DCT

3:16-cv-02581

Amgen Inc v. Sandoz Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 3:16-cv-02581, N.D. Cal., 05/12/2016
  • Venue Allegations: Venue is asserted based on Defendants' alleged collaboration to develop, manufacture, seek regulatory approval for, market, and sell the accused biopharmaceutical products within the Northern District of California.
  • Core Dispute: Plaintiff alleges that Defendant's submission of an abbreviated Biologics License Application (aBLA) for a biosimilar version of Amgen's Neulasta® product constitutes an act of infringement of two patents related to the product's composition and method of manufacture.
  • Technical Context: The technology involves pegfilgrastim, a biologic drug that combines a protein (G-CSF) with a polymer (PEG) to stimulate white blood cell production and reduce infection risk in chemotherapy patients.
  • Key Procedural History: This action arises under the Biologics Price Competition and Innovation Act (BPCIA). The complaint was filed following the parties' pre-suit information exchange, in which they agreed that U.S. Patent Nos. 8,940,878 and 5,824,784 would be the subject of an immediate infringement action. The ’784 patent expired in October 2015; infringement is alleged as a technical act based on the submission of the aBLA prior to expiration.

Case Timeline

Date Event
1994-10-12 U.S. Patent 5,824,784 Priority Date
1998-10-20 U.S. Patent 5,824,784 Issue Date
2009-06-25 U.S. Patent 8,940,878 Priority Date
2015-01-27 U.S. Patent 8,940,878 Issue Date
Prior to 2015-10 Sandoz submitted its aBLA to the FDA
2015-10-20 U.S. Patent 5,824,784 Expiration Date
2015-10-26 FDA accepts Sandoz aBLA for review
2015-11-00 Parties begin BPCIA information exchange
2016-04-12 Parties agree on patents for immediate infringement action
2016-05-12 Complaint Filing Date
2031-10-08 U.S. Patent 8,940,878 Expiration Date

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

U.S. Patent No. 8,940,878 - "Capture Purification Processes for Proteins Expressed in a Non-Mammalian System"

The Invention Explained

  • Problem Addressed: The patent addresses the difficulty of purifying proteins that are expressed in non-mammalian systems (e.g., E. coli). Such proteins are often produced in non-native or insoluble forms (inclusion bodies) that require complex refolding and dilution steps before they can be purified using standard techniques like Protein A affinity chromatography, a process which can be costly and inefficient at industrial scale (’878 Patent, col. 1:21-55).
  • The Patented Solution: The invention provides methods for capturing these proteins directly from either a raw cell lysate (if expressed in a soluble, non-native form) or a concentrated refold mixture (if expressed as an insoluble form) without a prior dilution step. The patent teaches that, contrary to prior expectations, the target protein can effectively bind to a separation matrix (e.g., Protein A resin) even in the presence of cell debris or refolding agents that were thought to inhibit such interactions (’878 Patent, col. 2:1-16; col. 4:45-59).
  • Technical Importance: This process simplifies the manufacturing workflow for recombinant proteins, potentially increasing yield and reducing the cost and complexity of purification at a commercial scale (’878 Patent, col. 4:40-44).

Key Claims at a Glance

  • The complaint asserts infringement of one or more unspecified claims (Compl. ¶80). Independent claim 1 is representative:
    • A method of purifying a protein expressed in a non-native soluble form in a non-mammalian expression system comprising:
    • (a) lysing a non-mammalian cell... to generate a cell lysate;
    • (b) contacting the cell lysate with a separation matrix...;
    • (c) washing the separation matrix; and
    • (d) eluting the protein... wherein the separation matrix is an affinity resin selected from... Protein A, Protein G and a synthetic mimetic affinity resin.

