DCT
1:18-cv-01064
Amgen Inc v. Hospira Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Amgen Inc. and Amgen Manufacturing, Limited (Delaware and Bermuda)
- Defendant: Hospira, Inc. and Pfizer Inc. (Delaware)
- Plaintiff’s Counsel: Richards, Layton & Finger, P.A. (lead Delaware counsel); Marshall, Gerstein & Borun LLP (of counsel)
- Case Identification: 1:18-cv-01064, D. Del., 07/18/2018
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because both Defendants are Delaware corporations.
- Core Dispute: Plaintiff alleges that the manufacturing process for Defendant's proposed biosimilar version of Amgen's NEUPOGEN® product infringes a patent related to methods for purifying proteins.
- Technical Context: The lawsuit concerns the field of biopharmaceutical manufacturing, specifically the purification of complex proteins (biologics) that are produced in non-mammalian expression systems like bacteria.
- Key Procedural History: The complaint arises under the Biologics Price Competition and Innovation Act (BPCIA). The complaint details the pre-suit information exchange process, alleging that Defendants provided "deficient and/or untimely disclosure" of their Abbreviated Biologic License Application (aBLA). After a series of disclosures and negotiations, the parties agreed that only the ’997 Patent would be the subject of the initial infringement action.
Case Timeline
| Date | Event |
|---|---|
| 2009-06-25 | ’997 Patent Priority Date |
| 2017-05-09 | ’997 Patent Issue Date |
| 2017-12-04 | Defendants notify Amgen of FDA acceptance of Hospira aBLA |
| 2017-12-11 | Defendants provide initial production of aBLA sections to Amgen |
| 2018-02-08 | Amgen discloses the '997 Patent to Defendants under the BPCIA |
| 2018-06-22 | Parties agree the '997 Patent will be the subject of this action |
| 2018-07-18 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
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: The patent addresses a challenge in manufacturing biologic drugs. When complex proteins are produced in non-mammalian systems (e.g., E. coli bacteria), they often form misfolded, insoluble aggregates called "inclusion bodies" (’997 Patent, col. 1:28-32). To become active, these proteins must be extracted, solubilized, and then "refolded" into their correct shape using a chemical mixture called a "refold solution." The patent states that prior art methods required this refold solution to be heavily diluted or its components removed before the protein could be captured on a purification medium like a Protein A resin, a step that is time-consuming and costly at industrial scale (’997 Patent, col. 1:45-54).
- The Patented Solution: The invention provides a simplified purification method where the refold solution, containing the protein of interest, can be applied directly to a separation matrix (such as a Protein A resin) without a prior dilution step (’997 Patent, Abstract; col. 4:55-65). The method allows the protein to bind to the matrix even in the presence of components like denaturants and aggregation suppressors, which were previously thought to interfere with this binding, thereby streamlining the manufacturing process (’997 Patent, col. 15:56-65).
- Technical Importance: This approach offers a significant process simplification by potentially eliminating a large-volume dilution step, which can reduce production time, resource consumption, and overall cost in the large-scale manufacturing of biologics (’997 Patent, col. 3:45-54).
Key Claims at a Glance
- The complaint identifies independent claim 9 as a representative claim (Compl. ¶59).
- The essential elements of independent claim 9 are:
- A method of purifying a protein expressed in a non-native limited solubility form in a non-mammalian expression system, comprising:
- (a) solubilizing the protein in a solution with a denaturant, a reductant, and a surfactant;
- (b) forming a refold solution that includes the solubilization solution and a refold buffer containing a denaturant, an aggregation suppressor, a protein stabilizer, and a redox component;
- (c) applying the refold solution directly to a separation matrix;
- (d) washing the matrix; and
- (e) eluting the purified protein from the matrix.
- The complaint alleges infringement of "one or more claims" and reserves the right to assert dependent claims (Compl. ¶58, ¶60).
III. The Accused Instrumentality
Product Identification
- The accused instrumentality is the process used to manufacture the "Hospira Filgrastim Biosimilar Product" (Compl. ¶10, ¶54). This product is a proposed biosimilar to Amgen's NEUPOGEN® (filgrastim) and is the subject of abbreviated Biologic License Application (aBLA) No. 761080 submitted to the FDA (Compl. ¶10).
Functionality and Market Context
- The product itself, filgrastim, is a recombinant form of human granulocyte-colony stimulating factor (G-CSF) used to treat neutropenia (a deficiency of certain white blood cells), often in cancer patients undergoing chemotherapy (Compl. ¶21-22). The infringement allegation is not directed at the product's clinical function, but rather at the method of its manufacture (Compl. ¶58, ¶60). The lawsuit is a statutory act of infringement under the BPCIA, triggered by the submission of the aBLA for the purpose of commercially manufacturing and selling the product in the U.S. (Compl. ¶14, ¶56).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint. The complaint's allegations are based on information provided by Defendants under the BPCIA's confidentiality provisions and are therefore described at a high level (Compl. ¶61).
