DCT
1:17-cv-01832
CyDex Pharma Inc v. Teva Pharma USA Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: CyDex Pharmaceuticals, Inc. (Delaware)
- Defendant: Teva Pharmaceuticals USA, Inc. (Delaware), Teva Pharmaceutical Industries Ltd. (Israel), and Actavis LLC (Delaware)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:17-cv-01832, D. Del., 12/20/2017
- Venue Allegations: Venue is alleged to be proper based on Defendants' corporate status in Delaware, their business contacts within the district, and their previous submissions to the jurisdiction of the court.
- Core Dispute: Plaintiff alleges that Defendants' submission of an Abbreviated New Drug Application (ANDA) seeking to market a generic version of the injectable drug EVOMELA® constitutes an act of infringement of three patents related to high-purity pharmaceutical excipient compositions.
- Technical Context: The technology involves sulfoalkyl ether cyclodextrins (SAE-CDs), which are used as excipients to enhance the solubility and stability of active pharmaceutical ingredients in drug formulations.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a notice letter on November 9, 2017, in which Defendants certified that the patents-in-suit are invalid, unenforceable, or will not be infringed by their proposed generic product. The asserted patents are listed in the U.S. Food and Drug Administration's "Orange Book" as covering the branded drug EVOMELA®.
Case Timeline
| Date | Event |
|---|---|
| 2008-04-28 | Earliest Priority Date for ’077 and ’088 Patents |
| 2012-02-28 | Earliest Priority Date for ’582 Patent |
| 2013-04-02 | U.S. Patent No. 8,410,077 Issued |
| 2015-12-01 | U.S. Patent No. 9,200,088 Issued |
| 2016-11-15 | U.S. Patent No. 9,493,582 Issued |
| 2017-11-09 | Plaintiff CyDex receives notice letter from Defendants |
| 2017-12-20 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
No probative visual evidence provided in complaint.
U.S. Patent No. 8,410,077
- Patent Identification: U.S. Patent No. 8,410,077, "Sulfoalkyl Ether Cyclodextrin Compositions," issued April 2, 2013 (Compl. ¶15).
The Invention Explained
- Problem Addressed: The patent's background section describes that while sulfoalkyl ether cyclodextrin (SAE-CD) compositions are useful for stabilizing drugs, impurities within these compositions can "reduce the shelf-life and potency of an active agent," creating a "continued need for SAE-CD compositions with higher purity" (’077 Patent, col. 2:10-18).
- The Patented Solution: The invention is a purified SAE-CD composition characterized by low levels of specific impurities. The specification explains that the "substantial removal of both a phosphate and a drug-degrading impurity" results in a composition that can be mixed with a drug to create a "high-stability formulation" (’077 Patent, col. 2:21-27). The composition is defined by quantitative limits on phosphate content and on a "drug-degrading agent," which is identified by its specific light absorption profile using UV/vis spectrophotometry (’077 Patent, Abstract).
- Technical Importance: Providing a higher-purity excipient enables the creation of more stable pharmaceutical products, which is critical for ensuring drug safety, efficacy, and a commercially viable shelf-life (’077 Patent, col. 2:10-18).
Key Claims at a Glance
- The complaint asserts infringement of at least Claim 1 (’077 Patent, Compl. ¶35).
- Independent Claim 1 requires:
- A sulfoalkyl ether cyclodextrin (SAE-CD) composition comprising a sulfoalkyl ether cyclodextrin having an average degree of substitution of 4.5 to 7.5;
- Less than 100 ppm of a phosphate;
- Wherein the composition has an absorption of less than 0.5 A.U. due to a drug-degrading agent;
- As determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the composition per mL of solution in a 1 cm path length cell.
- The complaint reserves the right to assert additional claims (Compl. ¶38).
U.S. Patent No. 9,200,088
- Patent Identification: U.S. Patent No. 9,200,088, "Sulfoalkyl Ether Cyclodextrin Compositions," issued December 1, 2015 (Compl. ¶16).
The Invention Explained
- Problem Addressed: Similar to the ’077 Patent, the background states that impurities in SAE-CD compositions can negatively affect the shelf-life and potency of drug formulations, necessitating compositions with higher purity (’088 Patent, col. 2:11-20).
- The Patented Solution: The invention provides a purified SAE-CD composition that can be "readily mixed with an active agent to provide a high-stability formulation" (’088 Patent, col. 2:26-28). This composition is defined by low levels of phosphate and a "UV-active impurity," which is quantified by a specific UV/vis absorption limit (’088 Patent, Abstract). The specification describes processes, such as treatment with activated carbon, to remove such impurities (’088 Patent, col. 5:14-30).
