1:21-cv-01252
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: Morris, Nichols, Arsht & Tunnell LLP; Covington & Burling LLP
- Case Identification: 1:21-cv-01252, D. Del., 09/27/2023
- Venue Allegations: Venue is alleged as proper in the District of Delaware because Defendant Apotex Corp. is a Delaware corporation, and Defendant Apotex Inc., a Canadian corporation, is subject to personal jurisdiction in the district. The complaint notes that Apotex does not contest venue for the purposes of this action.
- Core Dispute: Plaintiff alleges that Defendant's filing of an Abbreviated New Drug Application (ANDA) seeking to market a generic version of Plaintiff's Fintepla® (fenfluramine) oral solution constitutes an act of infringement of patents covering fenfluramine compositions and methods of their preparation.
- Technical Context: The technology relates to pharmaceutical chemistry, specifically methods for synthesizing high-purity fenfluramine and the resulting compositions, which are used for treating seizures associated with rare and severe forms of epilepsy, such as Dravet syndrome.
- Key Procedural History: The litigation was triggered by Defendant's filing of ANDA No. 216108 and its associated Notice of Certification under Paragraph IV, dated October 12, 2021, which asserted that U.S. Patent No. 10,947,183 is invalid, unenforceable, and/or will not be infringed. The ’183 patent is listed in the FDA's "Orange Book" for Fintepla®, while the ’510 patent is not.
Case Timeline
| Date | Event |
|---|---|
| 2015-12-22 | Earliest Priority Date for ’183 and ’510 Patents |
| 2019-07-16 | U.S. Patent No. 10,351,510 Issued |
| 2020-06-25 | FDA Approval of Zogenix's Fintepla® |
| 2021-03-16 | U.S. Patent No. 10,947,183 Issued |
| 2021-10-12 | Apotex Notice of Certification Letter Sent |
| 2023-09-27 | First Amended 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 addresses the need for highly pure active pharmaceutical ingredients (APIs) for use in pharmaceutical formulations, noting that impurities can cause drug product instability, loss of potency, and toxicity (’183 Patent, col. 5:5-10). The specific impurities of concern are trifluoromethyl-phenyl regioisomers of fenfluramine, which are reaction side products that can be difficult to remove (’183 Patent, col. 5:11-14).
- The Patented Solution: The patent claims a fenfluramine composition defined by its high purity, specifically one that contains a very low but non-zero amount of its trifluoromethyl-phenyl regioisomers. The invention is a composition where these specific regioisomers are present in a total amount of less than 0.2% by weight (’183 Patent, Abstract; col. 50:11-16). This level of purity makes the fenfluramine suitable for use as a pharmaceutical API (’183 Patent, col. 5:11-14).
- Technical Importance: Achieving and claiming a specific, high-purity profile for an API is critical in the pharmaceutical industry to meet regulatory standards for safety and efficacy, particularly for a compound like fenfluramine, which was previously withdrawn from the market due to safety concerns (’183 Patent, col. 1:15-20).
Key Claims at a Glance
- The complaint asserts at least claim 26, which is an independent claim (Compl. ¶¶ 72-73). The complaint also notes that Defendant’s detailed statement did not contain non-infringement arguments for claims 25-27 (Compl. ¶ 74).
- The essential elements of independent claim 26 are:
- A composition, comprising fenfluramine and at least one trifluoromethyl-phenyl regioisomer of fenfluramine,
- wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount that is greater than zero and less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine.
U.S. Patent No. 10,351,510 - "Fenfluramine Compositions and Methods of Preparing the Same" (Issued July 16, 2019)
The Invention Explained
- Problem Addressed: This patent, which is in the same family as the ’183 patent, addresses the same technical problem: the challenge of producing fenfluramine with a very low level of trifluoromethyl-phenyl regioisomers to ensure its suitability as a pharmaceutical API (’510 Patent, col. 5:1-14).
- The Patented Solution: The patent discloses a multi-step synthesis method designed to control and remove the problematic regioisomers. The core of the solution is a specific sequence of chemical reactions that includes a purification step via crystallization of an intermediate compound (2-(3-(trifluoromethyl)phenyl)acetic acid) to produce a purified intermediate having less than 0.2% by weight of the regioisomers before proceeding with the synthesis (’510 Patent, col. 49:60-63, Claim 1(b)). This ensures the final fenfluramine product also meets the high-purity standard.
- Technical Importance: The invention provides a reproducible and controlled manufacturing process for producing a high-purity API, which is essential for regulatory approval and for ensuring consistent quality and safety of a pharmaceutical product (’510 Patent, col. 5:1-5).
