DCT

1:23-cv-02406

Amgen Inc v. Sandoz Inc

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Key Events
Complaint

I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 1:23-cv-02406, D.N.J., 05/01/2023
  • Venue Allegations: Plaintiff alleges venue is proper in the District of New Jersey because Defendant Sandoz Inc. has its principal place of business in Princeton, NJ, and the filing of the Biologic License Application with the FDA—the act of infringement under 35 U.S.C. § 271(e)(2)(C)—was allegedly prepared and submitted from New Jersey.
  • Core Dispute: Plaintiff alleges that Defendants' proposed biosimilar versions of Amgen's Prolia® and XGEVA® products infringe twenty-two patents covering the active ingredient denosumab and methods of its manufacture and purification.
  • Technical Context: The technology relates to denosumab, a human monoclonal antibody that inhibits the RANKL protein to treat osteoporosis and prevent skeletal-related events in cancer patients.
  • Key Procedural History: This action arises under the Biologics Price Competition and Innovation Act (BPCIA). Plaintiff alleges that after Defendant submitted its Biologic License Application, it failed to provide "other information that describes the process or processes used to manufacture the biological product," as required by the BPCIA's pre-litigation information exchange framework. This alleged failure is cited as the basis for the present declaratory judgment action.

Case Timeline

Date Event
2001-06-26 Patent Priority Date for '736 and '418 Patents
2008-04-29 U.S. Patent No. 7,364,736 Issues
2010-06-01 FDA first approves Prolia (denosumab)
2010-11-01 FDA approves XGEVA (denosumab)
2011-04-19 U.S. Patent No. 7,928,205 Issues
2011-11-15 U.S. Patent No. 8,058,418 Issues
2015-04-21 U.S. Patent No. 9,012,178 Issues
2015-09-15 U.S. Patent No. 9,133,493 Issues
2016-01-05 U.S. Patent No. 9,228,168 Issues
2016-04-26 U.S. Patent No. 9,320,816 Issues
2016-05-03 U.S. Patent No. 9,328,134 Issues
2016-06-07 U.S. Patent No. 9,359,435 Issues
2016-11-01 U.S. Patent No. 9,481,901 Issues
2019-01-01 U.S. Patent No. 10,167,492 Issues
2019-12-24 U.S. Patent No. 10,513,723 Issues
2020-03-10 U.S. Patent No. 10,583,397 Issues
2020-11-03 U.S. Patent No. 10,822,630 Issues
2021-01-19 U.S. Patent No. 10,894,972 Issues
2021-08-03 U.S. Patent No. 11,077,404 Issues
2021-08-24 U.S. Patent No. 11,098,079 Issues
2021-09-28 U.S. Patent No. 11,130,980 Issues
2022-02-22 U.S. Patent No. 11,254,963 Issues
2022-04-12 U.S. Patent No. 11,299,760 Issues
2022-09-06 U.S. Patent No. 11,434,514 Issues
2022-12-13 Sandoz Inc informs Amgen Inc of its Biologic License Application (BLA) submission
2023-02-06 FDA accepts Sandoz's BLA for review
2023-02-10 Amgen sends letter to Sandoz identifying the Patents-In-Suit
2023-05-01 Complaint Filing Date

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

U.S. Patent No. 7,364,736 - Antibodies to OPGL

  • Issued: April 29, 2008

The Invention Explained

  • Problem Addressed: Human bones undergo a constant cycle of resorption (breakdown) and formation (Compl. ¶49). An imbalance favoring resorption, often mediated by the protein RANKL (also called OPGL) binding to its receptor RANK on osteoclast precursor cells, can lead to excessive bone loss and conditions like osteoporosis (Compl. ¶50-51; ’736 Patent, col. 1:25-30).
  • The Patented Solution: The invention is an isolated, fully human IgG2 monoclonal antibody, known as denosumab, that specifically binds to RANKL (Compl. ¶52-53). This binding prevents RANKL from interacting with RANK, thereby inhibiting the formation of mature osteoclasts and reducing bone breakdown (Compl. ¶53). The patent claims the antibody by reference to its specific heavy and light chain amino acid sequences (Compl. ¶56, ¶88; ’736 Patent, col. 28:53-56).
  • Technical Importance: Denosumab was the first biologic therapy approved to treat osteoporosis and can be administered every six months, a significant improvement in convenience and patient adherence over previous daily or weekly treatments (Compl. ¶58, ¶60).

