DCT

3:18-cv-11268

Amgen Inc v. Unichem Laboratories Ltd

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:18-cv-11268, D.N.J., 06/29/2018
  • Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey because Defendant is a foreign corporation and has engaged in continuous and systematic contacts with the state, including the filing of the Abbreviated New Drug Application (ANDA) that gives rise to this suit, which is directed at a drug product sold by a New Jersey-based corporation.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an ANDA to market generic versions of Plaintiff's OTEZLA® (apremilast) tablets constitutes an act of infringement of six U.S. patents covering the compound, its solid forms, compositions, and methods of use.
  • Technical Context: The technology concerns apremilast, an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), a class of drugs used to treat inflammatory conditions such as psoriatic arthritis and plaque psoriasis.
  • Key Procedural History: The litigation was initiated under the Hatch-Waxman Act following Defendant’s submission of an ANDA with a Paragraph IV certification, alleging that the patents-in-suit are invalid, unenforceable, or will not be infringed by its proposed generic product.

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 Approved Plaintiff's OTEZLA® (apremilast)
2015-04-28 U.S. Patent No. 9,018,243 Issued
2018-05-25 Defendant Sent Paragraph IV Certification Notice Letter
2018-06-29 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 Nov. 8, 2005)

The Invention Explained

  • Problem Addressed: The patent’s background describes the role of elevated levels of Tumor Necrosis Factor alpha (TNF-α) and the dysregulation of adenosine 3',5'-cyclic monophosphate (cAMP) in a wide range of inflammatory, autoimmune, and oncological diseases (Compl., Ex. B, ’940 Patent, col. 1:22-43). Existing inhibitors of phosphodiesterase type IV (PDE4), which can modulate these pathways, are described as lacking the necessary selectivity to achieve therapeutic effects at acceptable doses (’940 Patent, col. 1:63-2:6).
  • The Patented Solution: The invention claims methods of treating these diseases by administering the stereomerically pure (+)-enantiomer of a specific phenethylsulfone compound, now known as apremilast (’940 Patent, col. 3:20-28). The patent posits that isolating this specific stereoisomer from the racemic mixture provides increased potency and other therapeutic benefits, allowing for more effective treatment (’940 Patent, Abstract; col. 3:20-28). A method for synthesizing the compound is illustrated in Figure 1 of the patent (’940 Patent, Fig. 1).
  • Technical Importance: This approach represented an effort to improve the therapeutic index of a known class of compounds by isolating a single, more active enantiomer, potentially offering a better balance of efficacy and side effects for treating inflammatory conditions.

Key Claims at a Glance

  • The complaint asserts infringement of claims reciting methods of administering the compound (Compl. ¶43). Independent claim 1 is representative.
  • The essential elements of independent claim 1 include:
    • A method of treating diseases or disorders ameliorated by the inhibition of PDE4 in a patient
    • comprising 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 general allegations against "one or more claims" (Compl. ¶45).

U.S. Patent No. 7,427,638 - "(+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione: Methods of Using and Compositions Thereof" (Issued Sep. 23, 2008)

The Invention Explained

  • Problem Addressed: As with the ’940 Patent, this patent addresses the need for effective treatments for TNF-α and PDE4-mediated diseases, such as arthritis and psoriasis (’638 Patent, col. 2:11-46).
  • The Patented Solution: This patent claims pharmaceutical compositions and single unit dosage forms that contain the stereomerically pure (+)-enantiomer of apremilast (’638 Patent, col. 4:14-22). It covers the physical formulation of the drug substance into a product suitable for administration to patients, such as tablets or capsules, specifying dosage ranges (’638 Patent, col. 14:1-33).
  • Technical Importance: The invention provides specific, formulated drug products containing the purified active enantiomer, which is a necessary step to translate the compound into a usable and consistent medicine for patients.

Key Claims at a Glance

  • The complaint asserts infringement of claims reciting a pharmaceutical composition or a single unit dosage form (Compl. ¶64). Independent claims 1 and 7 are representative.
  • The essential elements of independent claim 7 include:
    • A single unit dosage form
    • which comprises about 1 mg to about 1000 mg of a stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylamino-isoindoline-1,3-dione or a pharmaceutically acceptable 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 but makes general allegations against "one or more claims" of the patent (Compl. ¶67).

U.S. Patent No. 7,659,302 - "Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione" (Issued Feb. 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 Feb. 9, 2010 (Compl. ¶26).
  • Technology Synopsis: This patent is a continuation of the ’638 Patent and similarly claims methods of treating various inflammatory diseases, including psoriasis and psoriatic arthritis, by administering the (+) enantiomer of apremilast (’302 Patent, Abstract).
  • Asserted Claims: The complaint asserts claims that recite methods of administering the compound (Compl. ¶88).
  • Accused Features: The accused features are Defendant's proposed generic apremilast tablets and its accompanying product label, which allegedly instructs users to perform the claimed methods of treatment (Compl. ¶89, ¶91).

