Roche Innovation Center Copenhagen A/s

Hoffmann-la Roche Inc.

Erik Daa Funder

Yong Wu

Dennis Jul Hansen

Konrad H Bleicher

Henrik Frydenlund Hansen

Troels Koch

Lykke Pedersen

Jacob Ravn

Nanna Albaek

Peter Hagedorn

Søren Ottosen

Jesper Worm

Susanne Kammler

Souphalone Luangsay

Sabine Sewing

Adrian Schaeublin

Heidi Rye Hudlebusch

Martins Katkevics

Dace Katkevica

Christoffer Sondergaard

Joerg Duschmalé

Erich Koller

Susanne Mohr

Tobias Nilsson

Søren V Rasmussen

Steffen Schmidt

Joerg Hoernschemeyer

Marianne Ravn Møller

Jette Dam Hedegaard

Alexander Herbert Stephan

Natascha Hruschka

Martina Brigitte Duschmalé

Meiling Li

Xi Shu

Brian Leonard

Daniel Turley

Johanna Marie Walther

Konrad Bleicher

Lars Joenson

The present invention relates to an optimized method for preparing a P(V) monomer of formula (IIIa) or (IIIb) from a nucleoside using DBU as a base at about 0.8 equivalent to nucleoside.

Process for preparing nucleotide P(V) monomers

The present invention relates to a novel process for preparing a compound of formula (III) and rhenium chelated MAG3 oligonucleotides.

Process for preparing rhenium chelated MAG3 oligonucleotides

The present disclosure provides antisense oligonucleotides targeting Regulator of telomere elongation helicase 1 (RTEL1). The disclosure also provides, enhanced antisense oligonucleotides targeting RTEL1 for use in treating and/or preventing a hepatitis B virus (HBV) infection. Also disclosed are pharmaceutical compositions and their use.

Enhanced oligonucleotides for inhibiting RTEL1 expression

The present invention relates to methods of synthesis of stereodefined oligonucleotides wherein the protected 5'-hydroxy terminus of a nucleoside or oligonucleotide attached to a solid support is first unprotected, followed by coupling an oxazaphospholidine phosphoramidite monomer to the now deprotected 5&#x2032;-hydroxy terminus, oxidizing the resultant phosphite triester intermediate with a sulfurizing reagent, and optionally washing the product. The method of synthesis of the present invention described above may be repeated to optionally elongate the stereodefined oligonucleotide being synthesized until the elongation cycle is intentionally terminated via deprotecting and cleavaging the resulting stereodefined oligonucleotide from the solid support. The oxazaphospholidine phosphoramidite monomer to be coupled in the present invention may optionally be chosen from Formula 1a and 1b. Generally, the present invention relates to enhanced synthesis methods wherein a single elongation cycle, optionally comprising repeated coupling and oxidation steps, results in an enhanced yield and higher purity of stereodefined phosphorothioate oligonucleotides.

Multiple coupling and oxidation method

The present invention relates to a method for preparing stereodefined phosphorothioate oligonucleotides, especially locked stereodefined phosphorothioate oligonucleotides with a high yield, using pyridinium acidic salts as a coupling activator.

Pyridinium salts as activators in the synthesis of stereodefined oligonucleotides

The present invention relates to the field of stereodefined phosphorothioate oligonucleotides and to stereodefining nucleoside monomers comprising an amine containing chiral auxiliary group, and methods of orthogonally protecting the nitrogen of chiral auxiliaries during oligonucleotide synthesis, preventing post elongation chain cleavage, increasing yield and purity of stereodefined phosphorothioate oligonucleotides.

Orthogonal protecting groups for the preparation of stereodefined phosphorothioate oligonucleotides

The present invention relates to antisense LNA oligonucleotides (oligomers) complementary to ATXN3 pre-mRNA sequences, which are capable of inhibiting the expression of ATXN3 protein. Inhibition of ATXN3 expression is beneficial for the treatment of spinocerebellar ataxia.

Antisense oligonucleotides targeting ATXN3

Stereodefined phosphorothioate oligonucleotides, related nucleoside monomers and methods of synthesis of both are described. The disclosed isobutyryl protected L-LNA-G monomers have following Formula 50 or 51 where Ris independently CHODMTr or CHOMMTr and R, when present, is cyanoethyl. The monomers have improved solubility and stability characteristics, resulting in improved efficacy in oligonucleotide synthesis.

Stereodefining L-monomers

The present invention relates to the synthesis of stereo-defined phosphorothioate oligonucleotides of formula I: 

Enhanced coupling of stereodefined oxazaphospholidine phosphoramidite monomers to nucleoside or oligonucleotide

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Hørsholm, Denmark

Erik Daa Funder