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: 1:18-cv-00262, D. Del., 02/15/2018
• Venue Allegations: Plaintiff alleges venue is proper because Defendant transacts business in Delaware, derives substantial revenue from the district, has previously submitted to the court's jurisdiction in other matters, and has agreed not to contest venue for the purposes of this action.
• Core Dispute: Plaintiff alleges that Defendant's filing of an Abbreviated New Drug Application (ANDA) for a generic version of the multiple myeloma drug KYPROLIS® (carfilzomib) constitutes an act of infringement of nine U.S. patents covering the compound, its formulation, and methods of its use.
• Technical Context: The technology concerns proteasome inhibitors, specifically the tetrapeptide epoxyketone carfilzomib, which represents a significant therapeutic advance for treating multiple myeloma, a type of hematologic cancer.
• Key Procedural History: The action arises under the Hatch-Waxman Act, prompted by Defendant’s submission of ANDA No. 209330 with a Paragraph IV certification. This certification asserts that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product. Plaintiff filed this complaint within the 45-day statutory window following receipt of Defendant's notice letter, triggering an automatic 30-month stay of FDA approval for the generic drug.

Case Timeline

Date	Event
2004-04-15	Earliest Priority Date for ’042, ’818, ’704, ’346, ’125, ’126, ’127, and ’297 Patents
2004-12-07	Earliest Priority Date for ’112 Patent
2007-06-19	U.S. Patent No. 7,232,818 Issues
2008-08-26	U.S. Patent No. 7,417,042 Issues
2009-02-17	U.S. Patent No. 7,491,704 Issues
2010-06-15	U.S. Patent No. 7,737,112 Issues
2011-01-01	FDA grants KYPROLIS® "Fast Track" designation (approx. date)
2012-03-06	U.S. Patent No. 8,129,346 Issues
2012-06-26	U.S. Patent Nos. 8,207,125, 8,207,126, 8,207,127, and 8,207,297 Issue
2012-07-20	FDA grants accelerated approval for KYPROLIS®
2018-01-02	Defendant sends Paragraph IV Notice Letter to Plaintiff
2018-02-15	Complaint Filed

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

U.S. Patent No. 7,417,042 - “Compounds For Enzyme Inhibition”

• Patent Identification: U.S. Patent No. 7,417,042 (the “’042 Patent”), entitled “Compounds For Enzyme Inhibition,” issued August 26, 2008 (Compl. ¶11).

The Invention Explained

• Problem Addressed: The patent family addresses a need for small-molecule inhibitors of the proteasome—a key component in cellular protein degradation—that possess improved specificity, stability, and potency over existing compounds (’818 Patent, col. 2:15-21).
• The Patented Solution: The invention provides peptide-based compounds, specifically those with an α',β'-epoxyketone structure, designed to bind irreversibly and selectively to N-terminal nucleophile hydrolases like the proteasome (’818 Patent, col. 2:26-31). This selective inhibition of proteasome activity, particularly the chymotrypsin-like activity, is described as having therapeutic utility, including anti-inflammatory properties and the ability to inhibit cell proliferation (’818 Patent, Abstract). The detailed description outlines how these compounds form covalent adducts with the N-terminal threonine of the proteasome’s active site, thereby blocking its function (’818 Patent, col. 4:5-14).
• Technical Importance: The development of potent and selective proteasome inhibitors provided a targeted mechanism for treating cancers such as multiple myeloma, an area with a previously unmet medical need (Compl. ¶¶ 20-21).

Key Claims at a Glance

• The complaint asserts independent claims 1 and 15, along with dependent claims 2-6, 16-24, and claim 37 (Compl. ¶38).
• The complaint does not provide sufficient detail for analysis of the specific claim elements.

U.S. Patent No. 7,232,818 - “Compounds For Enzyme Inhibition”

• Patent Identification: U.S. Patent No. 7,232,818 (the “’818 Patent”), entitled “Compounds For Enzyme Inhibition,” issued June 19, 2007 (Compl. ¶12).

