DCT
1:25-cv-01130
Arrowhead Pharma Inc v. Ionis Pharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Arrowhead Pharmaceuticals, Inc. (Delaware)
- Defendant: Ionis Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: Fish & Richardson P.C.
- Case Identification: 1:25-cv-01130, D. Del., 09/10/2025
- Venue Allegations: Venue is alleged to be proper in the District of Delaware because Defendant Ionis is a Delaware corporation and therefore resides in the district.
- Core Dispute: Plaintiff seeks a declaratory judgment that its investigational RNAi therapeutic, plozasiran, does not infringe Defendant's U.S. Patent No. 9,593,333, and/or that the patent is invalid.
- Technical Context: The technology concerns therapeutic methods for treating rare genetic lipid disorders by inhibiting the expression of apolipoprotein C-III (ApoCIII) to reduce dangerously high triglyceride levels.
- Key Procedural History: The complaint alleges that this declaratory judgment action was precipitated by a September 3, 2025 letter from Defendant Ionis accusing Plaintiff Arrowhead of infringement and threatening litigation over its plozasiran product, thereby creating a justiciable controversy.
Case Timeline
| Date | Event |
|---|---|
| 2013-02-14 | ’333 Patent Priority Date |
| 2017-03-14 | ’333 Patent Issue Date |
| 2023-03-20 | FDA grants Fast Track designation for plozasiran |
| 2024-09-10 | FDA grants Breakthrough Therapy designation for plozasiran |
| 2024-11-18 | Arrowhead submits New Drug Application for plozasiran |
| 2024-12-XX | FDA approves Ionis's drug Tryngolza® (olezarsen) |
| 2025-04-23 | Ionis sends letter to Arrowhead regarding promotion of plozasiran |
| 2025-05-22 | Arrowhead responds to Ionis's letter |
| 2025-09-03 | Ionis sends letter to Arrowhead alleging infringement of the ’333 Patent |
| 2025-09-10 | Complaint Filing Date |
| 2025-11-18 | Expected FDA PDUFA action date for plozasiran |
II. Technology and Patent(s)-in-Suit Analysis
- Patent Identification: U.S. Patent No. 9,593,333, “Modulation of apolipoprotein C-III (ApoCIII) expression in lipoprotein lipase deficient (LPLD) populations,” issued March 14, 2017. (Compl. ¶10).
The Invention Explained
- Problem Addressed: The patent addresses Fredrickson Type I dyslipidemia, also known as Lipoprotein Lipase Deficiency (LPLD) or Familial Chylomicronemia Syndrome (FCS). This is a rare genetic condition where patients cannot produce functionally active lipoprotein lipase (LPL), an enzyme essential for breaking down triglycerides (TGs). This deficiency leads to extremely high TG levels, which can cause life-threatening pancreatitis. Current management options, such as severe dietary fat restriction, have significant compliance challenges and limited efficacy. (’333 Patent, col. 2:6-44).
- The Patented Solution: The invention claims a method of treating LPLD by administering a compound that acts as an "ApoCIII specific inhibitor." ApoCIII is a protein that naturally inhibits LPL. The patent posits that reducing the expression of the inhibitor (ApoCIII) can provide a therapeutic benefit even in patients who have deficient levels of the enzyme (LPL) that ApoCIII acts upon. (’333 Patent, Abstract; col. 2:1-5).
- Technical Importance: The patented method proposes a therapeutic pathway for a rare "orphan" disease for which conventional TG-lowering drugs were not considered effective, suggesting a novel mechanism of action for this patient population. (’333 Patent, col. 2:28-34).
Key Claims at a Glance
- The complaint identifies independent claim 1 as illustrative. (Compl. ¶13).
- The essential elements of Claim 1 are:
- A method of treating or ameliorating lipoprotein lipase deficiency (LPLD) in an animal
- comprising administering a therapeutically effective amount of a compound comprising an ApoCIII specific inhibitor to the animal,
- where: administering the compound reduces a triglyceride level by at least 10%,
- thereby treating or ameliorating LPLD. (’333 Patent, col. 83:48-53).
- The complaint seeks a declaration that all claims of the patent are invalid or not infringed. (Compl. ¶41; Prayer for Relief ¶A-B).
III. The Accused Instrumentality
Product Identification
Plaintiff Arrowhead’s investigational therapeutic, plozasiran, formerly known as ARO-APOC3. (Compl. ¶¶2, 20).
Functionality and Market Context
- Plozasiran is described as a first-in-class RNA interference (RNAi) therapy designed to treat FCS by silencing the gene that produces ApoCIII. (Compl. ¶20). It is a double-stranded small interfering RNA molecule that, once inside a target cell, is taken up by the RNA-induced silencing complex (RISC). This complex then causes the cleavage and destruction of ApoCIII messenger RNA (mRNA), thereby preventing the production of the ApoCIII protein. (Compl. ¶¶15-16).
- The complaint distinguishes plozasiran’s mechanism as catalytic, where one RNAi molecule can destroy hundreds of mRNA strands, from the mechanism of Ionis’s own approved ASO drug, which is described as non-catalytic and consumed during its action. (Compl. ¶¶16, 27).