Key Claims at a Glance

  • The complaint asserts infringement of at least claim 3, which depends from independent claim 1 (Compl. ¶153).
  • Independent Claim 1:
    • An isolated antibody that binds to OPGL,
    • wherein the antibody is a full length human IgG2 antibody
    • comprising the amino acid sequence of SEQ ID NO: 2.

U.S. Patent No. 8,058,418 - Polynucleotides Encoding Heavy and Light Chains of Antibodies to OPGL

  • Issued: November 15, 2011

The Invention Explained

  • Problem Addressed: To commercially produce a biologic treatment like the denosumab antibody, a reliable method for its large-scale manufacture is required (Compl. ¶62). This necessitates having the precise genetic material that directs cells to produce the antibody.
  • The Patented Solution: The patent claims the isolated polynucleotide (i.e., DNA) sequences that encode the heavy and light polypeptide chains of the denosumab antibody (Compl. ¶91). These claimed sequences provide the genetic instructions for host cells to recombinantly produce the therapeutic antibody (’418 Patent, col. 1:53-60).
  • Technical Importance: These polynucleotide sequences are fundamental to the cell-based manufacturing process, enabling the consistent, large-scale production of denosumab for therapeutic use (Compl. ¶62).

Key Claims at a Glance

  • The complaint asserts infringement of at least claim 14, which depends from claim 8, which in turn depends from independent claim 1 (Compl. ¶164).
  • Independent Claim 1:
    • An isolated polynucleotide comprising a sequence that encodes a polypeptide that binds OPGL,
    • wherein the polypeptide is a heavy chain of a full length human IgG2 antibody and
    • comprises the amino acid sequence of SEQ ID NO: 2.

U.S. Patent No. 7,928,205 - Methods for Refolding of Recombinant Antibodies

  • Patent Identification: U.S. Patent No. 7928205, "Methods for Refolding of Recombinant Antibodies", issued April 19, 2011 (Compl. ¶94).
  • Technology Synopsis: The patent discloses methods for producing IgG2 antibodies. The claimed methods involve using a reduction/oxidation coupling reagent and an optional chaotropic agent to refold the antibodies into their correct conformation (Compl. ¶94).
  • Asserted Claims: At least claims 1 and 40 (Compl. ¶176).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶182).

U.S. Patent No. 9,012,178 - Dipeptides to Enhance Yield and Viability from Cell Cultures

  • Patent Identification: U.S. Patent No. 9012178, "Dipeptides to Enhance Yield and Viability from Cell Cultures", issued April 21, 2015 (Compl. ¶97).
  • Technology Synopsis: The patent claims methods of culturing recombinantly engineered mammalian cells in a serum-free medium. The yield and viability of the cell cultures are allegedly enhanced by adding specific dipeptides (Compl. ¶97-98).
  • Asserted Claims: At least claim 1 (Compl. ¶188).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶194).

U.S. Patent No. 9,133,493 - Method for Culturing Mammalian Cells to Improve Recombinant Protein Production

  • Patent Identification: U.S. Patent No. 9133493, "Method for Culturing Mammalian Cells to Improve Recombinant Protein Production", issued September 15, 2015 (Compl. ¶100).
  • Technology Synopsis: The patent claims methods for culturing mammalian cells that express a recombinant protein. The methods involve using independent feed media for tyrosine and cystine (Compl. ¶100).
  • Asserted Claims: At least claim 1 (Compl. ¶200).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶206).

U.S. Patent No. 9,228,168 - Feed Media

  • Patent Identification: U.S. Patent No. 9228168, "Feed Media", issued January 5, 2016 (Compl. ¶103).
  • Technology Synopsis: The patent discloses methods for stabilizing feed media used for culturing mammalian cells. The claimed method involves adding pyruvate to the media (Compl. ¶103).
  • Asserted Claims: At least claim 33 (Compl. ¶212).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶218).

