DCT
1:21-cv-01452
Novartis Pharma Corp v. Crystal Pharmaceutical Suzhou Co Ltd
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Novartis Pharmaceuticals Corporation (Delaware)
- Defendant: Crystal Pharmaceutical (Suzhou) Co., Ltd. (China)
- Plaintiff’s Counsel: McCarter & English, LLP; Venable LLP
- Case Identification: Novartis Pharmaceuticals Corporation v. Crystal Pharmaceutical (Suzhou) Co., Ltd., 1:21-cv-01452, D. Del., 10/14/2021
- Venue Allegations: Venue is alleged to be proper because Defendant is a foreign entity that may be sued in any judicial district. The complaint also states that Defendant agreed not to challenge personal jurisdiction or venue in the District of Delaware for actions concerning its Abbreviated New Drug Application (ANDA).
- Core Dispute: Plaintiff alleges that Defendant’s filing of an ANDA to market a generic version of Plaintiff's ENTRESTO® heart failure medication constitutes an act of patent infringement, as the proposed product's use would infringe a patent covering a specific dosage and titration regimen.
- Technical Context: The technology concerns a pharmaceutical method for treating chronic heart failure with reduced ejection fraction by administering a combination of sacubitril and valsartan according to a specific schedule of dose escalation.
- Key Procedural History: This action was initiated under the Hatch-Waxman Act following Defendant's submission of ANDA No. 213605 with a Paragraph IV certification against the patent-in-suit. Plaintiff asserts it filed this complaint within the 45-day statutory period following receipt of Defendant's notice letter, which preserves a 30-month stay of FDA approval for the generic product. The patent-in-suit is listed in the FDA's "Orange Book" as covering ENTRESTO®.
Case Timeline
| Date | Event |
|---|---|
| 2015-05-11 | ’667 Patent Priority Date |
| 2021-07-13 | ’667 Patent Issue Date |
| 2021-09-01 | Plaintiff receives notice letter of Defendant's ANDA filing |
| 2021-10-14 | Complaint Filing Date |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 11,058,667 - "Sacubitril-Valsartan Dosage Regimen for Treating Heart Failure"
- Patent Identification: U.S. Patent No. 11,058,667, "Sacubitril-Valsartan Dosage Regimen for Treating Heart Failure", issued July 13, 2021.
The Invention Explained
- Problem Addressed: The patent's background section describes that while the combination drug sacubitril/valsartan (LCZ696) is effective for heart failure, prior clinical trials provided "limited information on how the physician should initiate the LCZ696 therapy in clinical practice" (’667 Patent, col. 2:27-29). This was a particular concern for patients who were either new to this class of drugs (ACEI/ARB-naïve) or were previously taking low doses of older, related medications (’667 Patent, col. 2:29-31).
- The Patented Solution: The invention provides a specific, structured "up-titration" regimen to solve this problem. It comprises administering a twice-daily starting dose (e.g., 50 mg), followed by a twice-daily intermediate dose (e.g., 100 mg), and finally a twice-daily target dose (200 mg), with each titration step lasting for a defined period of weeks (’667 Patent, col. 20:40-63). This gradual dose escalation was found to be safer and more tolerable, particularly in reducing adverse events like hypotension, thereby increasing the probability that a patient could successfully reach and maintain the optimal therapeutic dose (’667 Patent, col. 20:12-17; Fig. 1).
- Technical Importance: The claimed regimen provides a standardized, evidence-based protocol to safely initiate a potent drug therapy, which is critical for managing the high morbidity and mortality associated with chronic heart failure (’667 Patent, col. 2:32-53).
Key Claims at a Glance
- The complaint asserts "one or more claims" of the ’667 patent (Compl. ¶22). The allegations most closely track independent claim 1.
- Independent Claim 1 of the ’667 Patent recites the essential elements of the regimen:
- A method of treating chronic heart failure with reduced ejection fraction.
- Administering a twice-daily target dose of 200 mg of sacubitril/valsartan in a 1:1 molar ratio.
- Reaching the target dose via a specific titration schedule: a 50 mg starting dose for "about 3 weeks to about 4 weeks," followed by a 100 mg dose for "about 3 weeks to about 4 weeks," then the 200 mg target dose.
- The regimen is for a specific human patient population: one who is either not taking a prior ACE inhibitor or ARB, or is taking a "low dose" of such a drug.
- The complaint does not identify specific dependent claims but reserves the right to assert them.
III. The Accused Instrumentality
Product Identification
- Defendant's proposed generic sacubitril/valsartan tablets, for which it seeks FDA approval via ANDA No. 213605 (the "Crystal ANDA Products") (Compl. ¶1, ¶5).
