DCT

3:18-cv-11219

Amgen Inc v. Aurobindo Pharma Ltd

Log In
Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-11219, D.N.J., 06/28/2018
  • Venue Allegations: Venue is alleged in the District of New Jersey based on Defendant Aurobindo Pharma U.S.A., Inc. having its principal place of business in the state. For Defendant Aurobindo Pharma Limited, a foreign corporation, venue is alleged to be proper in any judicial district.
  • Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) to the U.S. Food and Drug Administration (FDA) to market generic versions of Plaintiff's OTEZLA® (apremilast) tablets constitutes an act of patent infringement.
  • Technical Context: The technology concerns the pharmaceutical compound apremilast, a phosphodiesterase 4 (PDE4) inhibitor, and its use in treating inflammatory conditions such as psoriatic arthritis and psoriasis.
  • Key Procedural History: The action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a Paragraph IV Notice Letter from Defendants, dated May 25, 2018, which asserted that the patents-in-suit are invalid, unenforceable, or would not be infringed by the proposed generic products. The complaint was filed within the 45-day statutory window, triggering an automatic 30-month stay of FDA approval for the Defendants' ANDA.

Case Timeline

Date Event
2002-03-20 Earliest Priority Date for ’940, ’516, ’638, ’302, ’536, ’717 Patents
2003-01-07 Earliest Priority Date for ’101, ’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
2014-03-21 FDA approves Celgene’s OTEZLA® New Drug Application
2014-08-12 U.S. Patent No. 8,802,717 Issued
2014-03-14 Priority Date for ’854 Patent
2015-04-28 U.S. Patent No. 9,018,243 Issued
2018-01-23 U.S. Patent No. 9,872,854 Issued
2018-05-25 Celgene receives Paragraph IV Notice Letter from Aurobindo
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 describes that enhanced or unregulated production of Tumor Necrosis Factor alpha (TNF-α) and the activity of phosphodiesterase 4 (PDE4) are implicated in a wide range of inflammatory diseases, autoimmune diseases, cancers, and heart disease (’940 Patent, col. 1:20-2:46). Existing treatments, including some PDE4 inhibitors, may lack sufficient selectivity and carry undesirable side effects (’940 Patent, col. 1:53-62).
  • The Patented Solution: The invention is the stereomerically pure (+) enantiomer of a specific compound, apremilast, which is described as a potent inhibitor of both TNF-α and PDE4 (’940 Patent, col. 3:18-28). By isolating this specific stereoisomer, the invention purports to offer increased therapeutic potency and other benefits compared to the racemic mixture of both (+) and (-) enantiomers (’940 Patent, col. 3:21-28). The synthesis of this specific enantiomer is detailed in the specification (’940 Patent, Fig. 1; col. 21:4-22:48).
  • Technical Importance: The invention provided a specific, isolated stereoisomer for inhibiting TNF-α and PDE4, suggesting a path toward more targeted therapies for inflammatory conditions with a potentially improved safety profile compared to less selective compounds (’940 Patent, col. 3:18-28).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims, with independent method claim 1 being representative (Compl. ¶59).
  • Claim 1 requires:
    • 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 but makes a general allegation against the patent.

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 identifies psoriatic arthritis as a chronic inflammatory condition for which there is a significant need for safe and effective treatment methods, particularly for patients refractory to conventional therapies (’516 Patent, col. 2:25-48). The background details the pathophysiology of the disease, including the role of T-cells and cytokines like TNF-α (’516 Patent, col. 2:5-18).
  • The Patented Solution: The invention provides a method for treating, preventing, or managing psoriatic arthritis by administering the (+) enantiomer of apremilast, which is disclosed to be a TNF-α and PDE4 inhibitor (’516 Patent, col. 2:49-55). The patent provides data from a murine arthritis model to demonstrate the anti-arthritic activity of the compound (’516 Patent, col. 18:47-67; Fig. 4).
  • Technical Importance: This patent specifically claims a method of using apremilast for psoriatic arthritis, providing a targeted therapeutic approach for a disease that can be debilitating and for which treatment options were still developing (’516 Patent, col. 2:38-48).

Key Claims at a Glance

  • The complaint asserts infringement of one or more claims, with independent method claim 1 being representative (Compl. ¶80).
  • Claim 1 requires:
    • 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.
  • The complaint does not explicitly reserve the right to assert dependent 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,” issued September 23, 2008

  • Patent Identification: 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 (Compl. ¶37).
  • Technology Synopsis: This patent claims the (+) enantiomer of apremilast as a composition of matter, as well as pharmaceutical compositions containing it. The invention provides the specific, isolated active molecule for therapeutic use (’638 Patent, col. 3:9-17).
  • Asserted Claims: Claims reciting the compound, a pharmaceutical composition, or a single unit dosage form (Compl. ¶99).
  • Accused Features: The accused ANDA products are alleged to be pharmaceutical compositions and single unit dosage forms containing the claimed (+) enantiomer of 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

