DCT

1:17-cv-01811

Onyx Therap Inc v. DR Reddys Laboratories Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:17-cv-01811, D. Del., 12/18/2017
  • Venue Allegations: Venue is alleged to be proper as Defendants regularly transact business and derive substantial revenue from pharmaceutical sales in Delaware. For the purposes of this action, Defendants have agreed not to contest jurisdiction or venue.
  • Core Dispute: Plaintiff alleges that Defendants' filing of an Abbreviated New Drug Application (ANDA) to market a generic version of Plaintiff's KYPROLIS® (carfilzomib) constitutes an act of infringement of eight U.S. patents related to proteasome inhibitor compounds, compositions, and methods of use.
  • Technical Context: The technology concerns tetrapeptide epoxyketone compounds that function as proteasome inhibitors for the treatment of cancers, particularly multiple myeloma.
  • Key Procedural History: The action was initiated under the Hatch-Waxman Act following Defendants' submission of ANDA No. 209422 with a Paragraph IV certification, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed. The complaint was filed within the 45-day period following receipt of Defendants' notice letter, triggering a 30-month statutory stay of FDA approval for the proposed generic product.

Case Timeline

Date Event
2004-04-15 Earliest Priority Date Asserted (’818, ’704, ’346, ’125, ’126, ’127, ’297 Patents)
2004-08-06 Earliest Priority Date Asserted (’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 approves Onyx's KYPROLIS® (carfilzomib) for injection
2017-11-03 Defendants send Paragraph IV notice letter regarding ANDA No. 209422
2017-11-06 Plaintiff receives Defendants' notice letter
2017-12-18 Complaint filed

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

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

  • Issued: August 26, 2008

The Invention Explained

  • Problem Addressed: The patent family addresses a need for small-molecule inhibitors of proteasome activity that possess improved specificity, stability, and potency over existing compounds, which are necessary tools to study and therapeutically target the ubiquitin-proteasome pathway in eukaryotes (’818 Patent, col. 3:11-21).
  • The Patented Solution: The invention discloses a class of peptide-based compounds, specifically peptide epoxyketones, designed to efficiently, irreversibly, and selectively inhibit certain activities of N-terminal nucleophile (Ntn) hydrolases like the proteasome (’818 Patent, col. 3:25-31). These compounds are structured to form covalent adducts with the proteasome’s catalytic sites, thereby inhibiting its function and triggering apoptosis in cancer cells like those found in multiple myeloma (Compl. ¶30; ’818 Patent, col. 4:5-14).
  • Technical Importance: The development of potent and selective proteasome inhibitors provided a new class of antitumor agents for cancers, such as multiple myeloma, that depend on the proteasome pathway for survival and proliferation (Compl. ¶26, 30).

Key Claims at a Glance

  • The complaint asserts independent claim 1 and dependent claims 2-6, 15-24, and 37 (Compl. ¶45).
  • Independent Claim 1 defines a chemical compound of formula I, which is a class of peptide epoxyketones characterized by:
    • A specific tetrapeptide backbone structure.
    • An N-terminal functionalizing group.
    • Specific side chains at defined positions (R¹, R², R³, R⁴).
    • A C-terminal epoxyketone moiety.

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

  • Issued: June 19, 2007

The Invention Explained

  • Problem Addressed: As with the ’042 Patent, this patent addresses the need for potent and selective small-molecule inhibitors to explore the cellular and molecular roles of the proteasome, a key component of the protein degradation pathway implicated in numerous diseases (’818 Patent, col. 3:11-21).
  • The Patented Solution: The patent describes a class of peptide-based compounds containing a heteroatom-containing three-membered ring, such as an epoxide or aziridine, which can selectively inhibit specific activities of Ntn hydrolases like the 20S proteasome (’818 Patent, Abstract). The detailed description explains that these compounds are designed to selectively target the chymotrypsin-like activity of the proteasome, a key function for degrading proteins in cancer cells (’818 Patent, col. 3:45-50, 64-65).
  • Technical Importance: The selective inhibition of the proteasome’s chymotrypsin-like activity offers a targeted mechanism for therapeutic intervention in diseases like cancer and inflammatory conditions, with potentially fewer off-target effects than less selective inhibitors (’818 Patent, col. 3:51-58).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 38, and 49, and dependent claims 2-4, 23-25, and 50 (Compl. ¶56).
  • Independent Claim 1 defines a chemical compound of formula I, a broad genus of peptide epoxyketones characterized by:
    • A peptide structure with a defined number of backbone units.
    • Variable side chains (R¹, R², R³, R⁴).
    • An N-terminal functional group (R⁵).
    • A C-terminal group X, which includes an epoxide ring.

