DCT

1:17-cv-00449

Onyx Therap Inc v. Teva Pharma USA Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-00449, D. Del., 04/20/2017
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendant Teva Pharmaceuticals USA, Inc. is a Delaware corporation that markets and sells generic drugs in the district. Plaintiff further alleges that Defendant Teva Pharmaceutical Industries Ltd. works in concert with its U.S. subsidiary and that Delaware will be a destination for the accused product.
  • Core Dispute: Plaintiff alleges that Defendants' proposed generic carfilzomib product, for which they seek FDA approval via an Abbreviated New Drug Application (ANDA), will infringe nine U.S. patents covering the compound, its formulation, and its methods of use for treating multiple myeloma.
  • Technical Context: The technology relates to peptide-based proteasome inhibitors, a class of chemotherapeutic agents that function by disrupting the cellular machinery responsible for protein degradation, leading to apoptosis in cancer cells, particularly in multiple myeloma.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff's receipt of a Paragraph IV Notice Letter from Teva, which stated that Teva's ANDA filing included a certification that Plaintiff's patents are invalid, unenforceable, and/or will not be infringed by the proposed generic product. Plaintiff filed this complaint within the 45-day statutory window, triggering an automatic 30-month stay of FDA approval for Teva's ANDA.

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
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-XX KYPROLIS® (carfilzomib) receives FDA "Fast Track" designation
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, 8,207,297 Issue
2012-07-20 FDA grants accelerated approval for KYPROLIS® (carfilzomib)
2017-03-07 Plaintiff receives Teva's Paragraph IV Notice Letter
2017-04-20 Complaint Filed

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

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

The Invention Explained

  • Problem Addressed: The patent's background section describes a need for small molecule inhibitors of the proteasome—a key cellular component for protein degradation—that possess improved specificity, stability, and potency over existing compounds. Such improved inhibitors are needed to better explore the proteasome's role in cellular processes and to serve as more effective therapeutics (ʼ042 Patent, col. 2:11-20).
  • The Patented Solution: The invention provides peptide-based compounds that feature a heteroatom-containing, three-membered ring (such as an epoxide) at one end of the peptide chain. These molecules are designed to efficiently, irreversibly, and selectively inhibit N-terminal nucleophile (Ntn) hydrolases, with a particular focus on inhibiting the chymotrypsin-like activity of the 20S proteasome ('042 Patent, Abstract; col. 2:21-31). This targeted inhibition disrupts cellular protein turnover, which can induce apoptosis in cancer cells.
  • Technical Importance: The invention provided a class of highly potent and selective inhibitors for the proteasome, which was an established therapeutic target for cancers like multiple myeloma, offering the potential for improved efficacy and reduced off-target toxicity (Compl. ¶28).

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 of the '042 Patent recites:
    • A peptide comprising a specific multi-unit backbone structure.
    • The peptide is terminated with an epoxide or aziridine functional group.
    • Specific definitions for the side chains (R¹, R², R³, R⁴) extending from the peptide backbone, defined by Markush groups including alkyl and aralkyl moieties.
    • A specific N-terminal capping group structure defined as R⁵.

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

The Invention Explained

  • Problem Addressed: The patent addresses the same technical problem as the ʼ042 Patent: the need for small molecule inhibitors with increased specificity and potency for targeting the proteasome to serve as both research tools and therapeutic agents ('818 Patent, col. 2:11-20).
  • The Patented Solution: The invention discloses a class of peptide-based compounds, characterized as peptide α',β'-epoxides or α',β'-aziridines, that selectively and irreversibly inhibit N-terminal nucleophile (Ntn) hydrolases. The compounds are designed to target the chymotrypsin-like activity of the proteasome, disrupting protein degradation and thereby providing anti-inflammatory and anti-proliferative therapeutic effects ('818 Patent, Abstract; col. 3:56-65).
  • Technical Importance: This technology provided a novel class of compounds for selectively targeting the proteasome, a key regulator of cellular function, with potential applications in treating cancer and inflammatory diseases (Compl. ¶28).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 38, 49 and dependent claims 2-4, 23-25, 50 (Compl. ¶53).
  • Independent Claim 1 of the '818 Patent recites:
    • A compound of a specific chemical structure (Formula I).
    • The structure is a peptide backbone of at least three peptide units, capped at the C-terminus by an epoxide or aziridine ring.
    • The structure includes a specific N-terminal capping group defined by the formula N(R⁶)LQR⁷.
    • Specific definitions for the side chains (R¹, R², R³, R⁴) are provided through Markush groups.