U.S. Patent No. 5,824,784 - "N-Terminally Chemically Modified Protein Compositions and Methods"

The Invention Explained

  • Problem Addressed: The patent's background describes that chemically modifying proteins with polymers like polyethylene glycol (PEG) to improve their therapeutic properties often resulted in non-selective attachment. This created a heterogeneous mixture of products with the polymer attached at various sites (e.g., lysine residues, N-terminus), leading to unpredictable biological activity and inconsistent product quality (’784 Patent, col. 3:1-24).
  • The Patented Solution: The invention provides for a "substantially homogenous preparation" of a protein (specifically G-CSF) that is chemically modified with a polymer (PEGylated) selectively at its N-terminus. The patent also discloses that this specific N-terminal modification of G-CSF results in a product with unexpectedly superior stability compared to G-CSF modified at other sites, such as lysine residues (’784 Patent, Abstract; col. 4:50-54).
  • Technical Importance: The ability to create a uniform and more stable PEGylated protein product represented a significant advance for developing reliable and effective protein-based therapeutics with predictable pharmacokinetics (’784 Patent, col. 3:15-24).

Key Claims at a Glance

  • The complaint asserts infringement of one or more unspecified claims (Compl. ¶94). Independent claim 1 is representative:
    • A substantially homogenous preparation of N-terminally PEGylated G-CSF or analog thereof,
    • optionally in a pharmaceutically acceptable diluent, carrier or adjuvant,
    • said preparation being essentially free of G-CSF or analog thereof PEGylated at sites other than the N-terminus.

III. The Accused Instrumentality

Product Identification

  • The "Sandoz Pegfilgrastim Product," an intended biosimilar version of Amgen’s NEULASTA® (pegfilgrastim) (Compl. ¶68, ¶70).

Functionality and Market Context

  • The product is a biopharmaceutical designed to be a biosimilar of NEULASTA®, which is a form of recombinant human granulocyte-colony stimulating factor (G-CSF) chemically modified with a polyethylene glycol (PEG) molecule at its N-terminus (Compl. ¶65, ¶70).
  • Its therapeutic function is to decrease the incidence of infection in cancer patients receiving chemotherapy by stimulating the production of neutrophils (Compl. ¶66).
  • Sandoz submitted an abbreviated Biologics License Application (aBLA) to the FDA, seeking approval to commercially manufacture, use, and sell the product in the United States by relying on the safety and efficacy data of Amgen's NEULASTA® (Compl. ¶68, ¶71). The complaint alleges the product is designed to copy and compete with NEULASTA® and is manufactured at facilities including those of Sandoz GmbH (Austria) and Lek Pharmaceuticals d.d. (Slovenia) (Compl. ¶42, ¶51, ¶70).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

U.S. Patent 8,940,878 Infringement Allegations

The complaint alleges that Defendants' intended commercial manufacture of the Sandoz Pegfilgrastim Product will infringe one or more claims of the ’878 patent (Compl. ¶79, ¶80). It further alleges infringement under 35 U.S.C. § 271(g) based on the intended importation of the product into the United States after it is manufactured abroad by a process claimed in the patent (Compl. ¶86). However, the complaint does not provide specific factual allegations describing Sandoz's actual manufacturing or purification process. Therefore, a detailed claim-chart analysis is not possible based on the provided pleading. The core of the infringement allegation rests on the assertion that Sandoz will necessarily use a claimed purification method to produce its biosimilar product.

U.S. Patent 5,824,784 Infringement Allegations

The infringement allegation is a technical one under 35 U.S.C. § 271(e)(2)(C), which makes it an act of infringement to submit an aBLA for a drug claimed in a patent if the purpose is to obtain approval before the patent's expiration (Compl. ¶93). The complaint alleges Sandoz submitted its aBLA before the ’784 patent expired (Compl. ¶15, ¶64). The theory is that the Sandoz product, as a biosimilar of NEULASTA®, is a copy of a product covered by the claims.