Key Claims at a Glance
- The complaint asserts at least claim 1, which is an independent claim (Compl. ¶¶ 83, 90).
- The essential elements of independent claim 1 are:
- A method of preparing a fenfluramine active pharmaceutical ingredient, comprising four distinct chemical steps:
- (a) hydrolyzing a specific nitrile composition to produce an acetic acid composition;
- (b) purifying the acetic acid composition via crystallization to produce a purified intermediate having less than 0.2% by weight of trifluoromethyl-phenyl regioisomers;
- (c) reacting the purified intermediate to produce a ketone composition; and
- (d) reductively aminating the ketone composition to produce a crude fenfluramine composition also having less than 0.2% by weight of the regioisomers.
III. The Accused Instrumentality
Product Identification
Apotex's ANDA Product, identified as a proposed generic fenfluramine hydrochloride oral solution, 2.2 mg base/mL, intended as a generic copy of Zogenix's Fintepla® (Compl. ¶ 2).
Functionality and Market Context
The accused product is a pharmaceutical formulation containing fenfluramine as its active ingredient, intended for the treatment of seizures associated with Dravet syndrome (Compl. ¶¶ 2, 25-26). As this is an ANDA case, the product is not yet on the market. The lawsuit arises from Defendant's filing with the FDA to seek approval to market this generic product prior to the expiration of the Asserted Patents (Compl. ¶ 2). Plaintiff's Fintepla® product has Orphan Drug Exclusivity until June 25, 2027 (Compl. ¶ 45).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
’183 Patent Infringement Allegations
The complaint alleges that Apotex's filing of its ANDA is a statutory act of infringement of at least claim 26 under 35 U.S.C. § 271(e)(2)(A) (Compl. ¶ 72). The complaint notes that Apotex's Paragraph IV notification letter did not disclose any arguments that its ANDA Product would not infringe claims 25, 26, and 27 of the patent (Compl. ¶ 74).
| Claim Element (from Independent Claim 26) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A composition, comprising fenfluramine and at least one trifluoromethyl-phenyl regioisomer of fenfluramine... | The complaint alleges that Apotex’s ANDA product is a generic version of Fintepla® that contains a fenfluramine active ingredient. | ¶76 | col. 50:11-13 |
| ...wherein the at least one trifluoromethyl-phenyl regioisomer of fenfluramine is present in some amount that is greater than zero and less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers of fenfluramine. | The complaint alleges the ANDA product infringes the claim and states that Apotex did not provide non-infringement arguments regarding this limitation in its required disclosures. | ¶74, ¶76, ¶78 | col. 50:13-16 |
Identified Points of Contention
- Factual Question: The central dispute will likely be a factual one: does Apotex's proposed generic product, as specified in its ANDA, actually contain trifluoromethyl-phenyl regioisomers within the claimed range of "greater than zero and less than 0.2% by weight"? The case may turn on analytical chemistry evidence developed during discovery to determine the precise composition of Apotex's product.
- Procedural Question: A procedural issue may arise concerning the legal significance of Apotex's alleged failure to provide non-infringement arguments for this claim in its Paragraph IV notice letter, and what, if any, effect this has on the evidentiary burdens in the litigation (Compl. ¶ 74).
’510 Patent Infringement Allegations
The complaint seeks a declaratory judgment that the importation, sale, or use of Apotex's ANDA Product will infringe at least claim 1 of the ’510 patent under 35 U.S.C. § 271(g) because it is allegedly made by a patented process (Compl. ¶¶ 81, 90). Several paragraphs detailing Apotex's alleged manufacturing process are redacted, limiting a full public analysis of the infringement theory (Compl. ¶¶ 85-88).
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of preparing a fenfluramine active pharmaceutical ingredient, the method comprising: (a) hydrolyzing a...nitrile composition to produce a...acetic acid composition; | Based on information and belief, the complaint alleges Apotex's manufacturing process for its fenfluramine active ingredient includes a step corresponding to this limitation. The details supporting this belief are redacted. | ¶84 | col. 49:57-60 |
| (b) purifying the...acetic acid composition via crystallization to produce a purified...acetic acid having less than 0.2% by weight in total of trifluoromethyl-phenyl regioisomers; | The complaint alleges on information and belief that Apotex's process uses a method that infringes, which implies the use of a purification step via crystallization to achieve the required intermediate purity. Specific details are redacted. | ¶84 | col. 49:60-63 |
| (c) reacting the purified...acetic acid composition...to produce a...propan-2-one composition; and | The complaint alleges on information and belief that Apotex's manufacturing process includes a step corresponding to this limitation. The details supporting this belief are redacted. | ¶84 | col. 49:64-67 |
| (d) reductively aminating the...propan-2-one composition...to produce a crude fenfluramine composition having less than 0.2% by weight in total of...regioisomers... | The complaint alleges on information and belief that Apotex's manufacturing process includes a step corresponding to this limitation. The details supporting this belief are redacted. | ¶84 | col. 50:1-7 |
Identified Points of Contention
- Evidentiary Question: The primary question will be whether Apotex's manufacturing process, once revealed through discovery, practices all steps of the claimed method. The redactions in the complaint suggest Plaintiff has a basis for this belief, but the evidence is not public (Compl. ¶¶ 85-88).
