DCT
1:18-cv-01962
Silvergate Pharma Inc v. Bionpharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Silvergate Pharmaceuticals, Inc. (Delaware)
- Defendant: Bionpharma Inc. (Delaware)
- Plaintiff’s Counsel: Morris, Nichols, Arsht & Tunnell LLP
- Case Identification: 1:18-cv-01962, D. Del., 12/12/2018
- Venue Allegations: Venue is asserted as proper because Defendant is a corporation organized under the laws of the State of Delaware.
- Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic enalapril maleate oral solution constitutes an act of infringement of three patents related to stable liquid pharmaceutical formulations.
- Technical Context: The dispute is in the field of pharmaceutical formulations, specifically addressing the technical challenges of creating a stable, ready-to-use liquid version of a drug traditionally sold in solid tablet form.
- Key Procedural History: The complaint indicates this action was filed under the Hatch-Waxman Act, triggered by a notice letter from Defendant regarding its ANDA filing seeking to market a generic version of Plaintiff's EPANED® product. Plaintiff states that the patents-in-suit are listed in the U.S. Food and Drug Administration's "Orange Book" in connection with its New Drug Application (NDA) No. 208686 for EPANED®.
Case Timeline
| Date | Event |
|---|---|
| 2016-03-18 | Earliest Patent Priority Date |
| 2017-06-06 | U.S. Patent No. 9,669,008 Issues |
| 2017-11-07 | U.S. Patent No. 9,808,442 Issues |
| 2018-08-07 | U.S. Patent No. 10,039,745 Issues |
| 2018-10-30 | Defendant Notifies Plaintiff of ANDA Filing |
| 2018-12-12 | Complaint for Patent Infringement Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,669,008 - “Enalapril Formulations”
The Invention Explained
- Problem Addressed: The patent describes difficulties certain patient populations, such as children and the elderly, have swallowing solid oral dosage forms like tablets (’008 Patent, col. 5:9-13). It further notes that compounding tablets into liquid form can lead to inaccurate dosing, rapid instability of the active ingredient, and potential contamination ('008 Patent, col. 5:30-41).
- The Patented Solution: The invention provides a stable, ready-to-use oral liquid formulation of enalapril that avoids the need for reconstitution by a pharmacist ('008 Patent, col. 5:50-54). The solution achieves stability through a specific combination of a buffer (citric acid and sodium citrate), a preservative (sodium benzoate), and a sweetener (sucralose) in water, maintained at a pH below 3.5 ('008 Patent, Abstract; col. 2:10-17). This composition purportedly eliminates the need for stabilizers like mannitol and silicon dioxide, which were required in prior art powder formulations ('008 Patent, col. 5:42-54).
- Technical Importance: The invention provides a commercially-manufactured, stable liquid dosage form that allows for precise dosing and improved patient compliance for a widely used cardiovascular drug. ('008 Patent, col. 5:5-8).
Key Claims at a Glance
- The complaint asserts infringement of one or more unspecified claims (Prayer for Relief, ¶a). Independent claim 1 is representative.
- Independent Claim 1:
- A stable oral liquid formulation, comprising:
- (i) about 1 mg/ml enalapril maleate;
- (ii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate;
- (iii) about 1 mg/ml of a preservative that is sodium benzoate; and
- (iv) water;
- wherein the pH of the formulation is less than about 3.5;
- wherein the formulation is stable at about 5±3° C. for at least 12 months;
- wherein the stable oral liquid formulation has about 95% or greater of the initial enalapril amount and about 5% w/w or less total impurities or related substances at the end of the given storage period.
- The complaint does not explicitly reserve the right to assert dependent claims.
U.S. Patent No. 9,808,442 - “Enalapril Formulations”
The Invention Explained
- Problem Addressed: The patent addresses the same challenges as the '008 Patent, namely the difficulty of administering solid drug forms to certain patients and the instability of pharmacist-compounded liquid alternatives (’442 Patent, col. 5:9-41).
- The Patented Solution: The patent claims a method of treating hypertension by administering the stable enalapril oral liquid formulation. The technical basis for the formulation's stability—a controlled low-pH environment with specific excipients—is identical to that described in the ’008 Patent (’442 Patent, Abstract; col. 2:10-17).
- Technical Importance: This patent extends protection from the formulation itself to the specific medical use of that formulation for treating hypertension, a primary indication for enalapril. (’442 Patent, col. 1:15-22).
