Isis Pharmaceuticals, Inc.

Merck + Co., Inc.

Biota Scientific Management Pty Ltd

Other

Ciba-geigy Corporation

Merck Sharp + Dohme Corp.

Ciba-geigy Ag

Biota, Inc.

Isis Pharmacueticals, Inc.

Ionis Pharmaceuticals, Inc.

Phillip Dan Cook

Muthiah Manoharan

Yogesh S Sanghvi

Andrew Mamoru Kawasaki

Charles John Guinosso

David J Ecker

Oscar L Acevedo

Kelly G Sprankle

Thazha P Prakash

Balkrishen Bhat

Thomas W Bruice

Glenn D Hoke

Clarence Frank Bennett

Brett P Monia

Marija Prhavc

Haoyun An

Bruce S Ross

Kanda S Ramasamy

Kelly Teng

Pei Pei Kung

John S Kiely

David Brian Olsen

Yi Jin

Anne Bettina Eldrup

Peter W Davis

Gregory E Hardee

Robert H Springer

Vivek K Rajwanshi

Venkatraman Mohan

Allister S Fraser

Steven S Carroll

Pei-Pei Kung

Rich H Griffey

Susan M Freier

Vasulinga T Ravikumar

Guangyi Wang

Douglas L Cole

Normand Hebert

Lloyd G Tillman

Janet M Leeds

Jennifer L Brooks

Dennis Mulvey

Ching-Leou Teng

Nicholas A Boyle

Maria Eugenia Ariza

Patrick C Fagan

Kathleen D Tucker

Jean Jacques Vasseur

Francoise Debart

Martin A Maier

Richard Holmes Griffey

Michael E Jung

Malcolm Maccoss

Gerhard Baschang

Quanlai Song

Rahul C Mehta

Tingmin Wang

Daniel Peter McGee

John Nicholas Lambert

Michael V Templin

Yali Jennifer Tsai

Martin G Dunkel

Deborah K Ewing, Legal Representative

Vasanthankumar Rajappan

Kandasamy Sakthivel

Neelima Bhat

Daniel Peter Claude McGee

C Frank Bennett

Malcolm MacCoss

Jacqueline R Wyatt

Nicholas M Dean

Pierre Martin

Andrei P Guzaev

Karl-Heinz Altmann

Timothy A Vickers

Kevin P Anderson

Adrian Waldner

Ronnie C Hanecak

Kandasamy Ramasamy

Vickie L Brown-Driver

Tadeusz Krzysztof Wyrzykiewicz

Robert S Andrews

Robert L LaFemina

Alain De Mesmaeker

Amy L Simcoe

Gregory J Ewing

Jacques Lebreton

Vasanthakumar Rajappan

Normand Herbert

Becky Haly

Guity P Balow

Francois Morvan

Andrew Mamoro Kawasaki

Carrie A Rutkowski

Mario A Valenciano

Andrei P Guzzaev

Lawrence C Kuo

Dawn L Hall

Robert L Lafemina

The present invention relates to compositions and methods which enhance the local and systemic uptake and delivery of oligonucleotides and nucleic acids via non-parenteral routes of administration. Pharmaceutical compositions comprising oligonucleotides disclosed herein include, for systemic delivery, emulsion and microemulsion formulations for a variety of applications and oral dosage formulations. It has also surprisingly been discovered that oligonucleotides may be locally delivered to colonic sites by rectal enemas and suppositories in simple solutions, e.g., neat or in saline. Such pharmaceutical compositions of oligonucleotides may further include one or more penetration enhancers for the transport of oligonucleotides and other nucleic acids across mucosal membranes. The compositions and methods of the invention are utilized to effect the oral, buccal, rectal or vaginal administration of an antisense oligonucleotide to an animal in order to modulate the expression of a gene in the animal for investigative, therapeutic, palliative or prophylactic purposes.

Compositions and methods for non-parenteral delivery of oligonucleotides

The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such nucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the nucleoside compounds of the present invention.

Nucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase

The present invention relates to compositions and methods for the pulmonary delivery of nucleic acids, particularly oligonucleotides. In one preferred embodiment, the compositions and methods of the invention are utilized to effect the pulmonary delivery of an antisense oligonucleotide to an animal in order to modulate the expression of a gene in the animal for investigative, therapeutic or prophylactic purposes.

Composition and methods for the pulmonary delivery of nucleic acids

The present invention relates to compositions and methods which enhance the delivery of oligonucleotides and other nucleosidic moieties via topical routes of administration. Preferred compositions include liposomes or penetration enhancers for the delivery of such moieties to dermal and/or epidermal tissue in an animal for investigative, therapeutic or prophylactic purposes.

Compositions and methods for topical delivery of oligonucleotides

The present invention relates to nucleoside diphosphate mimics and nucleoside triphosphate mimics, which contain diphosphate or triphosphate moiety mimics and optionally sugar-modifications and/or base-modifications. The nucleotide mimics of the present invention, in a form of a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutical formulation, are useful as antiviral, antimicrobial, and anticancer agents. The present invention provides a method for the treatment of viral infections, microbial infections, and proliferative disorders. The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention optionally in combination with other pharmaceutically active agents.

Nucleotide mimics and their prodrugs

Nucelosides and nucleotides containing a tricyclic base portion thereof are useful for treating infectious diseases and proliferative disorders, such as viral infections or cancer respectively.

Tricyclic nucleosides or nucleotides as therapeutic agents

The present invention provides thionucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and/or for the treatment of hepatitis C infection. The invention also describes pharmaceutical compositions containing such thionucleoside compounds alone or in combination with other agents active against RNA-dependent RNA viral infection, in particular HCV infection. Also disclosed are methods of inhibiting RNA-dependent RNA polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with the thionucleoside compounds of the present invention.

Thionucleoside derivatives as inhibitors of RNA-dependent RNA viral polymerase

Nucleosides and nucleotides containing a tricyclic base portion thereof are useful for treating infectious diseases and proliferative disorders, such as viral infections or cancer respectively.

Linked nucleosides having at least one functionalized nucleoside that bears a substituent such as a steroid molecule, a reporter molecule, a non-aromatic lipophilic molecule, a reporter enzyme, a peptide, a protein, a water soluble vitamin, a lipid soluble vitamin, an RNA cleaving complex, a metal chelator, a porphyrin, an alkylator, a pyrene, a hybrid photonuclease/intercalator, or an aryl azide photo-crosslinking agent exhibit increased cellular uptake and other properties. The substituent can be attached at the 2'-position of the functionalized nucleoside via a linking group. If at least a portion of the remaining liked nucleosides are 2&#x2032;-deoxy-2&#x2032;-fluoro, 2&#x2032;-O-methoxy, 2&#x2032;-O-ethoxy, 2&#x2032;-O-propoxy, 2&#x2032;-O-aminoalkoxy or 2&#x2032;-O-allyloxy nucleosides, the substituent can be attached via a linking group at any of the 3&#x2032; or the 5&#x2032; positions of the nucleoside or on the heterocyclic base of the nucleoside or on the inter-nucleotide linkage linking the nucleoside to an adjacent nucleoside.

Derivatized oligonucleotides having improved uptake and other properties

Novel chiral compounds that mimic and/or modulate the activity of wild-type nucleic acids are disclosed. In general, the compounds are phosphorothioate oligonucleotides wherein the 5', and the 3&#x2032;-terminal internucleoside linkages are chirally Sp and internal internucleoside linkages are chirally Rp.

Oligonucleolotides having site specific chiral phosphorothioate internucleoside linkages

Compositions and methods are provided for the treatment and diagnosis of diseases amenable to modulation of the production of selected proteins. In accordance with preferred embodiments, oligonucleotides and oligonucleotide analogs are provided which are specifically hybridizable with a selected sequence of RNA or DNA wherein at least one of the 2'-deoxyfuranosyl moieties of the nucleoside unit is modified. Treatment of diseases caused by various viruses and other causative agents is provided.

Sugar modified oligonucleotides

Growing community of inventors

Fallbrook, CA, United States of America

Phillip Dan Cook