construction that includes compositions with up to 20% of the other isomer.
      • Evidence for a Narrower Interpretation: The same definition provides progressively narrower preferred embodiments, including "more preferably greater than about 90%," "even more preferably greater than about 95%," and "most preferably greater than about 97%" by weight of the desired stereoisomer (Compl. Ex. B, ’940 Patent, col. 6:22-34). This could be used to argue that the term, in context, implies a very high level of purity approaching the most preferred embodiment.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges inducement of infringement for all method-of-use patents. The basis for this allegation is that Sandoz will "knowingly and intentionally accompany" its product with a label and insert that include instructions for using the product in an infringing manner, thereby encouraging and instructing physicians and patients to directly infringe (Compl. ¶48, ¶70, ¶116).
  • Willful Infringement: The complaint alleges that Sandoz had "actual and constructive notice" of the patents-in-suit prior to filing its ANDA (Compl. ¶49, ¶71). It further alleges that Sandoz’s Paragraph IV certification, which challenges the patents, was made "without adequate justification," rendering the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶52, ¶74). These allegations of pre-suit knowledge form the basis for a claim of willfulness and for seeking enhanced damages and attorneys' fees.

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

  • A central issue will be one of patent validity: This case is a quintessential Hatch-Waxman dispute where the act of infringement is statutory. The core of the litigation will therefore not be whether the generic product, if launched, would infringe, but whether Sandoz can succeed in its assertion that Celgene's patents are invalid or unenforceable, thereby clearing the path for its generic product.
  • A second key question will concern the scope and durability of the patent portfolio: Celgene has asserted a wide-ranging "thicket" of nine patents covering the apremilast compound, its specific crystalline forms, and various methods of use, including specific dosing regimens. The case will test whether this multi-layered patent strategy is robust enough to withstand Sandoz's invalidity challenges across all asserted fronts, or if Sandoz can find a vulnerability in one category of claims (e.g., solid forms) that might allow it to design around others.