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

  • Issued: February 17, 2009
  • Technology Synopsis: This patent claims methods of treating cancer in a subject. The claimed method involves administering a pharmaceutical composition containing a peptide epoxyketone compound that inhibits proteasome activity (’704 Patent, Abstract; col. 63:25-34).
  • Asserted Claims: Independent claims 1, 22, 37, and 48 are asserted (Compl. ¶67).
  • Accused Features: The proposed product label for Defendants' generic carfilzomib will allegedly instruct healthcare providers to administer the product to treat multiple myeloma, a type of cancer, thereby inducing infringement of the claimed methods (Compl. ¶67).

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

  • Issued: March 6, 2012
  • Technology Synopsis: This patent claims methods for inhibiting an N-terminal nucleophile hydrolase, such as a proteasome. The method comprises contacting the hydrolase with a peptide epoxyketone compound (’346 Patent, Abstract; col. 63:23-33).
  • Asserted Claims: Independent claims 1, 22, 37, 48, 52, and 56 are asserted (Compl. ¶77).
  • Accused Features: The administration of Defendants' carfilzomib product is alleged to directly inhibit the proteasome, an N-terminal nucleophile hydrolase, thereby infringing the claimed methods (Compl. ¶77).

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

  • Issued: June 26, 2012
  • Technology Synopsis: This patent is directed to pharmaceutical compositions comprising a specific peptide epoxyketone compound, carfilzomib, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers (’125 Patent, Abstract; col. 63:39-49).
  • Asserted Claims: Independent claims 1, 18, and 27 are asserted (Compl. ¶87).
  • Accused Features: Defendants' proposed generic product is alleged to be a composition that comprises carfilzomib and is therefore covered by the patent's claims (Compl. ¶87).

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

  • Issued: June 26, 2012
  • Technology Synopsis: This patent claims a composition comprising carfilzomib that is prepared by a specific claimed method. The method involves steps like lyophilizing a solution containing the active ingredient to form a solid composition (’126 Patent, col. 63:23-38).
  • Asserted Claims: Independent claims 1, 7, and 16 are asserted (Compl. ¶98).
  • Accused Features: The complaint alleges that Defendants' proposed product is a composition comprising carfilzomib prepared by the claimed method of manufacture, and that its label will instruct reconstitution by a claimed method (Compl. ¶98).

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

  • Issued: June 26, 2012
  • Technology Synopsis: This patent claims a method of treating multiple myeloma in a subject. The method comprises administering a therapeutically effective amount of a pharmaceutical composition containing carfilzomib (’127 Patent, Abstract; col. 63:23-33).
  • Asserted Claims: Independent claims 1, 12, and 23 are asserted (Compl. ¶109).
  • Accused Features: The proposed product label for Defendants' generic carfilzomib will allegedly instruct its administration for the treatment of multiple myeloma, thereby inducing infringement of the claimed methods (Compl. ¶109).

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

  • Issued: June 26, 2012
  • Technology Synopsis: This patent claims a composition comprising carfilzomib prepared by a claimed method. The method includes steps such as lyophilizing a solution containing the compound and a cyclodextrin to create a solid composition (’297 Patent, Abstract; col. 63:24-40).
  • Asserted Claims: Independent claims 1, 10, and 19 are asserted (Compl. ¶119).
  • Accused Features: Defendants' proposed product is alleged to be a composition comprising carfilzomib prepared by the claimed methods (Compl. ¶119).

III. The Accused Instrumentality

  • Product Identification: The accused instrumentality is Defendants’ proposed generic carfilzomib 60 mg lyophilized powder for reconstitution and intravenous administration, which is the subject of ANDA No. 209422 (Compl. ¶4).
  • Functionality and Market Context: The proposed ANDA product contains carfilzomib as its active pharmaceutical ingredient (Compl. ¶38). 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. ¶30, 42). The product is intended for intravenous administration to treat patients with relapsed or refractory multiple myeloma (Compl. ¶38, 40). Defendants seek regulatory approval to market this product as a generic equivalent to Plaintiff’s KYPROLIS® prior to the expiration of the patents-in-suit (Compl. ¶4, 9).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

U.S. Patent No. 7,417,042 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound of formula I... The Proposed ANDA Product contains carfilzomib as its active ingredient. ¶45 col. 5:42-67
...wherein... R¹ is C₁₋₆aralkyl; R² is C₁₋₆alkyl; R³ is C₁₋₆aralkyl; R⁴ is C₁₋₆alkyl... The specific structure of carfilzomib allegedly meets the definitions for the R¹, R², R³, and R⁴ side chains. ¶45 col. 6:1-3
...and R⁵ is N(R⁶)LQR⁷; wherein... L is -C(O)-... and R⁷ is heterocyclylM-... The N-terminal morpholino-acetyl group of carfilzomib allegedly meets the structural requirements of the R⁵ limitation. ¶45 col. 6:10-18