The Invention Explained

• Problem Addressed: The patent’s background section describes the central role of the proteasome in cellular protein degradation and notes that while some small-molecule inhibitors exist, they "generally lack the specificity, stability, or potency necessary to explore and exploit the roles of the proteasome at the cellular and molecular level" (’818 Patent, col. 2:15-18).
• The Patented Solution: The invention discloses classes of molecules, namely peptide α',β'-epoxides and peptide α',β'-aziridines, that are designed to "bind efficiently, irreversibly and selectively to N-terminal nucleophile (Ntn) hydrolases" such as the proteasome (’818 Patent, col. 2:26-29). The patent describes peptide-based structures with at least three peptide units and a reactive epoxide or aziridine group at the C-terminus, which can selectively inhibit the chymotrypsin-like activity of the 20S proteasome (’818 Patent, Abstract). This targeted inhibition is presented as a solution to achieve therapeutic effects with greater specificity.
• Technical Importance: The patented compounds were designed to serve as "unique molecular probes" for exploring enzyme function in biological processes and were expected to possess anti-inflammatory and anti-proliferative activity, giving them significant therapeutic potential (’818 Patent, col. 3:55-59).

Key Claims at a Glance

• The complaint asserts independent claims 1 and 49, along with dependent claims 2-4, 23-25, 38, and 50 (Compl. ¶49).
• Independent Claim 1 recites, in relevant part:
  • A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
  • wherein formula (I) defines a class of tetrapeptides with an N-terminal capping group and a C-terminal α', β'-epoxy ketone or α', β'-aziridine ketone moiety, with numerous variables defining the specific amino acid side chains and other structural features.
• The complaint reserves the right to assert additional dependent claims.

U.S. Patent No. 7,491,704 - “Compounds For Enzyme Inhibition”

• Patent Identification: U.S. Patent No. 7,491,704 (the “’704 Patent”), entitled “Compounds For Enzyme Inhibition,” issued February 17, 2009 (Compl. ¶13).
• Technology Synopsis: This patent is part of the same family as the ’818 Patent and is directed to peptide epoxyketone compounds that function as proteasome inhibitors. The claims cover specific compounds and methods of using them to treat cancer.
• Asserted Claims: Claims 1, 22, 37, and 48 are identified as independent claims asserted in the complaint (Compl. ¶60).
• Accused Features: The complaint alleges that the proposed generic product, which contains carfilzomib and includes instructions for treating multiple myeloma, is covered by the asserted claims (Compl. ¶60).

U.S. Patent No. 7,737,112 - “Composition For Enzyme Inhibition”

• Patent Identification: U.S. Patent No. 7,737,112 (the “’112 Patent”), entitled “Composition For Enzyme Inhibition,” issued June 15, 2010 (Compl. ¶14).
• Technology Synopsis: This patent claims specific lyophilized pharmaceutical formulations. The invention addresses the need for a stable, soluble formulation for peptide epoxyketone inhibitors like carfilzomib, solving the problem of administering these otherwise poorly soluble compounds. The claimed solution involves formulating the active ingredient with a cyclodextrin, such as sulfobutyl ether beta-cyclodextrin (SBECD), and a buffer, such as citric acid.
• Asserted Claims: Claims 1, 14, 18, and 29 are identified as independent claims asserted in the complaint (Compl. ¶71).
• Accused Features: The complaint alleges the Proposed ANDA Product is covered by these claims because it contains carfilzomib, SBECD, and citric acid (Compl. ¶71).

U.S. Patent No. 8,129,346 - “Compounds For Enzyme Inhibition”

• Patent Identification: U.S. Patent No. 8,129,346 (the “’346 Patent”), entitled “Compounds For Enzyme Inhibition,” issued March 6, 2012 (Compl. ¶15).
• Technology Synopsis: This patent, also in the same family as the ’818 Patent, covers peptide epoxyketone compounds and their use. The claims are directed to methods of inhibiting an N-terminal nucleophile hydrolase, such as the proteasome, by administering one of the claimed compounds.
• Asserted Claims: Claims 1, 22, 37, 48, and 52 are identified as independent claims asserted in the complaint (Compl. ¶82).
• Accused Features: The complaint alleges that the proposed product label will instruct for the administration of carfilzomib to inhibit a hydrolase in a manner that infringes these method claims (Compl. ¶82).