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

  • Patent Identification: U.S. Patent No. 7491704, "Compounds For Enzyme Inhibition," issued February 17, 2009.
  • Technology Synopsis: This patent, part of the same family as the '818 and '042 patents, also claims peptide epoxyketone compounds that inhibit proteasome activity. The claimed compounds are useful for treating diseases characterized by proteasome activity, such as cancer.
  • Asserted Claims: Claims 1-3, 22-24, 31, 37, and 48 are asserted (Compl. ¶64).
  • Accused Features: The complaint alleges that the use of Teva's Proposed ANDA Product, which contains carfilzomib, will infringe because the product label will instruct its administration for treating cancer, specifically multiple myeloma (Compl. ¶64).

U.S. Patent No. 7,737,112 - "Composition for Enzyme Inhibition"

  • Patent Identification: U.S. Patent No. 7737112, "Composition for Enzyme Inhibition," issued June 15, 2010.
  • Technology Synopsis: This patent claims pharmaceutical compositions comprising a peptide-based proteasome inhibitor, a cyclodextrin, and a buffer. The formulation is designed to improve the solubility and stability of the active pharmaceutical ingredient.
  • Asserted Claims: Claims 1-9, 14, 18-24, and 29-32 are asserted (Compl. ¶75).
  • Accused Features: The complaint alleges infringement because Teva's Proposed ANDA Product is a composition that contains carfilzomib (the proteasome inhibitor), sulfobutyl ether beta-cyclodextrin (SBECD, a cyclodextrin), and citric acid (a buffer component) (Compl. ¶75).

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

  • Patent Identification: U.S. Patent No. 8129346, "Compounds For Enzyme Inhibition," issued March 6, 2012.
  • Technology Synopsis: This patent claims methods of treating various diseases, including cancer, by administering a peptide epoxyketone proteasome inhibitor. The claims are directed to methods of use for inhibiting an N-terminal nucleophile hydrolase.
  • Asserted Claims: Claims 1-3, 22-24, 37, 48, 49, and 52-60 are asserted (Compl. ¶86).
  • Accused Features: The complaint alleges that the use of Teva's Proposed ANDA Product will infringe because its label will instruct administration to inhibit proteasome activity in blood and tissue, thereby delaying tumor growth (Compl. ¶86).

U.S. Patent No. 8,207,125 - "Compounds For Enzyme Inhibition"

  • Patent Identification: U.S. Patent No. 8207125, "Compounds For Enzyme Inhibition," issued June 26, 2012.
  • Technology Synopsis: This patent claims specific compositions comprising a peptide epoxyketone compound. The claims are directed to the specific chemical structure of the proteasome inhibitor.
  • Asserted Claims: Claims 1, 4, 5, 7-10, 12, 13, 16, 18-25, and 27-30 are asserted (Compl. ¶97).
  • Accused Features: The complaint alleges that Teva's Proposed ANDA Product is a composition that comprises carfilzomib and therefore infringes the asserted claims (Compl. ¶97).

U.S. Patent No. 8,207,126 - "Compounds For Enzyme Inhibition"

  • Patent Identification: U.S. Patent No. 8207126, "Compounds For Enzyme Inhibition," issued June 26, 2012.
  • Technology Synopsis: This patent claims compositions comprising carfilzomib that are prepared by a claimed method, which includes steps like reconstituting a lyophilized powder.
  • Asserted Claims: Claims 1-5, 7-14, and 16-21 are asserted (Compl. ¶108).
  • Accused Features: The complaint alleges infringement because Teva’s product is a composition comprising carfilzomib and its label will instruct healthcare providers to reconstitute the product from a powder, thereby practicing the claimed method (Compl. ¶108).

