DCT
1:18-cv-01459
Eagle Pharma Inc v. Slayback Pharma LLC
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Eagle Pharmaceuticals, Inc. (Delaware)
- Defendant: Slayback Pharma LLC (Delaware)
- Plaintiff’s Counsel: Shaw Keller LLP
- Case Identification: 1:18-cv-01459, D. Del., 09/20/2018
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because the Defendant is a Delaware corporation and therefore resides in the district.
- Core Dispute: Plaintiff alleges that Defendant’s submission of an Abbreviated New Drug Application (ANDA) to the FDA for a generic version of Bendamustine Hydrochloride Injection constitutes an act of infringement of five patents covering stable, liquid formulations of the drug.
- Technical Context: The technology concerns pharmaceutical formulations designed to solve the chemical instability of bendamustine, an alkylating drug used to treat certain cancers, thereby enabling long-term storage in a ready-to-use liquid form.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Plaintiff’s receipt of notice letters from the Defendant. These letters contained a Paragraph IV Certification asserting that the patents-in-suit are invalid, unenforceable, or will not be infringed by the Defendant's proposed generic product. The asserted patents are listed in the FDA's "Orange Book" as covering Plaintiff's approved Bendamustine Hydrochloride Injection product. The complaint notes prior litigation between the parties involving other ANDA filings.
Case Timeline
| Date | Event |
|---|---|
| 2010-01-28 | Earliest Priority Date for all Patents-in-Suit |
| 2013-12-17 | U.S. Patent No. 8,609,707 Issues |
| 2016-02-23 | U.S. Patent No. 9,265,831 Issues |
| 2017-02-21 | U.S. Patent No. 9,572,796 Issues |
| 2017-02-21 | U.S. Patent No. 9,572,797 Issues |
| 2018-07-03 | U.S. Patent No. 10,010,533 Issues |
| 2018-08-08 | Slayback sends first Notice Letter to Eagle |
| 2018-08-09 | Slayback sends second Notice Letter to Eagle |
| 2018-09-20 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 8,609,707 - "Formulations of Bendamustine," Issued Dec. 17, 2013
The Invention Explained
- Problem Addressed: The patent’s background explains that bendamustine is unstable in aqueous solutions and degrades rapidly upon reconstitution from its commercially available lyophilized (freeze-dried) powder form. This instability, which produces impurities like HP1 and HP2, makes long-term storage in a liquid format challenging and the reconstitution process clinically inconvenient (’707 Patent, col. 1:40-59).
- The Patented Solution: The invention provides a non-aqueous, long-term storage stable liquid formulation of bendamustine. The solution uses a "pharmaceutically acceptable fluid" that comprises a mixture of polyethylene glycol (PEG) and propylene glycol (PG), combined with a stabilizing amount of an antioxidant, to prevent degradation and eliminate the need for reconstitution before use (’707 Patent, Abstract; col. 2:50-55).
- Technical Importance: The development of a stable, ready-to-use (RTU) liquid formulation of bendamustine represented a significant advance by improving convenience for healthcare providers and reducing the risk of chemical degradation associated with on-site reconstitution (’707 Patent, col. 1:56-62).
Key Claims at a Glance
- The complaint asserts "one or more claims" of the ’707 Patent (Compl. ¶31). Independent claim 1 is representative.
- The key elements of independent claim 1 (as corrected) include:
- A long term storage stable non-aqueous liquid bendamustine-containing composition, comprising:
- a) bendamustine or a pharmaceutically acceptable salt thereof, and
- b) a pharmaceutically acceptable fluid comprising
- i) about 90% polyethylene glycol and about 10% propylene glycol; and
- ii) a stabilizing amount of an antioxidant.
- The complaint reserves the right to assert other claims, including dependent claims.
U.S. Patent No. 9,265,831 - "Formulations of Bendamustine," Issued Feb. 23, 2016
The Invention Explained
- Problem Addressed: Like its parent, the ’831 Patent addresses the rapid degradation of bendamustine in reconstituted lyophilized powders and the need for a stable liquid formulation (’831 Patent, col. 1:47-60).
- The Patented Solution: This patent claims specific bendamustine compositions with defined stability characteristics. The claims focus on formulations containing a specific range of propylene glycol (5-10% by volume), polyethylene glycol, and a specified antioxidant. The stability is further defined by a functional limitation on the amount of impurities (total PG esters) present after storage for a set time at a specific temperature (’831 Patent, col. 13:21-42, Claim 1).
- Technical Importance: The invention provides specific formulations demonstrated to have superior long-term stability, quantified by the minimal formation of known degradants. This specificity is critical for creating a commercially viable RTU pharmaceutical product with a reliable shelf life (’831 Patent, col. 2:5-12).
Key Claims at a Glance
- The complaint asserts "one or more claims" of the ’831 Patent (Compl. ¶42). Independent claim 1 is representative.
