CyDex Pharma Inc v. Lupin Ltd

I. Executive Summary and Procedural Information

• Parties & Counsel:
  • Plaintiff: CyDex Pharmaceuticals, Inc. (Delaware)
  • Defendant: Lupin Limited (India) and Lupin Pharmaceuticals, Inc. (Delaware)
  • Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
• Case Identification: 1:19-cv-02043, D. Del., 10/29/2019
• Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Lupin Pharmaceuticals, Inc. is a Delaware corporation and therefore resides in the district, and Defendant Lupin Limited is a foreign entity that may be sued in any judicial district.
• Core Dispute: Plaintiff alleges that Defendants’ submission of an Abbreviated New Drug Application (ANDA) to the FDA, seeking to market a generic version of Plaintiff's EVOMELA® drug product, constitutes an act of patent infringement under the Hatch-Waxman Act.
• Technical Context: The technology relates to high-purity sulfoalkyl ether cyclodextrin compositions, which are used as pharmaceutical excipients to improve the solubility and stability of active drug ingredients.
• Key Procedural History: The lawsuit was triggered by a "Notice of Paragraph IV Certification" letter, dated September 13, 2019, in which Defendants notified Plaintiff of their ANDA filing for a generic version of EVOMELA®. The patents-in-suit are listed in the FDA's "Orange Book" as covering the EVOMELA® drug product.

Case Timeline

II. Technology and Patent(s)-in-Suit Analysis

U.S. Patent No. 9,200,088 - "Sulfoalkyl Ether Cyclodextrin Compositions," issued December 1, 2015

The Invention Explained

• Problem Addressed: The patent's background section describes that impurities present in sulfoalkyl ether cyclodextrin (SAE-CD) compositions can reduce the shelf-life and potency of an active pharmaceutical agent with which they are formulated (’088 Patent, col. 2:12-15).
• The Patented Solution: The invention provides for a purified SAE-CD composition characterized by low levels of specific impurities: phosphates and a "drug-degrading" or "UV-active" impurity. This latter impurity is identified by its characteristic absorption of ultraviolet light. By controlling for these impurities, the resulting composition can be mixed with an active agent to provide a high-stability formulation (’088 Patent, Abstract; col. 2:23-29).
• Technical Importance: The purity of excipients is critical in pharmaceutical development, as impurities can directly degrade the active drug, impacting the product's safety, efficacy, and approved shelf-life (’088 Patent, col. 2:12-15).

Key Claims at a Glance

• The complaint asserts infringement of at least Claim 1 (Compl. ¶25).
• Independent Claim 1 requires:
  • A sulfoalkyl ether cyclodextrin (SAE-CD) composition that can be readily mixed with an active agent;
  • The SAE-CD has an average degree of substitution of 4.5 to 7.5;
  • The composition contains less than 200 ppm of a phosphate; and
  • The composition has an absorption of less than 0.5 Absorbance Units (A.U.) due to a UV-active impurity, as measured by a specific spectrophotometry method at a wavelength of 245 nm to 270 nm.
• The complaint states that Defendants will induce infringement of "one or more claims" of the patent, reserving the right to assert others (Compl. ¶27).

U.S. Patent No. 9,493,582 - "Alkylated Cyclodextrin Compositions and Processes for Preparing and Using the Same," issued November 15, 2016

The Invention Explained

• Problem Addressed: The patent addresses the presence of impurities in alkylated cyclodextrin compositions that can reduce drug shelf-life and potency, with a particular focus on chloride impurities that can arise during manufacturing (’582 Patent, Abstract; col. 31:40-56).
• The Patented Solution: The invention claims a purified alkylated cyclodextrin composition defined by low levels of phosphate, chloride, and drug-degrading agents (also characterized by UV absorption). The patent also describes a manufacturing process involving specific purification steps, such as using phosphate-free activated carbon, to achieve this low-impurity composition (’582 Patent, Abstract; col. 3:5-24).
• Technical Importance: For certain active pharmaceutical ingredients that are sensitive to halides, controlling the level of chloride in the formulation is critical to prevent degradation and ensure long-term product stability (’582 Patent, col. 31:51-56).