Key Claims at a Glance
- The complaint asserts infringement of one or more unspecified claims (Prayer for Relief, ¶a). Independent claim 1 is representative.
- Independent Claim 1:
- A method of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation comprising:
- (i) about 1 mg/ml enalapril maleate;
- (ii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate;
- (iii) about 1 mg/ml of a preservative that is sodium benzoate; and
- (iv) water;
- wherein the pH of the stable oral liquid formulation is less than about 3.5;
- wherein the stable oral liquid formulation is stable at about 5±3° C. for at least 12 months; and
- wherein the stable oral liquid formulation has about 95% or greater of the initial enalapril amount and about 5% w/w or less total impurities or related substances at the end of the given storage period.
- The complaint does not explicitly reserve the right to assert dependent claims.
U.S. Patent No. 10,039,745 - “Enalapril Formulations”
Technology Synopsis
This patent, part of the same family as the ’008 and ’442 Patents, describes the same stable, ready-to-use enalapril oral liquid formulation designed to overcome the drawbacks of solid tablets and compounded liquids (’745 Patent, Abstract; col. 1:15-32). The claims of this patent recite ranges for the concentrations of the formulation's components, rather than the more specific "about" values recited in the earlier patents.
Asserted Claims
Independent claim 1 is representative (’745 Patent, col. 41:36-52).
Accused Features
The complaint alleges that Defendant’s ANDA product, being a generic version of EPANED®, will infringe the claims of the ’745 Patent (Compl. ¶¶ 21, 34).
III. The Accused Instrumentality
Product Identification
The "Bionpharma ANDA Product," which is Defendant's proposed generic version of Silvergate's EPANED® product (enalapril maleate oral solution) submitted for FDA approval via ANDA No. 212408 (Compl. ¶¶ 1, 20).
Functionality and Market Context
- The complaint alleges that by filing its ANDA, Defendant has represented to the FDA that its product has the same active ingredient, route of administration, dosage form, and strength as Silvergate's EPANED® product (Compl. ¶21). EPANED® is described as a ready-to-use oral solution for treating hypertension in adults and children, as well as heart failure and asymptomatic left ventricular dysfunction (Compl. ¶7).
- The complaint alleges that Bionpharma intends to engage in the commercial manufacture, use, and sale of its ANDA product in the U.S. promptly upon receiving FDA approval (Compl. ¶20).
IV. Analysis of Infringement Allegations
The complaint does not provide a claim chart or a detailed, element-by-element infringement analysis. The infringement theory is statutory under 35 U.S.C. § 271(e)(2)(A), where the filing of an ANDA for a drug claimed in a patent is an act of infringement. The complaint’s factual basis is that the Bionpharma ANDA Product is a generic copy of the EPANED® product and is therefore alleged to possess all the elements of the claimed formulation.
No probative visual evidence provided in complaint.
9,669,008 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A stable oral liquid formulation, comprising: (i) about 1 mg/ml enalapril maleate; | The Bionpharma ANDA Product is an oral liquid formulation alleged to have the same active ingredient and strength as Silvergate's product. | ¶21 | col. 40:1-2 |
| (ii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; | The Bionpharma ANDA Product is alleged to have the same dosage form and be bioequivalent, suggesting it contains the necessary excipients for a stable solution. | ¶21 | col. 40:2-4 |
| (iii) about 1 mg/ml of a preservative that is sodium benzoate; and (iv) water; | The Bionpharma ANDA Product is alleged to have the same dosage form and be bioequivalent, suggesting it contains the necessary excipients for a stable solution. | ¶21 | col. 40:4-6 |
| wherein the pH of the formulation is less than about 3.5; | The Bionpharma ANDA Product, as a bioequivalent formulation, is alleged to meet the claimed pH limitation necessary for stability. | ¶21 | col. 40:6-7 |
| wherein the formulation is stable at about 5±3° C. for at least 12 months... | The Bionpharma ANDA Product, as a bioequivalent formulation, is alleged to meet the claimed stability requirements. | ¶21 | col. 40:7-13 |
Identified Points of Contention
- Scope Questions: A central issue may be the interpretation of the term "about" preceding each concentration value in Claim 1. The infringement analysis will depend on whether the precise concentrations in Defendant's ANDA specification fall within the scope of the "about" ranges as construed by the court.
