DCT
3:18-cv-11212
Amgen Inc v. Macleods Pharma Ltd
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Celgene Corporation (New Jersey)
- Defendant: Macleods Pharmaceuticals Ltd. (India)
- Plaintiff’s Counsel: Saul Ewing Arnstein & Lehr LLP
- Case Identification: 3:18-cv-11212, D.N.J., 06/28/2018
- Venue Allegations: Venue is alleged to be proper as Defendant is a foreign corporation, and because Defendant directs business activities to New Jersey, including through a wholly-owned subsidiary with a principal place of business in the state.
- Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's OTEZLA® drug product constitutes infringement of a patent covering the active ingredient, apremilast.
- Technical Context: The technology concerns a specific, stereomerically pure chemical compound (a phosphodiesterase 4 inhibitor) used for the treatment of inflammatory conditions such as psoriatic arthritis and psoriasis.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a Paragraph IV Notice Letter from Defendant on May 22, 2018, which asserted that the patent-in-suit is invalid, unenforceable, or would not be infringed. The complaint notes that the branded product, OTEZLA®, was granted a five-year new chemical entity exclusivity period by the FDA, expiring March 21, 2019.
Case Timeline
| Date | Event |
|---|---|
| 2002-03-20 | ’638 Patent Priority Date |
| 2008-09-23 | ’638 Patent Issue Date |
| 2014-03-21 | FDA Approval for OTEZLA® |
| 2018-05-22 | Celgene Receives Paragraph IV Notice Letter |
| 2018-06-28 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
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,
- Patent Identification: U.S. Patent No. 7,427,638, titled (+)-2-[1-(3-Ethoxy-4-Methoxyphenyl)-2-Methylsulfonylethyl]-4-Acetylaminoisoindoline-1,3-Dione: Methods of Using and Compositions Thereof, issued September 23, 2008.
The Invention Explained
- Problem Addressed: The patent describes medical conditions associated with unregulated production of Tumor Necrosis Factor alpha (TNF-α) and the role of phosphodiesterase 4 (PDE4) in the inflammatory process. The background notes that while PDE4 inhibition can be therapeutic, existing inhibitors lacked selective action at acceptable doses (’638 Patent, col. 1:22-col. 2:67).
- The Patented Solution: The invention is a specific stereoisomer, the (+) enantiomer of a phenethylsulfone compound, which is asserted to be a potent inhibitor of PDE4 and TNF-α production. The patent discloses that this specific, "stereomerically pure" form is believed to have increased potency and other benefits compared to the racemic mixture (a 50/50 mix of the (+) and (-) enantiomers) (’638 Patent, Abstract; col. 3:22-29). The synthesis process to isolate this specific enantiomer is detailed in the specification (’638 Patent, Fig. 1; col. 21:5-22:67).
- Technical Importance: By isolating a single, more active enantiomer, the invention sought to provide a more effective therapeutic agent for inflammatory diseases that could potentially be administered at lower doses or have a better side-effect profile than the corresponding racemic mixture (’638 Patent, col. 3:22-29).
Key Claims at a Glance
- The complaint asserts infringement of claims that recite the compound itself or pharmaceutical compositions containing it (Compl. ¶38, ¶50). The key independent claims appear to be 1, 7, and 13.
- Independent Claim 1 (Composition):
- 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.
- Independent Claim 13 (Compound):
- Stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (-) isomer, or a pharmaceutically acceptable metabolite, salt, solvate or hydrate, thereof.
- The complaint alleges infringement of "one or more claims" of the patent without specifying further dependent claims (Compl. ¶41).
III. The Accused Instrumentality
Product Identification
- The accused instrumentalities are the generic 10 mg, 20 mg, and 30 mg apremilast tablets for which Macleods seeks FDA approval in its Abbreviated New Drug Application (ANDA) No. 211788 (Compl. ¶1).
Functionality and Market Context
- The accused products are intended to be generic versions of Celgene's OTEZLA® tablets (Compl. ¶25). The active ingredient, apremilast, is a PDE4 inhibitor indicated for treating adult patients with active psoriatic arthritis and moderate to severe plaque psoriasis (Compl. ¶18). Exhibit A to the complaint provides a dosage titration schedule for OTEZLA®, instructing a gradual increase in dosage from 10 mg on Day 1 to 30 mg twice daily by Day 6 to reduce gastrointestinal symptoms (Compl., Ex. A, p. 22, Table 1). The complaint alleges that Macleods seeks to market its generic products before the expiration of the ’638 Patent (Compl. ¶1).