- The key elements of independent claim 1 include:
- A non-aqueous liquid bendamustine-containing composition, comprising:
- a) bendamustine or a pharmaceutically acceptable salt thereof; and
- b) a pharmaceutically acceptable fluid comprising about 5% to about 10% by volume propylene glycol, polyethylene glycol, and a stabilizing amount of an antioxidant from a specific list;
- Wherein the composition has less than or equal to 0.11% total PG esters after 1 month of storage at about 5° C.; and
- Wherein the ratio of polyethylene glycol to propylene glycol is selected from a specified group (e.g., 95:5, 90:10).
Multi-Patent Capsule: U.S. Patent No. 9,572,796
- Patent Identification: U.S. Patent No. 9,572,796, "Formulations of Bendamustine," Issued Feb. 21, 2017.
- Technology Synopsis: This patent claims non-aqueous liquid bendamustine compositions comprising a mixture of PEG and PG (in a ratio from 95:5 to 50:50) and an antioxidant. The invention is distinguished by the claimed stability profile: having less than 5% total impurities after 15 months of storage at 5° C., as determined by HPLC (’796 Patent, Abstract; Claim 1).
- Asserted Claims: "one or more claims" (Compl. ¶49). Independent claims include 1 and 14.
- Accused Features: The Defendant's ANDA product is alleged to contain the same or equivalent ingredients (bendamustine, PG, PEG, and an antioxidant), which would allegedly result in the same claimed stability profile (Compl. ¶¶23, 25).
Multi-Patent Capsule: U.S. Patent No. 9,572,797
- Patent Identification: U.S. Patent No. 9,572,797, "Formulations of Bendamustine," Issued Feb. 21, 2017.
- Technology Synopsis: This patent claims methods of treating specific cancers (leukemia, Hodgkin's disease, multiple myeloma) by administering the stable liquid bendamustine formulations. The formulation is defined by its components (PEG, PG, antioxidant) and its stability characteristics, such as having less than or equal to 0.12% total PG esters after 15 days of storage at 25°C (’797 Patent, Abstract; Claim 16).
- Asserted Claims: "one or more claims" (Compl. ¶60). Independent claims include 1 and 16.
- Accused Features: The proposed labeling for the Defendant's ANDA product is alleged to instruct for administration to treat the same cancers claimed in the patent, thereby inducing infringement of the method claims (Compl. ¶¶26-27, 61).
Multi-Patent Capsule: U.S. Patent No. 10,010,533
- Patent Identification: U.S. Patent No. 10,010,533, "Formulations of Bendamustine," Issued July 3, 2018.
- Technology Synopsis: This patent claims liquid bendamustine compositions containing PEG, PG, and an antioxidant from a specified group. The claims are characterized by a stability requirement that the composition has less than or equal to 0.11% total PG esters after one month of storage at 5°C, and a specific ratio of PEG to PG (’533 Patent, Claim 1).
- Asserted Claims: "one or more claims" (Compl. ¶71). Independent claims include 1, 7, and 16.
- Accused Features: The Defendant's ANDA product is alleged to be a generic equivalent that contains the same active and inactive ingredients, which upon information and belief will meet the claimed stability and impurity profile (Compl. ¶¶23, 25).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is "Slayback's ANDA Product," a generic Bendamustine Hydrochloride Injection (100 mg/4 mL (25 mg/mL)) for which Slayback submitted Abbreviated New Drug Application No. 212230 to the FDA (Compl. ¶¶1, 20).
Functionality and Market Context
The product is a liquid formulation intended for intravenous injection as a generic alternative to Eagle’s branded product (Compl. ¶20). The complaint alleges, upon information and belief, that the product contains the active ingredient bendamustine hydrochloride, and the inactive ingredients propylene glycol, polyethylene glycol, and monothioglycerol (an antioxidant) (Compl. ¶¶23, 25). The proposed labeling for the product allegedly recommends its use for treating chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma, placing it in the market for cancer therapeutics (Compl. ¶¶26, 27).
