The country of origin of DNL126 (ETVSGSH) in bulk form and in dosage form

N349588
June 26, 2025
OT:RR:NC:N3:138
CATEGORY: Origin Ryan Mills Denali Therapeutics 161 Oyster Point Blvd South San Francisco, CA 94080 RE: The country of origin of DNL126 (ETV:SGSH) in bulk form and in dosage form Dear Mr. Mills: In your letter dated May 29, 2025, you requested a country of origin ruling on DNL126 (ETV:SGSH). This ruling request was submitted by Kirti Jadeja, Global Trade Advisory, Deloitte Tax LLP. DNL126 (ETV:SGSH) is an investigational enzyme replacement therapy designed to cross the blood brain barrier (BBB) for the potential treatment of MPS IIIA (Sanfilippo syndrome type A). It is an active pharmaceutical ingredient (API) composed of two SGSH enzymes fused to Denali’s propriety TV technology, an FC domain protein designed to cross BBB and enable delivery of the SGSH enzymes into cells and tissues throughout the body. It acts by targeting sulphamidase and is developed based on an enzyme transport vehicle (ETV) platform. DNL126 (ETV:SGSH), imported in 100 mg/5 mL vials, is an intravenously administered drug undergoing clinical trials for the treatment of Sanfilippo Syndrome A or MPS IIIA. MPS IIIA is a rare, genetic lysosomal storage disease that causes neurodegeneration, developmental and behavioral abnormalities, and early death in children. In your letter, you state the active pharmaceutical ingredient (API), DNL126 and the DNL126 drug product are manufactured in the United States (U.S.). The API (DNL126) is produced from starting materials by culturing living cells that are genetically engineered to express the API protein therapeutic under proprietary growing conditions. First, the unique molecular structure of the API, its research cell bank, and manufacturing process were invented in Denali’s laboratories in California. Next, the API protein sequence development; the research cell bank production; the research bank expansion as well as the expression of the API are performed in the United States. Afterwards, while still in the U.S., the API undergoes purification; formulation with excipients; filtration; packaging into HDPE bags and are frozen into the bulk DNL126 drug product. Later on, the frozen bulk DNL126 drug product is shipped from the U.S. into China to be filled into glass vials and packaged into the final dosage form DNL126 (ETV: SGSH) drug in 100 mg/5 mL vials. Finally, the

vials are then shipped back to the U.S. to undergo secondary packaging and labelling in accordance with FDA requirements to permit use in clinical trial testing. When determining the country of origin, the substantial transformation analysis is applicable. See, e.g., Headquarters Ruling Letter (“HQ”) H301619, dated November 6, 2018. The test for determining whether a substantial transformation will occur is whether an article emerges from a process with a new name, character, or use different from that possessed by the article prior to processing. See Texas Instruments Inc. v. United States, 681 F.2d 778 (C.C.P.A. 1982). This determination is based on the totality of the evidence. See National Hand Tool Corp. v. United States, 16 C.I.T. 308 (1992), aff’d, 989 F.2d 1201 (Fed. Cir. 1993). In this case, the API (DNL126) and the bulk DNL126 drug product are entirely made in the United Sates, and the country of origin will be the United States. The filling and packaging process of the bulk DNL126 drug product into 100 mg/5 mL vials in China does not result in a substantial transformation and the country of origin of the final drug product DNL126 (ETV: SGSH) imported in 100 mg/5 mL vials will be the United States. This merchandise may be subject to the Federal Food, Drug, and Cosmetic Act and/or The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (The Bioterrorism Act), which are administered by the U.S. Food and Drug Administration (FDA). Information on the Federal Food, Drug, and Cosmetic Act, as well as The Bioterrorism Act, can be obtained by calling the FDA at 1-888-463-6332, or by visiting their website at www.fda.gov. The holding set forth above applies only to the specific factual situation and merchandise description as identified in the ruling request. This position is clearly set forth in Title 19, Code of Federal Regulations (CFR), Section 177.9(b)(1). This section states that a ruling letter is issued on the assumption that all of the information furnished in the ruling letter, whether directly, by reference, or by implication, is accurate and complete in every material respect. In the event that the facts are modified in any way, or if the goods do not conform to these facts at time of importation, you should bring this to the attention of U.S. Customs and Border Protection (CBP) and submit a request for a new ruling in accordance with 19 CFR 177.2. Additionally, we note that the material facts described in the foregoing ruling may be subject to periodic verification by CBP. This ruling is being issued under the provisions of Part 177 of the Customs and Border Protection Regulations (19 C.F.R. 177). A copy of the ruling or the control number indicated above should be provided with the entry documents filed at the time this merchandise is imported. If you have any questions regarding the ruling, please contact National Import Specialist Judy Lee at [email protected].
Sincerely,
(for) Steven A. Mack Director National Commodity Specialist Division