- Technical Question: A key technical dispute may focus on step (b), "purifying...via crystallization." The analysis will question whether Apotex’s process, if it includes a purification step, uses "crystallization" as understood in the patent, or an alternative method (e.g., chromatography) to achieve the required purity, which might support a non-infringement argument.
V. Key Claim Terms for Construction
The Term: "trifluoromethyl-phenyl regioisomer of fenfluramine" (’183 Patent, Claim 26)
Context and Importance
This term defines the specific impurity that characterizes the patented composition. The infringement analysis for the ’183 patent will depend entirely on the identification and quantification of this substance in the accused product. Practitioners may focus on this term because its precise chemical definition will dictate the scope of required analytical testing.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The term is used broadly to refer to isomers of fenfluramine. The specification, incorporated by reference from the parent ’510 patent, states the term is used to refer to isomers where the trifluoromethyl group is at the 2- or 4-position on the phenyl ring, as opposed to the 3-position in fenfluramine (’510 Patent, col. 13:17-24).
- Evidence for a Narrower Interpretation: The patent consistently discusses the regioisomers in the context of being undesirable byproducts of a particular synthesis pathway. A party could suggest that the term should be understood in that specific context, although the claim itself is purely structural. The specification provides specific chemical structures for the 2- and 4-regioisomers (’510 Patent, col. 13:35-43).
The Term: "purifying the...composition via crystallization" (’510 Patent, Claim 1)
Context and Importance
This limitation defines the key process step for removing regioisomers at an intermediate stage of the synthesis. The infringement analysis for the ’510 patent may turn on whether Apotex's process includes a step that meets this definition. If Apotex uses a different purification technique, it could be a basis for a non-infringement defense.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The claim language is general, suggesting any process that uses the principles of crystallization to increase the purity of the intermediate acetic acid composition could fall within the claim's scope (’510 Patent, col. 49:60-61).
- Evidence for a Narrower Interpretation: The patent’s examples describe specific crystallization methods, such as using a solvent and anti-solvent system (e.g., ethyl acetate and n-heptane) to precipitate the purified solid (’510 Patent, col. 43:12-17). A party may argue that the term should be construed more narrowly to be limited to the types of crystallization processes disclosed in the specification's embodiments.
VI. Other Allegations
Indirect Infringement
The complaint does not plead specific counts for indirect infringement (inducement or contributory infringement). The prayer for relief includes a request for a declaratory judgment that future acts of making, using, or selling, or "inducing or contributing to such conduct," would constitute infringement, but the factual basis for knowledge and intent required for indirect infringement is not developed in the complaint's allegations (Compl. p. 16, ¶ D).
Willful Infringement
The complaint does not include an explicit allegation of willful infringement. It does allege that the complaint itself provides notice of the ’510 patent, which could potentially serve as a basis for alleging post-filing willful infringement at a later stage (Compl. ¶ 92). The prayer for relief seeks a finding of an "exceptional case" to entitle Plaintiff to attorneys' fees, which is a related but distinct legal standard (Compl. p. 16, ¶ E).
VII. Analyst’s Conclusion: Key Questions for the Case
This ANDA litigation appears to center on fundamental questions of chemical composition and manufacturing processes. The resolution of the case will likely depend on evidence developed during discovery. The key open questions are:
- A central issue will be one of compositional identity: Does Apotex’s proposed generic fenfluramine product, as described in its confidential ANDA submission, possess the specific purity profile claimed in the ’183 patent, namely containing trifluoromethyl-phenyl regioisomers in a total amount "greater than zero and less than 0.2% by weight"?
- A key evidentiary question will be one of process correspondence: Does Apotex's proprietary manufacturing process for its fenfluramine API align with the specific multi-step sequence recited in claim 1 of the ’510 patent, particularly the use of "crystallization" to purify an intermediate compound to the claimed level of purity?
- A procedural question may arise concerning the legal effect of omission: What is the consequence, if any, of Apotex’s alleged failure in its Paragraph IV notice letter to provide non-infringement arguments for the asserted composition claims of the ’183 patent, and does this impact the subsequent allocation of evidentiary burdens?