DCT
1:20-cv-00561
Amgen Inc v. Hospira Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Amgen Inc. (Delaware) and Amgen Manufacturing, Limited (Bermuda)
- Defendant: Hospira, Inc. (Delaware) and Pfizer Inc. (Delaware)
- Plaintiff’s Counsel: Richards, Layton & Finger, P.A.
- Case Identification: 1:20-cv-00561, D. Del., 04/24/2020
- Venue Allegations: Venue is alleged to be proper in the District of Delaware based on both Defendants being incorporated in the State of Delaware.
- Core Dispute: Plaintiff alleges that Defendant’s process for manufacturing its filgrastim biosimilar product, NIVESTYM®, infringes a patent related to methods for purifying proteins expressed in non-mammalian systems.
- Technical Context: The case concerns the large-scale purification of recombinant therapeutic proteins, a critical and complex step in biopharmaceutical manufacturing where efficiency gains can provide a significant competitive advantage.
- Key Procedural History: This action arises under the Biologics Price Competition and Innovation Act (BPCIA) following Defendant Hospira's submission of an abbreviated Biologic License Application (aBLA) for its biosimilar. The asserted patent is a continuation of a patent-in-suit in a related, pending litigation between the same parties, in which the court has already conducted a claim construction hearing. The complaint alleges that Defendants failed to comply with the BPCIA's statutory information exchange procedures for the newly issued patent, which Plaintiff contends provides a basis for a declaratory judgment action.
Case Timeline
| Date | Event |
|---|---|
| 2009-06-25 | '392 Patent Priority Date |
| 2018-07-20 | FDA approval for NIVESTYM® |
| 2018-09-24 | Alleged "Start Marketing Date" for NIVESTYM® |
| 2020-03-03 | '392 Patent Issue Date |
| 2020-04-24 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,577,392 - "Capture Purification Processes for Proteins Expressed in a Non-Mammalian System"
The asserted patent is U.S. Patent No. 10,577,392, issued on March 3, 2020 (’392 Patent).
The Invention Explained
- Problem Addressed: The patent describes a common problem in biomanufacturing: when therapeutic proteins are produced in non-mammalian systems like E. coli, they often form insoluble, non-functional aggregates known as "inclusion bodies." To become active, these proteins must be chemically solubilized and then carefully refolded. The patent states that the chemical "refold buffer" used in this process typically interferes with subsequent purification steps, such as affinity chromatography, forcing manufacturers to perform a large-volume dilution step that is time-consuming and costly at an industrial scale (’392 Patent, col. 1:28-57).
- The Patented Solution: The invention provides methods that circumvent the need for this dilution step. The core of the patented solution is the direct application of the entire "refold solution"—containing the refolded protein along with chemicals like denaturants and aggregation suppressors—onto a separation matrix. The process is based on the principle that the target protein can associate with the matrix even in the presence of the otherwise interfering components of the refold buffer, thereby streamlining the purification process (’392 Patent, Abstract; col. 4:55-65).
- Technical Importance: By eliminating a dilution step, this approach could significantly reduce the time, resources, and facility footprint required for large-scale protein purification, offering a material advantage in the production of biologics (’392 Patent, col. 1:52-57).
Key Claims at a Glance
- The complaint asserts infringement of at least Claim 22, which depends on independent Claim 10.
- The essential elements of independent Claim 10 are:
- A method of purifying a protein expressed in a non-native limited solubility form in E. coli.
- (a) expressing the protein in E. coli.
- (b) lysing the E. coli.
- (c) solubilizing the protein in a solution comprising one or more of a denaturant, a reductant, or a surfactant.
- (d) forming a refold solution comprising the solubilized protein and a refold buffer, with the refold buffer comprising one or more of a denaturant, an aggregation suppressor, a protein stabilizer, or a redox component.
- (e) applying the refold solution to a separation matrix and obtaining a purified protein.
- The complaint alleges infringement of at least dependent Claim 22, which further specifies the method of Claim 10 (’392 Patent, col. 24:30-33).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is the manufacturing process for the Hospira Filgrastim Biosimilar Product, which is marketed as NIVESTYM® (filgrastim-aafi) (Compl. ¶¶ 10, 54).
Functionality and Market Context
- NIVESTYM® is a biosimilar version of Amgen's NEUPOGEN® (filgrastim) product (Compl. ¶10). Filgrastim is a recombinant form of human granulocyte-colony stimulating factor ("G-CSF"), a protein that stimulates the production of neutrophils (a type of white blood cell) and is used to treat patients with neutropenia, often resulting from chemotherapy (Compl. ¶¶ 23-24).
- The complaint alleges that NIVESTYM® was designed to compete directly with NEUPOGEN® and was launched at a substantial price discount of over 30% to erode Amgen's market share and pricing power (Compl. ¶¶ 39, 60, 66). The complaint alleges that the accused process is the FDA-approved process used to manufacture NIVESTYM® (Compl. ¶54).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
Claim Chart Summary
The complaint alleges on "information and belief" that the process for manufacturing the Hospira Filgrastim Biosimilar Product meets the limitations of at least Claim 22 of the ’392 Patent (Compl. ¶96). The core allegations for the underlying independent claim are summarized below.