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 Feb. 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 Feb. 22, 2011 (Compl. ¶27).
  • Technology Synopsis: This patent claims specific crystalline forms (polymorphs) of apremilast, identified by characteristic peaks in an X-ray powder diffraction (XRPD) pattern (’101 Patent, Abstract). Polymorphs can affect a drug's stability, solubility, and manufacturability.
  • Asserted Claims: The complaint asserts claims reciting a specific solid form of the apremilast compound defined by XRPD peaks (Compl. ¶110).
  • Accused Features: The accused feature is the active pharmaceutical ingredient in Defendant's generic tablets, which is alleged to be a crystalline form of apremilast having the claimed XRPD pattern (Compl. ¶111).

U.S. Patent No. 8,455,536 - "Methods of Using (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione" (Issued Jun. 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 Jun. 4, 2013 (Compl. ¶28).
  • Technology Synopsis: This patent is a continuation of the ’302 Patent and claims methods of treating specific inflammatory diseases, such as psoriasis, by orally administering apremilast according to particular dosage regimens (’536 Patent, Abstract; col. 31:56-32:44).
  • Asserted Claims: The complaint asserts claims that recite methods of administering the compound (Compl. ¶132).
  • Accused Features: The accused features are Defendant's proposed generic apremilast tablets and its accompanying product label, which allegedly instructs users to perform the claimed methods of treatment (Compl. ¶133, ¶135).

U.S. Patent No. 9,018,243 - "Solid Forms Comprising (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione, Compositions Thereof, and Uses Thereof" (Issued Apr. 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, Compositions Thereof, and Uses Thereof," Issued Apr. 28, 2015 (Compl. ¶29).
  • Technology Synopsis: This patent is a continuation of the ’101 Patent and claims methods of administering specific crystalline forms of apremilast, including Form B, which is defined by a characteristic XRPD pattern (’243 Patent, Abstract; col. 59:1-21).
  • Asserted Claims: The complaint asserts claims reciting methods of administering a form of the compound having a specified XRPD pattern (Compl. ¶154).
  • Accused Features: The accused features are the act of administering Defendant's generic tablets, which are alleged to contain a solid form of apremilast having the claimed XRPD pattern, in accordance with the product's label (Compl. ¶155, ¶157).

III. The Accused Instrumentality

  • Product Identification: The accused products are Defendant Unichem's proposed generic apremilast tablets in 10 mg, 20 mg, and 30 mg dosage strengths, for which Unichem seeks FDA approval via ANDA No. 211819 (Compl. ¶1, ¶31).
  • Functionality and Market Context: The complaint alleges that Unichem's products contain apremilast as the active pharmaceutical ingredient and are intended for oral use to treat psoriatic arthritis and plaque psoriasis (Compl. ¶18, ¶31, ¶44). The complaint further alleges that the proposed product label for Unichem's products will contain instructions for use that are substantially similar to those for Celgene's OTEZLA®, thereby directing medical professionals and patients to use the generic drug in an infringing manner (Compl. ¶46, ¶56). A dosage titration schedule from the OTEZLA label, which the complaint alleges Unichem's label will be similar to, is provided in the complaint as part of Exhibit A (Compl., Ex. A, p. 44, Table 1). Unichem seeks to market these products as lower-cost generic versions of OTEZLA® prior to the expiration of the patents-in-suit (Compl. ¶1, ¶30).

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 The complaint alleges Unichem will induce infringement by providing a product label instructing administration for FDA-approved indications, such as psoriatic arthritis and psoriasis, which are PDE4-mediated diseases. ¶46; Ex. A, p. 43 col. 7:51-8:14
which comprises administering to a patient in need of such treatment a therapeutically effective amount The proposed product label is alleged to instruct physicians and patients to administer specific doses (10, 20, or 30 mg) determined to be therapeutically effective for the indicated diseases. ¶46; Ex. A, p. 44 col. 13:5-20
of stereomerically pure (+)-2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione... The complaint alleges on information and belief that Unichem's Infringing ANDA Products contain this active pharmaceutical ingredient. ¶44 col. 3:20-25
  • Identified Points of Contention:
    • Scope Questions: A central question for inducement will be whether the final, FDA-approved label for Unichem's product instructs administration for a disease that is covered by the claims. The scope of "diseases or disorders ameliorated by the inhibition of PDE4" may be a point of dispute.
    • Technical Questions: The complaint alleges infringement based on the content of a proposed product label. An evidentiary question will be whether the instructions on that label, if followed, would result in direct infringement by a patient or physician.