U.S. Patent No. 9,320,816 - Methods of Treating Cell Culture Media for Use in a Bioreactor

  • Patent Identification: U.S. Patent No. 9320816, "Methods of Treating Cell Culture Media for Use in a Bioreactor", issued April 26, 2016 (Compl. ¶106).
  • Technology Synopsis: The patent claims methods for treating cell culture media to support mammalian cell growth in a bioreactor. The process involves using ultraviolet C light and filtration (Compl. ¶106).
  • Asserted Claims: At least claim 1 (Compl. ¶224).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶230).

U.S. Patent No. 9,328,134 - Carbohydrate Phosphonate Derivatives as Modulators of Glycosylation

  • Patent Identification: U.S. Patent No. 9328134, "Carbohydrate Phosphonate Derivatives as Modulators of Glycosylation", issued May 3, 2016 (Compl. ¶109).
  • Technology Synopsis: The patent discloses methods of making proteins with modified glycosylation. The process involves adding non-naturally occurring small sugar compounds to cell culture media to modulate the glycosylation pattern (Compl. ¶109).
  • Asserted Claims: At least claim 35 (Compl. ¶236).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶242).

U.S. Patent No. 9,359,435 - Methods for Modulating Mannose Content of Recombinant Proteins

  • Patent Identification: U.S. Patent No. 9359435, "Methods for Modulating Mannose Content of Recombinant Proteins", issued June 7, 2016 (Compl. ¶112).
  • Technology Synopsis: The patent describes methods for modulating the high-mannose glycoform content of a recombinant protein during a mammalian cell culture (Compl. ¶112).
  • Asserted Claims: At least claim 1 (Compl. ¶248).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶254).

U.S. Patent Nos. 9,481,901; 10,894,972; and 11,434,514 - Methods for Increasing Mannose Content of Recombinant Proteins

  • Patent Identification: Group of related patents titled "Methods for Increasing Mannose Content of Recombinant Proteins", issued November 1, 2016; January 19, 2021; and September 6, 2022, respectively (Compl. ¶115, ¶118, ¶121).
  • Technology Synopsis: These patents claim methods for influencing the high mannose glycoform content of a recombinant protein. The methods involve adding mannose sugars during a production phase and manipulating the mannose to total hexose ratio in the cell culture and feed media (Compl. ¶115, ¶118, ¶121).
  • Asserted Claims: At least claim 1 ('901 Patent); claim 3 ('972 Patent); claim 1 ('514 Patent) (Compl. ¶260, ¶272, ¶284).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶266, ¶278, ¶290).

U.S. Patent Nos. 10,167,492 and 10,822,630 - Process for Manipulating the Level of Glycan Content of a Glycoprotein

  • Patent Identification: Related patents titled "Process for Manipulating the Level of Glycan Content of a Glycoprotein", issued January 1, 2019 and November 3, 2020, respectively (Compl. ¶124, ¶127).
  • Technology Synopsis: These patents claim methods for influencing the fucosylated glycan content of a recombinant protein (Compl. ¶124, ¶127).
  • Asserted Claims: At least claim 1 for both patents (Compl. ¶296, ¶308).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶302, ¶314).

U.S. Patent Nos. 10,513,723 and 11,254,963 - Methods for Influencing High Mannose Glycoform Content

  • Patent Identification: U.S. Patent No. 10513723, "Decreasing Ornithine Production to Decrease High Mannose Glycoform Content of Recombinant Proteins", issued Dec. 24, 2019; and U.S. Patent No. 11254963, "Increasing Ornithine Accumulation to Increase High Mannose Glycoform Content of Recombinant Proteins", issued Feb. 22, 2022 (Compl. ¶130, ¶133).
  • Technology Synopsis: These patents claim methods of influencing the high-mannose glycoform content of a recombinant protein by either decreasing ornithine production or increasing ornithine accumulation (Compl. ¶130, ¶133).
  • Asserted Claims: At least claim 1 for both patents (Compl. ¶320, ¶332).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶326, ¶338).

U.S. Patent Nos. 10,583,397 and 11,077,404 - Process Control Systems and Methods for Use with Filters

  • Patent Identification: Related patents titled "Process Control Systems and Methods for Use with Filters and Filtration Processes", issued March 10, 2020 and August 3, 2021, respectively (Compl. ¶136, ¶139).
  • Technology Synopsis: These patents claim systems and methods used to control flow filtration in the production and/or purification of recombinant proteins (Compl. ¶136, ¶139).
  • Asserted Claims: At least claim 13 ('397 Patent) and claim 14 ('404 Patent) (Compl. ¶344, ¶356).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶350, ¶362).