Functionality and Market Context
- The act of infringement alleged is the submission of the ANDA itself, which seeks approval to market a generic drug prior to the expiration of the ’667 patent (Compl. ¶26). The substantive infringement theory is based on the proposed use of the Crystal ANDA Products. The complaint alleges that the product labeling for the generic drug, if approved, "must contain instructions for practicing a regimen for the treatment of chronic heart failure" that will directly infringe one or more claims of the ’667 patent (Compl. ¶29). These instructions would guide physicians, caregivers, and patients on how to administer the drug, allegedly leading to direct infringement (Compl. ¶29). No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
’667 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A regimen for treating chronic heart failure with reduced ejection fraction, comprising administering to a human patient in need thereof a twice-daily target dose of 200 mg of (i) sacubitril... with (ii) valsartan... | The complaint alleges that the labeling for the Crystal ANDA Products will direct their use in a regimen for treating chronic heart failure with a twice-daily target dose of 200 mg of the combined drug. | ¶29 | col. 20:40-44 |
| wherein the twice daily target dose 200 mg is reached after a titration with a twice daily starting dose of 50 mg... for from about 3 weeks to about 4 weeks, followed by a twice daily dose of 100 mg... for from about 3 weeks to about 4 weeks... | The complaint alleges Defendant's product label will instruct reaching the target dose via a specific titration schedule, starting at 50 mg and escalating to 100 mg. | ¶29 | col. 20:50-58 |
| wherein the human patient is not taking an ACE inhibitor or an ARB or is taking a low dose of an ACE inhibitor or an ARB before initiating treatment with (i) and (ii). | The complaint alleges the product label will contain instructions for this specific patient population (those not taking or on a low dose of a prior, related drug). | ¶29 | col. 20:58-63 |
- Identified Points of Contention:
- Scope Questions: A central question will be whether the language of Defendant's proposed product label falls squarely within the scope of the claim limitations. For example, does the term "from about 3 weeks to about 4 weeks" read on the specific duration of titration steps that will be instructed on the generic drug's label? The use of "about" suggests some flexibility, the extent of which may become a focus of dispute.
- Technical Questions: The primary evidentiary issue will be a comparison of text, not a dispute over physical operation. The key question is whether the instructions on Defendant's proposed label will, in fact, direct users to perform every step of the claimed method. The complaint alleges the label must do so to secure approval for the same indications as ENTRESTO®, a point that will require factual development (Compl. ¶29).
V. Key Claim Terms for Construction
The Term: "a low dose" (of an ACE inhibitor or ARB)
Context and Importance: This term defines a key patient sub-population to which claim 1 is directed. The definition of "low dose" is critical to determining the scope of infringement, as it distinguishes the patients covered by this claim from those on higher doses of prior therapies. Practitioners may focus on this term because if Defendant's label provides instructions that apply only to patients on what would be considered a "high dose," it could potentially design around this claim.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The term "low dose" in independent claim 1 is not explicitly defined within that claim, which could support an argument for construing it according to its plain and ordinary meaning in the context of cardiology.
- Evidence for a Narrower Interpretation: The specification provides a specific, quantitative benchmark, stating that a lower dose of an ACEI or ARB "is equivalent to <10 mg of enalapril per day" (’667 Patent, col. 6:46-49). Dependent claim 14 recites this exact limitation (’667 Patent, col. 22:13-16). This specific definition in the patent provides strong intrinsic evidence for a narrow construction.
The Term: "from about 3 weeks to about 4 weeks"
Context and Importance: This phrase dictates the duration for the first two stages of the titration regimen in claim 1. Infringement will depend on whether the timing instructions on Defendant's product label fall within this claimed range.
Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent's description of the clinical study mentions two different up-titration schedules: a "Condensed" regimen over 3 weeks total and a "Conservative" regimen over 6 weeks total (’667 Patent, Fig. 1; col. 18:26-30). A party could argue that this context, along with the use of "about," supports a flexible interpretation of the claimed duration for each step.
- Evidence for a Narrower Interpretation: Dependent claim 2 recites a more specific regimen where the 50 mg dose is administered "for about 3 weeks" and the 100 mg dose is administered "for about 3 weeks" (’667 Patent, col. 21:20-24). The doctrine of claim differentiation could be invoked to argue that the range "from about 3 weeks to about 4 weeks" in claim 1 must mean something different and more specific than the "about 3 weeks" recited in claim 2.
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced infringement, asserting that Defendant, with knowledge of the ’667 patent, will encourage and promote infringement by providing a product label that instructs physicians and patients to follow the patented method (Compl. ¶29). Contributory infringement is also alleged on the basis that the Crystal ANDA Products are "especially made or especially adapted for use" in the infringing regimen and are not suitable for substantial non-infringing use (Compl. ¶30).
- Willful Infringement: The complaint does not use the term "willful infringement," but it does seek a declaration that the case is "exceptional" and requests attorney's fees pursuant to 35 U.S.C. § 285 (Compl. ¶41). The basis for knowledge is Defendant's filing of a Paragraph IV certification, which required it to certify that the ’667 patent is invalid or will not be infringed by its proposed product (Compl. ¶5).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of label interpretation: Will the final, FDA-approved instructions for Defendant's generic product direct medical professionals to follow a dosage and titration regimen that meets every limitation of an asserted claim, or will there be a material difference in the patient population, dosage amounts, or titration timing?
- A key legal question will be one of claim scope: Can the term "about," as used in the claim's time-based limitations (e.g., "from about 3 weeks to about 4 weeks"), be construed to cover the specific titration schedule described in Defendant's label, or is there a legally significant mismatch that allows for a finding of non-infringement?
- A central evidentiary question will be whether Defendant’s product is suitable for substantial non-infringing use. The viability of the contributory infringement claim will depend on whether there are established, non-infringing ways to prescribe and use generic sacubitril/valsartan for treating heart failure that do not follow the patented up-titration regimen.