DCT

2:17-cv-01235

Amgen Inc v. Mylan Inc

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I. Executive Summary and Procedural Information

  • Parties & Counsel:
  • Case Identification: 2:17-cv-01235, W.D. Pa., 02/07/2019
  • Venue Allegations: Venue is alleged to be proper in the Western District of Pennsylvania as Defendant Mylan Inc. is a Pennsylvania corporation with its principal place of business in the district, and Defendant Mylan Pharmaceuticals Inc. is alleged to have a regular and established place of business in Pennsylvania.
  • Core Dispute: Plaintiffs allege that Defendants' manufacturing process for its biosimilar drug Fulphila™ infringes two patents covering methods for purifying proteins using specialized chromatography techniques.
  • Technical Context: The technology relates to large-scale protein purification, a critical and complex part of manufacturing biologic drugs, where efficiency and purity are paramount for commercial viability and patient safety.
  • Key Procedural History: This action arises under the Biologics Price Competition and Innovation Act (BPCIA). The complaint states the parties engaged in the statutory pre-litigation information exchanges, or "patent dance," following Defendants' submission of an Abbreviated Biologics License Application (aBLA) for Fulphila™, a biosimilar to Plaintiffs' product Neulasta®. Defendants subsequently received FDA approval and launched Fulphila™ in the U.S. market after the initial complaint was filed.

Case Timeline

Date Event
2004-01-30 U.S. Patent No. 8,273,707 Priority Date
2009-06-25 U.S. Patent No. 9,643,997 Priority Date
2012-09-25 U.S. Patent No. 8,273,707 Issue Date
2017-02-07 FDA accepts Mylan's aBLA for review
2017-03-02 Mylan provides Amgen with access to the Mylan aBLA
2017-05-01 Amgen discloses the ’707 Patent to Mylan
2017-05-09 U.S. Patent No. 9,643,997 Issue Date
2017-06-07 Amgen discloses the ’997 Patent to Mylan
2017-10-10 FDA issues a Complete Response Letter for the Mylan aBLA
2018-06-04 Mylan receives FDA approval for Fulphila™
2018-07-09 Mylan begins marketing and selling Fulphila™ in the United States
2019-02-07 First Amended and Supplemental Complaint Filing Date

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

U.S. Patent No. 8,273,707 - "Process For Purifying Proteins"

  • Issued: September 25, 2012

The Invention Explained

  • Problem Addressed: In large-scale commercial manufacturing, purifying proteins using hydrophobic interaction chromatography (HIC) requires high concentrations of salt to make the protein bind to the column. However, these high salt levels can be detrimental to the protein's stability, increase viscosity, and lead to protein loss and reduced purity (ʻ707 Patent, col. 4:38-48).
  • The Patented Solution: The invention proposes a method to increase the "dynamic capacity" of an HIC column—the amount of protein it can purify in a single cycle—by using a specific combination of a first and a second salt (e.g., citrate and sulfate) rather than a high concentration of a single salt. This dual-salt approach allows for more efficient protein binding at lower overall salt concentrations, improving the efficiency of the purification process ('707 Patent, Abstract; col. 2:9-24).
  • Technical Importance: By increasing the load capacity of a crucial purification step, the invention allows for a reduction in the number of manufacturing cycles needed to purify a given batch of protein, which can lead to significant cost and time savings in the production of biopharmaceuticals ('707 Patent, col. 2:42-49).

Key Claims at a Glance

  • The complaint asserts at least claims 1, 2, 6, 8, 10, and 11, with Claim 1 being the sole independent claim recited (Compl. ¶120).
  • Independent Claim 1 requires:
    • A process for purifying a protein on a hydrophobic interaction chromatography column such that the dynamic capacity of the column is increased.
    • Mixing a preparation containing the protein with a combination of a first salt and a second salt.
    • Loading the mixture onto the column.
    • Eluting the protein.
    • The first and second salts must be selected from the group of: citrate and sulfate, citrate and acetate, or sulfate and acetate.
    • The concentration of each salt in the mixture must be between about 0.1 M and about 1.0 M.
  • The complaint does not explicitly reserve the right to assert other dependent claims but asserts a non-exhaustive list of claims.

U.S. Patent No. 9,643,997 - "Capture Purification Processes for Proteins Expressed in a Non-Mammalian System"

  • Issued: May 9, 2017

The Invention Explained

  • Problem Addressed: When therapeutic proteins (especially those with an Fc region, like antibodies) are produced in non-mammalian systems such as E. coli, they are often expressed in a misfolded, insoluble state known as "inclusion bodies." Purifying them requires a complex "refolding" process, and the chemical components of the refolding solution were believed to interfere with the protein's ability to bind to standard purification resins like Protein A, necessitating a cumbersome and costly dilution step ('997 Patent, col. 1:28-51).
  • The Patented Solution: The patent discloses a simplified method where, after solubilizing and refolding the protein in a specialized chemical solution (containing denaturants, aggregation suppressors, etc.), this entire "refold solution" is applied directly to a separation matrix. This process bypasses the conventional, large-volume dilution step that was previously thought to be essential ('997 Patent, Abstract; col. 2:51-60).
  • Technical Importance: Eliminating the large-scale dilution step streamlines the manufacturing process for microbially-expressed proteins, reducing processing time, resource consumption, and costs, thereby making it more feasible for industrial-scale production ('997 Patent, col. 2:45-51).

