DCT
1:21-cv-01533
Zogenix Inc v. Apotex Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Zogenix, Inc. (Delaware) and Zogenix International Ltd. (England and Wales)
- Defendant: Apotex Inc. (Canada) and Apotex Corp. (Delaware)
- Plaintiff’s Counsel: Barnard, Mezzanotte, Pinnie, Seelaus & Kraft, LLP
- Case Identification: 1:21-cv-01533, D. Del., 10/28/2021
- Venue Allegations: Venue is alleged to be proper as to Apotex Corp. because it is a Delaware corporation, and as to Apotex Inc. because it is a foreign corporation subject to personal jurisdiction in the district.
- Core Dispute: Plaintiff alleges that Defendant’s filing of an Abbreviated New Drug Application (ANDA) for a generic version of the epilepsy drug Fintepla® constitutes an act of infringement of patents covering purified fenfluramine compositions and a controlled distribution system for the drug.
- Technical Context: The technology concerns fenfluramine, a drug used to treat rare and severe forms of childhood epilepsy, and methods to mitigate its known risk of cardiovascular side effects through high-purity formulations and a risk-managed distribution system.
- Key Procedural History: This is a Hatch-Waxman action initiated in response to Defendant’s Paragraph IV certification, which asserts the patents-in-suit are invalid and/or not infringed. The patents are listed in the FDA’s Orange Book for Plaintiff’s Fintepla® product, which has Orphan Drug Exclusivity until June 2027. Fenfluramine was previously withdrawn from the U.S. market in the 1990s due to cardiac safety concerns, and the currently approved Fintepla® product is subject to a mandatory Risk, Evaluation, and Mitigation Strategy (REMS) to manage these risks.
Case Timeline
| Date | Event |
|---|---|
| 2014-09-29 | ’331 Patent Priority Date |
| 2015-09-29 | FDA confirms withdrawal of prior fenfluramine products (Pondimin®, Ponderex®) |
| 2015-12-22 | ’183 Patent Priority Date |
| 2020-06-25 | FDA approves Zogenix's Fintepla® for Dravet syndrome |
| 2021-03-16 | ’183 Patent, "Fenfluramine Compositions and Methods of Preparing the Same," Issues |
| 2021-03-16 | ’331 Patent, "Control System for Control of Distribution of Medication," Issues |
| 2021-10-12 | Apotex sends Paragraph IV Notice Letter to Zogenix |
| 2021-10-28 | Complaint Filed |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 10,947,183, "Fenfluramine Compositions and Methods of Preparing the Same," issued March 16, 2021
The Invention Explained
- Problem Addressed: The patent background explains that while fenfluramine is effective as an anticonvulsant, its history is complicated by its market withdrawal due to risks of "cardiac valvulopathy and pulmonary hypertension" (’183 Patent, col. 1:16-21). Furthermore, conventional synthesis methods can produce undesirable "trifluoromethyl regioisomers," which are reaction side products that are difficult to separate from the main compound (’183 Patent, col. 13:15-24).
- The Patented Solution: The invention provides methods to synthesize a fenfluramine composition that is substantially pure. The process involves specific chemical reaction and purification steps, such as crystallization of an intermediate acid, designed to yield an active pharmaceutical ingredient containing very low levels of regioisomer impurities (’183 Patent, Abstract; col. 14:15-37). The goal is to produce a composition with less than 0.2% by weight of these regioisomers, enhancing the product's safety profile (’183 Patent, col. 8:43-48).
- Technical Importance: By providing a method to create a highly purified form of fenfluramine, the invention aimed to enable the drug's safe re-introduction for treating severe epilepsy by minimizing impurities that could contribute to adverse effects (’183 Patent, col. 1:16-28).
Key Claims at a Glance
- The complaint asserts independent claim 25 (’183 Patent, cl. 25; Compl. ¶67).
- Claim 25 requires:
- A composition, comprising fenfluramine and at least one tri-fluoromethyl-phenyl regioisomer of fenfluramine,
- wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount that is less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine.
- The complaint alleges infringement of "at least claim 25" (Compl. ¶74).