- Plozasiran is alleged to be highly effective, with Phase 3 clinical trial results showing reductions in triglycerides of up to 80% and ApoC3 levels of up to 94%. (Compl. ¶22). The drug is currently under FDA review, with a decision expected by November 18, 2025. (Compl. ¶24).
IV. Analysis of Infringement Allegations
This is a declaratory judgment action where the Plaintiff, Arrowhead, alleges non-infringement. The complaint outlines its non-infringement theory but does not include a formal claim chart exhibit. The following table summarizes Arrowhead's primary non-infringement argument as presented in the complaint.
’333 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Non-Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating or ameliorating lipoprotein lipase deficiency (LPLD) in an animal comprising administering... a compound comprising an ApoCIII specific inhibitor... | Plozasiran is a double-stranded RNAi therapeutic that operates by catalytically destroying mRNA via the cellular RISC pathway. The complaint alleges this mechanism is distinct from the single-stranded antisense oligonucleotide (ASO) inhibitor disclosed in the ’333 patent and thus falls outside the valid scope of the claims. | ¶15, ¶27, ¶45 | col. 7:62-8:4; col. 68:51-64 |
Identified Points of Contention
- Scope Questions: The central dispute concerns the scope of the term "ApoCIII specific inhibitor." The complaint suggests that because the ’333 Patent only discloses an antisense oligonucleotide (ASO) inhibitor, the claims cannot be validly construed to cover Arrowhead's mechanistically distinct RNAi therapeutic. (Compl. ¶¶13, 39, 45). This raises the question of whether the claim term is limited to the technologies disclosed and enabled in the specification.
- Technical Questions: The complaint emphasizes the different mechanisms of action between plozasiran (catalytic, RISC-based, double-stranded RNAi) and the technology associated with Ionis (non-catalytic, RNase H-based, single-stranded ASO). (Compl. ¶27). An evidentiary question may be whether these technical differences are sufficient to place plozasiran outside the literal scope of the claims or the doctrine of equivalents.
- Invalidity as a Defense: Arrowhead’s non-infringement position is intertwined with its invalidity argument. It alleges the patent fails to provide sufficient written description and enablement for the full, broad scope of "any form of... ApoC3 specific inhibitor," as required by 35 U.S.C. § 112, because it discloses only a single species of inhibitor. (Compl. ¶¶13, 39).
V. Key Claim Terms for Construction
The Term
"ApoCIII specific inhibitor"
Context and Importance
The definition of this term is dispositive for both infringement and validity. A broad construction covering any agent that reduces ApoCIII expression, regardless of its molecular structure or mechanism, could support a finding of infringement. A narrower construction, limited by the patent's disclosure to antisense technology, would support Arrowhead's non-infringement position and its related invalidity arguments under § 112. Practitioners may focus on this term because it represents a potential mismatch between broad claim language and a narrow technical disclosure.
Intrinsic Evidence for Interpretation
- Evidence for a Broader Interpretation: The patent’s own definition section provides an expansive definition: an “ApoCIII specific inhibitor” refers to “any agent capable of specifically inhibiting the expression of ApoCIII mRNA and/or the expression or activity of ApoCIII protein,” including “nucleic acids (including antisense compounds), peptides, antibodies, small molecules, and other agents.” (’333 Patent, col. 7:62–8:4).
- Evidence for a Narrower Interpretation: The specification’s only working example describes a clinical trial for ISIS 304801, an antisense oligonucleotide. (’333 Patent, col. 68:51–76:20). The detailed description and summary of the invention also appear to focus exclusively on antisense technology. Parties may argue that the claim scope should be limited to what the inventors demonstrated they possessed and enabled at the time of filing. (Compl. ¶39).
VI. Other Allegations
Indirect Infringement
Arrowhead seeks a declaration that it has not and will not infringe, "directly or indirectly." (Compl. ¶44). The complaint does not, however, provide sufficient detail for analysis of any specific allegations related to induced or contributory infringement.
Willful Infringement
This allegation is not applicable, as the complaint is a declaratory judgment action for non-infringement and invalidity initiated by the accused infringer.
No probative visual evidence provided in complaint.
VII. Analyst’s Conclusion: Key Questions for the Case
The resolution of this declaratory judgment action will likely depend on the court’s determination of the following open questions:
- A core issue will be one of claim scope versus enablement: Is the broad functional term “ApoCIII specific inhibitor,” which on its face could cover multiple drug modalities, adequately described and enabled under 35 U.S.C. § 112 by a specification that provides only a single working example of an antisense oligonucleotide? This question directly links Arrowhead's non-infringement and invalidity arguments.
- A key technical and legal question will be one of mechanistic distinction: Does Arrowhead's plozasiran—a double-stranded, catalytic RNAi therapeutic using the RISC pathway—fall within the legal scope of a claim originating from a patent focused on single-stranded antisense technology that relies on a different enzymatic pathway (RNase H)?