U.S. Patent No. 11,098,079 - Charging Depth Filtration of Antigen-Binding Proteins

  • Patent Identification: U.S. Patent No. 11098079, "Charging Depth Filtration of Antigen-Binding Proteins", issued August 24, 2021 (Compl. ¶142).
  • Technology Synopsis: The patent claims methods of using a charged depth filter to purify an antigen-binding protein (Compl. ¶142).
  • Asserted Claims: At least claim 1 (Compl. ¶368).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶374).

U.S. Patent Nos. 11,299,760 and 11,130,980 - Use of Monensin to Regulate Glycosylation of Recombinant Proteins

  • Patent Identification: Related patents titled "Use of Monensin to Regulate Glycosylation of Recombinant Proteins", issued April 12, 2022 and September 28, 2021, respectively (Compl. ¶145, ¶148).
  • Technology Synopsis: These patents disclose methods of regulating the high mannose glycoform content of denosumab by adding monensin to the cell culture (Compl. ¶145, ¶148).
  • Asserted Claims: At least claim 1 for both patents (Compl. ¶380, ¶392).
  • Accused Features: Defendants' manufacturing process for its denosumab biosimilar product is alleged to infringe (Compl. ¶386, ¶398).

III. The Accused Instrumentality

  • Product Identification: Defendants’ proposed denosumab biosimilar product(s), intended as biosimilar versions of Amgen’s Prolia® and XGEVA® products (Compl. ¶1).
  • Functionality and Market Context: The accused product is a biologic drug whose active ingredient is denosumab, a human IgG2 monoclonal antibody that binds to human RANKL (Compl. ¶52-53). By binding to RANKL, it prevents the activation of osteoclasts, which are cells responsible for bone breakdown, thereby increasing bone mineral density and reducing fracture risk (Compl. ¶53). The complaint alleges, based on the Biologic License Application ("BLA") provided by Sandoz, that the active ingredient in Defendants' product is denosumab (Compl. ¶68). The complaint heavily redacts the specific technical details of the accused product and its manufacturing processes, stating that such information is derived from the confidential BLA (Compl. ¶68-71). No probative visual evidence provided in complaint.

IV. Analysis of Infringement Allegations

U.S. Patent No. 7,364,736 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An isolated antibody that binds to OPGL, The complaint alleges on information and belief that the active ingredient in Defendants' proposed biosimilar product is an antibody that binds to OPGL (also known as RANKL). ¶52-53, ¶68 col. 27:66-28:2
wherein the antibody is a full length human IgG2 antibody The complaint alleges that denosumab, the active ingredient in Amgen's reference products and allegedly in Defendants' biosimilar product, is a human IgG2 monoclonal antibody. ¶52, ¶68 col. 28:53-56
comprising the amino acid sequence of SEQ ID NO: 2. The complaint alleges, based on the BLA, that the active ingredient in Defendants' proposed product is denosumab, which the '736 Patent specification defines as comprising the heavy chain amino acid sequence of SEQ ID NO: 2. ¶56, ¶68 col. 28:55-56
  • Identified Points of Contention:
    • Scope Questions: A central question will be one of structural identity. The infringement analysis will depend on evidence from the confidential BLA to determine if the Sandoz product's amino acid sequence, post-translational modifications, and overall structure fall within the scope of "an isolated antibody ... comprising the amino acid sequence of SEQ ID NO: 2."
    • Technical Questions: What evidence does the complaint provide, beyond redacted references to the BLA (Compl. ¶68), that Sandoz's product is a "full length human IgG2 antibody"? The dispute will likely focus on detailed analytical characterization data comparing the Sandoz biosimilar to the claimed antibody structure.