U.S. Patent Nos. 8,207,125; 8,207,126; 8,207,127; and 8,207,297 - “Compounds For Enzyme Inhibition”

• Patent Identification: These four patents (the “’125, ’126, ’127, and ’297 Patents”) were all issued on June 26, 2012, share the title “Compounds For Enzyme Inhibition,” and belong to the same patent family as the ’818 Patent (Compl. ¶¶ 16-19).
• Technology Synopsis: These patents cover various aspects of the core invention, including specific compositions comprising carfilzomib, methods of manufacturing such compositions, and methods of using them to treat diseases like multiple myeloma.
• Asserted Claims: The complaint asserts various claims from each patent, including independent claims 1 and 27 of the ’125 Patent; 1, 7, and 16 of the ’126 Patent; 1, 12, 19, and 23 of the ’127 Patent; and 1, 10, and 19 of the ’297 Patent (Compl. ¶¶ 93, 104, 115, 127).
• Accused Features: The complaint broadly alleges that the Proposed ANDA Product, its composition, its method of manufacture (including reconstitution), and its intended use for treating multiple myeloma are covered by the claims of these respective patents (Compl. ¶¶ 93, 104, 115, 127).

III. The Accused Instrumentality

Product Identification

The accused instrumentality is Defendant Breckenridge's "Proposed ANDA Product," a generic version of Plaintiff’s KYPROLIS® (carfilzomib) for injection, identified as the subject of ANDA No. 209330 (Compl. ¶¶ 3, 5).

Functionality and Market Context

• The product is a lyophilized powder containing the active pharmaceutical ingredient carfilzomib, intended for intravenous use after reconstitution (Compl. ¶¶ 23, 31). Carfilzomib is a tetrapeptide epoxyketone that functions as a proteasome inhibitor (Compl. ¶24). Its mechanism of action involves irreversibly binding to the N-terminal threonine-containing active sites of the 20S proteasome, which leads to an accumulation of protein in multiple myeloma cells and triggers apoptosis (Compl. ¶24).
• The Proposed ANDA Product is intended to be a bioequivalent generic version of KYPROLIS®, a commercially successful drug approved for treating relapsed or refractory multiple myeloma (Compl. ¶¶ 5, 20, 32). The complaint highlights clinical data showing KYPROLIS® nearly doubled progression-free survival in patients compared to the previous standard of care, bortezomib (VELCADE®) (Compl. ¶21).

No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

The complaint alleges infringement of nine patents. For each patent, the infringement theory is predicated on the allegation that the Defendant’s Proposed ANDA Product either is the claimed composition or will be used according to the claimed method. The complaint’s allegations are conclusory and do not map specific product features to individual claim limitations.

For example, regarding the ’818 Patent, the complaint alleges that the Proposed ANDA Product is covered by the asserted claims "because it contains carfilzomib as its active ingredient" (Compl. ¶49). For the ’112 Patent, the complaint alleges infringement because the product "contains carfilzomib, sulfobutyl ether beta-cyclodextrin (SBECD), and citric acid" (Compl. ¶71). For the method patents, the complaint alleges that the proposed product label "will have instructions" for administering the product in a way that infringes (Compl. ¶¶ 60, 82). The complaint does not provide sufficient detail for the creation of a claim chart mapping elements of the asserted claims to features of the accused product.

Identified Points of Contention

• Scope Questions: A central question for the composition-of-matter patents (e.g., ’818 Patent) will be whether the specific chemical structure of carfilzomib, as specified in the ANDA, falls within the scope of the asserted claims. For the formulation patent (e.g., ’112 Patent), a key issue may be whether the term "a buffer," as used in the claims, can be construed to read on the specific citric acid formulation in the accused product, and whether the claimed ratios and properties are met.
• Technical Questions: A primary evidentiary question will be whether the product described in the ANDA is, in fact, the composition claimed in the patents. While the active ingredient is identified as carfilzomib, infringement of formulation claims will depend on the precise quantities and properties of all components in the final lyophilized product, including excipients and potential impurities. For method-of-use claims, the key technical question will be whether the instructions for use in the defendant’s proposed product label direct medical professionals to perform each and every step of the claimed methods.

