DCT
3:18-cv-11081
Amgen Inc v. Mankind Pharma Ltd
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Celgene Corporation (Delaware)
- Defendant: Mankind Pharma Ltd. (India)
- Plaintiff’s Counsel: Saul Ewing Arnstein & Lehr LLP
- Case Identification: 3:18-cv-11081, D.N.J., 06/26/2018
- Venue Allegations: Venue is alleged to be proper because Defendant is a foreign corporation.
- Core Dispute: Plaintiff alleges that Defendant's filing of an Abbreviated New Drug Application (ANDA) for generic versions of Plaintiff's OTEZLA® (apremilast) tablets constitutes an act of infringement of patents covering the apremilast compound and specific solid forms thereof.
- Technical Context: The technology relates to pharmaceutical compositions for treating inflammatory diseases, specifically a stereomerically pure active ingredient (apremilast) and its stable crystalline forms.
- Key Procedural History: The litigation was triggered by Defendant's submission of ANDA No. 211734 to the U.S. Food and Drug Administration (FDA) with a Paragraph IV Certification, asserting that the patents-in-suit are invalid, unenforceable, or would not be infringed. Plaintiff received notice of this certification on May 14, 2018, and filed this complaint within the 45-day statutory window, triggering a potential 30-month stay on FDA approval of the ANDA.
Case Timeline
| Date | Event |
|---|---|
| 2002-03-20 | Priority Date for ’638 and ’101 Patents |
| 2008-09-23 | ’638 Patent Issued |
| 2011-02-22 | ’101 Patent Issued |
| 2014-03-21 | FDA Approval of OTEZLA® (apremilast) |
| 2018-05-14 | Plaintiff Received Defendant's Paragraph IV Notice Letter |
| 2018-06-26 | Complaint Filed |
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, and Methods of Synthesis and Compositions Thereof,” Issued September 23, 2008 (’638 Patent)
The Invention Explained
- Problem Addressed: The patent background describes that enhanced production of tumor necrosis factor alpha (TNF-α) and inactivation of adenosine 3’,5’-cyclic monophosphate (cAMP) by phosphodiesterase 4 (PDE4) are implicated in a number of inflammatory and autoimmune diseases (Compl., Ex. B, ’638 Patent, col. 1:24-65). It further notes that existing PDE4 inhibitors at the time lacked the necessary selective action at therapeutically acceptable doses (Compl., Ex. B, ’638 Patent, col. 2:65-col. 3:1).
- The Patented Solution: The invention provides the stereomerically pure (+)-enantiomer of a specific phenethylsulfone compound, known as apremilast. This specific, isolated enantiomer is claimed to inhibit both TNF-α and PDE4, and is purported to have increased potency and other benefits compared to the racemic (mixed enantiomer) version of the compound (Compl., Ex. B, ’638 Patent, col. 3:23-31). The patent discloses methods for synthesizing this specific enantiomer, as illustrated in its Figure 1 (Compl., Ex. B, ’638 Patent, Fig. 1).
- Technical Importance: By isolating a single, more active enantiomer, the invention offered the potential for a more potent and selective therapy for inflammatory conditions like psoriasis and psoriatic arthritis, with a potentially improved side-effect profile compared to the racemic mixture.
Key Claims at a Glance
- The complaint alleges infringement of claims that recite the compound itself or pharmaceutical compositions containing it (Compl. ¶38, ¶50). Independent claim 1 is representative of the asserted composition claims.
- Independent Claim 1:
- 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 reserves the right to assert additional claims.
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 (’101 Patent)
The Invention Explained
- Problem Addressed: The patent addresses the technical challenge that a single pharmaceutical compound can exist in different solid-state forms (polymorphs), each having distinct physical properties such as stability, solubility, and manufacturing characteristics. The unpredictable appearance of a new, less soluble polymorph can disrupt manufacturing and even lead to product withdrawal (Compl., Ex. C, ’101 Patent, col. 3:7-41).
- The Patented Solution: The invention identifies and characterizes specific crystalline forms of apremilast. The patent particularly describes "Form B," a specific polymorph defined by a unique set of peaks in an X-ray powder diffraction (XRPD) analysis, which provides a fingerprint for that crystal structure (Compl., Ex. C, ’101 Patent, col. 19:62-col. 20:20). Figure 5 of the patent provides a representative XRPD pattern for this Form B (Compl., Ex. C, ’101 Patent, Fig. 5).
- Technical Importance: Identifying and claiming a specific, stable crystalline form of apremilast is critical for ensuring manufacturing consistency, product stability, and predictable bioavailability, which are essential for regulatory approval and reliable patient outcomes.
Key Claims at a Glance
- The complaint alleges infringement of claims reciting a form of apremilast having a specific XRPD pattern (Compl. ¶62, ¶73). Independent claim 1 is representative.
- Independent Claim 1:
- A Form B crystal form of the compound of Formula (I) [apremilast],
- which is enantiomerically pure, and
- which has an X-ray powder diffraction pattern comprising peaks at about 10.1, 13.5, 20.7, and 26.9 degrees 2θ.
- The complaint reserves the right to assert additional claims.
III. The Accused Instrumentality
Product Identification
The accused products are Mankind's proposed generic versions of OTEZLA® (apremilast) in 10 mg, 20 mg, and 30 mg tablets, for which Mankind seeks FDA approval via ANDA No. 211734 (Compl. ¶1, ¶26).
