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Claims for Patent: 7,015,315

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Claims for Patent: 7,015,315

Title:Gapped oligonucleotides
Abstract: Oligonucleotides and other macromolecules are provided which have increased nuclease resistance, substituent groups for increasing binding affinity to complementary strand, and subsequences of 2'-deoxy-erythro-pentofuranosyl nucleotides that activate RNase H. Such oligonucleotides and macromolecules are useful for diagnostics and other research purposes, for modulating the expression of a protein in organisms, and for the diagnosis, detection and treatment of other conditions susceptible to oligonucleotide therapeutics.
Inventor(s): Cook; Phillip Dan (Vista, CA), Monia; Brett P. (Carlsbad, CA)
Assignee: ISIS Pharmaceuticals, Inc. (Carlsbad, CA)
Application Number:08/465,866
Patent Claims: 1. An oligonucleotide which is specifically hybridizable with single-stranded DNA or RNA and which comprises a sequence of nucleotide units, wherein said sequence is divided into: a first region having 2'-O-alkyl substituted nucleotide units in which said 2'-O-alkyl substituent has as least 2 carbon atoms, and a second region composed of nucleotide units having 2'-deoxy sugar moieties, said nucleotide units of at least one of said first or second regions being connected by phosphorothioate linkages.

2. The oligonucleotide of claim 1 wherein said nucleotide units of said first and second regions are connected by phosphorothioate linkages.

3. The oligonucleotide of claim 1 wherein said nucleotide units of said first region are connected by phosphodiester linkages and said nucleotide units of said second region are connected by phosphorothioate linkages.

4. The oligonucleotide of claim 1 wherein said nucleotide units of said first region are connected by phosphorothioate linkages and said nucleotide units of said second region are connected by phosphodiester linkages.

5. The oligonucleotide of claim 1 wherein said second region has at least three nucleotide units.

6. The oligonucleotide of claim 1 wherein said second region has at least five nucleotide units.

7. The oligonucleotide of claim 1 having 5 to 50 nucleotide units.

8. The oligonucleotide of claim 1 having a third region, said third region having 2'-O-alkyl substituted nucleotide units, wherein said second region is positioned between said first and third regions.

9. The oligonucleotide of claim 8 wherein said nucleotide units of said first, second and third regions are connected by phosphorothioate linkages.

10. The oligonucleotide of claim 8 wherein said nucleotide units of said first and third regions are connected by phosphodiester linkages and said nucleotide units of said second region are connected by phosphorothioate linkages.

11. The oligonucleotide of claim 8 wherein said nucleotide units of said first and third regions are connected by phosphorothioate linkages and said nucleotide units of said second region are connected by phosphodiester linkages.

12. The oligonucleotide of claim 8 wherein said second region has at least three nucleotide units.

13. The oligonucleotide of claim 8 wherein said second region has at least five nucleotide units.

14. The oligonucleotide of claim 8 having 5 to 50 nucleotide units.

15. The oligonucleotide of claim 8 wherein said nucleotide units of said first region are connected by phosphodiester linkages and said nucleotide units of said second and third regions are connected by phosphorothioate linkages.

16. The oligonucleotide of claim 1 wherein at least one nucleotide unit of said first region is a 2'-O-alkyl-O-alkyl nucleotide unit.

17. An oligonucleotide which is specifically hybridizable with single-stranded DNA or RNA and which comprises a sequence of nucleotide units, wherein said sequence is divided into a first region having 2'-O-alkyl substituted nucleotide units and a second region composed of nucleotide units having 2'-deoxy sugar moieties, wherein said nucleotide units of said first region are connected by phosphodiester linkages and said nucleotide units of said second region are connected by phosphorothioate linkages.

18. The oligonucleotide of claim 17 wherein said second region has at least three nucleotide units.

19. The oligonucleotide of claim 17 wherein said second region has at least five nucleotide units.

20. The oligonucleotide of claim 17 having 5 to 50 nucleotide units.

21. The oligonucleotide of claim 17 having a third region, said third region having 2'-O-alkyl substituted nucleotide units, wherein said second region is positioned between said first and third regions.

22. The oligonucleotide of claim 17 wherein at least one nucleotide unit of said first region is a 2'-O-alkyl-O-alkyl nucleotide unit.

23. The oligonucleotide of claim 21 wherein said nucleotide units of said third region are connected by phosphorothioate linkages.

24. The oligonucleotide of claim 21 wherein said nucleotide units of said third region are connected by phosphodiester linkages.

25. The oligonucleotide of claim 21 wherein said second region has at least three nucleotide units.

26. The oligonucleotide of claim 21 wherein said second region has at least five nucleotide units.

27. The oligonucleotide of claim 21 having 5 to 50 nucleotide units.

28. An oligonucleotide which is specifically hybridizable with single-stranded DNA or RNA and which comprises a sequence of nucleotide units, wherein said sequence is divided into: a first region having 2'-O-alkyl substituted nucleotide units in which said 2'-O-alkyl substituent has as least 2 carbon atoms, said nucleotide units of said first region being connected either only by phosphodiester linkages or only by phosphorothioate linkages; and a second region composed of nucleotide units having 2'-deoxy sugar moieties, said nucleotide units of at least one of said first or second regions being connected by phosphorothioate linkages.

29. An oligonucleotide which is specifically hybridizable with single-stranded DNA or RNA and which comprises a sequence of nucleotide units, wherein said sequence is divided into: a first region having 2'-O-alkyl substituted nucleotide units in which said 2'-O-alkyl substituent has as least 2 carbon atoms; and a second region composed of nucleotide units having 2'-deoxy sugar moieties; and a third region having 2'-O-alkyl substituted nucleotide units; wherein said second region is positioned between said first and third regions, said nucleotide units of at least one of said first or second regions is connected by phosphorothioate linkages; and said nucleotide units of said first region or said third region are connected either only by phosphodiester linkages or only by phosphorothioate linkages.

30. An oligonucleotide which is specifically hybridizable with single-stranded DNA or RNA and which comprises a sequence of nucleotide units, wherein said sequence is divided into a first region having 2'-O-alkyl substituted nucleotide units and a second region composed of nucleotide units having 2'-deoxy sugar moieties, wherein said nucleotide units of said first region are connected only by phosphodiester linkages and said nucleotide units of said second region are connected by phosphorothioate linkages.
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