DCT

1:17-cv-01235

Onyx Therap Inc v. Qilu Pharma Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-01235, D. Del., 08/30/2017
  • Venue Allegations: Venue is alleged based on Defendants transacting business in Delaware and deriving substantial revenue from the state. For the purposes of this action, Defendants have agreed not to contest venue.
  • Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of the cancer drug KYPROLIS® (carfilzomib) constitutes an act of infringement of eight patents related to peptide-based proteasome inhibitors and their methods of use.
  • Technical Context: The technology relates to proteasome inhibitors, a class of compounds that disrupt cellular protein degradation pathways and are used as chemotherapeutic agents, particularly for the treatment of multiple myeloma.
  • Key Procedural History: This lawsuit was initiated under the Hatch-Waxman Act after Plaintiff received a Paragraph IV certification notice from Defendants. The notice asserted that the patents-in-suit are invalid, unenforceable, or will not be infringed by the proposed generic product, thereby triggering the patent infringement action.

Case Timeline

Date Event
2004-04-15 Earliest Priority Date for ’818, ’704, ’346, ’125, ’126, ’127, ’297 Patents
2004-08-06 Earliest Priority Date for ’042 Patent
2007-06-19 U.S. Patent No. 7,232,818 Issued
2008-08-26 U.S. Patent No. 7,417,042 Issued
2009-02-17 U.S. Patent No. 7,491,704 Issued
2012-03-06 U.S. Patent No. 8,129,346 Issued
2012-06-26 U.S. Patent Nos. 8,207,125; 8,207,126; 8,207,127; and 8,207,297 Issued
2012-07-20 FDA grants approval for Plaintiff's KYPROLIS® (carfilzomib) product
2017-07-20 Plaintiff receives Defendants' ANDA notice letter
2017-08-30 Complaint Filing Date

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

No probative visual evidence provided in complaint.

U.S. Patent No. 7,417,042 - "Compounds For Enzyme Inhibition," Issued August 26, 2008 (’042 Patent)

The Invention Explained

  • Problem Addressed: The patent's background section describes a need for small molecule inhibitors for a class of enzymes known as N-terminal nucleophile (Ntn) hydrolases, which includes the proteasome. The patent notes that existing inhibitors often lack the necessary specificity, stability, or potency to be effective as research tools or therapeutic agents (’042 Patent, col. 1:11-2:20).
  • The Patented Solution: The invention provides a class of peptide-based compounds, including peptide epoxides, that are designed to potently, selectively, and irreversibly inhibit proteasome activity (’042 Patent, col. 2:40-44). The solution combines a peptide backbone, which confers specificity for the enzyme's active site, with a reactive epoxide functional group that forms a covalent bond with the N-terminal threonine residue of the proteasome’s catalytic subunits, thereby inactivating the enzyme (’042 Patent, col. 3:4-14; Abstract).
  • Technical Importance: This approach provides for highly selective inhibitors of the proteasome’s chymotrypsin-like activity without substantially inhibiting other proteases, offering a targeted mechanism for therapeutic intervention in diseases like cancer (’042 Patent, col. 2:45-50).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claims 2-6, 15-24, and 37 (Compl. ¶42).
  • Independent Claim 1 requires:
    • A compound having a structure of formula I, or a pharmaceutically acceptable salt thereof.
    • Formula I defines a tetrapeptide analog with specific stereochemistry.
    • The structure includes a terminal epoxide ring.
    • The structure includes various side chains (R groups) defined by specific chemical classes.

U.S. Patent No. 7,232,818 - "Compounds For Enzyme Inhibition," Issued June 19, 2007 (’818 Patent)

The Invention Explained

  • Problem Addressed: The patent addresses the same technical problem as the ’042 Patent: a need for potent and selective small molecule inhibitors of Ntn hydrolases, such as the proteasome, for use as therapeutic agents and research probes (’818 Patent, col. 1:11-2:20).
  • The Patented Solution: The patented solution is a class of peptide α',β'-epoxides and α',β'-aziridines that efficiently and irreversibly bind to Ntn hydrolases (’818 Patent, col. 2:26-31). As described in the detailed description, these molecules are designed with a peptide portion for selective targeting and an epoxide or aziridine warhead that covalently binds to the N-terminal nucleophilic residue (e.g., threonine) of the enzyme's active site, thereby achieving potent and specific inhibition (’818 Patent, col. 3:4-14).
  • Technical Importance: The invention provided a class of highly selective inhibitors for the chymotrypsin-like activity of the proteasome, enabling targeted disruption of cellular processes regulated by the proteasome, such as NF-κB activation, with potential anti-inflammatory and anti-cancer effects (’818 Patent, col. 2:45-56).

Key Claims at a Glance

  • The complaint asserts independent claims 1 and 49 and dependent claims 2-4, 23-25, 38, and 50 (Compl. ¶53).
  • Independent Claim 1 requires:
    • A compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof.
    • Formula I defines a class of tetrapeptide analogs.
    • The structure includes a terminal epoxide or aziridine ring.
    • The structure includes a specific N-terminal functional group defined as N(R⁶)LQR⁷.
    • The structure includes various side chains defined by Markush groups of chemical moieties.

