DCT
1:18-cv-00191
Hospira Inc v. Jiangsu Hengrui Medicine Co Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Hospira, Inc. (Delaware)
- Defendant: Jiangsu Hengrui Medicine Co., Ltd. (China)
- Plaintiff’s Counsel: Connolly Gallagher LLP
- Case Identification: 1:18-cv-00191, D. Del., 02/01/2018
- Venue Allegations: Plaintiff alleges venue is proper in the District of Delaware based on Defendant's submission of an Abbreviated New Drug Application (ANDA) seeking approval to market its products throughout the United States, including Delaware.
- Core Dispute: Plaintiff alleges that Defendant’s submission of an ANDA to the FDA for generic dexmedetomidine hydrochloride injection products constitutes an act of infringement of four patents covering ready-to-use formulations and methods of treatment associated with Plaintiff's branded drug, PRECEDEX™.
- Technical Context: The technology concerns patient-ready, premixed pharmaceutical formulations of the sedative dexmedetomidine, which are designed to be administered without prior dilution, thereby aiming to reduce medication errors and contamination risks in clinical settings.
- Key Procedural History: The action was initiated under the Hatch-Waxman Act following Plaintiff's receipt on December 19, 2017, of a Notice Letter from Defendant. The letter included a Paragraph IV Certification asserting that the patents-in-suit are invalid and/or not infringed by Defendant's proposed generic products. The complaint notes that for most claims, the stated basis for the certification is alleged invalidity rather than non-infringement.
Case Timeline
| Date | Event |
|---|---|
| 1999-12-17 | FDA approves original New Drug Application for PRECEDEX™ |
| 2012-01-04 | Earliest Priority Date for all Patents-in-Suit |
| 2013-03-13 | FDA approves first amendment to PRECEDEX™ NDA for a premix formulation |
| 2013-06-04 | U.S. Patent No. 8,455,527 issues |
| 2014-02-11 | U.S. Patent No. 8,648,106 issues |
| 2014-11-14 | FDA approves second amendment to PRECEDEX™ NDA for a premix formulation |
| 2016-04-26 | U.S. Patent No. 9,320,712 issues |
| 2017-04-11 | U.S. Patent No. 9,616,049 issues |
| 2017-12-19 | Plaintiff receives Defendant’s ANDA Notice Letter |
| 2018-02-01 | Complaint filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,455,527 - Methods of Treatment Using a Dexmedetomidine Premix Formulation
The Invention Explained
- Problem Addressed: The patent describes that, historically, dexmedetomidine was supplied as a concentrate that required a dilution step before it could be administered to a patient (Compl. ¶15; ’527 Patent, col. 2:58-60). This process created "inconvenience, and risk of possible contamination or overdose due to human error" (’527 Patent, col. 2:62-64).
- The Patented Solution: The invention is a method of providing sedation by administering a "patient-ready, premixed" formulation of dexmedetomidine that does not require reconstitution or dilution prior to administration (’527 Patent, col. 1:15-20). The patent discloses that such premixed formulations were discovered to remain "stable and active after prolonged storage," thus avoiding the risks associated with bedside dilution (’527 Patent, col. 3:1-3).
- Technical Importance: The development of a stable, ready-to-use injectable formulation provided a significant safety and efficiency advantage in clinical practice by eliminating a manual preparation step.
Key Claims at a Glance
- The complaint asserts infringement of at least one claim but does not specify which claims (Compl. ¶25). Independent claim 1 is representative of the method claims.
- Claim 1 Elements:
- A method of providing sedation to a patient in need thereof
- comprising administering... an effective amount of a composition
- wherein the composition comprises dexmedetomidine or a pharmaceutically acceptable salt thereof at a concentration of about 0.005 to about 50 µg/mL
- wherein the composition is a ready to use liquid pharmaceutical composition for parenteral administration
- disposed within a sealed glass container
U.S. Patent No. 8,648,106 - Dexmedetomidine Premix Formulation
The Invention Explained
- Problem Addressed: The ’106 Patent addresses the same problem as the ’527 Patent: the risks and inconveniences associated with diluting concentrated drug formulations prior to use (’106 Patent, col. 2:1-4).
- The Patented Solution: This patent claims the composition itself, focusing on a specific, objective measure of its stability. The invention is a "ready to use" liquid pharmaceutical composition of dexmedetomidine in a sealed glass container that maintains its concentration within a narrow range (a decrease of no more than about 2%) for an extended period (at least five months) (’106 Patent, col. 2:7-12; Claim 1).