Functionality and Market Context
The accused products contain apremilast as the active pharmaceutical ingredient and are intended for oral use to treat psoriatic arthritis and plaque psoriasis (Compl. ¶17, ¶26). By filing an ANDA, Mankind seeks to market these tablets as bioequivalent and therapeutically equivalent generic substitutes for Celgene's branded OTEZLA® product prior to the expiration of the patents-in-suit (Compl. ¶1, ¶25).
IV. Analysis of Infringement Allegations
'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, or a pharmaceutically acceptable salt...thereof | On information and belief, Mankind’s Infringing ANDA Products are pharmaceutical compositions that contain (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione (apremilast) as the active ingredient. | ¶39, ¶40 | col. 4:50-57 |
| and a pharmaceutically acceptable carrier, excipient or diluent. | Mankind's Infringing ANDA Products are formulated as single unit dosage forms (tablets) which necessarily include pharmaceutically acceptable carriers or excipients. | ¶40 | col. 13:42-45 |
Identified Points of Contention
- Scope Questions: The complaint alleges that Mankind does not contest infringement of the ’638 Patent, suggesting the primary dispute will be over patent validity (Compl. ¶45). However, a latent infringement question is whether Mankind's product meets the claim requirement of being "stereomerically pure" and "substantially free of its (-) isomer", a term defined in the patent's specification to mean, at a minimum, greater than 80% purity of the (+) enantiomer (Compl., Ex. B, '638 Patent, col. 6:15-33).
'101 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A Form B crystal form of the compound... which has an X-ray powder diffraction pattern comprising peaks at about 10.1, 13.5, 20.7, and 26.9 degrees 2θ. | On information and belief, Mankind’s Infringing ANDA Products contain a crystalline form of apremilast that has the specified X-ray powder diffraction pattern peaks characteristic of Form B. | ¶63, ¶74 | col. 19:62-67 |
Identified Points of Contention
- Technical Questions: Similar to the ’638 Patent, the complaint alleges Mankind does not contest infringement of the ’101 Patent (Compl. ¶68). The central factual question for the court, however, will be whether the specific solid form of apremilast used in Mankind's ANDA product actually possesses the claimed XRPD peaks. This determination will require analysis of confidential data from Mankind's ANDA and expert testimony on crystallographic analysis.
V. Key Claim Terms for Construction
The Term: "stereomerically pure... substantially free of its (-) isomer" (’638 Patent, Claim 13, incorporated into composition claims).
Context and Importance: This term is central to defining the required purity of the active ingredient. The patent’s core assertion is that the purified (+)-enantiomer is superior to the racemate. The construction of this term will set the threshold for how much of the inactive or less active (-)-isomer is permissible in an infringing product.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language itself does not provide a specific numerical percentage, which might suggest reliance on a plain and ordinary meaning understood by a person of skill in the art.
- Evidence for a Narrower Interpretation: The specification provides an explicit definition, stating a "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% by weight of one stereoisomer" (Compl., Ex. B, ’638 Patent, col. 6:15-33). This language provides strong support for a specific, numerically defined range of purity.
The Term: "about" (’101 Patent, Claim 1).
Context and Importance: This term modifies the numerical locations of the XRPD peaks that define the claimed "Form B." Because XRPD measurements are subject to experimental variance, the scope of "about" will determine how much deviation from the recited peak values is allowed before a product is considered non-infringing. Practitioners may focus on this term because even slight differences in crystal structure can result in shifts in XRPD peaks.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The term "about" is used to provide some flexibility beyond the precise numbers recited, acknowledging the inherent variability in XRPD measurements.
- Evidence for a Narrower Interpretation: The patent specification provides numerous tables and figures depicting the XRPD data with high precision (e.g., Compl., Ex. C, ’101 Patent, Fig. 5). A party could argue that "about" should be construed narrowly to cover only the typical, minor instrument variations acknowledged in the field, preventing the claim from covering different polymorphic forms. The specification notes that XRPD peak positions can vary by approximately "±0.2° 2θ" (Compl., Ex. C, ’101 Patent, col. 51:65-67), providing a potential basis for a specific numerical construction.
VI. Other Allegations
Indirect Infringement
The complaint alleges that upon FDA approval, Mankind will induce infringement by marketing and distributing its ANDA products with a product label and insert containing instructions for administration that are substantially similar to those for OTEZLA® (Compl., Ex. A). Following these instructions for the treatment of psoriatic arthritis or psoriasis would allegedly cause physicians and patients to directly infringe method of treatment claims (Compl. ¶42, ¶65).
Willful Infringement
The complaint does not contain a separate count for willful infringement. However, it alleges that Mankind had "actual and constructive notice" of the patents-in-suit prior to filing its ANDA (Compl. ¶43, ¶66). It further alleges that Mankind's conduct renders the case "exceptional" under 35 U.S.C. § 285, which is a basis for seeking attorneys' fees often associated with findings of willful infringement or litigation misconduct (Compl. ¶46, ¶69).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central evidentiary question will be one of structural identity: Does the solid form of apremilast in Mankind's ANDA products, as a matter of scientific fact, exhibit the specific X-ray powder diffraction pattern claimed in the ’101 Patent for "Form B," or is it a different, non-infringing polymorph?
- A core issue will be one of definitional scope: How much of the inactive (-)-isomer is permissible before a product is no longer considered "stereomerically pure" and "substantially free" of that isomer under the '638 Patent? The court's construction of this term, likely guided by the patent's explicit definitions, will be critical.
- Given that the complaint alleges non-infringement is not being contested by the defendant for either patent, the ultimate disposition of the case will likely depend on the validity of the asserted patent claims. This question, which is the basis for Mankind's Paragraph IV certification, will require the court to consider prior art and other statutory requirements for patentability.