Key Claims at a Glance

  • The complaint asserts infringement of the patent and recites Claim 9 as representative (Compl. ¶141).
  • Independent Claim 9 requires a method of purifying a protein expressed in a non-native limited solubility form in a non-mammalian expression system, comprising:
    • (a) Solubilizing the expressed protein in a solubilization solution containing a denaturant, a reductant, and/or a surfactant.
    • (b) Forming a refold solution comprising the solubilization solution and a refold buffer, where the refold buffer contains a denaturant, an aggregation suppressor, a protein stabilizer, and/or a redox component.
    • (c) Applying the refold solution to a separation matrix.
    • (d) Washing the separation matrix.
    • (e) Eluting the protein from the separation matrix.
  • The complaint does not explicitly reserve the right to assert other dependent claims.

III. The Accused Instrumentality

Product Identification

  • The accused instrumentality is the manufacturing process for Defendants' Fulphila™ (pegfilgrastim-jmdb) product (Compl. ¶120, ¶141). Fulphila™ itself is a biosimilar version of Plaintiffs' Neulasta® (pegfilgrastim) product (Compl. ¶16, ¶64).

Functionality and Market Context

  • The accused instrumentality is a multi-step biopharmaceutical manufacturing process. The complaint alleges this process involves, among other things, protein purification on a hydrophobic interaction chromatography column and purification of a protein expressed in a non-mammalian system in a limited solubility form (Compl. ¶120, ¶141).
  • Fulphila™ is alleged to be the first FDA-approved biosimilar to Neulasta® and was launched to compete directly with it (Compl. ¶84). The complaint alleges that Fulphila™ was introduced at a wholesale acquisition cost reflecting a 33% discount to Neulasta®, an action intended to cause price erosion and loss of sales for Plaintiffs' product (Compl. ¶90-91, ¶100-101).

IV. Analysis of Infringement Allegations

No probative visual evidence provided in complaint.

’707 Patent Infringement Allegations

Claim Element (from Independent Claim 1) Alleged Infringing Functionality Complaint Citation Patent Citation
A process for purifying a protein on a hydrophobic interaction chromatography column... The complaint alleges that in the process to manufacture the Mylan Pegfilgrastim Product, Defendants practice a process for purifying a protein on a hydrophobic interaction chromatography column as defined in the patent. ¶120 col. 15:8-12
...such that the dynamic capacity of the column is increased for the protein... The complaint alleges the process satisfies this limitation, but does not provide specific facts regarding how or to what extent the dynamic capacity is increased. ¶120 col. 15:9-11
...mixing a preparation containing the protein with a combination of a first salt and a second salt, The complaint alleges that in Defendants' process, a preparation containing protein becomes mixed with a first salt and a second salt as recited in the claim. ¶120 col. 15:12-14
...loading the mixture onto a hydrophobic interaction chromatography column, and eluting the protein, The complaint alleges that in Defendants' process, after the protein is loaded onto the column in the presence of the combination of salts, the protein is eluted. ¶120 col. 15:15-16
...wherein the first and second salts are selected from the group consisting of citrate and sulfate, citrate and acetate, and sulfate and acetate, respectively... The complaint's general allegation that Defendants' process satisfies each limitation of the claim implies the salts used are from this group. ¶120 col. 15:16-18
...wherein the concentration of each of the first salt and the second salt in the mixture is between about 0.1 M and about 1.0. The complaint alleges the concentration of the salts in the Defendants' process falls within the claimed range or is equivalent to a concentration within the range. ¶120 col. 15:18-20
  • Identified Points of Contention:
    • Functional Questions: A central question will be evidentiary: what proof can be shown that Defendants' process results in the functional outcome of an "increased" "dynamic capacity" for the protein, as required by the claim's preamble? The complaint's allegations on this point are conclusory (Compl. ¶120).
    • Scope Questions: The analysis may focus on whether the specific combination of buffering agents and salts used in Defendants' manufacturing process constitutes "a combination of a first salt and a second salt" as defined by the patent, particularly given the limited number of salt pairings explicitly claimed.

