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AssigneeAvecia Biotechnology Inc.
InventorsJin-Yan Tang, Nandkumar Bongle, Jose Gonzalez, Warren E. Schwartz
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The present invention comprises an improved method of synthesizing oligonucleotides. The method comprises employing dinucleotides (or “dimer blocks”) as the basic synthetic unit building block. The method results in extremely high purity oligonucleotides in which the N−1 content is very low, generally less than 1-2% of the full length, N, oligonucleotide. We have found that synthesis using dinucleotide phosphorothioates results in oligonucleotides having very little phosphodiester content. Furthermore, we have found that the amount of dimer required in each coupling step can be less than about 6 and is preferably about 2 equivalents. Synthesis of oligonucleotides according to the dimer block approach described herein can also be conducted without the capping step that has heretofore been deemed necessary after each coupling.
In a method of synthesizing an oligonucleotide by solid phase synthesis in which a nascent solid support-bound oligonucleotide is elongated by stepwise coupling with a dimer block, the improvement comprising coupling the dimer block to the nascent solid support-bound oligonucleotide by contacting the nascent solid support-bound oligonucleotide with 6 or fewer equivalents of the dimer block in each coupling step.
In a method of solid phase synthesis of an oligonucleotide by the phosphoramidite method employing dimer blocks, the improvement comprising omitting the capping step subsequent to each coupling step.
A population of oligonucleotide phosphorothioates having a total purity of 98% or more.
A method of manufacturing a N-mer oligonucleotide composition of ultrahigh purity, the method comprising
A population of synthetic oligonucleotide phosphorothioates wherein one or both of the N−1 or N+x content is less than 0.15%.
A composition of matter comprising synthetic oligonucleotides, wherein one or both of the N−1 or N+x content is less than 0.15%.
Dependencies are inferred from the claim text.