Martek Biosciences Corporation

Mpeg La, L.l.c.

Jonathan Miles Brown

Hans-Peter Vornlocher

Philipp Hadwiger

Frank Elbert Anderson, Iii

Steven William Homans

Philip Edward Coughlin

Charles Tobias Weller

Kristin K H Neuman

Carrie Ann Zimmerman-Wilson

Eddie James Oliver, Jr

James E Dahlman

Hao Chen

Richard J Radmer

Fc Thomas Allnutt

Frank Elbert Anderson

Eddie James Oliver

The present invention relates to methods of administering to a subject multimeric oligonucleotides having monomeric subunits joined by linkers. The multimeric oligonucleotides have a molecular weight of at least about 45 kD and other characteristics, such that their clearance due to glomerular filtration is reduced. The present invention also relates to such multimeric oligonucleotides and methods of synthesizing such multimeric oligonucleotides.

Multimeric oligonucleotides having decreased kidney clearance

Defined multi-conjugate oligonucleotides can have predetermined sizes and compositions. For example, in various embodiment, defined multi-conjugate oligonucleotides can have advantageous properties, for example in the form of defined multi-conjugate siRNA (i.e., including two, three or more siRNA) having enhanced intracellular delivery and/or multi-gene silencing effects. In various embodiment, the defined multi-conjugate oligonucleotides can be synthesized via new synthetic intermediates and methods. The defined multi-conjugate oligonucleotides can be used, for example, in reducing gene expression, biological research, treating or preventing medical conditions, or to produce new or altered phenotypes in cells or organisms.

Defined multi-conjugates oligonucleotides

Defined multi-conjugate oligonucleotides

The invention is concerned with determining the three-dimensional structure of biological macromolecules such as proteins. In particular, it is concerned with methods for rapidly determining protein structure by NMR, by providing methods for simplifying NMR spectra using labeled proteins prepared from specifically isotopically labeled amino acids having at least two isotopes of 13C, 15N and 2H in the backbone, and methods for making these labeled proteins, e.g., by cultivation of a microbial culture containing said labeled amino acids.

13C, 15N, 2H labeled proteins for NMR structure determinations and their preparation

This invention is concerned with determining the three-dimensional structure of biological macromolecules such as proteins. In particular, it is concerned with methods for rapidly determining protein structure by NMR, by providing methods for simplifying NMR spectra using labeled proteins prepared from specifically isotopically labeled amino acids having at least two isotopes of 13C, 15N and 2H in the backbone, and methods for making these labeled proteins, e.g., by cultivation of a microbial culture containing said labeled amino acids.

13C,15N ,2H labeled proteins for NMR structure determinations and their preparation

Peptidic molecules suitable for three dimensional NMR structure determination are provided which have been substituted with .sup.13 C and/or .sup.15 N in the backbone and/or at the .alpha.-carbon with .sup.2 H but not otherwise in the sidechains of the amino acid residues. One or more amino acids, amino acid species or substantially all of the amino acid residues of the molecule may be so substituted. A method of making the substituted peptidic molecules substituted in this manner is provided.

Peptidic molecules which have been isotopically substituted with .sup.13

A method for determining three-dimensional structural information of a protein which involves producing the protein in a form substantially labeled with .sup.13 C of .sup.15 N or both substantially labeled with .sup.15 N and .sup.13 C and partially labeled with .sup.2 H and subjecting the protein to nuclear magnetic resonance spectroscopic analysis. The isotopically labeled protein is produced by a method which involves producing a substantially labeled microbial protein hydrolysate, subjecting the protein hydrolysate to cation exchange chromatography to produce a partially purified labeled amino acid mixture, subjecting the partially purified labeled amino acid mixture to anion exchange chromatography to produce a purified labeled amino mixture and supplementing the purified labeled amino acid mixture with isotopically labeled cysteine and optionally with isotopically labeled glutamine and asparagine.

Compositions and methods for protein structural determinations

Combinatorial libraries of labeled biochemical compounds and methods for producing such combinatorial libraries comprising the steps of producing labeled individual units, combining at least two of the labeled individual units so as to produce a labeled biochemical compound, and repeating this process at least once so as to produce a combinatorial library of labeled biochemical compounds. Also, methods for determining the conformation of a biochemical compound which comprise producing a combinatorial library of labeled biochemical compounds, contacting the combinatorial library of labeled biochemical compounds with a target receptor molecule so that a selected labeled biochemical compound binds to the target receptor molecule, and determining the conformation of the selected labeled biochemical compound when bound to the receptor molecule.

Combinatorial libraries of labeled biochemical compounds and methods for

A method for determining three-dimensional structural information of a protein involves producing the protein in a form substantially labeled with .sup.13 C or .sup.15 N or both and subjecting the protein to nuclear magnetic resonance spectroscopic analysis. The isotopically labeled protein is produced by a method which involves producing a substantially labeled microbial protein hydrolysate, subjecting the protein hydrolyzate to cation exchange chromatography to produce a partially purified labeled amino acid mixture, subjecting the partially purified labeled amino acid mixture to anion exchange chromatography to produce a purified labeled amino acid mixture and supplementing the purified labeled amino acid mixture with isotopically labeled cysteine.

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Silver Spring, MD, United States of America

Jonathan Miles Brown