’997 Patent Infringement Allegations

Claim Element (from Independent Claim 9) Alleged Infringing Functionality Complaint Citation Patent Citation
A method of purifying a protein expressed in a non-native limited solubility form in a non-mammalian expression system comprising: Defendants are alleged to practice a process for purifying a protein expressed in such a form and system. ¶141 col. 22:36-39
(a) solubilizing the expressed protein in a solubilization solution comprising one or more of...a denaturant;...a reductant; and...a surfactant; Defendants' process is alleged to use a solubilization solution comprising one or more of a denaturant, reductant, and surfactant. ¶141 col. 22:40-45
(b) forming a refold solution comprising the solubilization solution and a refold buffer, the refold buffer comprising one or more of...a denaturant;...an aggregation suppressor;...a protein stabilizer; and...a redox component; Defendants' process is alleged to form a refold solution comprising the solubilization solution and a refold buffer, which in turn comprises one or more of a denaturant, aggregation suppressor, protein stabilizer, and redox component. ¶141 col. 22:46-52
(c) applying the refold solution to a separation matrix under conditions suitable for the protein to associate with the matrix; The complaint alleges that Defendants' refold solution is applied to a separation matrix under conditions suitable for the protein to associate with it. ¶141 col. 22:53-55
(d) washing the separation matrix; and The complaint alleges that Defendants' separation matrix is washed. ¶141 col. 22:56
(e) eluting the protein from the separation matrix. The complaint alleges that Defendants' protein is eluted from the separation matrix. ¶141 col. 22:57
  • Identified Points of Contention:
    • Technical Questions: A key factual dispute may arise over whether the specific chemical agents used in Defendants' manufacturing process meet the definitions of "denaturant," "aggregation suppressor," and "protein stabilizer" as those terms are used in the patent.
    • Scope Questions: The infringement analysis will likely turn on the definition of "non-native limited solubility form." The question for the court will be whether the state of the protein in Defendants' process—as it is expressed and before solubilization—falls within the scope of this term, which the patent specification links to inclusion bodies ('997 Patent, col. 2:42).

V. Key Claim Terms for Construction

  • Patent: '707 Patent

    • The Term: "such that the dynamic capacity of the column is increased" (Claim 1)
    • Context and Importance: This is a functional limitation in the preamble that is central to the invention's purported novelty. Infringement requires not only performing the steps but also achieving this specific result. Practitioners may focus on this term because its construction will dictate the type and quantity of evidence required to prove infringement, and whether the preamble is limiting.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The specification broadly describes the invention as providing "combinations of salts useful for increasing the dynamic capacity of an HIC column" ('707 Patent, col. 2:9-12), which might suggest any measurable increase over a single-salt process suffices.
      • Evidence for a Narrower Interpretation: The specification and figures provide specific examples of dynamic capacity increases for particular antibodies under defined conditions (e.g., Table 1, Table 3). A party could argue the term should be interpreted in light of these examples, potentially requiring a significant or commercially meaningful increase, not a de minimis one.

  • Patent: '997 Patent

    • The Term: "applying the refold solution to a separation matrix" (Claim 9)
    • Context and Importance: This step is the core of the invention, as it claims the direct application of the refold solution without the conventional dilution step. The scope of "refold solution" is critical; if Mylan's process involves any intermediate step that could be characterized as dilution or removal of components before applying the protein to the matrix, infringement may be avoided.
    • Intrinsic Evidence for Interpretation:
      • Evidence for a Broader Interpretation: The term itself is straightforward. A party could argue it simply means causing the solution containing the refolded protein to come into contact with the matrix, regardless of minor adjustments. The patent repeatedly emphasizes eliminating the "dilution step," suggesting the focus is on avoiding large-volume dilutions ('997 Patent, col. 1:48-51).
      • Evidence for a Narrower Interpretation: The claim requires applying the refold solution itself, which is defined as containing specific components like denaturants and aggregation suppressors ('997 Patent, col. 22:46-52). A party could argue that if any of these components are removed or their concentrations materially altered before the mixture contacts the matrix, then what is being "applied" is no longer the "refold solution" as claimed.

VI. Other Allegations

  • Indirect Infringement: The complaint's infringement counts are based on direct infringement under 35 U.S.C. § 271(e)(2)(C)(i) (the artificial act of infringement by filing an aBLA for a future product) and § 271(g) (importation into the U.S. of a product made by a process patented in the U.S.). While the prayer for relief includes boilerplate language for inducing infringement, the factual allegations in the body of the complaint focus on Defendants' own acts of manufacturing and seeking regulatory approval.
  • Willful Infringement: The complaint does not contain an explicit allegation of willful infringement. However, it alleges that the case is "exceptional" and seeks attorneys' fees under 35 U.S.C. § 285 (Compl. ¶132, ¶153). The factual basis for this appears to be Defendants' knowledge of the patents, which was obtained during the BPCIA "patent dance" information exchanges prior to the commercial launch of Fulphila™ (Compl. ¶77-80).

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

This dispute centers on whether Defendants' specific, confidential manufacturing process for a biosimilar drug falls within the scope of Plaintiffs' patented purification methods. The case will likely turn on two central questions:

  1. A key evidentiary question will be one of process-to-claim mapping: Can Plaintiffs demonstrate through discovery that the precise sequence of steps, chemical components, and concentrations used in Defendants' commercial-scale manufacturing process for Fulphila™ meet each limitation of the asserted patent claims?
  2. A core issue will be one of functional and definitional scope: How will the court construe crucial claim terms? For the '707 patent, this involves the functional requirement that "dynamic capacity... is increased," while for the '997 patent, it involves the technical definitions of the starting material ("non-native limited solubility form") and the components of the "refold solution" that is applied directly to the separation matrix.