| Claim Element (from Independent Claim 10) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of purifying a protein expressed in a non-native limited solubility form in E. coli. | The accused process is used for purifying a protein expressed in a non-native limited solubility form in E. coli. | ¶96 | col. 23:7-10 |
| (b) lysing the E. coli; | The accused process includes a step of lysing the E. coli. | ¶96 | col. 23:13 |
| (c) 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; | The accused process includes a step of solubilizing the protein in a solution containing one or more of a denaturant, reductant, and surfactant. | ¶96 | col. 23:14-18 |
| (d) forming a refold solution comprising the solubilized protein 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; | The accused process includes forming a refold solution that comprises the solubilized protein and a refold buffer containing one or more of a denaturant, aggregation suppressor, protein stabilizer, and redox component. | ¶96 | col. 23:19-24 |
| (e) applying the refold solution to a separation matrix...and obtaining a purified protein. | The accused process includes applying the refold solution to a separation matrix to obtain a purified protein. | ¶96 | col. 23:25-27 |
| Limitation from Dependent Claim 22: the separation matrix is: a non-affinity resin selected from the group consisting of: ion exchange, mixed mode, and a hydrophobic interaction resin. | The separation matrix used in the accused process is a non-affinity resin from the group consisting of ion exchange, mixed mode, and a hydrophobic interaction resin. | ¶96 | col. 24:30-33 |
Identified Points of Contention
- Evidentiary Questions: The complaint's infringement allegations are made "on information and belief" and are conclusory (Compl. ¶96). A central issue will be what evidence Plaintiff can obtain through discovery from Defendants' confidential aBLA to prove that the accused manufacturing process actually meets each limitation of the asserted claims.
- Scope Questions: A likely point of dispute will be whether the specific chemical agents and process conditions used by Defendants fall within the scope of the patent's claim terms. For example, a key question will be whether a specific chemical used in the accused process functions as an "aggregation suppressor" or "protein stabilizer" as those terms are understood in the context of the patent.
- Doctrine of Equivalents: While the complaint alleges literal infringement, the parties may also dispute infringement under the doctrine of equivalents. This raises the question of whether any step in the accused process performs substantially the same function, in substantially the same way, to achieve substantially the same result as a claimed element, even if it is not literally identical.
V. Key Claim Terms for Construction
The Term: "refold solution"
Context and Importance
This term is at the heart of the invention, as the method hinges on applying this specific solution directly to the separation matrix. Its construction will be critical, as infringement will depend on whether Defendants' process mixture qualifies as the claimed "refold solution." Practitioners may focus on this term because the claim defines it by what its constituent "refold buffer" comprises, making the definition of those underlying components (e.g., "aggregation suppressor") determinative.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: Claim 10 states the refold buffer comprises "one or more of" a list of four component types, which may suggest that not all component types are required for a mixture to qualify as a "refold buffer" (’392 Patent, col. 23:21-24). The specification also provides extensive and non-limiting lists of chemicals that can serve as each component type (’392 Patent, col. 14:30-64).
- Evidence for a Narrower Interpretation: A party could argue that the specific examples in the patent, such as the refold buffer in Example 2 which contains specific concentrations of arginine, urea, glycerol, cysteine, and cystamine, should guide the term's meaning to require a similarly functional combination of components (’392 Patent, col. 19:25-28).
The Term: "aggregation suppressor"
Context and Importance
This is a functional limitation within the definition of the "refold buffer" and, by extension, the "refold solution." The dispute will turn on what chemical properties a compound must have to qualify. A narrow definition could exclude the specific agents used in the accused process, while a broad one could encompass them.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The specification provides a non-exhaustive list of examples, including amino acids (arginine, proline), polyols, and surfactants, suggesting the term covers a wide range of chemical classes that serve the function of preventing protein aggregation (’392 Patent, col. 5:46-54).
- Evidence for a Narrower Interpretation: A party might argue from the patent's context that an "aggregation suppressor" must be a distinct component from a "denaturant" or "protein stabilizer," potentially limiting the term's scope if the accused process uses a single chemical alleged to perform multiple functions. The specification lists arginine under both "aggregation suppressor" and "protein stabilizer," creating a potential ambiguity for construction (’392 Patent, col. 5:47, col. 5:62).
VI. Other Allegations
Indirect Infringement
While the prayer for relief includes a request to enjoin inducement of infringement, the substantive counts focus on direct infringement under 35 U.S.C. § 271(e)(2)(C) (the artificial act of infringement via aBLA submission) and § 271(g) (importation of a product made by a patented process) (Compl. ¶¶ 88-113; Prayer for Relief ¶D). The complaint does not plead specific facts to support a claim for induced infringement of the manufacturing method claims.
Willful Infringement
The complaint does not contain an explicit allegation of willful infringement. However, it does seek a declaration that the case is "exceptional" and an award of attorneys' fees under 35 U.S.C. § 285 (Compl. ¶106). This claim may be based on the alleged litigation conduct within the BPCIA framework, such as the alleged failure to provide a timely statutory disclosure, rather than on pre-suit knowledge of infringement of the newly-issued ’392 Patent (Compl. ¶¶ 80-81).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central evidentiary question will be whether Plaintiff can prove, based on Defendants' confidential aBLA and other discovery, that the specific combination of chemicals, concentrations, and process steps used to manufacture NIVESTYM® falls within the boundaries of the asserted claims. The "information and belief" pleading standard of the complaint will have to be substantiated with factual evidence.
- The outcome will likely depend on a core claim construction dispute: how broadly will the court define the functional components of the "refold solution," such as "aggregation suppressor" and "protein stabilizer"? Whether the specific agents in Defendants' process meet these definitions will be a determinative issue for infringement.
- A key procedural issue will be the legal consequence, if any, of Defendants' alleged failure to provide a timely disclosure for the '392 Patent under the BPCIA's "patent dance" provisions. This could impact not only the procedural posture of the declaratory judgment claim but also Plaintiff's argument that this is an "exceptional case" warranting an award of attorneys' fees.