U.S. Patent No. 7,491,704 (’704 Patent) - "Compounds For Enzyme Inhibition," Issued February 17, 2009

  • Technology Synopsis: This patent claims peptide-based compounds, including peptide epoxyketones, that function as inhibitors of Ntn hydrolases such as the proteasome. The claims are directed at specific classes of these compounds for use in treating diseases like cancer.
  • Asserted Claims: Claims 1-3, 22-24, 37, and 48 are asserted (Compl. ¶64). Claim 1 is independent.
  • Accused Features: The complaint alleges that the use of the Proposed ANDA Product, which contains carfilzomib, to treat cancer (specifically multiple myeloma) as directed by its proposed label will infringe the patent (Compl. ¶64).

U.S. Patent No. 8,129,346 (’346 Patent) - "Compounds For Enzyme Inhibition," Issued March 6, 2012

  • Technology Synopsis: The patent claims methods of using peptide-based proteasome inhibitors to treat various diseases. The technology involves administering a therapeutically effective amount of a compound, such as carfilzomib, to inhibit an N-terminal nucleophile hydrolase.
  • Asserted Claims: Claims 1-3, 22-24, 37, 48-49, and 52-60 are asserted (Compl. ¶75). Claim 1 is independent.
  • Accused Features: The complaint alleges that the use of the Proposed ANDA Product as instructed on its label to inhibit an N-terminal nucleophile hydrolase (the 20S proteasome) will infringe the patent (Compl. ¶75).

U.S. Patent No. 8,207,125 (’125 Patent) - "Compounds For Enzyme Inhibition," Issued June 26, 2012

  • Technology Synopsis: This patent claims pharmaceutical compositions comprising specific peptide epoxyketone compounds, including carfilzomib, along with a pharmaceutically acceptable carrier. The technology covers the formulation of these proteasome inhibitors into deliverable drug products.
  • Asserted Claims: Claims 1, 4, 5, 7-10, 12, 13, 16, 18-25, and 27-30 are asserted (Compl. ¶86). Claim 1 is independent.
  • Accused Features: The Proposed ANDA Product itself, as a composition comprising carfilzomib, is alleged to infringe (Compl. ¶86).

U.S. Patent No. 8,207,126 (’126 Patent) - "Compounds For Enzyme Inhibition," Issued June 26, 2012

  • Technology Synopsis: This patent claims pharmaceutical compositions comprising a peptide epoxyketone, such as carfilzomib, prepared by a claimed method. The technology covers not just the compound itself but also compositions resulting from a specific manufacturing or preparation process.
  • Asserted Claims: Claims 1-5, 7-14, and 16-21 are asserted (Compl. ¶97). Claim 1 is independent.
  • Accused Features: The complaint alleges that the Proposed ANDA Product and its method of manufacture are covered by the patent, specifically referencing the instructions for reconstituting the lyophilized powder before use (Compl. ¶97).

U.S. Patent No. 8,207,127 (’127 Patent) - "Compounds For Enzyme Inhibition," Issued June 26, 2012

  • Technology Synopsis: The patent claims methods of treating hematopoietic cancers, such as multiple myeloma, by administering a pharmaceutical composition containing a specific peptide epoxyketone, such as carfilzomib.
  • Asserted Claims: Claims 1, 12-17, 19, 20, and 23-27 are asserted (Compl. ¶108). Claim 1 is independent.
  • Accused Features: The use of the Proposed ANDA Product to treat multiple myeloma, as instructed by its proposed label, is alleged to infringe (Compl. ¶108).

U.S. Patent No. 8,207,297 (’297 Patent) - "Compounds For Enzyme Inhibition," Issued June 26, 2012

  • Technology Synopsis: This patent claims pharmaceutical compositions comprising carfilzomib that are prepared by specific claimed methods, similar to the '126 Patent.
  • Asserted Claims: Claims 1-8, 10-17, and 19-24 are asserted (Compl. ¶119). Claim 1 is independent.
  • Accused Features: The Proposed ANDA Product, as a composition comprising carfilzomib prepared by the claimed methods, is alleged to infringe (Compl. ¶119).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is Defendants' "Proposed ANDA Product," a generic version of Onyx's KYPROLIS® for injection (Compl. ¶¶4, 9).

Functionality and Market Context

  • The Proposed ANDA Product is a 60 mg lyophilized powder for reconstitution containing the active pharmaceutical ingredient carfilzomib (Compl. ¶4). Carfilzomib is a tetrapeptide epoxyketone that functions as a proteasome inhibitor by irreversibly binding to the N-terminal threonine-containing active sites of the 20S proteasome (Compl. ¶28).
  • The complaint alleges that the proposed product, upon approval, will be marketed for intravenous administration to treat relapsed or refractory multiple myeloma (Compl. ¶¶4, 35). It further alleges the product will be sold with instructions for use that substantially copy those of KYPROLIS®, including directions for reconstituting the lyophilized powder and administering it to patients (Compl. ¶37).