  • Patent Identification: 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 (Compl. ¶38).
  • Technology Synopsis: This patent claims methods of treating various inflammatory and autoimmune diseases, including psoriasis and Crohn's disease, by administering the (+) enantiomer of apremilast (’302 Patent, Abstract).
  • Asserted Claims: Claims reciting methods of administering apremilast (Compl. ¶122).
  • Accused Features: The accused ANDA products contain apremilast, and their proposed labeling is alleged to instruct their use for patented methods (Compl. ¶¶123, 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

  • Patent Identification: 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 (Compl. ¶39).
  • Technology Synopsis: This patent is directed to 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 valuable (’101 Patent, col. 3:6-42).
  • Asserted Claims: Claims reciting a form of apremilast having an XRPD pattern with certain specified peaks (Compl. ¶143).
  • Accused Features: The accused ANDA products are alleged to contain a form of apremilast that has the claimed XRPD pattern (Compl. ¶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

  • Patent Identification: 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 (Compl. ¶40).
  • Technology Synopsis: This patent claims methods of treating psoriasis by orally administering apremilast. It is a targeted method-of-use patent for a specific disease (’536 Patent, Abstract; claim 10).
  • Asserted Claims: Claims reciting methods of administering apremilast (Compl. ¶164).
  • Accused Features: The accused ANDA products contain apremilast, and their proposed labeling is alleged to instruct their use for treating psoriasis (Compl. ¶¶165, 167).

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

  • Patent Identification: 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 (Compl. ¶41).
  • Technology Synopsis: This patent claims methods of treating various arthritic conditions, including psoriatic arthritis and rheumatoid spondylitis, by administering apremilast (’717 Patent, Abstract).
  • Asserted Claims: Claims reciting methods of administering apremilast (Compl. ¶185).
  • Accused Features: The accused ANDA products contain apremilast, and their proposed labeling is alleged to instruct their use for treating arthritic conditions (Compl. ¶¶186, 188).

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

  • Patent Identification: 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 (Compl. ¶42).
  • Technology Synopsis: This patent, like the ’101 Patent, is directed to specific crystalline forms of apremilast. It claims "Form B," characterized by a distinct XRPD pattern, providing another stable and defined solid form of the active pharmaceutical ingredient (’243 Patent, Abstract; claim 1).
  • Asserted Claims: Claims reciting methods of administering a form of apremilast having a specific XRPD pattern (Compl. ¶206).
  • Accused Features: The accused ANDA products are alleged to contain a form of apremilast that has the claimed XRPD pattern (Compl. ¶207).

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

  • Patent Identification: U.S. Patent No. 9,872,854, “Methods For the Treatment of Psoriatic Arthritis Using Apremilast,” issued January 23, 2018 (Compl. ¶43).
  • Technology Synopsis: This patent claims methods of treating psoriatic arthritis with apremilast, specifically reciting an escalating dosing schedule (titration). This schedule is intended to manage gastrointestinal side effects (’854 Patent, col. 5:8-21; Compl., Ex. A at 59).
  • Asserted Claims: Claims reciting methods of administering apremilast (Compl. ¶227).
  • Accused Features: The accused ANDA products contain apremilast, and their proposed labeling is alleged to instruct the use of an infringing dosing schedule (Compl. ¶¶228, 230).

III. The Accused Instrumentality

Product Identification

  • The accused products are Aurobindo’s proposed generic 10 mg, 20 mg, and 30 mg tablets of apremilast, for which Aurobindo seeks FDA approval via ANDA No. 211716 (Compl. ¶1).

Functionality and Market Context

  • The complaint alleges that the accused products contain the active pharmaceutical ingredient (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, which is the same active ingredient in Celgene’s OTEZLA® product (Compl. ¶¶45, 58).
  • The functionality of the accused products is for oral administration to treat psoriatic arthritis and psoriasis, as the complaint alleges Aurobindo's proposed product labeling will be substantially similar to that of OTEZLA® (Compl. ¶60; Ex. A). Exhibit A to the complaint, the OTEZLA® Prescribing Information, contains a “Dosage Titration Schedule” table which details an escalating dosing regimen for initiating therapy (Compl., Ex. A at 59).
  • The complaint alleges that Aurobindo intends to commercially manufacture, market, and sell the accused products in the United States upon receiving FDA approval, prior to the expiration of the patents-in-suit (Compl. ¶¶1, 19).

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 The proposed product label for Aurobindo's ANDA Products will allegedly instruct physicians and patients to use the product to treat psoriatic arthritis and psoriasis, which are PDE4-mediated diseases. ¶60; Ex. A col. 7:10-21
which comprises administering to a patient in need of such treatment a therapeutically effective amount The proposed product label allegedly includes instructions for dosing that constitute a therapeutically effective amount for the indicated conditions. ¶60; Ex. A col. 13:50-14:20
of stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione...or a pharmaceutically acceptable...salt, or solvate thereof. Aurobindo’s ANDA Products are alleged to contain the specified stereomerically pure (+) enantiomer of apremilast as the active pharmaceutical ingredient. ¶58 col. 5:5-6:66

