DCT
2:25-cv-08609
Ionis Pharma Inc v. Arrowhead Pharma Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Ionis Pharmaceuticals, Inc. (Delaware)
- Defendant: Arrowhead Pharmaceuticals, Inc. (Delaware)
- Plaintiff’s Counsel: Umhofer, Mitchell & King LLP; Williams & Connolly LLP
- Case Identification: 2:25-cv-08609, C.D. Cal., 09/11/2025
- Venue Allegations: Venue is alleged in the Central District of California because Defendant Arrowhead resides in the district, maintaining its principal place of business in Pasadena, California.
- Core Dispute: Plaintiff alleges that Defendant’s forthcoming drug, plozasiran, for treating the rare genetic disorder familial chylomicronemia syndrome (FCS), will infringe a patent covering methods of treating lipoprotein lipase deficient populations by inhibiting the protein apolipoprotein C-III (ApoCIII).
- Technical Context: The technology involves genetic medicine, specifically antisense and RNA interference therapeutics, designed to treat rare metabolic disorders characterized by dangerously high levels of triglycerides in the blood.
- Key Procedural History: The complaint alleges that Plaintiff’s own FDA-approved drug for FCS, Tryngolza®, is listed in the FDA’s Orange Book along with the patent-in-suit. Plaintiff also alleges it sent a notice letter to Defendant approximately one week before filing suit, and that Defendant filed a declaratory judgment action in the District of Delaware the day before this complaint was filed.
Case Timeline
| Date | Event |
|---|---|
| 2013-02-14 | ’333 Patent - Earliest Priority Date |
| 2017-03-14 | ’333 Patent - Issue Date |
| 2018-12-01 | Arrowhead announces clinical trials for plozasiran in FCS |
| 2024-12-01 | Ionis’s Tryngolza® (olezarsen) approved and launched in U.S. |
| 2025-01-17 | Arrowhead’s New Drug Application (NDA) for plozasiran accepted by FDA |
| 2025-09-03 | Ionis sends pre-suit notice letter to Arrowhead |
| 2025-09-05 | Arrowhead acknowledges receipt of Ionis's letter |
| 2025-09-10 | Arrowhead files declaratory judgment action in District of Delaware |
| 2025-09-11 | Complaint filed |
| 2025-11-18 | Arrowhead’s anticipated PDUFA date for plozasiran approval |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Patent No. 9,593,333 - "Modulation of apolipoprotein C-III (ApoCIII) expression in lipoprotein lipase deficient (LPLD) populations"
- 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.
The Invention Explained
- Problem Addressed: The patent addresses the treatment of individuals with lipoprotein lipase deficiency (LPLD), a severe genetic disorder also known as Familial Chylomicronemia Syndrome (FCS) (’333 Patent, col. 2:6-15). In these patients, the enzyme responsible for clearing triglycerides from the blood, lipoprotein lipase (LPL), is non-functional. The patent notes that because the target protein, ApoCIII, functions by inhibiting LPL, it would be "unexpected that inhibition of ApoCIII would have a beneficial effect in LPL deficient (LPLD) subjects" (’333 Patent, col. 2:2-5).
- The Patented Solution: The invention is the discovery that administering an inhibitor of ApoCIII can, contrary to expectations, effectively reduce triglyceride levels even in patients who lack functional LPL (’333 Patent, Abstract; col. 2:51-54). The patented method involves administering an ApoCIII-specific inhibitor, such as an antisense compound, to treat LPLD populations, thereby providing a novel therapeutic option where none previously existed (’333 Patent, col. 3:3-9).
- Technical Importance: This approach represented a potential breakthrough for a patient population with a severe "orphan" disease for which conventional triglyceride-lowering drugs were ineffective and management was limited to extremely restrictive diets (Compl. ¶22-23; ’333 Patent, col. 2:27-33).
Key Claims at a Glance
- The complaint asserts independent claim 1 and dependent claims 2-7, 9, 10, 14, 15, 18, and 20-23 (Compl. ¶47).
- Independent Claim 1:
- 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,
- wherein: administering the compound reduces a triglyceride level by at least 10%, thereby treating or ameliorating LPLD.
- The complaint states that infringement will be of "at least" the listed claims, reserving the right to assert others (Compl. ¶47).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is the investigational drug plozasiran (Compl. ¶9).
Functionality and Market Context
- Plozasiran is described as an "investigational RNA interference (RNAi) therapeutic designed to reduce production of apolipoprotein C-III (APOC3)" (Compl. ¶52, ¶55). The complaint alleges that Arrowhead is seeking FDA approval to market plozasiran for the treatment of FCS, the same indication as LPLD (Compl. ¶50). Clinical trial data cited in the complaint states that plozasiran achieved a median 80% reduction in triglycerides from baseline (Compl. ¶54).
- The complaint positions plozasiran as a "copycat product" intended to compete directly with Ionis's own approved ApoCIII inhibitor, Tryngolza® (olezarsen), for the same patient population (Compl. ¶7-9, ¶31).