U.S. Patent No. 8,058,418 Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
An isolated polynucleotide comprising a sequence that encodes a polypeptide that binds OPGL, The complaint alleges that Defendants' process to manufacture their denosumab biosimilar product uses a polynucleotide that encodes an antibody that binds OPGL. ¶91, ¶170 col. 25:1-3
wherein the polypeptide is a heavy chain of a full length human IgG2 antibody and comprises the amino acid sequence of SEQ ID NO: 2. The complaint alleges that the denosumab antibody made by the process of the '418 Patent is the active ingredient of Defendants' product (Compl. ¶170). The patent specification discloses that SEQ ID NO: 1 is the polynucleotide encoding the heavy chain of SEQ ID NO: 2 (’418 Patent, SEQ ID NO: 1). Infringement is asserted under 35 U.S.C. § 271(g) for importing a product made by a patented process. ¶165, ¶169, ¶170 col. 25:1-6
  • Identified Points of Contention:
    • Scope Questions: Does the act of importing the final denosumab protein into the U.S. constitute infringement of a patent claiming the polynucleotide used in an upstream manufacturing step abroad? The complaint asserts infringement under 35 U.S.C. § 271(g), which will require Plaintiff to show the antibody is "made by a process patented in the United States" (Compl. ¶165).
    • Technical Questions: What evidence does the complaint provide that Sandoz's manufacturing process actually uses a polynucleotide "comprising a sequence that encodes" the specific polypeptide of SEQ ID NO: 2? This is a factual question that will depend entirely on the contents of the confidential BLA.

V. Key Claim Terms for Construction

  • The Term: "isolated antibody" ('736 Patent, claim 1)

    • Context and Importance: The definition of "isolated" will be critical to determining if the purified denosumab in Defendants' final drug product meets this limitation. Practitioners may focus on this term because its scope could determine whether the claim reads on a highly purified antibody in a pharmaceutical composition versus one in a less pure, intermediate state.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The term could be construed broadly to mean an antibody that has been removed from its natural environment of the host cell culture (Compl. ¶52-53).
      • Evidence for a Narrower Interpretation: The specification's focus on creating a "fully human antibody" for therapeutic use suggests "isolated" may imply a certain level of purity required for a pharmaceutical product, potentially narrowing the claim scope (’736 Patent, col. 2:63-65).

  • The Term: "comprising the amino acid sequence" ('736 Patent, claim 1)

    • Context and Importance: "Comprising" is an open-ended transition phrase. The key issue will be whether Sandoz's biosimilar antibody contains the exact sequence of SEQ ID NO: 2, and whether any additional features (e.g., post-translational modifications, minor sequence variations) prevent it from infringing.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The standard legal interpretation of "comprising" means "including but not limited to." This may support a finding of infringement even if the Sandoz product contains minor additional elements, as long as it includes the entirety of SEQ ID NO: 2.
      • Evidence for a Narrower Interpretation: The patent repeatedly emphasizes the specific, disclosed heavy and light chain sequences as conferring the antibody's "unique binding properties" (Compl. ¶56). A defendant may argue that any deviation from the exact structure, including different glycosylation patterns, results in a molecule that does not function in the same way and thus falls outside a properly construed claim.

VI. Other Allegations

  • Indirect Infringement: The complaint makes general allegations of induced infringement for many of the asserted manufacturing patents, stating on "information and belief" that Defendants' "active inducement thereof, constitutes acts of infringement" (e.g., Compl. ¶177, ¶189, ¶201). The complaint does not plead specific facts detailing the acts of inducement, such as providing instructions or manuals for using the patented methods.
  • Willful Infringement: The complaint alleges willfulness on two grounds. First, it alleges Defendants had constructive notice of the '736 and '418 patents prior to filing their BLA due to Amgen's patent marking for its Prolia and XGEVA products (Compl. ¶63). Second, it alleges Defendants had actual notice of all Patents-In-Suit as of at least February 10, 2023, when Amgen sent Sandoz a letter identifying each patent (Compl. ¶65).

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

  • A central procedural question will be one of statutory compliance: did Sandoz's pre-litigation disclosures satisfy the BPCIA's requirement to provide both a copy of the BLA and "such other information that describes the process or processes used to manufacture the biological product"? The court's resolution of this issue, which Amgen frames as a "willful failure" by Sandoz (Compl. ¶83), may influence the early trajectory of the case.
  • The primary substantive issue will be one of technical identity: for the product patents, does the accused biosimilar have the same amino acid sequence and structural characteristics as the claimed denosumab antibody? For the extensive portfolio of manufacturing patents, the question is one of process duplication: do the confidential manufacturing steps detailed in Sandoz's BLA—from cell culture and feeding strategies to protein refolding and purification—fall within the scope of the methods claimed in Amgen's patents?