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A substantially homogenous preparation of N-terminally PEGylated G-CSF or analog thereof, The Sandoz Pegfilgrastim Product is alleged to be a biosimilar of NEULASTA®, which the complaint defines as a preparation of N-terminally PEGylated G-CSF. ¶65, ¶70, ¶92 col. 4:1-3
said preparation being essentially free of G-CSF or analog thereof PEGylated at sites other than the N-terminus. The Sandoz product is alleged to copy NEULASTA®, which is described as being specifically conjugated at the N-terminus, implying it is free from modifications at other sites. ¶65, ¶70, ¶92 col. 4:50-54

Identified Points of Contention

  • Technical Questions: For the ’878 patent, the central issue is factual: what process do Defendants actually use to purify their pegfilgrastim product? The complaint does not provide evidence that Sandoz's process involves the direct capture from a lysate or refold buffer as required by the claims.
  • Scope Questions: For the ’784 patent, the dispute may center on the definition of "substantially homogenous" and "essentially free." The case raises the question of whether the Sandoz product, as described in its aBLA, meets the specific level of N-terminal purity and uniformity required by these claim terms.

V. Key Claim Terms for Construction

  • The Term: "substantially homogenous preparation" (from ’784 Patent, Claim 1)
  • Context and Importance: The definition of this term is critical because it quantifies the level of purity and uniformity of the claimed product composition. The infringement analysis for the ’784 patent will depend on whether Sandoz's product, described in its aBLA, meets this standard. Practitioners may focus on this term because Sandoz could argue either that its product has a different homogeneity profile or that the term is indefinite without a clearer quantitative boundary.
  • Intrinsic Evidence for Interpretation:
    • Evidence for a Broader Interpretation: The specification provides numerical targets, stating a preparation may be "at least 90% monopolymer/protein conjugate" and preferably higher, which could be argued to set a flexible, rather than absolute, standard (’784 Patent, col. 5:24-29).
    • Evidence for a Narrower Interpretation: The language in Claim 1 requiring the preparation to be "essentially free of G-CSF... PEGylated at sites other than the N-terminus" suggests a very high degree of specificity is required (’784 Patent, col. 25:1-3). The specification's emphasis on the superior stability of the N-terminally modified form could be used to argue that the claims are directed only to preparations that have achieved this specific, highly pure state (’784 Patent, col. 4:50-54).

VI. Other Allegations

  • Indirect Infringement: The prayer for relief seeks to enjoin acts of contributory infringement and inducement with respect to the ’878 patent (Compl. p. 21, ¶E). However, the complaint's factual allegations do not specify acts that would constitute inducement (e.g., providing instructions to a third party to perform the claimed method) or contributory infringement.
  • Willful Infringement: The complaint does not contain an explicit allegation of willful infringement. It does, however, request a finding that the case is "exceptional" for the purpose of awarding attorneys' fees under 35 U.S.C. § 285 (Compl. p. 21, ¶F). The basis for this request appears to be the general context of Defendants' conduct under the BPCIA statutory scheme rather than specific allegations of pre-suit knowledge or egregious behavior.

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

  • A central evidentiary question will be one of process mapping: Can Amgen obtain and present evidence demonstrating that Sandoz's confidential manufacturing process for its pegfilgrastim biosimilar practices the specific steps of the asserted '878 patent claims, particularly the direct capture of a non-native protein from a complex mixture without prior dilution? The current complaint lacks such factual allegations.
  • A key legal and factual question will be one of product definition: For the expired ’784 patent, the dispute will turn on whether the Sandoz product, as characterized in its aBLA, falls within the scope of a "substantially homogenous preparation... essentially free" of non-N-terminal variants. This requires both construing the meaning of these terms and a technical comparison of the accused product's composition against that construction.
  • A determinative issue will be the application of BPCIA-specific law: How will the court adjudicate a claim of "artificial" infringement under 35 U.S.C. § 271(e)(2)(C) for the expired ’784 patent, where the alleged infringing act is the pre-expiration regulatory submission rather than ongoing commercial sales, and what remedies, if any, are available for such an act?