DCT
4:25-cv-05696
Ascendis Pharma AS v. BioMarin Pharmaceutical Inc
I. Executive Summary and Procedural Information
- Parties & Counsel:
- Plaintiff: Ascendis Pharma A/S, Ascendis Pharma Growth Disorders A/S, and Ascendis Pharma, Inc. (Denmark/Delaware)
- Defendant: BioMarin Pharmaceutical Inc. (Delaware)
- Plaintiff’s Counsel: Latham & Watkins LLP
- Case Identification: 3:25-cv-05696, N.D. Cal., 07/07/2025
- Venue Allegations: Venue is alleged to be proper in the Northern District of California because Defendant BioMarin maintains its corporate headquarters and principal place of business in San Rafael, California, within the district.
- Core Dispute: Plaintiff seeks a declaratory judgment that its investigational drug product, TransCon CNP, does not infringe Defendant’s patent related to modified variants of C-type natriuretic peptide (CNP).
- Technical Context: The technology concerns modified biologic drugs designed to treat bone growth disorders, such as achondroplasia, by increasing the therapeutic molecule's stability and duration of action in the body.
- Key Procedural History: This declaratory judgment action was filed in direct response to a complaint filed by BioMarin against Ascendis at the U.S. International Trade Commission (ITC) on April 1, 2025. The ITC action, which alleges infringement of the same patent by the same accused product, establishes the "actual controversy" between the parties that provides the jurisdictional basis for this lawsuit. The accused product is currently an investigational drug under priority review by the U.S. Food & Drug Administration (FDA) and is not yet commercially available.
Case Timeline
| Date | Event |
|---|---|
| 2009-05-20 | RE48,267 Patent Priority Date |
| 2020-10-20 | RE48,267 Patent Issue Date |
| 2025-03-31 | Ascendis submits New Drug Application (NDA) for TransCon CNP to FDA |
| 2025-04-01 | BioMarin files ITC complaint against Ascendis alleging infringement of RE'267 Patent |
| 2025-06-02 | Ascendis announces FDA acceptance of NDA for priority review |
| 2025-07-07 | Ascendis files this Complaint for Declaratory Judgment |
| 2025-11-30 | FDA Prescription Drug User Fee Act (PDUFA) goal date for TransCon CNP review |
II. Technology and Patent(s)-in-Suit Analysis
U.S. Reissue Patent No. RE48,267 - "VARIANTS OF C-TYPE NATRIURETIC PEPTIDE"
The patent-in-suit is U.S. Reissue Patent No. RE48,267, issued October 20, 2020 (the ’267 Patent).
The Invention Explained
- Problem Addressed: The patent's background section explains that the therapeutic potential of naturally occurring C-type natriuretic peptide (CNP) for treating skeletal dysplasias like achondroplasia is severely limited by its very short plasma half-life of approximately 2.6 minutes in humans, which makes it difficult to maintain effective therapeutic concentrations (RE’267 Patent, col. 3:25-34).
- The Patented Solution: The invention addresses this problem by creating modified "CNP variants." These variants are designed to have improved pharmaceutical properties, such as an increased half-life, by attaching other molecules, including synthetic polymers like polyethylene glycol (PEG), to the CNP peptide. This modification is intended to protect the peptide from rapid degradation in the body, thereby allowing for sustained therapeutic activity and less frequent dosing (RE’267 Patent, Abstract; col. 4:51-58).
- Technical Importance: The development of long-acting biologics represents a significant advance in treating chronic conditions by enhancing drug stability, reducing dosing frequency, and improving patient quality of life (RE’267 Patent, col. 3:35-42).
Key Claims at a Glance
- The complaint identifies independent claims 15 and 18 as being asserted by BioMarin in the related ITC action (Compl. ¶25).
- Independent Claim 15 includes the following essential elements:
- A macromolecule capable of releasing a CNP variant
- comprising a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage
- wherein hydrolysis of the hydrolysable linkage releases the CNP variant
- Independent Claim 18 includes the following essential elements:
- A sustained release CNP variant formulation
- comprising a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage
- The complaint notes that dependent claims 16-17, 19-20, and 31-48 were also asserted in the ITC complaint (Compl. ¶25).
III. The Accused Instrumentality
Product Identification
The accused instrumentality is Ascendis’s investigational drug product, TransCon CNP (navepegritide) (Compl. ¶16).
Functionality and Market Context
- TransCon CNP is described as a prodrug of CNP administered once weekly to provide continuous exposure of active CNP for the treatment of achondroplasia in children (Compl. ¶18, ¶19-20).
- The complaint alleges that, in contrast to the technology described in the ’267 Patent, TransCon CNP is an inactive prodrug in its conjugated (PEGylated) form (Compl. ¶27).
- It is further alleged that TransCon CNP does not release the active CNP molecule through hydrolysis, the mechanism required by the asserted claims (Compl. ¶27).
- The complaint states that TransCon CNP has been imported into the United States exclusively for purposes reasonably related to seeking FDA approval, such as for use in clinical trials, and has not been sold or offered for sale commercially (Compl. ¶20, ¶23).
- No probative visual evidence provided in complaint.