Key Claims at a Glance

• The complaint asserts infringement of at least Claim 27 (Compl. ¶33).
• Independent Claim 27 requires:
  • An alkylated cyclodextrin composition;
  • The alkylated cyclodextrin has an average degree of substitution of 2 to 9;
  • The composition contains less than 500 ppm of a phosphate;
  • The composition contains 0.07% (w/w) or less of a chloride; and
  • The composition has an absorption of less than 1 A.U., as measured by a specific spectrophotometry method at a wavelength of 245 nm to 270 nm.
• The complaint states that Defendants will induce infringement of "one or more claims" of the patent, reserving the right to assert others (Compl. ¶35).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is the "Lupin ANDA Product," a proposed generic version of EVOMELA® (Captisol®-enabled Melphalan HCl) for Injection, 50 mg/vial (Compl. ¶1, ¶6). The act of infringement alleged under 35 U.S.C. § 271(e)(2)(A) is the submission of ANDA No. 213569 to the FDA for this product (Compl. ¶1).

Functionality and Market Context

The Lupin ANDA Product is intended to be a generic equivalent to the brand-name drug EVOMELA® (Compl. ¶1). The complaint alleges that the product, as described in its ANDA, contains an alkylated cyclodextrin composition that meets the specific purity and compositional limitations of the asserted patents (Compl. ¶25, ¶33). The ANDA relies on the innovator's data to demonstrate bioequivalence, and upon approval, Defendants intend to manufacture and sell the product in the United States (Compl. ¶21, ¶6).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’9,200,088 Infringement Allegations

• Identified Points of Contention:
  • Factual Questions: The complaint's allegations are made on "information and belief," which is standard in ANDA litigation prior to discovery. The central dispute will be factual: does the composition described in Lupin's ANDA actually meet all the quantitative limitations of Claim 1, including the average degree of substitution, the parts-per-million limit on phosphate, and the specific UV absorption threshold?
  • Scope Questions: What constitutes a "UV-active impurity" may become a point of contention. The analysis will question whether this term should be interpreted broadly to mean any compound that absorbs light in the specified range or more narrowly to mean specific degradation products discussed in the patent's specification.

’9,493,582 Infringement Allegations

• Identified Points of Contention:
  • Factual Questions: Similar to the analysis of the ’088 Patent, the dispute will primarily turn on the actual characteristics of the Lupin ANDA Product. Discovery will be necessary to determine if the product's excipient meets the numerical limits for degree of substitution, phosphate, chloride, and UV absorption as claimed.
  • Technical Questions: A technical question for the case is whether the single excipient used in the Lupin ANDA Product simultaneously satisfies the distinct sets of limitations recited in the asserted claims of both patents.

V. Key Claim Terms for Construction

• The Term: "UV-active impurity" (’088 Patent, Claim 1)
• Context and Importance: The quantitative limit on UV absorption is a central element of the asserted claim. The definition of the impurity responsible for this absorption is therefore critical to determining infringement. Practitioners may focus on this term because its scope will dictate the evidence needed to prove or disprove that the accused product meets this limitation.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification repeatedly equates this impurity with a "drug-degrading agent" or "drug-degrading impurity" (’088 Patent, col. 2:25-26, 32-33), suggesting a functional definition based on the impurity's effect on an active drug and its UV-absorptive property, rather than its specific chemical structure.
  • Evidence for a Narrower Interpretation: The detailed description and figures provide examples of how such impurities can be formed through thermal and caustic degradation and list specific chemical compounds that may result, such as "2-furaldehyde" and "5-hydroxymethyl-2-furaldehyde" (’088 Patent, col. 11:16-24, col. 22:3-6). A party could argue the term should be limited to these or structurally similar degradation products.

VI. Other Allegations

• Indirect Infringement: The complaint alleges that upon FDA approval, Defendants would induce infringement by marketing and distributing the Lupin ANDA Product with prescribing instructions for health care professionals and end users, thereby encouraging acts of direct infringement (Compl. ¶27, ¶35).
• Willful Infringement: The complaint alleges Defendants had actual and constructive knowledge of the patents-in-suit prior to filing the ANDA, and that filing the ANDA with a request for approval before patent expiration constitutes an act of infringement (Compl. ¶28, ¶36). The complaint further alleges the case is "exceptional" under 35 U.S.C. § 285 (Compl. ¶38).

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

• A central evidentiary question will be one of compositional identity: will discovery of Defendants’ ANDA filing and product samples confirm that the proposed generic excipient simultaneously meets all the specific quantitative limitations—average degree of substitution, parts-per-million levels of phosphate and chloride, and UV absorption thresholds—recited in the asserted claims of both patents?
• A key legal question will be one of definitional scope: can the term "UV-active impurity," which the patents functionally describe as a "drug-degrading agent," be construed broadly based on its spectrophotometric properties, or will the court limit its meaning to the specific chemical degradation byproducts disclosed in the specifications?