- Technical Importance: The development of higher-purity excipients as claimed allows for more stable and reliable injectable drug products, a key consideration in pharmaceutical manufacturing (’088 Patent, col. 2:11-20).
Key Claims at a Glance
- The complaint asserts infringement of at least Claim 1 (’088 Patent, Compl. ¶44).
- Independent Claim 1 requires:
- A sulfoalkyl ether cyclodextrin (SAE-CD) composition that can be readily mixed with an active agent;
- Comprising a sulfoalkyl ether cyclodextrin with an average degree of substitution of 4.5 to 7.5;
- Less than 200 ppm of a phosphate;
- Wherein the composition has an absorption of less than 0.5 A.U. due to a UV-active impurity;
- As determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the composition per mL of solution in a 1 cm path length cell.
- The complaint reserves the right to assert additional claims (Compl. ¶47).
U.S. Patent No. 9,493,582
- Patent Identification: U.S. Patent No. 9,493,582, "Alkylated Cyclodextrin Compositions and Processes for Preparing and Using the Same," issued November 15, 2016 (Compl. ¶17).
- Technology Synopsis: This patent addresses impurities in alkylated cyclodextrin compositions, with a particular focus on reducing chloride content, which can be detrimental to the stability of certain active drugs (’582 Patent, Abstract; col. 2:60-67). The invention provides both a process for making and the resulting low-chloride, high-purity alkylated cyclodextrin composition, which also has low levels of drug-degrading agents, thereby improving formulation stability (’582 Patent, Abstract).
- Asserted Claims: The complaint asserts infringement of at least independent Claim 27 (Compl. ¶53).
- Accused Features: The complaint alleges that the Actavis ANDA Product contains an alkylated cyclodextrin composition meeting the specific quantitative limits of Claim 27 regarding the average degree of substitution, phosphate levels, chloride levels (0.07% w/w or less), and UV/vis absorption (Compl. ¶53).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is the "Actavis ANDA Product," a proposed generic version of EVOMELA® (Captisol®-enabled Melphalan HCl) for Injection, described in Abbreviated New Drug Application No. 209323 (Compl. ¶1, ¶23).
Functionality and Market Context
- The product is an injectable formulation of the chemotherapy drug melphalan that uses a sulfoalkyl ether cyclodextrin composition as a pharmaceutical excipient (Compl. ¶1, ¶21). The act of infringement alleged is the submission of the ANDA to the FDA seeking approval to manufacture, use, and sell this product in the United States before the expiration of the patents-in-suit (Compl. ¶33, ¶42, ¶51). The complaint alleges that the ANDA references and relies upon the New Drug Application for EVOMELA® and contains data demonstrating bioequivalence (Compl. ¶30).
IV. Analysis of Infringement Allegations
8,410,077 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A sulfoalkyl ether cyclodextrin (SAE-CD) composition comprising a sulfoalkyl ether cyclodextrin having an average degree of substitution of 4.5 to 7.5... | The Actavis ANDA Product allegedly contains an SAE-CD composition with an average degree of substitution of 4.5 to 7.5. | ¶35 | col. 2:28-29 |
| ...and less than 100 ppm of a phosphate... | The accused composition allegedly contains less than 100 ppm of a phosphate. | ¶35 | col. 2:29-30 |
| ...wherein the SAE-CD composition has an absorption of less than 0.5 A.U. due to a drug-degrading agent, as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length. | The accused composition allegedly has an absorption of less than 0.5 A.U. due to a drug-degrading agent, measured under the conditions specified in the claim. | ¶35 | col. 2:30-34 |
- Identified Points of Contention:
- Evidentiary Questions: The complaint's infringement allegations directly recite the language of Claim 1. A primary point of contention will be factual and evidentiary: does the composition described in the Actavis ANDA, or the product that would be manufactured under it, actually meet the specific quantitative limitations for the average degree of substitution, phosphate concentration (<100 ppm), and UV absorption (<0.5 A.U.)?
- Scope Questions: The case may raise the question of how to define "drug-degrading agent." The dispute could center on whether this term requires proof that an impurity actually degrades the specific active ingredient (melphalan) in the accused product, or whether it is defined solely by the instrumental UV absorption test recited in the claim language itself.