IV. Analysis of Infringement Allegations
The complaint seeks a declaratory judgment of non-infringement, refuting allegations made by BioMarin in a separate ITC proceeding. The following chart summarizes Ascendis’s stated bases for non-infringement.
RE48,267 Infringement Allegations
| Claim Element (from Independent Claim 15) | Alleged Non-Infringing Functionality (per Ascendis) | Complaint Citation | Patent Citation |
|---|---|---|---|
| A macromolecule capable of releasing a CNP variant... | Ascendis alleges its TransCon CNP is a prodrug that is inactive in its conjugated form, whereas the patent specification allegedly describes and supports only PEGylated conjugates that are active in their conjugated form. | ¶27 | col. 22:55-65 |
| ...a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage... | The complaint asserts that the linkage in TransCon CNP is not a "hydrolysable linkage" as required by the claim. | ¶27 | col. 270:1 |
| ...wherein hydrolysis of the hydrolysable linkage releases the CNP variant. | Ascendis alleges that its TransCon CNP product does not release CNP through a mechanism of hydrolysis. | ¶27 | col. 270:2-3 |
| Claim Element (from Independent Claim 18) | Alleged Non-Infringing Functionality (per Ascendis) | Complaint Citation | Patent Citation |
| A sustained release CNP variant formulation... | The complaint alleges that TransCon CNP is not "formulated" for sustained release using "polymeric systems" in the manner described in the patent specification. | ¶27 | col. 88:63-89:7 |
Identified Points of Contention
- Technical Questions: A primary technical dispute will concern the chemical mechanism of action. What is the specific chemical reaction that releases active CNP from the TransCon CNP prodrug, and does that reaction meet the legal definition of "hydrolysis" as required by the claims? The complaint's assertion that the product "does not release CNP through hydrolysis" suggests a fundamental operational difference (Compl. ¶27).
- Scope Questions: The dispute raises the question of whether the claim term "CNP variant" is limited to polymer-peptide conjugates that are themselves biologically active, as Ascendis argues is supported by the specification, or if it can be construed more broadly to read on inactive prodrugs. A similar question arises for Claim 18 regarding whether a single prodrug molecule constitutes a "sustained release... formulation" or if the term requires additional components as described in the patent's embodiments.
V. Key Claim Terms for Construction
"hydrolysable linkage"
- Context and Importance: This term is dispositive. Ascendis's core non-infringement theory is that its product's release mechanism is not "hydrolysis." The construction of this term will determine whether the accused product's mode of action falls within the claim scope.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: A party may argue that because the patent does not provide an explicit, limiting definition, the term should be given its plain and ordinary meaning, which could encompass any linkage that breaks in the presence of water under physiological conditions.
- Evidence for a Narrower Interpretation: The complaint suggests a narrow definition requiring the "incorporation of a water molecule" (Compl. ¶27). The patent specification's examples, such as the use of "NHS-ester" chemistry for PEGylation, may be cited as contextually limiting the term to specific classes of chemical bonds known to be susceptible to simple hydrolysis (RE’267 Patent, col. 82:59-62).
"CNP variant"
- Context and Importance: Practitioners may focus on this term because Ascendis contrasts its allegedly inactive prodrug with what it characterizes as the patent's disclosure of active PEGylated conjugates. If "CNP variant" is construed to require activity in the conjugated state, it may provide a basis for non-infringement.
- Intrinsic Evidence for Interpretation:
- Evidence for a Broader Interpretation: The term is defined structurally in the claims and specification without an explicit requirement of activity in the conjugated state. A party could argue the term refers to the modified CNP molecule itself, regardless of its activity before the active portion is released.
- Evidence for a Narrower Interpretation: The specification states that "the CNP variants of the disclosure advantageously retain CNP activity" and may have "greater than at least 50%... of the biological activity of wild-type CNP22" (RE’267 Patent, col. 22:55-65). This language may support an argument that the claimed "variant" must itself be biologically active.
VI. Other Allegations
Indirect Infringement
The complaint seeks a declaratory judgment of non-infringement for both direct and indirect infringement, in response to BioMarin's allegations in the ITC action (Compl. ¶25; Prayer for Relief A). The complaint does not provide sufficient detail from the ITC filing for analysis of the specific factual basis for the indirect infringement allegations.
VII. Analyst’s Conclusion: Key Questions for the Case
This declaratory judgment action appears positioned to resolve several fundamental disputes ahead of the potential commercial launch of Ascendis's product. The outcome will likely depend on the court's resolution of the following questions:
- A core issue will be one of chemical mechanism: Does the release of active CNP from the TransCon prodrug occur via a chemical pathway that constitutes "hydrolysis" of a "hydrolysable linkage," or is there a non-infringing technical difference in its mode of action?
- A second key issue is one of definitional scope: Is the term "CNP variant," as claimed in the ’267 Patent, limited to polymer-peptide conjugates that are themselves biologically active, or can it be construed to cover an inactive prodrug that releases an active peptide?
- Finally, for claim 18, a dispositive question will be the boundary between a molecule and a formulation: Does a single, long-acting prodrug molecule itself constitute a "sustained release... formulation," or does that claim term require a composition with additional release-controlling excipients as described in the patent's specification?