’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 this form. | ¶60 | col. 22:36-39 |
| (a) solubilizing the expressed protein in a solubilization solution comprising one or more of the following: (i) a denaturant; (ii) a reductant; and (iii) a surfactant; | Defendants' process allegedly solubilizes the protein in a solution containing a denaturant, reductant, and surfactant. | ¶60 | col. 22:40-42 |
| (b) forming a refold solution comprising the solubilization solution and a refold buffer, the refold buffer comprising one or more of the following: (i) a denaturant; (ii) an aggregation suppressor; (iii) a protein stabilizer; and (iv) a redox component; | Defendants' process allegedly forms a refold solution comprising the solubilization solution and a refold buffer with a denaturant, aggregation suppressor, protein stabilizer, and redox component. | ¶60 | col. 22:43-50 |
| (c) applying the refold solution to a separation matrix under conditions suitable for the protein to associate with the matrix; | Defendants' process allegedly applies the refold solution to a separation matrix for protein association. | ¶60 | col. 22:51-53 |
| (d) washing the separation matrix; and | Defendants' process allegedly includes a step of washing the separation matrix. | ¶60 | col. 22:54 |
| (e) eluting the protein from the separation matrix. | Defendants' process allegedly includes a step of eluting the protein from the separation matrix. | ¶60 | col. 22:55 |
- Identified Points of Contention:
- Evidentiary Questions: The complaint explicitly states that it cannot repeat the detailed factual basis for infringement due to BPCIA confidentiality rules (Compl. ¶61). A primary issue for the court will be examining the confidential evidence from Hospira's aBLA to determine if the accused manufacturing process actually performs each claimed step using the types of components recited in the claim.
- Technical Questions: A key technical question will be whether the specific chemicals and concentrations used in the accused process fall within the scope of the general categories required by the claim (e.g., "denaturant," "aggregation suppressor"). The complaint's allegation of infringement "literally or under the doctrine of equivalents" suggests a potential dispute over whether Hospira's specific process parameters are equivalent to, if not identical to, those covered by the claims (Compl. ¶58).
V. Key Claim Terms for Construction
- The Term: "refold solution"
- Context and Importance: The composition of this solution is central to the invention. The definition of this term will be critical because the infringement analysis depends on whether the mixture that Defendants apply to their separation matrix qualifies as a "refold solution" as claimed.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: Claim 9 itself defines the term functionally as "comprising the solubilization solution and a refold buffer" (’997 Patent, col. 22:43-44). The use of the open-ended term "comprising" suggests the solution can include other, unlisted components.
- Evidence for a Narrower Interpretation: The patent provides specific examples of refold buffers, such as one containing "arginine, urea, glycerol, cysteine, and cystamine" (’997 Patent, col. 19:26-28). A party could argue that the term should be interpreted in light of these specific embodiments.
- The Term: "applying the refold solution to a separation matrix"
- Context and Importance: This limitation embodies the core advance over the prior art, which allegedly required dilution. Practitioners may focus on this term because the dispute will likely center on whether the accused process is truly "direct application" or involves an intermediate step that could be characterized as dilution or component removal, thereby avoiding infringement.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The plain language suggests any action that brings the refold solution into contact with the matrix.
- Evidence for a Narrower Interpretation: The specification repeatedly contrasts the invention with prior art that required dilution or removal of components from the refold mixture (’997 Patent, col. 1:49-54). This context could be used to argue that the claim requires the application of a substantially unaltered refold solution, and that any pre-processing of the solution before it contacts the matrix falls outside the claim's scope.
VI. Other Allegations
- Indirect Infringement: The factual allegations in the main infringement count focus on direct infringement by Defendants through their manufacturing activities (Compl. ¶56-60). However, the prayer for relief seeks to enjoin Defendants from "contributing to or inducing anyone to do the same" (Compl., p. 17, ¶C), which preserves the option to pursue indirect infringement theories.
- Willful Infringement: The complaint does not contain a specific count for willful infringement. However, it requests a declaration that the case is "exceptional" and an award of attorneys' fees under 35 U.S.C. § 285 (Compl., p. 17, ¶E). This request may be based on allegations regarding Defendants' "deficient and/or untimely disclosure" during the BPCIA's pre-suit information exchange (Compl. ¶44).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue will be one of evidentiary proof: Given the BPCIA's confidentiality framework, the complaint is necessarily general. The case will depend on what the confidential evidence in Hospira's aBLA reveals about its manufacturing process and whether Amgen can demonstrate, on a component-by-component and step-by-step basis, that this secret process meets the limitations of claim 9.
- The dispute will also raise a core question of claim scope: Does the phrase "applying the refold solution to a separation matrix" prohibit any form of intermediate processing of that solution, or does it only proscribe a traditional, large-volume dilution step? The outcome may turn on whether Hospira's process includes a step that, while not a classic dilution, can be characterized as sufficiently altering the refold solution to place the process outside the scope of the patent.