U.S. Patent No. 7,427,638 Infringement Allegations

Claim Element (from Independent Claim 7) Alleged Infringing Functionality Complaint Citation Patent Citation
A single unit dosage form The complaint identifies Unichem's accused products as tablets. ¶31 col. 14:14-22
which comprises about 1 mg to about 1000 mg of a stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylamino-isoindoline-1,3-dione... Unichem's accused tablets are alleged to contain 10 mg, 20 mg, or 30 mg of the specified active pharmaceutical ingredient. ¶31, ¶65 col. 14:14-22
and a pharmaceutically acceptable carrier, excipient or diluent. The complaint alleges that Unichem's products are "pharmaceutical compositions or single unit dosage forms," which inherently contain excipients necessary to form a tablet. ¶66 col. 14:21-22
  • Identified Points of Contention:
    • Scope Questions: A potential issue could be whether the term "about" in "about 1 mg to about 1000 mg" provides a scope that Unichem's specific 10, 20, and 30 mg doses unambiguously fall within.
    • Technical Questions: The primary technical question will likely relate to the infringement of other patents in the family concerning specific solid forms of apremilast. For this patent, the analysis may focus on whether Unichem's specific combination of excipients alters the properties of the composition in a way that distinguishes it from the claimed invention.

V. Key Claim Terms for Construction

  • The Term: "therapeutically effective amount" (from Claim 1 of the ’940 Patent)

  • Context and Importance: This term is fundamental to nearly all method-of-treatment claims. Its construction is critical because infringement of the method depends on administering an amount of the drug sufficient to achieve a therapeutic outcome for a claimed disease. Practitioners may focus on this term because its definition could be tied to specific clinical endpoints or dosage ranges disclosed in the patent.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent specification lists a wide array of diseases and disorders that can be treated, from cancers to inflammatory diseases, suggesting the term should be read broadly to mean any amount that provides a benefit for any of these conditions ('940 Patent, col. 3:29-4:5). The specification also provides a broad dosage range of "from about 1 mg to about 1000 mg per day" ('940 Patent, col. 13:12-14).
    • Evidence for a Narrower Interpretation: The detailed examples in the patent focus on specific in-vitro and in-vivo animal models, measuring specific biological markers like TNF-α inhibition ('940 Patent, col. 22:51-28:50). A party could argue that a "therapeutically effective amount" must be an amount sufficient to produce the specific effects demonstrated in those examples, potentially limiting the claim's scope.

  • The Term: "stereomerically pure" (from Claim 1 of the ’940 Patent and Claim 7 of the ’638 Patent)

  • Context and Importance: This term is critical because the patents distinguish the invention from the prior art racemic mixture. The precise level of purity required to meet this limitation will be a central issue. A dispute could arise over whether Unichem's product, which may contain trace amounts of the (-)-enantiomer, meets the "stereomerically pure" limitation.

  • Intrinsic Evidence for Interpretation:

    • Evidence for a Broader Interpretation: The patent defines "stereomerically pure" as a composition that is "substantially free of other stereoisomers," and further quantifies this as comprising "greater than about 80% by weight of one stereoisomer" ('638 Patent, col. 6:15-24). This explicit definition could be argued as controlling and setting a clear, relatively broad standard.
    • Evidence for a Narrower Interpretation: The patent repeatedly emphasizes the benefits of isolating the (+)-enantiomer and describes a synthesis that results in a product with 98.4% enantiomeric excess ('638 Patent, col. 22:18-20). A party might argue that the term, in the context of the entire specification, should be construed to require a higher level of purity, such as that achieved in the patent's own examples (e.g., >95% or >97%), to be considered "pure."

VI. Other Allegations

  • Indirect Infringement: The complaint alleges that upon FDA approval, Unichem will actively induce infringement of the method-of-use patents (’940, ’302, ’536, ’243 Patents) under 35 U.S.C. § 271(b). This allegation is based on the assertion that Unichem's product label and product insert will instruct physicians and patients to administer the generic apremilast tablets in a manner that directly infringes one or more method claims (Compl. ¶46, ¶91, ¶135, ¶157).
  • Willful Infringement: The complaint alleges that Unichem had actual and constructive notice of the patents-in-suit prior to filing its ANDA (Compl. ¶47, ¶69, ¶92, ¶114, ¶136, ¶158). It further alleges that Unichem's conduct in filing its ANDA with a Paragraph IV certification without an adequate basis renders the case "exceptional" under 35 U.S.C. § 285, which is a basis for seeking enhanced damages and attorneys' fees (Compl. ¶49, ¶72, ¶95, ¶117, ¶139, ¶160).

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

  • A core issue will be one of chemical and physical form: will expert analysis of Unichem’s ANDA product, particularly through techniques like X-ray powder diffraction, demonstrate that it contains the specific crystalline polymorphs of apremilast claimed in the ’101 and ’243 patents, or will Unichem have successfully designed around these "solid form" patents?
  • A key legal question will be one of induced infringement: will the final FDA-approved label for Unichem’s generic product contain instructions for dosages and indications that fall squarely within the scope of the method-of-use claims in the ’940, ’302, and ’536 patents, thereby encouraging direct infringement by end-users?
  • A central dispute will likely be the construction of claim scope: how will the court define terms like "stereomerically pure" and "therapeutically effective amount"? The interpretation of these terms will determine the breadth of Celgene's patent protection and whether Unichem's product and its intended use fall within the claims.