DCT
1:16-cv-01013
Onyx Therap Inc v. Qilu Pharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Onyx Therapeutics, Inc. (Delaware)
- Defendant: Qilu Pharma, Inc. (Pennsylvania) and Qilu Pharmaceutical Co., Ltd. (China)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:16-cv-01013, D. Del., 11/01/2016
- Venue Allegations: Venue is alleged based on Defendants transacting business in Delaware, deriving substantial revenue from product sales in the state, and the proposed generic product being destined for sale in Delaware.
- Core Dispute: Plaintiff alleges that Defendants’ filing of an Abbreviated New Drug Application (ANDA) for a generic version of the cancer drug KYPROLIS® constitutes an act of infringement of a patent covering pharmaceutical formulations.
- Technical Context: The technology relates to formulations designed to improve the solubility and enable intravenous administration of proteasome inhibitors, a class of drugs used to treat multiple myeloma.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff’s receipt of a notice letter from Defendants regarding ANDA No. 209528. The notice included a Paragraph IV certification alleging that the patent-in-suit is invalid, unenforceable, and/or will not be infringed by the proposed generic product.
Case Timeline
| Date | Event |
|---|---|
| 2004-12-07 | ’112 Patent Priority Date |
| 2010-06-15 | ’112 Patent Issue Date |
| 2012-07-20 | FDA grants accelerated approval for KYPROLIS® |
| 2016-09-14 | Date of Defendants' ANDA Notice Letter |
| 2016-09-21 | Plaintiff receives Defendants' ANDA Notice Letter |
| 2016-11-01 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,737,112 - Composition for Enzyme Inhibition
- Patent Identification: U.S. Patent No. 7,737,112, "Composition for Enzyme Inhibition," issued June 15, 2010.
The Invention Explained
- Problem Addressed: The patent’s background section identifies that certain potent proteasome inhibitors, such as peptide epoxy ketones, have low aqueous solubility, which makes it difficult to create pharmaceutical formulations with optimal bioavailability for administration to patients (ʼ112 Patent, col. 1:25-29).
- The Patented Solution: The invention addresses this solubility problem by formulating the proteasome inhibitor with a cyclodextrin, particularly a substituted cyclodextrin. The specification explains that these cyclodextrins significantly enhance the solubility of the inhibitors, thereby facilitating their administration (ʼ112 Patent, Abstract; col. 1:33-37). The patent further describes balancing solubility and chemical stability by controlling the formulation’s pH, often with a buffer, noting that pH can have competing effects on these two properties (ʼ112 Patent, col. 2:31-44; Figs. 1-2).
- Technical Importance: This formulation technology enables the practical therapeutic use of a class of otherwise hard-to-administer drug compounds, allowing for effective delivery of these proteasome inhibitors for cancer treatment (ʼ112 Patent, col. 1:13-18).
Key Claims at a Glance
- The complaint asserts independent claims 1, 18, 21, 27, and 29.
- Independent Claim 1, the broadest composition claim, recites the following essential elements:
- A pharmaceutical composition comprising
- a practically insoluble peptide epoxy ketone proteasome inhibitor or a pharmaceutically acceptable salt thereof
- and a substituted cyclodextrin selected from hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin (SBECD).
- The complaint asserts infringement of dependent claims 2-9, 14, 19-20, 22-24, and 30-32 (Compl. ¶37).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is Defendants' "Proposed ANDA Product," identified as a generic carfilzomib 60 mg lyophilized powder for reconstitution and intravenous administration (Compl. ¶4).
Functionality and Market Context
- The Proposed ANDA Product is a generic version of Plaintiff's KYPROLIS® (carfilzomib) injection, a treatment for multiple myeloma (Compl. ¶9). The active ingredient, carfilzomib, is described as a tetrapeptide epoxyketone that functions as a proteasome inhibitor (Compl. ¶20).
- The complaint alleges that the proposed generic product contains carfilzomib, sulfobutyl ether beta-cyclodextrin (SBECD) as a solubilizing agent, and citric acid (Compl. ¶37). The proposed product labeling is alleged to instruct healthcare providers on reconstituting the lyophilized powder for intravenous administration to treat multiple myeloma, mirroring the use of KYPROLIS® (Compl. ¶¶ 33-34).