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) bendamustine or a pharmaceutically acceptable salt thereof | Slayback’s ANDA Product contains the active ingredient bendamustine hydrochloride. | ¶23 | col. 12:65-67 |
| b) a pharmaceutically acceptable fluid comprising i) about 90% polyethylene glycol and about 10% propylene glycol | Slayback’s ANDA Product contains propylene glycol and polyethylene glycol. | ¶25 | col. 13:1-3 |
| and ii) a stabilizing amount of an antioxidant. | Slayback’s ANDA Product contains monothioglycerol, which is an antioxidant. | ¶25 | col. 13:4-6 |
’831 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| b) a pharmaceutically acceptable fluid comprising; i) about 5% to about 10% by volume propylene glycol, ii) polyethylene glycol | Slayback’s ANDA Product contains propylene glycol and polyethylene glycol. | ¶25 | col. 13:25-26 |
| and iii) a stabilizing amount of an antioxidant selected from the group consisting of thioglycerol, monothioglycerol... | Slayback's ANDA Product contains monothioglycerol, an antioxidant listed in the claim's Markush group. | ¶25 | col. 13:28-34 |
| the bendamustine-containing composition having less than or equal to 0.11% total PG esters at about 1 month of storage at about 5° C. | The complaint alleges that the manufacture and use of Slayback's ANDA Product will infringe, which implies that the product possesses the claimed stability characteristics. | ¶42 | col. 13:35-38 |
Identified Points of Contention
- Scope Questions: A central dispute will likely involve whether the term "about" as used in claims reciting specific percentages (e.g., "about 90% polyethylene glycol") can be interpreted to cover the precise concentrations in Slayback's formulation. The complaint alleges the ingredients are present in the "same or equivalent amounts" (Compl. ¶25), which leaves open the factual question of whether Slayback’s formulation falls literally within the claimed ranges or, alternatively, infringes under the doctrine of equivalents.
- Technical Questions: For claims that include functional limitations based on stability (e.g., "less than or equal to 0.11% total PG esters" in the ’831 Patent), the infringement analysis will turn on factual evidence. The complaint does not provide test data for Slayback’s product, raising the question of whether discovery will show that the accused product inherently meets these negative limitations on impurity levels.
V. Key Claim Terms for Construction
The Term: "a stabilizing amount of an antioxidant"
- Context and Importance: The definition of this term is critical for determining infringement, as the parties may dispute whether the quantity of antioxidant in the accused product is sufficient to perform the claimed function. Practitioners may focus on this term because Slayback could argue its concentration of monothioglycerol serves a different primary purpose or is too low to provide the claimed "stabilizing" effect.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification defines "stabilizing amount" functionally as "those amounts which increase or enhance the stability of the bendamustine" (’707 Patent, col. 3:56-60). This language could support an interpretation where any amount that produces a measurable stabilizing effect, however small, meets the limitation.
- Evidence for a Narrower Interpretation: The patent discloses specific working examples with antioxidant concentrations such as 2.5 mg/mL or 5 mg/mL (’707 Patent, Tables 3, 7). A party could argue that a "stabilizing amount" must be an amount sufficient to achieve the "long term storage stable" characteristic of the invention, potentially limiting the term to concentrations similar to those proven effective in the specification.
The Term: "about"
- Context and Importance: This term modifies nearly all quantitative values in the claims (e.g., "about 90%," "about 10%"). Its construction will determine the permissible range of deviation from the stated values and will be central to the literal infringement analysis.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The specification discloses multiple embodiments with varying ratios of PEG and PG (e.g., 90:10, 75:25, 50:50) that all achieve the inventive purpose (’707 Patent, Table 5). This may suggest that the invention is not limited to a precise numerical value and that "about" should be construed to cover a range of values that achieve a similar result.
- Evidence for a Narrower Interpretation: The existence of different patents and claims in the family that recite different and sometimes overlapping numerical ranges could be used to argue that each range is distinct. This might support a narrower construction of "about" to prevent the scope of one claim from improperly subsuming another.
VI. Other Allegations
- Indirect Infringement: The complaint alleges that Slayback will induce infringement of the asserted method claims by providing a product label that instructs and encourages physicians and other healthcare providers to administer the ANDA product for the claimed indications of treating chronic lymphocytic leukemia and non-Hodgkin lymphoma (Compl. ¶¶61, 63-64). It further alleges contributory infringement, stating that Slayback’s product is especially made for an infringing use and is not suitable for a substantial non-infringing use (Compl. ¶¶65).
- Willful Infringement: The complaint alleges that Slayback acted with full knowledge of the patents-in-suit, as evidenced by its Paragraph IV certification, and without a reasonable basis for believing its product would not infringe (Compl. ¶¶38, 45, 56, 67, 74).
VII. Analyst’s Conclusion: Key Questions for the Case
- A central factual question will be one of compositional identity: Will discovery reveal that the precise formulation of Slayback’s ANDA product—specifically, its ratios of polyethylene glycol to propylene glycol and the concentration of its antioxidant—falls within the numerical ranges recited in the asserted claims, particularly when accounting for the term "about"?
- A key evidentiary issue will concern inherent properties: Does Slayback's proposed generic product, as formulated, necessarily meet the stability and impurity profiles that are recited as express limitations in several of the asserted claims (e.g., the "less than X% total PG esters" limitations), and what evidence will be required to prove or disprove this?
- A critical legal question will be one of claim scope: How will the court construe the term "a stabilizing amount," and will infringement require a showing of a particular threshold of stabilization, or will any measurable enhancement of stability suffice?