DCT

1:18-cv-00132

Onyx Therap Inc v. Apotex Inc

Log In

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:18-cv-00132, D. Del., 01/24/2018
  • Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware because Defendant Apotex Corp. is a Delaware corporation and because both defendants conduct continuous and systematic business in the district, including selling pharmaceutical products.
  • Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) seeking to market a generic version of Plaintiff’s multiple myeloma treatment KYPROLIS® (carfilzomib) constitutes an act of infringement of nine patents owned by Plaintiff.
  • Technical Context: The technology concerns peptide-based epoxyketone compounds that function as proteasome inhibitors, a class of drugs used in oncology to induce cancer cell death (apoptosis), particularly in the treatment of multiple myeloma.
  • Key Procedural History: This action was initiated under the Hatch-Waxman Act following Apotex's submission of ANDA No. 211185 with a Paragraph IV certification, asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by its proposed generic product. Plaintiff filed this complaint within the 45-day statutory window after receiving Apotex's notice letter, triggering a potential 30-month stay of FDA approval for Apotex's ANDA.

Case Timeline

Date Event
2004-04-15 Priority Date for ’818, ’704, ’346, ’125, ’126, ’127, ’297 Patents
2004-08-06 Priority Date for ’042 Patent
2004-12-07 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
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 approval for Plaintiff's KYPROLIS®
2017-12-14 Plaintiff receives Defendant's ANDA Notice Letter
2018-01-24 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 addresses the need for small-molecule inhibitors of N-terminal nucleophile (Ntn) hydrolases, such as the proteasome, that have increased site specificity, stability, and potency compared to existing compounds, which often lack these properties ('042 Patent, col. 2:12-21).
  • The Patented Solution: The invention provides peptide-based compounds, such as peptide epoxyketones, that are designed to efficiently and selectively inhibit specific activities of Ntn hydrolases ('042 Patent, Abstract). These compounds feature a peptide backbone of three or more units and a heteroatom-containing three-membered ring (e.g., an epoxide) that is believed to form a covalent adduct with the N-terminal nucleophile of the target enzyme, thereby irreversibly inhibiting it ('042 Patent, col. 3:5-14).
  • Technical Importance: This class of compounds provided highly selective inhibitors of the chymotrypsin-like activity of the proteasome, offering a targeted mechanism for therapeutic intervention in diseases like cancer where proteasome function is a key regulator of cell growth and survival ('042 Patent, col. 2:22-34).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 15, and 37 (Compl. ¶ 43).
  • Independent Claim 1 is directed to a class of peptide compounds defined by a core chemical structure (Formula III) having specified variable groups (R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹), an epoxide or aziridine ring (defined by X), and various linking and backbone units, or a pharmaceutically acceptable salt thereof ('042 Patent, col. 54:50-col. 55:46).
  • The complaint reserves the right to assert dependent claims (Compl. ¶ 43).

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

The Invention Explained

  • Problem Addressed: The patent identifies a need for small-molecule inhibitors for the proteasome that possess greater specificity, stability, or potency than prior art compounds, which are often insufficient for exploring the roles of the proteasome at a cellular level ('818 Patent, col. 2:15-21).
  • The Patented Solution: The invention discloses peptide-based compounds, including peptide α',β'-epoxides and α',β'-aziridines, which are described as binding efficiently, irreversibly, and selectively to N-terminal nucleophile hydrolases like the proteasome ('818 Patent, col. 2:25-31). The compounds consist of a peptide backbone linked to an epoxide or aziridine functional group, which is designed to form a covalent adduct with the enzyme's active site, thereby inhibiting specific proteolytic activities such as the chymotrypsin-like activity of the 20S proteasome ('818 Patent, col. 3:5-14).
  • Technical Importance: The claimed compounds are described as potent and selective proteasome inhibitors useful as molecular probes to study enzyme function and as having therapeutic potential for treating conditions such as cancer and inflammatory diseases ('818 Patent, col. 2:32-3:3).

Key Claims at a Glance

  • The complaint asserts independent claims 1, 23, 38, and 49 (Compl. ¶ 54).
  • Independent Claim 1 is directed to a class of peptide compounds defined by a generic chemical structure (Formula I) with specified variable groups, an epoxide or aziridine ring, and various side chains, or a pharmaceutically acceptable salt thereof ('818 Patent, col. 65:27-col. 67:2).
  • The complaint reserves the right to assert dependent claims (Compl. ¶ 54).