IV. Analysis of Infringement Allegations
The complaint alleges that the submission of ANDA No. 209528 is a technical act of infringement under 35 U.S.C. § 271(e)(2) and that the commercial manufacture and sale of the Proposed ANDA Product would constitute direct infringement (Compl. ¶¶ 38, 40). No probative visual evidence provided in complaint.
’112 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition comprising | The Proposed ANDA Product is a lyophilized powder for reconstitution, which is a pharmaceutical composition. | ¶4 | col. 49:42 |
| a practically insoluble peptide epoxy ketone proteasome inhibitor or a pharmaceutically acceptable salt thereof | The active ingredient in the Proposed ANDA Product is carfilzomib, which the complaint identifies as a tetrapeptide epoxyketone and a proteasome inhibitor. | ¶20, ¶31 | col. 49:43-45 |
| and a substituted cyclodextrin selected from hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin (SBECD). | The Proposed ANDA Product is alleged to contain sulfobutyl ether beta-cyclodextrin (SBECD). | ¶37 | col. 49:45-48 |
Identified Points of Contention
- Scope Questions: The core of the infringement case as presented in the complaint appears to be a direct, literal infringement theory. A potential question for the court is whether the term "practically insoluble," as defined in the patent, accurately describes the carfilzomib active ingredient in the specific formulation of the Proposed ANDA Product.
- Technical Questions: Since this is an ANDA case based on a Paragraph IV certification, the central dispute is more likely to be patent validity (e.g., obviousness) rather than infringement. The complaint does not detail Defendants' non-infringement or invalidity theories, but the filing of the Paragraph IV certification itself signals that Defendants will contest the patent's enforceability or its application to their product (Compl. ¶25).
V. Key Claim Terms for Construction
- The Term: "practically insoluble"
- Context and Importance: This term is a critical limitation defining the type of proteasome inhibitor covered by the claims. Its construction is central because if the accused product's active ingredient were found not to be "practically insoluble," the product would fall outside the scope of Claim 1. Practitioners may focus on this term as a potential, albeit narrow, avenue for a non-infringement defense.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent’s background section makes a general statement about the "low aqueous solubility of some of these compounds," which could support a more general understanding of the term as characteristic of the class of inhibitors ('112 Patent, col. 1:25-27).
- Evidence for a Narrower Interpretation: The patent specification provides an explicit definition, stating that the term "refers to proteasome inhibitors that generally have a solubility of less than 0.1 mg/mL in water" ('112 Patent, col. 32:34-36). This explicit definition strongly suggests a specific, quantifiable threshold will be applied, limiting the scope of the term.
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced infringement, stating that Defendants' proposed product label will instruct healthcare providers to reconstitute and administer the Proposed ANDA Product. This act of reconstitution and administration, according to the complaint, will directly infringe the claims of the ’112 Patent, and Defendants' instructions will therefore induce that infringement (Compl. ¶¶ 33-34, 41).
- Willful Infringement: Willfulness is alleged based on Defendants' knowledge of the ’112 Patent, demonstrated by their submission of a Paragraph IV certification against it (Compl. ¶¶ 28, 44). The complaint further alleges that Defendants "lacked a good faith basis for alleging invalidity" and that the case is "exceptional" under 35 U.S.C. § 285 (Compl. ¶46).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue for the court will be one of patent validity: Given the complaint's straightforward infringement allegations, the case will likely turn on Defendants' asserted defenses of invalidity (e.g., obviousness), which were signaled by their Paragraph IV certification but are not detailed in the complaint. The key question will be whether it was obvious to a person of ordinary skill in the art to combine a known solubilizing agent like SBECD with a peptide epoxy ketone like carfilzomib to achieve a stable, injectable formulation.
- A secondary, but potentially dispositive, question will be one of definitional scope: Does the carfilzomib active pharmaceutical ingredient, as formulated in the Proposed ANDA Product, meet the patent's specific quantitative definition of being "practically insoluble"? While the complaint's allegations suggest it does, this remains a potential point of factual and legal dispute.