- Technical Questions: A key factual dispute may arise over whether the Bionpharma ANDA Product actually meets the functional limitations of being "stable" as defined in the claim (i.e., retaining ≥95% of the initial enalapril amount with ≤5% impurities after 12 months at 5±3° C.). This will depend on the chemical analysis and stability data for Defendant's specific formulation.
9,808,442 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating hypertension in a subject comprising administering... | Bionpharma's ANDA filing seeks approval to market its product for the same indications as EPANED®, including hypertension. | ¶¶7, 21 | col. 39:49-50 |
| a therapeutically effective amount of a stable oral liquid formulation... | Defendant's proposed product label will allegedly instruct physicians and patients to administer the formulation for treating hypertension, which would constitute inducement to infringe. | ¶¶21, 31 | col. 39:50-52 |
| [recitation of the formulation components] | The Bionpharma ANDA Product is alleged to be the same formulation recited in the claim, as described for the '008 Patent. | ¶21 | col. 39:52 - col. 40:9 |
Identified Points of Contention
- Scope Questions: In addition to the claim scope questions identified for the ’008 Patent’s formulation claims, analysis of this method claim will raise the question of whether Defendant’s proposed product label instructs users to perform every step of the claimed method.
- Technical Questions: The underlying technical questions regarding the composition and stability of the accused product, as noted for the ’008 Patent, are equally applicable here, as infringement of the method claim requires the use of the claimed formulation.
V. Key Claim Terms for Construction
Term for Construction: "about"
- Context and Importance: This term appears before every quantitative limitation of the formulation's ingredients (e.g., "about 1 mg/ml enalapril maleate"). The scope of infringement will hinge on how much numerical variance "about" permits. Practitioners may focus on this term because even minor differences in Defendant's formulation could be used to argue non-infringement if the term is construed narrowly.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent consistently uses "about" in the claims and summary, suggesting the inventors did not intend to be limited to the exact numerical values stated (’008 Patent, col. 2:10-17).
- Evidence for a Narrower Interpretation: The specification provides examples with precise values (e.g., exactly "1.0" mg/ml enalapril maleate) without using "about," which may suggest the term is meant to cover only minor experimental variability ('008 Patent, Table A-1). Furthermore, the existence of the related '745 Patent, which explicitly claims broad numerical ranges, could be used to argue that the patentees knew how to claim a broader scope and chose not to in the '008 Patent.
Term for Construction: "stable"
- Context and Importance: Stability is the central technical advantage claimed by the invention. The claim itself provides a functional definition: "stable... has about 95% or greater of the initial enalapril amount and about 5% w/w or less total impurities or related substances at the end of the given storage period." While the term is defined, disputes may arise over the testing methodologies required to prove or disprove stability under this definition.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim language itself defines the term, and this definition should control. The specification discusses stability generally as the goal of the invention, supporting the application of the claim's explicit definition (’008 Patent, col. 5:50-54).
- Evidence for a Narrower Interpretation: The patent includes detailed examples showing stability data under specific HPLC testing conditions and time points ('008 Patent, Tables C-2, D-2). A party might argue that the term "stable" should be interpreted in light of these specific examples and testing parameters.
VI. Other Allegations
Indirect Infringement
The complaint alleges facts to support induced infringement of the ’442 Patent. It asserts that Bionpharma had knowledge of the patent and, by filing an ANDA seeking approval to market its product for treating hypertension, intends for its proposed product label to instruct end-users to perform the patented method (Compl. ¶31). The complaint also asserts there are no substantial non-infringing uses for the product (Compl. ¶31).
Willful Infringement
The complaint alleges that Bionpharma had "actual knowledge" of all three patents-in-suit prior to filing its ANDA and knew the filing was an act of infringement (Compl. ¶¶ 26, 31, 36). This forms the basis for a claim of willful infringement.
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: how broadly will the court construe the term "about" as applied to the precise concentrations of ingredients in the asserted claims, and will that construction cover the specific formulation detailed in Defendant's confidential ANDA filing?
- A key evidentiary question will be one of factual compliance: does the Bionpharma ANDA Product, based on the data submitted to the FDA, in fact meet the specific functional requirements for pH and long-term stability as explicitly defined in the patent claims?
- For the method-of-use claims of the '442 Patent, the case will also turn on the content of Defendant's proposed product label: does the label's language direct or encourage medical professionals and patients to administer the formulation in a way that performs all the steps of the claimed method of treating hypertension?