IV. Analysis of Infringement Allegations

The complaint alleges that the very act of filing ANDA No. 209528 constitutes a technical act of infringement under 35 U.S.C. § 271(e)(2) (Compl. ¶¶43, 54). The substantive allegations for the two lead patents are summarized below.

’042 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound having a structure of formula I... The Proposed ANDA Product contains carfilzomib, which is alleged to be a compound covered by the asserted claims. ¶42 col. 51:50-52:25
or a pharmaceutically acceptable salt thereof. The Proposed ANDA Product is or contains a pharmaceutically acceptable form of carfilzomib. ¶4 col. 39:6-40:8

’818 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound having a structure of formula (I)... The Proposed ANDA Product contains carfilzomib as its active ingredient, which is alleged to be a compound of formula (I). ¶53 col. 5:55-6:67
wherein... R⁵ is N(R⁶)LQR⁷ The Proposed ANDA Product contains carfilzomib, which has a terminal chemical group alleged to fall within the definition of N(R⁶)LQR⁷. ¶53 col. 6:21
or a pharmaceutically acceptable salt thereof. The Proposed ANDA Product is or contains a pharmaceutically acceptable form of carfilzomib. ¶4 col. 39:6-40:8

Identified Points of Contention

  • Scope Questions: In an ANDA case where the active ingredient is identical, infringement disputes often focus on the specific scope of claim terms rather than the basic mechanism of action. A potential question is whether the full scope of the asserted claims is valid in light of the prior art, an issue that Defendants' Paragraph IV certification raises but which is not detailed in the complaint (Compl. ¶32). For the composition-by-process claims, a dispute may arise as to whether Defendants' manufacturing process is captured by the claim language.
  • Technical Questions: The complaint bases its infringement allegations on "information and belief" that the Proposed ANDA Product contains carfilzomib and will be used according to an infringing label. A central evidentiary question will be what proof Plaintiff develops during discovery regarding the exact composition, method of manufacture, and final approved labeling of Defendants' product to demonstrate that it meets every limitation of the asserted claims.

V. Key Claim Terms for Construction

  • The Term: "peptide α',β'-epoxy ketone" (appears in the specification of both patents, e.g., ’818 Patent, col. 3:5)
  • Context and Importance: This term describes the core chemical class of the invention. The definition of "peptide" and the specific structural requirements of the "α',β'-epoxy ketone" moiety will be critical for determining the scope of the composition claims. Practitioners may focus on this term because any ambiguity could either narrow the claims to the specific embodiments disclosed or broaden them to cover related structures, directly impacting the infringement analysis against Qilu's specific formulation.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification describes peptides as having a "repeating backbone structure with side chains" and states they can include both natural and non-naturally occurring amino acids, D-amino acids, and various backbone modifications, suggesting the term "peptide" is not limited to traditional definitions (’818 Patent, col. 3:33-4:44, col. 5:10-44).
    • Evidence for a Narrower Interpretation: The claims themselves, such as Claim 1 of the ’818 Patent, recite a specific tetrapeptide structure with four defined side-chain positions. A defendant may argue that the term, in the context of the claims, should be limited to structures with this specific number and arrangement of peptide units, rather than any molecule with at least one peptide bond.

VI. Other Allegations

Indirect Infringement

  • The complaint alleges that Defendants will induce infringement by providing a product label that will instruct healthcare providers to reconstitute and administer the Proposed ANDA Product to treat multiple myeloma in a manner that directly infringes one or more method claims of the patents-in-suit (Compl. ¶¶37-38, 46).

Willful Infringement

  • The complaint alleges that Defendants had knowledge of the patents-in-suit at the time they filed their ANDA, as evidenced by their Paragraph IV certification (Compl. ¶¶34, 47, 58). This alleged pre-suit knowledge forms the basis for the assertion that any subsequent infringement upon FDA approval will be willful and intentional (Compl. ¶¶49, 60). The complaint also asserts that Defendants lacked a good faith basis for their invalidity and non-infringement allegations, supporting a claim for an exceptional case under 35 U.S.C. § 285 (Compl. ¶¶51, 62).

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

  • A central issue will be one of patent validity: can Defendants prove by clear and convincing evidence that the asserted claims are invalid for reasons such as obviousness or lack of enablement, thereby overcoming the patents’ statutory presumption of validity and clearing a path for their generic product?
  • A second key question will relate to claim scope and infringement: for the patents claiming compositions "prepared by" specific methods (e.g., ’126 and ’297 patents), a dispositive issue may be whether the manufacturing and reconstitution process for Defendants' Proposed ANDA Product falls within the literal scope of the claimed methods.
  • A final core issue will be one of induced infringement: assuming the method-of-use claims are found valid, will the final, FDA-approved product label for Defendants’ generic carfilzomib inevitably lead healthcare providers to use the product in a manner that directly infringes the patented methods of treatment, thereby making Defendants liable for inducement?