’516 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of treating psoriatic arthritis, The proposed product label for Aurobindo’s ANDA Products will allegedly instruct physicians and patients to use the product specifically for the treatment of psoriatic arthritis. ¶81; Ex. A col. 2:30-48
which comprises administering to a patient in need of such treatment a therapeutically effective amount The proposed product label allegedly includes instructions for administering therapeutically effective amounts of the drug, including a specific titration schedule, for psoriatic arthritis. ¶81; Ex. A col. 5:51-6:11
of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, or a pharmaceutically acceptable salt or solvate thereof... Aurobindo's ANDA Products are alleged to contain the specified (+) enantiomer of apremilast as the active pharmaceutical ingredient. ¶79 col. 8:20-47
substantially free of its (-) enantiomer. The API in Aurobindo's ANDA Products is alleged to be the (+) enantiomer, and thus substantially free of the (-) enantiomer as required by the claim. ¶79 col. 4:35-51

Identified Points of Contention

  • Scope Questions: A central question may be the scope of "stereomerically pure" and "substantially free of its (-) enantiomer." The patents describe this with varying degrees of purity (e.g., >90%, >95%, >97%). The dispute may center on whether Aurobindo's API meets the claimed purity level (’940 Patent, col. 6:21-34). It also raises the question of whether the method claims require administration of a product meeting this purity level throughout its shelf life.
  • Technical Questions: For patents claiming specific solid forms (e.g., ’101 Patent, ’243 Patent), a technical question will be whether Aurobindo's proposed generic product contains the specific crystalline polymorphs as defined by the XRPD peaks recited in the claims (Compl. ¶¶143, 206). Infringement analysis will depend on physical characterization of Aurobindo's product. For the ’854 Patent, a key question will be whether the dosing regimen instructed on Aurobindo's label is the same as the claimed escalating dosing schedule.

V. Key Claim Terms for Construction

The Term: "stereomerically pure" (’940 Patent, claim 1) / "substantially free of its (-) enantiomer" (’516 Patent, claim 1)

  • Context and Importance: These related terms are foundational to the composition claims and are incorporated into the method claims. The scope of these terms defines the required purity of the active ingredient. Practitioners may focus on these terms because even a small percentage of the (-) enantiomer in Aurobindo's product could potentially support a non-infringement argument if the court adopts a narrow construction.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The term "substantially" is not absolute, which may support an interpretation that allows for some quantity of the other enantiomer. The specification does not appear to provide a specific definition that would strictly limit the term beyond its ordinary meaning.
    • Evidence for a Narrower Interpretation: The ’940 Patent specification provides several explicit, narrowing definitions, stating a "typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer...more preferably greater than about 90%...even more preferably greater than about 95%...and most preferably greater than about 97%" of the (+) isomer (’940 Patent, col. 6:21-34). A party may argue these explicit definitions should control the claim's scope.

The Term: "treating"

  • Context and Importance: This term is central to all asserted method-of-use patents. Its construction determines what action constitutes infringement. The dispute may involve whether "treating" requires achieving a specific clinical outcome (e.g., a certain percentage reduction in PASI score for psoriasis) or if it is met simply by administering the drug for the indicated disease, regardless of outcome.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The ’516 Patent defines "treating" to include prophylactic administration and managing the disease, which suggests a broad scope beyond just curing or achieving a specific clinical result (’516 Patent, col. 5:1-15).
    • Evidence for a Narrower Interpretation: The clinical trial data presented in the patents discusses specific endpoints, such as ACR 20/50/70 responses in arthritis, which could be argued to provide context for what the inventors considered an effective "treatment" (’516 Patent, col. 17:1-9). A party may argue that "treating" should be limited to administration that is at least capable of achieving such results.

VI. Other Allegations

Indirect Infringement

  • The complaint alleges induced infringement for all method patents. The basis for inducement is the allegation that Aurobindo's product label and instructions will be "substantially similar" to Celgene's FDA-approved label for OTEZLA® and will therefore "actively induce physicians and other healthcare professionals, resellers, pharmacies, and end users" to use the generic product in an infringing manner (Compl. ¶¶60, 81, 103, 125, 167, 188, 209, 230).

Willful Infringement

  • The complaint asserts that Aurobindo had "actual and constructive notice" of the patents-in-suit prior to filing its ANDA and that it had "no reasonable basis" for its Paragraph IV certification of non-infringement or invalidity (Compl. ¶¶61, 82). This forms the basis for a potential claim of willful infringement, which could lead to enhanced damages if infringement is found after the product launches.

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

  • A core issue will be one of chemical composition and purity: can Celgene prove that Aurobindo's proposed generic product will contain the apremilast active ingredient at a purity level that falls within the scope of the "stereomerically pure" and "substantially free of its (-) enantiomer" limitations as construed by the court, particularly for the patents covering compositions and solid forms?
  • A second central question will be one of induced infringement of methods: does Aurobindo's proposed product label instruct users to perform the exact methods claimed in the patents, including not only the treatment of specific diseases like psoriatic arthritis but also specific escalating dosing schedules, thereby creating liability for inducement?
  • A determinative issue, though not detailed in the complaint, will be validity: can Aurobindo present clear and convincing evidence that the asserted claims—covering the specific enantiomer, its solid forms, and its methods of use for particular inflammatory diseases—are invalid as being anticipated by or obvious over the prior art?