9,200,088 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A sulfoalkyl ether cyclodextrin (SAE-CD) composition that can be readily mixed with an active agent... | The Actavis ANDA Product allegedly contains an SAE-CD composition that can be readily mixed with an active agent. | ¶44 | col. 2:26-28 |
| ...comprising a sulfoalkyl ether cyclodextrin having an average degree of substitution of 4.5 to 7.5 and less than 200 ppm of a phosphate... | The accused composition allegedly includes an SAE-CD with an average degree of substitution of 4.5 to 7.5 and less than 200 ppm of a phosphate. | ¶44 | col. 2:30-32 |
| ...wherein the SAE-CD composition has an absorption of less than 0.5 A.U. due to a UV-active impurity as determined by UV/vis spectrophotometry at a wavelength of 245 nm to 270 nm for an aqueous solution containing 300 mg of the SAE-CD composition per mL of solution in a cell having a 1 cm path length. | The accused composition allegedly has an absorption of less than 0.5 A.U. due to a UV-active impurity, measured under the conditions specified in the claim. | ¶44 | col. 2:32-36 |
- Identified Points of Contention:
- Evidentiary Questions: As with the ’077 Patent, the analysis will depend on evidence from the ANDA or product testing to determine if the accused composition meets the claim's quantitative limits for degree of substitution, phosphate concentration (<200 ppm), and UV absorption.
- Scope Questions: The construction of the term "UV-active impurity" may be disputed. A question may arise as to whether this term covers any substance that absorbs light in the specified UV range, or if it must be construed more narrowly in the context of the patent's focus on impurities that compromise drug stability. The preamble language "that can be readily mixed with an active agent" may also be a point of contention regarding whether it is a limiting feature of the claim.
V. Key Claim Terms for Construction
The Term: "drug-degrading agent" (from Claim 1 of the ’077 Patent)
Context and Importance: The definition of this term is critical for determining infringement of the ’077 Patent. Its construction will determine whether satisfying the claim's UV absorption test is sufficient for infringement, or if Plaintiff must also prove that the impurity causing the absorption has a chemically degrading effect on the active drug in the formulation.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language itself defines the "drug-degrading agent" by its method of detection: "as determined by UV/vis spectrophotometry..." (’077 Patent, col. 53:17-23). This may support an interpretation where any impurity causing the specified absorption meets the definition, regardless of its specific chemical properties.
- Evidence for a Narrower Interpretation: The patent's background links impurities to a reduction in "shelf-life and potency of an active agent" (’077 Patent, col. 2:10-12). A defendant may argue this context requires the "drug-degrading agent" to be an impurity that is proven to have a deleterious effect on the specific drug with which it is formulated.
The Term: "UV-active impurity" (from Claim 1 of the ’088 Patent)
Context and Importance: This term is central to the infringement analysis for the ’088 Patent. Its scope will determine whether any impurity that absorbs UV light meets the limitation, or if it is limited to impurities that are otherwise detrimental to the formulation. Practitioners may focus on the distinction between this term and the "drug-degrading agent" term in the related ’077 Patent.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The plain meaning of "UV-active impurity" suggests any unwanted substance that absorbs UV light. The claim quantifies this impurity solely by its absorption properties under specified test conditions, which may support a broad construction that is not tied to chemical reactivity (’088 Patent, col. 53:40-45).
- Evidence for a Narrower Interpretation: The specification's objective is to provide compositions for "high-stability formulation[s]" by removing impurities that "reduce the shelf-life and potency" of drugs (’088 Patent, col. 2:11-14, 26-28). This context could support an argument that the term should be limited to those UV-active impurities that are known to be, or are proven to be, detrimental to drug stability.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that upon approval of the ANDA, Defendants will induce infringement by providing prescribing instructions and user manuals that will encourage healthcare professionals and end-users to use the accused product in an infringing manner (Compl. ¶38, ¶47, ¶56). The allegations are based on Defendants' alleged knowledge of the patents and their intent for the product to be used as instructed (Compl. ¶38, ¶47, ¶56).
- Willful Infringement: While the term "willful" is not explicitly used, the complaint alleges facts that support such a claim. It asserts that Defendants had "actual and constructive knowledge" of the patents-in-suit prior to filing the ANDA and were aware that filing the ANDA would constitute infringement (Compl. ¶39, ¶48, ¶57). The complaint further alleges that Defendants have "no reasonable basis" for asserting non-infringement, which could form the basis for an exceptional case finding under 35 U.S.C. § 285 (Compl. ¶40, ¶49, ¶58, ¶59).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of evidentiary proof: The complaint's allegations for all three patents rely on specific, quantitative thresholds for chemical composition and purity. The case will likely depend on analytical chemistry evidence from the ANDA filing and expert testing to determine whether the accused generic product's composition actually falls within the numerical limits recited in the asserted claims.
- A key legal question will be one of definitional scope: The dispute may turn on the construction of the terms "drug-degrading agent" (’077 Patent) and "UV-active impurity" (’088 Patent). The court will need to decide whether these terms are defined solely by the instrumental UV absorption tests set forth in the claims, or if they must be construed more narrowly to require evidence that the impurities have a functionally detrimental effect on the stability of the active drug.