- Technical Importance: By claiming a specific, long-term stability profile, the patent protects the key technical achievement that makes a premixed, commercial formulation viable.
Key Claims at a Glance
- The complaint asserts infringement of at least one claim but does not specify which claims (Compl. ¶31). Independent claim 1 is representative of the composition claims.
- Claim 1 Elements:
- A ready to use liquid pharmaceutical composition for parenteral administration to a subject
- comprising dexmedetomidine or a pharmaceutically acceptable salt thereof disposed within a sealed glass container
- wherein the liquid pharmaceutical composition when stored in the glass container for at least five months exhibits no more than about 2% decrease in the concentration of dexmedetomidine
U.S. Patent No. 9,320,712 - Dexmedetomidine Premix Formulation
- Technology Synopsis: This patent is directed to a ready-to-use liquid pharmaceutical composition for parenteral administration comprising dexmedetomidine disposed within a sealed glass container, where the active ingredient is specifically formulated as a hydrochloride salt (’712 Patent, Claim 1). This continues the theme of claiming specific, stable, ready-to-use formulations to avoid the problems of prior art concentrates.
- Asserted Claims: At least one claim is asserted (Compl. ¶37).
- Accused Features: The "Proposed Hengrui Dexmedetomidine Products," which are described as dexmedetomidine hydrochloride injections in vials (Compl. ¶¶ 20, 37).
U.S. Patent No. 9,616,049 - Dexmedetomidine Premix Formulation
- Technology Synopsis: This patent claims a ready-to-use liquid pharmaceutical composition comprising dexmedetomidine in a sealed glass container having a pH of about 2 to about 10 (’049 Patent, Claim 1). The patent family describes pH as a factor that can affect the adsorption of the dexmedetomidine molecule, and thus its stability and potency over time.
- Asserted Claims: At least one claim is asserted (Compl. ¶43).
- Accused Features: The "Proposed Hengrui Dexmedetomidine Products," which are dexmedetomidine hydrochloride injections in vials (Compl. ¶¶ 20, 43).
III. The Accused Instrumentality
Product Identification
- The "Proposed Hengrui Dexmedetomidine Products" for which Defendant submitted ANDA No. 209065 to the FDA (Compl. ¶4, p. 2).
Functionality and Market Context
- The accused products are described as "Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection, 4 mcg/mL, in 20 mL, 50 mL, and 100 mL vials" (Compl. ¶20). These are ready-to-use injectable formulations intended to be generic equivalents to Plaintiff’s PRECEDEX™ premix product (Compl. p. 2).
- As this is a Hatch-Waxman action, the act of infringement alleged is the submission of the ANDA itself, which seeks approval to market these products for the same indications as the branded drug prior to the expiration of the patents-in-suit (Compl. ¶24).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
The complaint alleges that Defendant’s proposed product will meet every limitation of at least one claim of each asserted patent (Compl. ¶¶ 25, 31, 37, 43). The infringement theory is based on the product characteristics described in Defendant's ANDA submission (Compl. ¶20).
- 8,455,527 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of providing sedation to a patient... comprising administering... an effective amount of a composition... | The proposed package insert for Defendant's product will allegedly instruct physicians and other healthcare providers to administer the product to provide sedation to patients (Compl. ¶26). | ¶26 | col. 25:26-29 |
| wherein the composition comprises dexmedetomidine... at a concentration of about 0.005 to about 50 µg/mL... | Defendant’s proposed product is a dexmedetomidine hydrochloride injection at a concentration of 4 mcg/mL, which is within the claimed range (Compl. ¶20). | ¶20 | col. 25:29-32 |
| wherein the composition is a ready to use liquid pharmaceutical composition for parenteral administration... | The proposed product is a liquid injection that does not require dilution before parenteral administration. | ¶20 | col. 25:33-35 |
| disposed within a sealed glass container. | The proposed product is supplied in vials, which are understood to be sealed glass containers. | ¶20 | col. 26:1 |
Identified Points of Contention:
- Scope Questions: For the method claims of the ’527 Patent, a central question for the court may be whether the instructions for use in Defendant's proposed product label will direct, encourage, or instruct clinicians to perform each step of the claimed method, thereby satisfying the requirements for induced infringement.
- Technical Questions: While the product's 4 mcg/mL concentration appears to literally meet the claim's concentration range, a potential dispute could arise over the meaning of "about," though this may be less likely given how far the value is from the range boundaries.