U.S. Patent No. 8,207,127 - "Compounds For Enzyme Inhibition"

  • Patent Identification: U.S. Patent No. 8207127, "Compounds For Enzyme Inhibition," issued June 26, 2012.
  • Technology Synopsis: This patent claims methods of treating hematopoietic cancer, such as multiple myeloma, by administering a composition containing a peptide epoxyketone like carfilzomib.
  • Asserted Claims: Claims 1, 12-17, 19, 20, and 23-27 are asserted (Compl. ¶119).
  • Accused Features: The complaint alleges that use of Teva’s Proposed ANDA Product will infringe because its label will instruct administration to treat multiple myeloma (Compl. ¶119).

U.S. Patent No. 8,207,297 - "Compounds For Enzyme Inhibition"

  • Patent Identification: U.S. Patent No. 8207297, "Compounds For Enzyme Inhibition," issued June 26, 2012.
  • Technology Synopsis: This patent claims compositions comprising carfilzomib prepared by specified methods.
  • Asserted Claims: Claims 1-8, 10-17, and 19-24 are asserted (Compl. ¶130).
  • Accused Features: The complaint alleges infringement because Teva’s product is a composition comprising carfilzomib that is prepared by the claimed methods (Compl. ¶130).

III. The Accused Instrumentality

Product Identification

The accused product is Teva's "proposed generic carfilzomib 60 mg lyophilized powder for reconstitution and for intravenous administration" (the "Proposed ANDA Product"), which is the subject of ANDA No. 210170 (Compl. ¶4).

Functionality and Market Context

  • The Proposed ANDA Product contains the active ingredient carfilzomib, which is a proteasome inhibitor (Compl. ¶35). Carfilzomib is described as a tetrapeptide epoxyketone that inhibits proteasome function by irreversibly binding to the N-terminal threonine-containing active sites of the 20S proteasome (Compl. ¶28). This inhibition leads to an accumulation of proteins in multiple myeloma cells, triggering apoptosis and killing the cancer cells (Compl. ¶28). The product is a lyophilized powder intended to be reconstituted for intravenous use to treat patients with relapsed or refractory multiple myeloma (Compl. ¶4, ¶35, ¶37).
  • The complaint alleges that the Proposed ANDA Product is a generic version of Onyx's KYPROLIS®, a commercially successful drug that demonstrated in clinical trials an ability to almost double progression-free survival in patients compared to a prior standard of care (Compl. ¶8, ¶25).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

'042 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A peptide comprising at least three peptide units... The Proposed ANDA Product contains carfilzomib, which is a tetrapeptide epoxyketone. ¶28, ¶42 col. 3:4-5
...having a structure of formula I or a pharmaceutically acceptable salt thereof The Proposed ANDA Product is a composition comprising carfilzomib as its active ingredient, which is alleged to be covered by the claims of the '042 Patent. ¶42 col. 5:32-41
wherein X is O or NH... Carfilzomib contains an epoxide functional group, where X is O. ¶28 col. 5:5-10
R¹, R², R³, and R⁴ are each independently selected from [a specified Markush group] The complaint alleges that the specific amino acid side chains of carfilzomib fall within the definitions provided for R¹, R², R³, and R⁴ in the asserted claims. ¶42 col. 5:11-17
R⁵ is N(R⁶)LQR⁷... The complaint alleges that the N-terminal group of carfilzomib falls within the definition provided for R⁵ in the asserted claims. ¶42 col. 5:18
  • Identified Points of Contention:
    • Scope Questions: A central issue will be whether the specific chemical structure of carfilzomib falls entirely within the scope of the Markush groups defining the peptide side chains (R¹, R², R³, R⁴) and the N-terminal cap (R⁵) as recited in Claim 1 of the ’042 Patent. The litigation may focus on whether any ambiguity in the definitions of terms like "C1-6alkyl" or "heterocyclylM" creates a non-infringement argument for Teva.
    • Technical Questions: The complaint's infringement theory rests on the allegation that the accused product "contains carfilzomib" (Compl. ¶42). A key factual question will be the precise chemical identity and purity of Teva's active pharmaceutical ingredient and whether it meets every structural limitation of the asserted claims.