U.S. Patent No. 10,950,331, "Control System for Control of Distribution of Medication," issued March 16, 2021
The Invention Explained
- Problem Addressed: The patent identifies the risks inherent in distributing medication for severe epilepsy, where any "delay or error can have disastrous results" (’331 Patent, col. 2:9-11). It critiques prior art drug distribution systems (e.g., for Xyrem and Thalidomid) as unsuitable for epilepsy, particularly for drugs with serious side effects that require specialized physician oversight and ongoing patient monitoring (’331 Patent, col. 2:12-68).
- The Patented Solution: The invention describes a centralized, computer-implemented system for controlling medication distribution. The system uses a central controller and a patient database to manage prescriptions (’331 Patent, Fig. 3). A key feature is that authorization for a first prescription is dependent on initial medical tests. The system is then programmed to schedule subsequent mandatory tests—specifically including an echocardiogram to monitor heart health—before any further prescriptions can be authorized. The controller is programmed to inhibit authorization if test results are unsatisfactory (’331 Patent, Abstract; cl. 1).
- Technical Importance: This system creates a closed loop between prescribing a potentially risky drug and verifying patient safety, making continued access to the medication contingent upon successful completion of specific, centrally-managed safety monitoring protocols (’331 Patent, col. 3:41-51).
Key Claims at a Glance
- The complaint asserts independent claim 1 (’331 Patent, cl. 1; Compl. ¶77).
- Claim 1 is a method claim that requires, among other steps:
- Providing a data storage facility and a central controller coupled to a communication network.
- Programming the central controller to output a first prescription authorization only after a patient has passed one or more initial medical tests.
- Programming the controller to schedule subsequent tests, at least one of which must be an echocardiographic imaging test.
- Making continued receipt of medication contingent on satisfactory results from the echocardiography assessment.
- Programming the controller to inhibit prescription authorization upon unsatisfactory test results.
- Managing prescription parameters (e.g., dosage) and reporting data to a regulatory agency.
- The complaint alleges infringement of "at least claim 1" (Compl. ¶89).
III. The Accused Instrumentality
Product Identification
"Apotex's ANDA Product," a proposed generic fenfluramine hydrochloride oral solution (2.2 mg base/mL), which is a generic copy of Zogenix's Fintepla® product (Compl. ¶¶ 1-2).
Functionality and Market Context
As a generic drug submitted for FDA approval, the Apotex ANDA Product is intended to be a therapeutic equivalent to Fintepla® for the treatment of seizures associated with Dravet syndrome (Compl. ¶¶ 2, 25-26). The complaint alleges that to gain approval, Apotex's product will be sold with "a product label and REMS substantially the same as for the FDA-approved Fintepla® product" (Compl. ¶63). The FDA requires a REMS for all fenfluramine products to protect patients from "heart-valve abnormalities," a key safety concern (Compl. ¶43). The complaint includes a table from the FDA's Orange Book listing the asserted patents for Fintepla® (Compl. ¶48).
IV. Analysis of Infringement Allegations
'183 Patent Infringement Allegations
| Claim Element (from Independent Claim 25) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A composition, comprising fenfluramine and at least one tri-fluoromethyl-phenyl regioisomer of fenfluramine, | The complaint alleges Apotex has submitted an ANDA for a generic version of Fintepla® that "contains a fenfluramine active ingredient." | ¶71 | col. 8:26-30 |
| wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount that is less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine. | The complaint alleges that Apotex's Detailed Statement, sent with its Paragraph IV notice, "did not disclose any arguments that its ANDA Product would not infringe claims 25, 26, and 27." | ¶69 | col. 8:43-48 |
- Identified Points of Contention:
- Evidentiary Question: The core of the dispute over the ’183 Patent will be factual. The complaint does not present direct evidence that Apotex’s ANDA Product meets the specific <0.2% purity limitation. Instead, it bases its infringement allegation on Apotex's alleged failure to provide a non-infringement argument in its notice letter (Compl. ¶69). The case may turn on whether Apotex’s product actually satisfies this claim element, which will require discovery into the specifics of Apotex's formulation and manufacturing process.
