DCT
1:19-cv-00071
Onyx Therap Inc v. Breckenridge Pharmaceutical Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Onyx Therapeutics, Inc. (Delaware)
- Defendant: Breckenridge Pharmaceutical, Inc. (Florida)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:19-cv-00071, D. Del., 01/11/2019
- Venue Allegations: Plaintiff alleges venue is proper because Defendant transacts business in Delaware and has previously submitted to the jurisdiction of the court in prior litigation.
- Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of Plaintiff’s cancer drug KYPROLIS® (carfilzomib) constitutes an act of infringement of three patents covering the active compound and its pharmaceutical composition.
- Technical Context: The technology concerns small-molecule proteasome inhibitors, a class of drugs used in oncology, particularly for the treatment of multiple myeloma, a type of blood cancer.
- Key Procedural History: The complaint states that this action follows prior lawsuits filed in October 2016 and February 2018 against the same Defendant concerning its ANDA for different dosage strengths (60 mg/vial and 30 mg/vial) of the same generic carfilzomib product. This suit was initiated after Plaintiff received a notice letter on November 29, 2018, regarding an amendment to the ANDA to include a 10 mg/vial strength.
Case Timeline
| Date | Event |
|---|---|
| 2004-08-06 | Earliest Priority Date for ’042 and ’125 Patents |
| 2004-12-07 | Priority Date for ’112 Patent |
| 2008-08-26 | ’042 Patent Issued |
| 2010-06-15 | ’112 Patent Issued |
| 2012-06-26 | ’125 Patent Issued |
| 2012-07-20 | FDA grants accelerated approval for KYPROLIS® (carfilzomib) |
| 2016-09-XX | Defendant notifies Plaintiff of ANDA filing for 60 mg/vial product |
| 2016-10-XX | Plaintiff commences first action against Defendant |
| 2018-01-XX | Defendant notifies Plaintiff of ANDA amendment for 30 mg/vial product |
| 2018-02-XX | Plaintiff commences second action against Defendant |
| 2018-11-29 | Plaintiff receives notice of ANDA amendment for 10 mg/vial product |
| 2019-01-11 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 7,417,042 - Compounds For Enzyme Inhibition
(Issued Aug. 26, 2008)
The Invention Explained
- Problem Addressed: The patent’s background section describes the cellular machinery for protein degradation, centered on the proteasome. It notes that while some small-molecule proteasome inhibitors existed, there was a need for new compounds with improved specificity, stability, and potency to better serve as therapeutic agents and research tools (’042 Patent, col. 2:8-18).
- The Patented Solution: The invention provides a class of peptide-based compounds, specifically peptide epoxyketones, that contain a reactive, three-membered epoxide ring. This structure is designed to bind irreversibly and selectively to certain enzymes, particularly the N-terminal nucleophile (Ntn) hydrolases that constitute the active sites of the proteasome, thereby inhibiting their function (’042 Patent, Abstract; col. 3:55-64).
- Technical Importance: This approach provided potent and highly selective inhibitors of the proteasome's chymotrypsin-like activity, a key target for anti-cancer therapies such as the treatment of multiple myeloma (Compl. ¶¶ 18, 20).
Key Claims at a Glance
- The complaint asserts Claims 23 and 24 (Compl. ¶32). Claim 24 recites the specific chemical structure of the compound carfilzomib.
- Essential elements of Claim 24 include:
- A tetrapeptide backbone
- Specific amino acid side chains (isobutyl, phenylmethyl, isobutyl, phenylethyl)
- An N-terminal morpholino-acetyl capping group
- A C-terminal epoxyketone functional group with specific stereochemistry
- The complaint does not explicitly reserve the right to assert dependent claims for this patent.
U.S. Patent No. 7,737,112 - Composition For Enzyme Inhibition
(Issued June 15, 2010)
The Invention Explained
- Problem Addressed: The patent background states that peptide epoxy ketones such as carfilzomib have low aqueous solubility, which presents a significant challenge for creating pharmaceutical formulations with "optimal bioavailability," particularly for intravenous use (’112 Patent, col. 1:21-26).