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

  • Technology Synopsis: This patent covers peptide epoxyketone compounds that selectively inhibit proteasome activity. The invention is directed to both the chemical compounds themselves and methods of using them to treat cancer by inhibiting enzyme activity.
  • Asserted Claims: Independent claims 1, 22, 37, and 48 are asserted (Compl. ¶ 65).
  • Accused Features: The complaint alleges that the use of the Proposed ANDA Product, which contains carfilzomib, to treat cancer such as multiple myeloma will infringe the ’704 Patent (Compl. ¶ 65).

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

  • Technology Synopsis: This patent is directed to pharmaceutical compositions that include a peptide-based proteasome inhibitor. It specifically claims formulations comprising the active ingredient along with particular excipients, including sulfobutyl ether beta-cyclodextrin (SBECD) and a buffer such as citric acid, to improve solubility and stability.
  • Asserted Claims: Independent claims 1, 18, and 29 are asserted (Compl. ¶ 76).
  • Accused Features: The complaint alleges that the Proposed ANDA Product is a composition that contains carfilzomib, SBECD, and citric acid, thereby infringing the ’112 Patent (Compl. ¶ 76).

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

  • Technology Synopsis: This patent covers methods of using peptide epoxyketone compounds to inhibit an N-terminal nucleophile hydrolase, such as the proteasome. The claimed methods involve administering the compound, which then irreversibly binds to the enzyme's active sites.
  • Asserted Claims: Independent claims 1, 22, 37, 48, and 52 are asserted (Compl. ¶ 87).
  • Accused Features: The complaint alleges that the label for the Proposed ANDA Product will instruct users to administer it in a manner that infringes the ’346 Patent, specifically by inhibiting proteasome activity to delay tumor growth (Compl. ¶ 87).

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

  • Technology Synopsis: This patent claims specific peptide epoxyketone compounds, including a compound identified as carfilzomib by its chemical structure. The claims are directed to the composition of matter itself.
  • Asserted Claims: Independent claims 1, 18, and 27 are asserted (Compl. ¶ 98).
  • Accused Features: The complaint alleges that the Proposed ANDA Product is a composition comprising carfilzomib and therefore infringes the ’125 Patent (Compl. ¶ 98).

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

  • Technology Synopsis: This patent is directed to compositions comprising a specific peptide epoxyketone (carfilzomib) that are prepared by a claimed method. The method includes steps related to the formulation and reconstitution of a lyophilized powder.
  • Asserted Claims: Independent claims 1 and 16 are asserted (Compl. ¶ 109).
  • Accused Features: The complaint alleges the Proposed ANDA Product's label will instruct healthcare providers to reconstitute the product in a manner that infringes the claimed method (Compl. ¶ 109).

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

  • Technology Synopsis: This patent claims methods of treating multiple myeloma by administering a therapeutically effective amount of a specific peptide epoxyketone compound (carfilzomib).
  • Asserted Claims: Independent claims 1, 12, 19, and 23 are asserted (Compl. ¶ 120).
  • Accused Features: The complaint alleges the Proposed ANDA Product contains carfilzomib and its label will instruct its use for treating multiple myeloma, thereby infringing the ’127 Patent (Compl. ¶ 120).

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

  • Technology Synopsis: This patent is directed to compositions containing a specific peptide epoxyketone (carfilzomib) prepared by claimed methods, similar to the ’126 patent.
  • Asserted Claims: Independent claims 1, 10, and 19 are asserted (Compl. ¶ 132).
  • Accused Features: The complaint alleges that Apotex's product is a composition comprising carfilzomib prepared by the claimed methods, infringing the ’297 Patent (Compl. ¶ 132).

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is Apotex's "Proposed ANDA Product," a generic carfilzomib 30 mg lyophilized powder for reconstitution and intravenous administration, which is the subject of ANDA No. 211185 (Compl. ¶ 4).

Functionality and Market Context

  • The Proposed ANDA Product is alleged to be a generic version of Onyx's KYPROLIS® (carfilzomib) for injection (Compl. ¶ 9). The complaint alleges that carfilzomib, the active pharmaceutical ingredient, is a proteasome inhibitor that irreversibly binds to the proteasome's active sites, causing an accumulation of protein in multiple myeloma cells and triggering apoptosis (Compl. ¶ 29). The complaint further alleges that Apotex's product will have instructions for use that substantially copy those of KYPROLIS® for treating multiple myeloma and for reconstituting the lyophilized powder before injection (Compl. ¶ 38). Apotex seeks FDA approval to market this product as a bioequivalent generic alternative to KYPROLIS® prior to the expiration of the patents-in-suit (Compl. ¶¶ 33, 37).
    No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

