The Dimethoxytrityl Resin Product Anchored Sequential Synthesis Method (DMT PASS):  A Conceptually Novel Approach to Oligonucleotide Synthesis

Presented is a conceptually novel approach to oligonucleotide synthesis referred to herein as dimethoxytrityl resin product anchored sequential synthesis (DMT PASS). The DMT PASS process is characterized by the reaction of a 3‘-protected nucleoside or oligonucleotide with an excess of a nucleotide 3‘-phosphoramite or H-phosphonate which is bound to a dimethoxytrityl functionalized polystyrene resin. As a result, successfully coupled oligonucleotide product is then attached to the solid support, allowing for removal and potential recovery of starting materials. The protected oligonucleotide product is then released and subjected to an aqueous/organic extractive purification, which serves to remove monomeric impurities. The PASS process is anticipated to provide for the cost-effective manufacture of oligonucleotides on a scale which would allow for clinical development and pharmaceutical product commercialization. Herein we describe some aspects of our process development progress and discuss preliminary applications of the process to the synthesis of short oligodeoxyribonucleotide sequences, as well as a number of challenges confronting the PASS development effort.