- The Patented Solution: The invention addresses the solubility problem by creating a pharmaceutical composition that combines the proteasome inhibitor with a cyclodextrin, which is a type of oligosaccharide known to form inclusion complexes with poorly soluble molecules, thereby enhancing their solubility in water. The patent further describes using a buffer to control the pH of the solution to optimize both solubility and chemical stability (’112 Patent, col. 2:30-34, Fig. 1-2).
- Technical Importance: This formulation technology enabled the development of a stable, soluble, injectable version of carfilzomib, making the potent compound clinically viable as an intravenously administered cancer therapy (Compl. ¶17).
Key Claims at a Glance
- The complaint asserts Claims 31 and 32 (Compl. ¶43). Independent Claim 31 is representative of the formulation technology.
- Essential elements of Claim 31 include:
- A pharmaceutical composition comprising the compound carfilzomib (recited by structure) or a salt thereof
- In an aqueous solution
- Containing 10% (w/v) sulfobutyl ether beta-cyclodextrin (SBECD)
- And 10 mM citric acid
- Adjusted to pH 3.5
- The complaint does not explicitly reserve the right to assert dependent claims for this patent.
U.S. Patent No. 8,207,125 - Compounds For Enzyme Inhibition
(Issued June 26, 2012)
- Technology Synopsis: This patent, like the ’042 Patent, is directed to peptide-based compounds containing an epoxide functional group that act as inhibitors of N-terminal nucleophile hydrolases such as the proteasome (’125 Patent, Abstract). The patent claims specific peptide epoxyketone structures for use in treating conditions like cancer.
- Asserted Claims: Claim 1 (Compl. ¶54).
- Accused Features: The complaint alleges that Defendant’s proposed generic product infringes because its active pharmaceutical ingredient is carfilzomib, the compound recited in Claim 1 of the ’125 Patent (Compl. ¶54).
III. The Accused Instrumentality
Product Identification
- Defendant Breckenridge’s proposed generic carfilzomib, powder for intravenous injection, 10 mg/vial strength, which is the subject of Abbreviated New Drug Application (ANDA) No. 209330 (Compl. ¶3, ¶22).
Functionality and Market Context
- The accused product is a generic version of Plaintiff’s KYPROLIS® drug product (Compl. ¶5). Its active ingredient, carfilzomib, is a tetrapeptide epoxyketone that functions as a proteasome inhibitor (Compl. ¶18, ¶25). The complaint alleges the product is intended for intravenous use after reconstitution to treat relapsed or refractory multiple myeloma, a type of blood cancer (Compl. ¶25, ¶27). The complaint further alleges that the proposed product contains carfilzomib, sulfobutyl ether beta-cyclodextrin (SBECD), and citric acid as excipients (Compl. ¶43).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
’042 Patent Infringement Allegations
| Claim Element (from Claim 24) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A compound having the specific chemical structure of carfilzomib | The active ingredient in the Proposed 10 mg/vial ANDA Product is carfilzomib. | ¶32 | col. 29:53-67 |
- Identified Points of Contention:
- Factual Question: The primary issue for this compound claim is one of identity. What evidence does the complaint provide, beyond "information and belief," that the active pharmaceutical ingredient manufactured by the Defendant for its ANDA product is, in fact, the exact chemical structure claimed in the ’042 Patent?