V. Key Claim Terms for Construction

The Term: "a peptide α',β'-epoxy ketone" (’818 Patent, Claim 1)

• Context and Importance: This term defines the core chemical class of the invention in the primary composition-of-matter patents. The construction of this term is critical because it establishes the foundational scope of the claimed compounds. Practitioners may focus on this term because any ambiguity could open avenues for a non-infringement argument based on a subtle structural difference in the accused product.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The specification describes the inhibitors as belonging to "classes of molecules known as peptide α',β'-epoxides" and provides a generic chemical structure (Formula I) with broadly defined variables, suggesting the term is intended to encompass a wide range of compounds sharing this functional core (’818 Patent, col. 2:26-27, col. 5:53-67).
  • Evidence for a Narrower Interpretation: The specification heavily emphasizes tetrapeptide structures (e.g., Formula II) and provides numerous specific examples with four amino acid residues (’818 Patent, col. 6:51-67). A party might argue that the term, when read in light of the specification as a whole, should be understood as limited to tetrapeptide structures or those with similar properties to the disclosed embodiments.

The Term: "composition" (’112 Patent, Claim 1)

• Context and Importance: This term appears in the preamble of the formulation patent. Its construction will determine whether the claim is limited to a specific combination of ingredients or can be read more broadly. In pharmaceutical cases, the definition of "composition" versus "comprising" can be pivotal in determining whether the presence of unrecited excipients in the accused product avoids infringement.
• Intrinsic Evidence for Interpretation:
  • Evidence for a Broader Interpretation: The claim uses the transitional phrase "comprising," which is generally understood to be open-ended, meaning the presence of additional, unrecited ingredients does not necessarily avoid infringement.
  • Evidence for a Narrower Interpretation: A party could argue that the detailed description of specific formulations, which list precise components and their functions, provides a context that limits the scope of "composition" to the combinations disclosed, particularly if those unrecited ingredients materially alter the properties of the formulation, such as its stability or dissolution profile.

VI. Other Allegations

Indirect Infringement

The complaint alleges active inducement of infringement for the method claims. This allegation is based on the assertion that Defendant’s proposed product label will substantially copy the KYPROLIS® label and will instruct healthcare providers to reconstitute and administer the drug to treat multiple myeloma in a manner that directly infringes (Compl. ¶¶ 33-34, 42). The complaint also pleads contributory infringement, alleging that the Proposed ANDA Product will have no substantial non-infringing use (Compl. ¶¶ 36, 42).

Willful Infringement

The complaint does not use the word "willful" but lays the groundwork for such a claim. It alleges that Defendant had knowledge of the patents-in-suit when it filed its ANDA with a Paragraph IV certification and that Defendant "is knowingly and intentionally infringing" the patents (Compl. ¶¶ 30, 45). The complaint further alleges that Defendant "lacked a good faith basis" for its invalidity and non-infringement positions and that the case is "exceptional" under 35 U.S.C. § 285 (Compl. ¶47).

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

• A central issue will be one of claim scope versus invalidity: do the asserted composition and formulation claims, when properly construed, read on the product specified in Breckenridge's ANDA, and if so, are those claims valid over the prior art? This question encapsulates the classic tension in ANDA litigation, where a broad claim construction favorable for infringement may render the claim more vulnerable to an invalidity challenge.
• A key procedural and substantive question will be one of patent portfolio strength: Onyx has asserted a large family of nine patents covering the compound, its specific formulation, and its methods of use. A core issue for the litigation will be whether this "picket fence" of patents effectively forecloses all commercially viable paths for a generic competitor or if Breckenridge can successfully invalidate or design around a critical patent in the portfolio, such as the formulation patent (’112 Patent), to enable market entry.
• An underlying evidentiary question will be one of good faith: did Breckenridge have a good faith basis for its Paragraph IV certification that the nine asserted patents are invalid or not infringed? The outcome of this question will determine whether Onyx can succeed on its claim for enhanced damages and attorneys' fees under the "exceptional case" standard.