U.S. Patent No. 7,232,818 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. ¶56 col. 5:45-60
...wherein R¹, R², R³, and R⁴ are each independently selected from C₁₋₆alkyl... C₁₋₆aralkyl... The specific side chains of carfilzomib allegedly meet the definitions for the R¹, R², R³, and R⁴ groups. ¶56 col. 6:10-14
...R⁵ is N(R⁶)LQR⁷... The N-terminal group of carfilzomib allegedly meets the structural requirements of the R⁵ limitation. ¶56 col. 6:19-20

Identified Points of Contention

  • Scope Questions: In an ANDA litigation context where the generic product is a bioequivalent copy, a central question for the court will be one of claim scope. Defendants' non-infringement defense, as outlined in their Paragraph IV letter, may depend on arguing for a narrow construction of the chemical structures defined in the claims that carfilzomib purportedly does not satisfy. This could relate to stereochemistry, impurities, or crystalline forms not explicitly detailed in the complaint.
  • Technical Questions: A primary technical question, although standard for this stage of litigation, is what evidence exists that Defendants’ proposed product contains the specific carfilzomib compound as claimed. While the complaint alleges this based on the ANDA filing, discovery will be required to confirm the precise chemical and physical properties of the accused API and formulation (Compl. ¶38, 45). For method-of-manufacture claims, a key question will be whether Defendants’ manufacturing process, which is not detailed in the complaint, practices the claimed steps (Compl. ¶98).

V. Key Claim Terms for Construction

  • The Term: A compound of formula I
  • Context and Importance: This term appears in the independent composition of matter claims of both the ’042 and ’818 Patents. The central dispute over direct infringement will hinge on whether Defendants’ carfilzomib product falls within the structural boundaries of "formula I" as defined in the patents. Practitioners may focus on this term because any non-infringement argument for the API itself must establish a distinction between the accused product and this claimed chemical structure.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification of the ’818 Patent defines the variables within formula I (e.g., R¹, R², R³, R⁴, R⁵) using broad Markush groups that encompass numerous possible chemical moieties, suggesting the formula is intended to cover a wide genus of compounds (’818 Patent, col. 4:45-65, col. 5:10-22).
    • Evidence for a Narrower Interpretation: The specification also discloses specific preferred embodiments and examples of compounds within the genus (’818 Patent, col. 6:23-40). A party might argue that statements regarding these specific examples or the "invention" as a whole could be used to narrow the scope of the broader formulaic definition to cover only certain stereoisomers or preferred structures.

VI. Other Allegations

  • Indirect Infringement: The complaint alleges both induced and contributory infringement for all asserted patents. Inducement is primarily based on the allegation that Defendants’ proposed product labeling will instruct and encourage healthcare providers to use the product in ways that infringe the method-of-use and method-of-treatment claims (Compl. ¶47, 49, 60, 69, 71, 79, 81, 89, 91, 100, 102, 111, 113, 121, 123). Contributory infringement is based on the allegation that the product has no substantial non-infringing uses (Compl. ¶43).
  • Willful Infringement: The complaint alleges that Defendants had knowledge of the patents-in-suit at the time of their ANDA submission and are "knowingly and intentionally" infringing (Compl. ¶37, 52, 63, 73, 83, 94, 105, 115, 125). It is further alleged that Defendants lacked a good faith basis for their Paragraph IV certification, which forms the basis for a request that the case be found exceptional under 35 U.S.C. § 285 (Compl. ¶54, 65, 75, 85, 96, 107, 117, 127).

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

  • A central issue will be one of validity: can Defendants establish by clear and convincing evidence that the asserted patent claims are invalid, likely on grounds of obviousness based on prior art proteasome inhibitors or anticipation? This question is the typical focal point of Hatch-Waxman litigation.
  • A key question for infringement will be one of claim scope and construction: while infringement appears direct, the case may turn on whether Defendants can successfully argue for a narrow construction of the claimed chemical structures (e.g., limited to a specific polymorph or stereoisomer) that its proposed generic product does not meet.
  • An important evidentiary question for the method claims will concern inducement: does the language of Defendants’ proposed product label, which the complaint alleges will substantially copy the innovator's label, actively instruct users to perform the patented methods of treatment and administration, thereby satisfying the requirements for induced infringement?