IV. Analysis of Infringement Allegations
Claim Chart Summary
- The infringement action is based on the submission of the ANDA under 35 U.S.C. § 271(e)(2). The central allegation is that the product described in the ANDA contains the patented compound.
| Claim Element (from Independent Claim 13) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| Stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (-) isomer... | The complaint alleges, on information and belief, that "Macleods’s Infringing ANDA Products contain (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione." | ¶39 | col. 5:5-42 |
Identified Points of Contention
- Scope Questions: A primary question for the court may concern the scope of the terms "stereomerically pure" and "substantially free of its (-) isomer." The patent specification provides an explicit definition, stating "stereomerically pure" comprises "greater than about 80% by weight of one stereoisomer... and less than about 20% by weight of other stereoisomers," with preferred embodiments having higher purity levels (’638 Patent, col. 6:12-33). The resolution of the infringement claim may depend on whether the product detailed in Macleods's ANDA meets this claimed purity threshold.
- Technical Questions: A significant factual question is whether Macleods's generic product is, in fact, the claimed (+) enantiomer and whether it is "substantially free" of the (-) isomer. However, the complaint alleges that in its Notice Letter, "Macleods does not allege non-infringement of one or more claims of the ’638 Patent" (Compl. ¶45). If accurate, this suggests Macleods may not contest infringement, focusing its defense instead on the patent's validity or enforceability.
V. Key Claim Terms for Construction
- The Term: "substantially free of its (-) isomer"
- Context and Importance: The invention's asserted novelty and benefit derive from isolating the (+) enantiomer from its (-) counterpart. The definition of this term is therefore critical to determining the boundary between the patented invention and, for example, a racemic mixture or a less pure formulation. Practitioners may focus on this term because its quantitative nature makes it a clear potential line of demarcation for infringement.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent specification provides an explicit definition for the related term "stereomerically pure," which could be argued to inform the meaning of "substantially free." This definition sets a floor at "greater than about 80% by weight of one stereoisomer" (’638 Patent, col. 6:20-22). A party could argue this establishes the broadest possible scope contemplated by the inventors.
- Evidence for a Narrower Interpretation: The same section of the specification provides increasingly narrow preferred ranges: "more preferably greater than about 90%," "even more preferably greater than about 95%," and "most preferably greater than about 97%" of the desired stereoisomer (’638 Patent, col. 6:24-33). Furthermore, the working examples detail the synthesis of the compound with very high enantiomeric excess (e.g., 98.4% ee and 99.2% ee) (’638 Patent, col. 22:62-67). A party could argue these examples and preferences suggest a person of ordinary skill would understand the term to require a higher degree of purity than the 80% floor.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that upon approval, Macleods will induce infringement by providing a product label and insert with instructions for using the generic product in a manner that infringes the ’638 Patent. This inducement is allegedly directed at healthcare professionals and end users (Compl. ¶42).
- Willful Infringement: The complaint alleges that Macleods had actual notice of the ’638 Patent prior to filing its ANDA, partly due to the patent's listing in the FDA's Orange Book (Compl. ¶22, ¶43). The complaint further alleges that Macleods's conduct in certifying the patent as invalid or unenforceable was undertaken without adequate justification, rendering the case "exceptional" under 35 U.S.C. § 285 (Compl. ¶46).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue appears to be one of patent validity: The complaint asserts that Macleods did not allege non-infringement in its Paragraph IV notification (Compl. ¶45), suggesting the primary legal battle will be over Macleods's challenges to the validity and/or enforceability of the ’638 Patent. The specific grounds for this challenge (e.g., obviousness over the prior art racemic compound) will likely form the core of the controversy.
- Should infringement become a contested issue, the case will turn on a question of definitional scope and evidentiary proof: Can the claim term "substantially free of its (-) isomer" be construed to read on the specific formulation described in Macleods's confidential ANDA filing? The outcome would depend on the court's construction of the term and the evidence produced during discovery regarding the precise characteristics of the accused generic product.