'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 covered by the claims of the '818 Patent. ¶53 col. 5:44-59
wherein each A is independently selected from C=O... The carfilzomib molecule contains peptide bonds, which include C=O moieties. ¶28 col. 5:60-61
X is selected from O, NH, and N─C1-6alkyl... Carfilzomib contains an epoxide functional group, where X is O. ¶28 col. 5:9-10
R¹, R², R³, and R⁴ are each independently selected from [a specified Markush group] The complaint alleges that the specific amino acid side chains of carfilzomib fall within the definitions provided for R¹, R², R³, and R⁴ in the asserted claims. ¶53 col. 6:18-25
R⁵ is N(R⁶)LQR⁷... The complaint alleges that the N-terminal group of carfilzomib, which is a morpholinoacetyl group, falls within the definition provided for R⁵ in the asserted claims. ¶28, ¶53 col. 6:26
  • Identified Points of Contention:
    • Scope Questions: Similar to the '042 Patent, a primary point of contention will be the construction of the Markush groups in Claim 1 of the ’818 Patent. Infringement will depend on whether the specific N-terminal morpholino group and amino acid side chains of carfilzomib are encompassed by the claim's definitions for R⁵, R¹, R², R³, and R⁴.
    • Technical Questions: As this is an ANDA case, discovery will likely focus on the precise methods Teva uses to synthesize carfilzomib and whether those methods result in a compound, including any polymorphs or stereoisomers, that meets all limitations of the asserted claims.

V. Key Claim Terms for Construction

  • The Term: "heterocyclylM-" (within the definition of R⁷ in Claim 1 of the '818 Patent)
  • Context and Importance: The active ingredient carfilzomib contains a morpholino group at its N-terminus. The infringement analysis for the '818 Patent will depend on whether this morpholino group is properly classified as a "heterocyclylM-" structure as required by the claim. Practitioners may focus on this term because the N-terminal cap is a key structural feature distinguishing different peptide inhibitors.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification of the '818 Patent explicitly lists "morpholino" as an example of a "heterocyclyl" group ('818 Patent, col. 6:12-14). This could support an interpretation that a morpholino group attached via a linker (the "M" moiety) falls within the claim's scope.
    • Evidence for a Narrower Interpretation: Defendants may argue that the specific embodiments or examples in the patent only disclose a limited subset of "heterocyclylM-" groups, potentially suggesting a narrower construction that might exclude the specific morpholinoacetyl structure of carfilzomib. The specification's description of preferred embodiments could be cited to argue for a more limited scope ('818 Patent, col. 8:12-14).

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement for all asserted patents. The factual basis is that Defendants' proposed product labeling will allegedly substantially copy the labeling for KYPROLIS® and will instruct healthcare providers to reconstitute and administer the product to treat multiple myeloma in a manner that directly infringes the asserted claims (Compl. ¶37, ¶38, ¶44, ¶64). The complaint also alleges that the product will have no substantial non-infringing use (Compl. ¶40).
  • Willful Infringement: The complaint alleges that Defendants had knowledge of the Patents-in-Suit when they filed ANDA No. 210170 with a Paragraph IV Certification (Compl. ¶34). This alleged pre-suit knowledge, combined with the allegation that Defendants "knowingly and intentionally" infringe, forms the basis for willfulness (Compl. ¶49, ¶60). The complaint further alleges that Defendants "lacked a good faith basis" for their invalidity and non-infringement positions, seeking a finding that the case is exceptional under 35 U.S.C. § 285 (Compl. ¶51, ¶62).

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

  • A core issue will be one of definitional scope: Does the specific chemical structure of carfilzomib, including its N-terminal morpholinoacetyl group and its particular stereochemistry, fall within the literal scope of the Markush groups recited in the asserted composition of matter claims? The dispute will likely center on the proper construction of terms defining the peptide's constituent parts.
  • A key evidentiary question for the formulation patent ('112 Patent) will be one of compositional identity: Does Teva's proposed formulation, which contains carfilzomib, sulfobutyl ether beta-cyclodextrin, and citric acid, meet every limitation of the asserted formulation claims, including any specific ratios or properties required by those claims?
  • A central legal question for the method-of-use patents will be induced infringement: Assuming direct infringement by clinicians is established, can Onyx prove that Teva's proposed product label would encourage, recommend, or promote an infringing use with the specific intent to cause infringement, or does the label also describe substantial non-infringing uses?