DCT
1:17-cv-01833
Onyx Therap Inc v. MSN Laboratories Pvt Ltd
Key Events
Complaint
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Onyx Therapeutics, Inc. (Delaware)
- Defendant: MSN Pharmaceuticals, Inc. (Delaware) and MSN Laboratories Private Limited (India)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:17-cv-01833, D. Del., 12/20/2017
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant MSN Pharmaceuticals, Inc. is a Delaware corporation, and both Defendants are alleged to conduct substantial business in the state and intend for the accused product to be sold there.
- Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's multiple myeloma drug, KYPROLIS®, constitutes an act of infringement of a patent covering the drug's formulation.
- Technical Context: The technology concerns pharmaceutical compositions that use cyclodextrins as solubilizing agents to enable the effective administration of a class of cancer drugs known as peptide epoxy ketone proteasome inhibitors.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 209526 with a Paragraph IV certification. Plaintiff received a notice letter from Defendants on November 10, 2017, and filed this complaint within the statutory 45-day window, triggering a stay of FDA approval for the generic product. The patent-in-suit is listed in the FDA's "Orange Book" for KYPROLIS®.
Case Timeline
| Date | Event |
|---|---|
| 2004-12-07 | ’112 Patent Priority Date |
| 2010-06-15 | ’112 Patent Issue Date |
| 2012-07-20 | FDA grants approval for KYPROLIS® |
| 2017-11-09 | Date of Defendants' notice letter to Plaintiff |
| 2017-12-20 | 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 addresses the low aqueous solubility of certain potent proteasome inhibitors, specifically peptide epoxy ketones. This poor solubility makes it "difficult to formulate compositions with optimal bioavailability" for therapeutic use (’112 Patent, col. 1:25-27).
- The Patented Solution: The invention is a pharmaceutical formulation that combines a "practically insoluble" proteasome inhibitor with a cyclodextrin, which acts as a solubilizing agent to significantly enhance the drug's solubility (’112 Patent, col. 1:35-37; Abstract). The detailed description and associated figures show that the inventors optimized the formulation by balancing solubility and chemical stability, which are both dependent on pH and can be competing factors (’112 Patent, col. 2:30-44; Figs. 1-2). For example, Figure 1 shows that lower pH increases solubility, while Figure 2 shows that very low pH can decrease chemical stability over time.
- Technical Importance: This formulation technology provides a method for delivering a class of otherwise difficult-to-administer therapeutic compounds, enabling their use as injectable drugs for treating diseases like cancer (’112 Patent, col. 1:16-27).
Key Claims at a Glance
- The complaint asserts independent claims 1, 18, and 29, among others (Compl. ¶38).
- Independent Claim 1, a 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 reserves the right to assert numerous dependent claims (Compl. ¶38).
III. The Accused Instrumentality
Product Identification
- Defendants' proposed generic carfilzomib for injection, the subject of ANDA No. 209526 (the "Proposed ANDA Product") (Compl. ¶¶ 8-9).
Functionality and Market Context
- The Proposed ANDA Product is a generic version of Plaintiff's KYPROLIS®, a proteasome inhibitor used to treat relapsed or refractory multiple myeloma (Compl. ¶¶ 9, 22). It is a lyophilized (freeze-dried) powder intended for intravenous injection after being reconstituted (Compl. ¶¶ 21, 34).
- The complaint alleges the Proposed ANDA Product contains the active ingredient carfilzomib, along with sulfobutyl ether beta-cyclodextrin (SBECD) and citric acid (Compl. ¶38).
- The complaint alleges KYPROLIS® is a significant therapy, citing clinical data showing it nearly doubled progression-free survival compared to a previous standard of care for relapsed multiple myeloma (Compl. ¶19). Defendants seek to market a generic equivalent.
IV. Analysis of Infringement Allegations
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 alleged to be a pharmaceutical composition. | ¶38 | col. 49:42 |
| a practically insoluble peptide epoxy ketone proteasome inhibitor or a pharmaceutically acceptable salt thereof | The Proposed ANDA Product contains carfilzomib, which the complaint identifies as a proteasome inhibitor and a tetrapeptide epoxyketone. | ¶¶22, 38 | col. 49:43-45 |
| and a substituted cyclodextrin selected from hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin (SBECD). | The Proposed ANDA Product contains sulfobutyl ether beta-cyclodextrin (SBECD). | ¶38 | col. 49:45-47 |
- Identified Points of Contention:
- Scope Questions: This being an ANDA case based on a Paragraph IV certification, the primary dispute will center on the defendant's asserted defenses of non-infringement and/or invalidity (Compl. ¶27). A potential question for the court is whether the term "pharmaceutical composition" requires specific excipients or properties beyond the explicitly recited inhibitor and cyclodextrin, which could create a non-infringement argument.
- Technical Questions: A key factual question for infringement will be whether carfilzomib, as formulated in the Proposed ANDA Product, meets the definition of a "practically insoluble" inhibitor as that term is used and defined in the patent.
V. Key Claim Terms for Construction
- The Term: "practically insoluble"
- Context and Importance: This term is a lynchpin of the asserted claims, as it defines the active pharmaceutical ingredients for which the claimed formulation is necessary. Infringement will depend on whether carfilzomib falls within the scope of this term. Practitioners may focus on this term because the defendant's non-infringement defense could argue that its specific carfilzomib formulation is not "practically insoluble" as defined by the patent.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification provides an explicit definition, stating the term refers to inhibitors that "generally have a solubility of less than 0.1 mg/mL in water," and notes the invention "also encompasses" inhibitors with even lower solubilities of "less than 0.05 mg/mL and even less than 0.01 mg/mL" (’112 Patent, col. 32:34-38). This provides a clear, quantitative upper bound that may support a broader application.
- Evidence for a Narrower Interpretation: A party might argue that the term should be understood in the functional context of the problem solved—i.e., that the insolubility must be significant enough to "make[] it difficult to formulate compositions with optimal bioavailability" (’112 Patent, col. 1:25-27). This could support a narrower interpretation tied to a functional limitation rather than just the numerical threshold.
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced infringement, asserting that Defendants' product labeling will instruct healthcare providers to reconstitute and administer the Proposed ANDA Product in a manner that directly infringes the ’112 Patent. The complaint alleges these instructions will "substantially copy" those for KYPROLIS® (Compl. ¶¶ 34, 35).
- Willful Infringement: Willfulness is alleged based on pre-suit knowledge. The complaint states Defendants were aware of the ’112 Patent at the time they filed the ANDA, as evidenced by their Paragraph IV certification (Compl. ¶29). The complaint further alleges that Defendants "knowingly and intentionally" infringe and "lacked a good faith basis for alleging invalidity" (Compl. ¶¶ 45, 47).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of validity: given that SBECD is a known solubilizing agent, the court will likely have to decide whether it would have been obvious to a person of ordinary skill in the art to combine it with a peptide epoxy ketone like carfilzomib to solve the known problem of poor aqueous solubility. The patentee may argue that the need to carefully balance the competing effects of pH on solubility and stability, as taught in the patent, rendered the solution non-obvious.
- The case may also turn on a question of definitional scope: does the term "practically insoluble", as defined in the specification, unambiguously cover the carfilzomib active ingredient in Defendants' specific ANDA formulation? While the complaint makes a direct allegation of infringement, the defendants' non-infringement challenge will require the court to resolve the scope of this critical claim limitation.