Source: http://www.google.com/patents/US7575902?dq=645576
Timestamp: 2015-03-01 17:16:47
Document Index: 177620441

Matched Legal Cases: ['Application No. 02', 'Application No. 02', 'Application No. 02', 'Application No. 02', 'Application No. 02', 'Application No. 02']

R5 is selected from hydrogen and �OH;
6. The method of claim 1, wherein R5 is �OH.
R5 is selected from H, halogen groups, �R, �OR, and �NR2, wherein R is selected from H, C1-C6 alkyl, and C5-C14 aryl;
wherein R5 and R6 are the same or different, and are independently selected from the group consisting of H, Cl, F, �R, �OR, �NR2 or halogen groups, where each R is independently H, C1-C6 alkyl or C5-C14 aryl. The reaction composition is incubated under appropriate conditions to generate at least one primer extension product comprising one or more of the at least one universal nucleotides and one or more of the at least one specific terminators. One or more of the at least one primer extension products are separated, wherein the separating comprises at least one mobility-dependent analysis technique. One or more of the at least one primer extension products is detected.
wherein R5 and R6 are the same or different, and are independently selected from the group consisting of H, Cl, F, �R, �OR, �NR2 or halogen groups, where each R is independently H, C1-C6 alkyl or C5-C14 aryl. The reaction composition is incubated under appropriate conditions to generate at least one primer extension product comprising one or more of the at least one universal nucleotides. One or more of the at least one primer extension products is released from one or more of the at least one target nucleic acid templates. The incubating and releasing are repeated to generate a plurality of primer extension products. One or more of the plurality of primer extension products is separated, wherein the separating comprises at least one mobility-dependent analysis technique. One or more of the plurality of primer extension products is detected.
wherein R5 and R6 are the same or different, and are independently selected from the group consisting of H, Cl, F, �R, �OR, �NR2 or halogen groups, where each R is independently H, C1-C6 alkyl or C5-C14 aryl. The reaction composition is incubated under appropriate conditions to generate at least one second primer extension product. One or more of the at least one second primer extension products is released from one or more of the at least one first primer extension products. The incubating and releasing are repeated to generate a plurality of second primer extension products. One or more of the plurality of second primer extension products is separated, wherein the separating comprises at least one mobility-dependent analysis technique. One or more of the plurality of second primer extension products is detected.
wherein R5 and R6 are the same or different, and are independently selected from the group consisting of H, Cl, F, �R, �OR, �NR2 or halogen groups, where each R is independently H, C1-C6 alkyl or C5-C14 aryl.
FIG. 2: FIG. 2 shows the structures of several non-limiting exemplary universal nucleotides. (A) 2′-deoxy-7-azaindole-5′-triphosphate (d7AITP), (B) 2′-deoxy-6-methyl-7-azaindole-5′-triphosphate (dM7AITP), (C) 2′-deoxy-pyrrollpyrizine-5′-triphosphate (dPPTP), (D) 2′-deoxy-imidizopyridine-5′-triphosphate (dimPyTp), (E) 2′-deoxy-isocarbostyril-5′-triphosphate (dICSTP), (F) 2′-deoxy-propynyl-7-azaindole-5′-triphosphate (dP7AITP), (G) 2′-deoxy-propynylisocarbostyril-5′-triphosphate (dPICSTP), and (H) 2′-deoxy-allenyl-7-azaindole-5′-triphosphate (dA7AITP). �R,� as used in this figure, is the deoxyribose moiety of the nucleotide.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of �or� means �and/or� unless stated otherwise. Furthermore, the use of the term �including,� as well as other forms, such as �includes� and �included,� is not limiting.
The term �nucleotide base,� as used herein, refers to a substituted or unsubstituted aromatic ring or rings. In some embodiments, the aromatic ring or rings contain at least one nitrogen atom. In some embodiments, the nucleotide base is capable of forming Watson-Crick and/or Hoogsteen hydrogen bonds with an appropriately complementary nucleotide base. Exemplary nucleotide bases and analogs thereof include, but are not limited to, naturally occurring nucleotide bases adenine, guanine, cytosine, uracil, thymine, and analogs of the naturally occurring nucleotide bases, e.g., 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, N6-Δ2-isopentenyladenine (61A), N6-Δ2-isopentenyl-2-methylthioadenine (2ms6iA), N2-dimethylguanine (dmG), 7-methylguanine (7mG), inosine, nebularine, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O6-methylguanine, N6-methyladenine, O4-methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, pyrazolo[3,4-D]pyrimidines (see, e.g., U.S. Pat. Nos. 6,143,877 and 6,127,121 and PCT published application no. WO 01/38584), ethenoadenine, indoles such as nitroindole and 4-methylindole, and pyrroles such as nitropyrrole. In some embodiments, nucleotide bases are universal nucleotide bases. Some exemplary nucleotide bases can be found, e.g., in Fasman, 1989, Practical Handbook of Biochemistry and Molecular Biology, pp. 385-394, CRC Press, Boca Raton, Fla., and the references cited therein.