’042 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A compound having a structure of formula (III) or a pharmaceutically acceptable salt thereof... [structure depicted] The Proposed ANDA Product is alleged to be covered by the asserted claims because it contains carfilzomib as its active ingredient. ¶43 col. 54:50-67
  • Identified Points of Contention:
    • Scope Questions: Claim 1 of the ’042 Patent is a genus claim covering a class of compounds defined by multiple variable chemical groups. A central question will be whether carfilzomib, the active ingredient in the Proposed ANDA Product, falls within the specific structural limitations of the claimed genus as properly construed. The analysis may focus on whether the specific side chains and N-terminal group of carfilzomib meet the definitions provided for the variables in the Markush group of Claim 1.
    • Technical Questions: The complaint's infringement theory rests on the allegation that the accused product "contains carfilzomib" (Compl. ¶ 43). The case may turn on evidence establishing the precise chemical structure, including stereochemistry, of the active ingredient in Apotex's ANDA product and whether that structure is a species described by 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) or a pharmaceutically acceptable salt thereof... [structure depicted] The Proposed ANDA Product is alleged to be covered by the asserted claims because it contains carfilzomib as its active ingredient. ¶54 col. 65:27-44
  • Identified Points of Contention:
    • Scope Questions: Similar to the ’042 Patent, Claim 1 of the ’818 Patent is a genus claim. A key question will be whether the chemical structure of carfilzomib is encompassed by the scope of Formula I. Disputes may arise over the interpretation of the variable groups (e.g., L, Q, R⁵, R⁷) that define the N-terminus of the claimed peptide structure.
    • Technical Questions: As with the ’042 patent, a core technical question will be whether the chemical compound manufactured by Apotex for its ANDA product has the exact structure, including all stereochemical configurations, required by the asserted claims of the ’818 Patent.

V. Key Claim Terms for Construction

The complaint does not provide sufficient detail to identify specific claim terms that are likely to be in dispute. However, in ANDA litigation involving genus claims covering a specific commercial embodiment, claim construction often focuses on the variable groups that define the boundaries of the chemical structure.

  • The Term: "R⁵" (as used in Formula I of the ’818 Patent and a similar term in Formula III of the '042 Patent)
  • Context and Importance: This term defines the N-terminal cap of the peptide structure. Carfilzomib contains a morpholinoacetyl group at this position. The definition of "R⁵" (which is "N(R⁶)LQR⁷") and its constituent parts ("L", "Q", "R⁷") is critical to determining whether carfilzomib literally infringes, as it dictates what specific chemical structures are permitted at the N-terminus.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides broad definitions for the constituent parts of R⁵. For example, "L" can be absent or can be C=O, "Q" can be absent, and "R⁷" can be "heterocyclylM-", where "heterocyclyl" includes morpholino and "M" can be absent ('818 Patent, col. 65:38-66). Parties may argue this language supports a broad reading that covers the morpholinoacetyl group of carfilzomib.
    • Evidence for a Narrower Interpretation: The specification also provides numerous specific examples and preferred embodiments for these variables ('818 Patent, col. 67:23-col. 68:48). A party may argue that these specific embodiments should guide the interpretation of the claim terms, potentially limiting the scope of what structures are covered by "R⁵".

VI. Other Allegations

  • Indirect Infringement: The complaint alleges induced infringement for patents with method-of-use claims. The basis for this allegation is that Apotex's Proposed ANDA Product label will instruct healthcare providers to administer the product to treat multiple myeloma, thereby encouraging and instructing the performance of the patented methods (Compl. ¶¶ 38, 39, 65, 87, 120). The complaint also alleges that the Proposed ANDA Product will have no substantial non-infringing use (Compl. ¶ 41).
  • Willful Infringement: Willfulness is alleged based on Apotex's pre-suit knowledge of the patents-in-suit, evidenced by its filing of a Paragraph IV certification with its ANDA (Compl. ¶ 35). The complaint asserts that Defendants "knowingly and intentionally" infringe the patents and lacked a good faith basis for their allegations of invalidity and non-infringement (Compl. ¶¶ 50, 52).

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

  • A central issue will be one of claim scope and construction: For the patents claiming a genus of compounds (e.g., ’042 and ’818 patents), the key question is whether the specific chemical structure of carfilzomib falls within the scope of the properly construed claims. For patents claiming specific formulations (e.g., ’112 patent), the question will be whether Apotex's formulation, including its excipients, meets all claim limitations.
  • A second core issue will be patent validity: Apotex's Paragraph IV certification necessarily asserts that the patents-in-suit are invalid or not infringed. The case will likely involve significant disputes over whether the claimed inventions are obvious or anticipated by the prior art, a standard defense in ANDA litigation.
  • A key evidentiary question will be one of direct infringement: The dispute will require a technical comparison between the chemical composition specified in Apotex's confidential ANDA submission and the limitations of the asserted patent claims. The outcome will depend on factual evidence establishing the exact nature of the Proposed ANDA Product and its proposed method of use.