8,648,106 Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A ready to use liquid pharmaceutical composition for parenteral administration... | Defendant's proposed product is a liquid dexmedetomidine injection for parenteral administration that does not require dilution before use. | ¶20 | col. 25:19-20 |
| comprising dexmedetomidine or a pharmaceutically acceptable salt thereof disposed within a sealed glass container... | The product is a dexmedetomidine hydrochloride injection supplied in vials. | ¶20 | col. 25:20-22 |
| wherein the liquid pharmaceutical composition when stored in the glass container for at least five months exhibits no more than about 2% decrease in the concentration of dexmedetomidine. | The complaint does not provide sufficient detail for analysis of this element, but an ANDA filer must demonstrate that its proposed generic product has stability comparable to the reference listed drug. | ¶31 | col. 25:22-25 |
- Identified Points of Contention:
- Evidentiary Questions: The key dispute for the ’106 Patent will likely be factual and evidentiary. The court will need to examine the stability data for the proposed generic product, as submitted in Defendant's ANDA, to determine if it meets the quantitative "no more than about 2% decrease" limitation.
- Scope Questions: The term "about 2%" may become a point of contention if Defendant's stability data shows a potency decrease close to this value, raising the question of how much variance is permissible under the term "about."
V. Key Claim Terms for Construction
The Term: "ready to use"
Context and Importance: This term is central to distinguishing the patented invention from prior art dexmedetomidine concentrates that required dilution. Its construction will be critical for both infringement and validity analyses, as it defines the core feature of the product.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines a "premix" or "premixture" as a "pharmaceutical formulation that does not require reconstitution or dilution prior to administration to a patient" (’527 Patent, col. 3:50-54). This language may support a construction covering any formulation that is directly administrable from its primary packaging without a dilution step.
- Evidence for a Narrower Interpretation: The specification also states that such compositions are suitable for administration "upon removing the compositions from a sealed container or vessel" (’527 Patent, col. 4:1-3). A defendant could potentially argue this implies a specific level of immediacy or lack of intermediate handling steps, though the patent's explicit mention of "vials" and "ampoules" may counter such an argument (’527 Patent, col. 9:22-23).
The Term: "about" (as in "about 2% decrease")
Context and Importance: This term of degree defines the scope of the stability limitation in the ’106 Patent. Its interpretation is critical to determining whether the stability profile of Defendant's product falls within the claim scope. Practitioners may focus on this term because small differences in stability data could determine the outcome of infringement.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification uses "about" to mean "within an acceptable error range for the particular value as determined by one of ordinary skill in the art," which could include "a range of up to 20%, preferably up to 10%" (’527 Patent, col. 5:25-32). Plaintiff may cite this definition to argue for a flexible interpretation that covers standard analytical variability.
- Evidence for a Narrower Interpretation: A defendant might argue that in the context of a specific quantitative limit like "2%," the term "about" should be construed more narrowly to mean only minor rounding or measurement error, and that the patentee's broad definition in the specification is not applicable to this specific claim limitation.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Defendant will induce infringement of the method claims by "providing information and instructions for use of its products in the proposed package insert" that will accompany the product (Compl. ¶¶ 26, 32, 38, 44).
- Willful Infringement: The complaint alleges that Defendant was aware of the existence of the patents-in-suit prior to filing its ANDA (Compl. ¶¶ 21, 27, 33, 39, 45). The prayer for relief requests a declaration that the case is exceptional under 35 U.S.C. § 285, which could support an award of attorneys' fees (Compl. Prayer for Relief ¶H).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central issue for the court will be one of validity, specifically obviousness: Given the known risks and inconveniences of diluting drug concentrates, can Defendant demonstrate with clear and convincing evidence that it would have been obvious for a skilled formulator to create a stable, patient-ready, 4 mcg/mL liquid dexmedetomidine formulation with the claimed stability profile at the time of the invention?
- A key evidentiary question will be one of technical compliance: Does the stability data contained within Defendant's confidential ANDA submission demonstrate that its proposed product meets the quantitative limitation of exhibiting "no more than about 2% decrease" in concentration after five months of storage, as required by claims of the ’106 patent?
- The analysis of induced infringement will likely turn on a question of label interpretation: Will Defendant's proposed FDA package insert necessarily instruct clinicians to perform every step of the patented methods of sedation, or does the label allow for substantial non-infringing uses?