IV. Analysis of Infringement Allegations
No probative visual evidence provided in complaint.
’333 Patent Infringement Allegations
| Claim Element (from Independent Claim 1) | Alleged Infringing Functionality | Complaint Citation | Patent Citation |
|---|---|---|---|
| A method of treating or ameliorating lipoprotein lipase deficiency (LPLD) in an animal | Arrowhead is seeking FDA approval to market plozasiran for the treatment of familial chylomicronemia syndrome (FCS), which the complaint states is also known as LPLD. | ¶50 | col. 3:3-6 |
| comprising administering a therapeutically effective amount of a compound comprising an ApoCIII specific inhibitor to the animal, | Plozasiran is alleged to be an ApoCIII specific inhibitor, and its future prescribing information will allegedly instruct physicians to administer a therapeutically effective amount for the treatment of patients with LPLD. | ¶51-53 | col. 7:62-65 |
| wherein: administering the compound reduces a triglyceride level by at least 10%, thereby treating or ameliorating LPLD. | Arrowhead’s public statements regarding its Phase 3 clinical trial data allegedly show that plozasiran administration reduces triglyceride levels by a median of 80%, which is in excess of the claimed 10% reduction. | ¶54 | col. 21:14-22 |
Identified Points of Contention
- Scope Questions: A central dispute may concern the scope of the term "ApoCIII specific inhibitor" and the related term "antisense compound" from dependent claim 3. The complaint alleges plozasiran is a "small-interfering RNA ('siRNA')" therapeutic (Compl. ¶55). The question for the court may be whether Arrowhead’s RNAi/siRNA technology falls within the patent’s definition of these terms, which were primarily associated with Ionis's single-stranded antisense oligonucleotide (ASO) technology at the time of the invention.
- Technical Questions: As infringement is alleged based on future conduct, a key question will be whether the final, FDA-approved labeling and instructions for use for plozasiran direct medical professionals to perform all the steps of the claimed method. The complaint's allegations are based on Arrowhead's NDA submission, clinical trial data, and press releases (Compl. ¶50, ¶53).
V. Key Claim Terms for Construction
- The Term: "antisense compound" (from dependent claim 3)
- Context and Importance: The complaint alleges that plozasiran is both an siRNA and an "antisense compound" (Compl. ¶55, ¶56). The definition of "antisense compound" is therefore critical, as Arrowhead may argue its siRNA product, which operates through the RNA interference (RNAi) pathway, is a distinct technology from the antisense oligonucleotides (ASOs) that form the basis of the patent's specific embodiments.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The patent’s definition section explicitly includes siRNAs within its definition: ""Antisense compound" means an oligomeric compound... Examples of antisense compounds include single-stranded and double-stranded compounds, such as, antisense oligonucleotides, siRNAs, shRNAs, ssRNAi..." (’333 Patent, col. 7:31-36).
- Evidence for a Narrower Interpretation: A party could argue that the patent’s specific embodiments and examples, which describe a "5-10-5 MOE gapmer" chemistry (e.g., ’333 Patent, col. 68:65-col. 69:10), teach a classic ASO structure designed for RNase H-mediated degradation, a different biological mechanism than that used by siRNAs. This could be used to argue that the claims, when read in light of the specification, should be limited to ASO-type compounds.
VI. Other Allegations
- Indirect Infringement: The complaint alleges induced infringement under 35 U.S.C. § 271(b) and contributory infringement under § 271(c) (Compl. p. 12). The inducement allegation is based on the claim that Arrowhead’s future product labeling will instruct physicians and patients to administer plozasiran in a manner that directly infringes the method claims (Compl. ¶60). The contributory infringement allegation is based on the assertion that plozasiran has no substantial non-infringing use (Compl. ¶61).
- Willful Infringement: The complaint alleges that Arrowhead knew of or was willfully blind to the ’333 patent (Compl. ¶30-31, ¶59). The basis for this allegation includes Arrowhead's alleged review of a scientific publication by Ionis that disclosed the parent patent application, the listing of the ’333 patent in the FDA’s Orange Book for a competing product, Arrowhead’s own securities filings acknowledging third-party patent rights, and a direct pre-suit notice letter sent by Ionis to Arrowhead (Compl. ¶30-34, ¶37, ¶58).
VII. Analyst’s Conclusion: Key Questions for the Case
- A core issue will be one of definitional scope: can the term "antisense compound," as used in the patent, be construed to cover Arrowhead's siRNA therapeutic? The case may turn on whether the patent's broad explicit definition, which includes siRNAs, controls over its specific embodiments, which describe a different class of antisense technology (ASOs).
- A second key question will relate to infringement and willfulness: assuming the claims are construed to cover plozasiran, what is the strength of the evidence that Arrowhead had pre-suit knowledge of the patent and an affirmative intent to induce infringement? The multiple alleged sources of knowledge cited in the complaint—including public records like the Orange Book and a direct notice letter—will be central to this inquiry.