’112 Patent Infringement Allegations
| Claim Element (from Independent Claim 31) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A pharmaceutical composition comprising a compound having the structure [of carfilzomib]... | The Proposed 10 mg/vial ANDA Product contains carfilzomib as its active ingredient. | ¶43 | col. 50:15-20 |
| ...in an aqueous solution containing 10% (w/v) SBECD... | The Proposed 10 mg/vial ANDA Product contains sulfobutyl ether beta-cyclodextrin (SBECD) and is intended for reconstitution into an aqueous solution for intravenous use. | ¶43, ¶27 | col. 4:64-67 |
| ...and 10 mM citric acid adjusted to pH 3.5. | The Proposed 10 mg/vial ANDA Product contains citric acid, and its proposed label allegedly instructs reconstitution and administration in a manner that will result in the claimed pH. | ¶43, ¶27-28 | col. 4:54-58 |
- Identified Points of Contention:
- Scope Questions: The infringement analysis for this composition claim raises questions about quantitative scope. Does the Defendant’s formulation, upon reconstitution according to its proposed product label, result in a solution containing precisely "10% (w/v) SBECD," "10 mM citric acid," and a "pH 3.5"? The Defendant may seek to argue that its formulation uses different concentrations or a different final pH to design around these explicit limitations.
V. Key Claim Terms for Construction
For the ’042 Patent, whose asserted claim recites a specific chemical structure, claim construction is not anticipated to be a central issue.
For the ’112 Patent:
- The Term: "10% (w/v) SBECD" (from Claim 31)
- Context and Importance: This term defines a precise concentration of a key excipient. Practitioners may focus on this term because infringement depends on whether the accused formulation, after reconstitution, meets this exact quantitative requirement. Any deviation in the accused product's concentration could be the basis for a non-infringement defense.
- Evidence for a Broader Interpretation: The complaint does not provide sufficient detail for analysis of arguments for a broader interpretation, as the claim language is specific. Parties might look to the prosecution history for arguments related to equivalence.
- Evidence for a Narrower Interpretation: The claim recites the value "10%" without qualifying language such as "about" or "approximately." The patent specification discloses this specific concentration in a working example, suggesting it is a deliberate and optimized value (’112 Patent, col. 47:56-57).
- The Term: "pH 3.5" (from Claim 31)
- Context and Importance: This term defines the specific acidity of the final aqueous solution. This is critical because the patent’s own data demonstrates that both the solubility and chemical stability of carfilzomib are highly dependent on pH (’112 Patent, Fig. 1-2). Infringement hinges on whether the accused product's reconstituted solution has this exact pH.
- Evidence for a Broader Interpretation: The complaint does not provide sufficient detail for analysis of arguments for a broader interpretation.
- Evidence for a Narrower Interpretation: The patent specification describes the technical trade-off between solubility (favored by lower pH) and stability (favored by higher pH), indicating that the selected pH is a specific, optimized value (’112 Patent, col. 4:32-44). The claim's recitation of a specific value to one decimal place, "3.5," may support an argument that the term should be narrowly construed.
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced infringement for all asserted patents. The factual basis for inducement is the allegation that Defendant’s proposed product labeling will instruct healthcare providers to reconstitute and administer the generic product to treat multiple myeloma, which will cause them to directly infringe the asserted claims (Compl. ¶¶ 34, 36, 45, 47, 56, 58).
- Willful Infringement: The complaint alleges that Defendant had knowledge of the Patents-in-Suit when it filed its ANDA and its subsequent amendments with a Paragraph IV certification (Compl. ¶24, ¶37, ¶48, ¶59). It further alleges that Defendant is "knowingly and intentionally infringing" the patents (Compl. ¶39, ¶50, ¶61).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of factual identity and equivalence: Does the active ingredient in Breckenridge’s product correspond precisely to the chemical structure of carfilzomib as claimed in the ’042 and ’125 patents? Further, will Breckenridge's product, when reconstituted per its label, result in a formulation that meets the specific quantitative limitations of the ’112 Patent's composition claims, or does it contain different concentrations of excipients or a different pH that could support a non-infringement argument?
- A key evidentiary question will be one of proof of composition: What technical evidence will be presented regarding the precise quantitative make-up of the accused generic product after it is reconstituted as instructed by its proposed label? The dispute over infringement of the ’112 Patent will likely depend on analytical chemistry data comparing the accused formulation to the specific concentration and pH values recited in the claims.