'331 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating...patients with fenfluramine comprising: providing a data storage facility...a central controller... | The complaint alleges that Apotex's generic product will require a REMS "substantially the same" as the Fintepla® REMS, which is required by the FDA to manage cardiac risks. This REMS allegedly embodies the claimed system. | ¶¶43, 63, 85 | col. 11:1-12 |
| the central controller being programed to output...a first authorization...dependent upon satisfactory results of...initial medical tests... | The proposed label and REMS for the Apotex product will allegedly instruct and encourage prescribers and the healthcare system to perform the claimed method steps, including authorizing prescriptions based on initial tests. | ¶¶63, 85 | col. 13:51-60 |
| further programed to schedule one or more subsequent tests...wherein at least one of said subsequent medical tests is an echocardiographic imaging test...[and treatment continues] only on entry of satisfactory...results... | The complaint alleges that Apotex’s required REMS will necessarily include cardiovascular monitoring via echocardiograms as a condition for continued treatment, thereby inducing performance of this claimed step. | ¶¶43, 63, 85 | col. 14:8-22 |
- Identified Points of Contention:
- Scope Questions: The dispute will likely focus on whether Apotex's proposed label and REMS will induce infringement of every limitation of the method claim. Key questions will be whether the combination of actors involved in the generic REMS (e.g., doctors, patients, pharmacies, and Apotex itself) collectively performs all the steps as managed by a "central controller" as defined by the patent. Apotex may argue its REMS is structured differently or does not meet certain claim limitations, such as the specific manner in which data is reported or prescriptions are inhibited.
V. Key Claim Terms for Construction
'183 Patent
- The Term: "composition" (Claim 25)
- Context and Importance: The definition of this term is significant because the infringement allegation is against Apotex's finished "ANDA Product" (Compl. ¶2), which includes both the active ingredient and excipients. Practitioners may focus on this term to determine if the claim is directed only to the final drug product or more broadly to the fenfluramine active pharmaceutical ingredient (API) itself, which could have implications for infringement and damages.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The claim uses the open-ended term "comprising fenfluramine," which typically does not exclude other components and could be read to cover the API within a larger formulation (’183 Patent, cl. 25).
- Evidence for a Narrower Interpretation: The specification repeatedly discusses "pharmaceutical compositions" in the context of formulations including "pharmaceutically acceptable" carriers and excipients, which could support an argument that the claim is limited to a formulated drug product ready for administration (’183 Patent, col. 21:5-15).
'331 Patent
- The Term: "central controller" (Claim 1)
- Context and Importance: This term is fundamental to the architecture of the claimed method. Its construction will determine whether the claim requires a single, unitary entity that performs all control functions or if it can be read on a more distributed system of coordinated actors operating under a REMS protocol. The viability of the inducement theory depends on the REMS system mapping onto this claimed structure.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent states the controller has "one or more processors coupled to a communication network," which suggests that the functions could be distributed across multiple networked components rather than being housed in a single device (’331 Patent, cl. 1).
- Evidence for a Narrower Interpretation: The figures and detailed description depict a "central control system 10" with a "server 18" as the hub, which could be argued to teach a more physically centralized or singular control architecture (’331 Patent, Fig. 3; col. 11:21-26).
VI. Other Allegations
- Indirect Infringement: The complaint explicitly alleges induced infringement of the ’331 Patent. It asserts that Apotex's marketing of its generic product with a "substantially similar" label and REMS will demonstrate a "specific intent to actively encourage infringement of claim 1" by prescribers, pharmacists, and others in the treatment chain (Compl. ¶¶ 85-86).
- Willful Infringement: The complaint does not contain an explicit claim for willful infringement. However, it alleges that Apotex had pre-suit knowledge of the ’331 Patent because it was listed in the Orange Book prior to Apotex's ANDA filing (Compl. ¶¶ 82-84). These allegations could form the basis for a later claim of willfulness. The complaint seeks a finding that the case is "exceptional" under 35 U.S.C. § 285, which is often tied to findings of willful infringement or litigation misconduct (Compl. ¶90.D).
VII. Analyst’s Conclusion: Key Questions for the Case
- A key evidentiary question will be one of factual proof: For the ’183 Patent, does Apotex's proposed generic product in fact contain less than 0.2% by weight of fenfluramine regioisomers? The resolution of this issue will depend on technical evidence from Apotex's manufacturing process, as the complaint currently relies on procedural inference rather than direct factual allegation.
- A core legal issue will be one of induced infringement: For the ’331 Patent, does the combination of Apotex's proposed product label and its FDA-mandated REMS protocol necessarily instruct or encourage a collection of healthcare actors to perform every step of the complex, controlled method required by claim 1, or is there a functional or legal distinction between the proposed generic distribution scheme and the patent’s highly specific "central controller" architecture?