wherein R5 and R6 are the same or different, and are independently selected from the group consisting of H, Cl, F, �R, �OR, �NR2 or halogen groups, where each R is independently H, C1-C6 alkyl or C5-C14 aryl, and wherein R7 is selected from the group consisting of H, Cl, F, �R′, �OR′, �NR′12 or halogen groups, where each R′ is independently H, monophosphate, diphosphate, triphosphate, C1-C6 alkyl or C5-C14 aryl. In some embodiments, the 2′-carbon atom is substituted with one or more of the same or different Cl, F, �R, �OR, �NR2 or halogen groups, where each R is independently H, C1-C6 alkyl or C5-C14 aryl. Exemplary riboses include, but are not limited to, 2′-(C1-C6)alkoxyribose, 2′-(C5-C14)aryloxyribose, 2′,3′-didehydroribose, 2′-deoxy-3′-haloribose, 2′-deoxy-3′-fluororibose, 2′-deoxy-3′-chlororibose, 2′-deoxy-3′-aminoribose, 2′-deoxy-3′-(C1-C6)alkyl ribose, 2′-deoxy-3′-(C1-C6)alkoxyribose and 2′-deoxy-3′-(C5-C14)aryloxyribose, ribose, 2′-deoxyribose, 2′,3′-dideoxyribose, 2′-haloribose, 2′-fluororibose, 2′-chlororibose, and 2′-alkylribose, e.g., 2′-O-methyl, 4′-α-anomeric nucleotides, 1′-α-anomeric nucleotides, 2′-4′- and 3′-4′-linked and other 3�7 locked� or �LNA,� bicyclic sugar modifications (see, e.g., PCT published application nos. WO 98/22489, WO 98/39352, and WO 99/14226). Exemplary LNA sugar analogs within a polynucleotide include, but are not limited to, the structures:
The term �specific nucleotide,� as used herein, refers to an extendable nucleotide that can be incorporated into a polynucleotide strand by a polymerase during a primer extension reaction, and will not pair with more than one different pairing type of nucleotide in a template strand, where the nucleotide in the template strand is not a universal nucleotide. For example, C is a specific nucleotide, even though it pairs specifically with both G and I, since G and I are not different pairing types of nucleotides. Similarly, C is a specific nucleotide, even though it pairs with both G and a universal nucleotide. Specific nucleotides may be naturally-occurring nucleotides, e.g., adenine, cytosine, guanine, thymine or uracil. Specific nucleotides may also be nucleotide analogs that pair in a template sequence-specific manner. The term �universal nucleotide,� as used herein, refers to an extendable nucleotide that can be incorporated into a polynucleotide strand by a polymerase during a primer extension reaction, and pairs with more than one pairing type of specific nucleotide. In some embodiments, the universal nucleotide pairs with any specific nucleotide. In some embodiments, the universal nucleotide pairs with four pairing types of specific nucleotides or analogs thereof. In some embodiments, the universal nucleotide pairs with three pairing types of specific nucleotides or analogs thereof. In some embodiments, the universal nucleotide pairs with two pairing types of specific nucleotides or analogs thereof. The pairing of a universal nucleotide with two or more pairing types of specific nucleotides will be referred to as non-template sequence-specific pairing.
The terms �universal nucleotide base� and �universal base� are used interchangeably and, as used herein, refer to the base portion of a universal nucleotide. The universal nucleotide base may include an aromatic ring moiety, which may or may not contain nitrogen atoms. In some embodiments, a universal base may be covalently attached to the C-1′ carbon of a pentose sugar to make a universal nucleotide. In some embodiments, a universal nucleotide base does not hydrogen bond specifically with another nucleotide base. In some embodiments, a universal nucleotide base may interact with adjacent nucleotide bases on the same nucleic acid strand by hydrophobic stacking. Universal nucleotides include, but are not limited to, 2′-deoxy-7-azaindole-5′-triphosphate (d7AITP), 2′-deoxy-isocarbostyril-5′-triphosphate (dICSTP), 2′-deoxy-propynylisocarbostyril-5′-triphosphate (dPICSTP), 2′-deoxy-6-methyl-7-azaindole-5′-triphosphate (dM7AITP), 2′-deoxy-imidizopyridine-5′-triphosphate (dimPyTp), 2′-deoxy-pyrrollpyrizine-5′-triphosphate (dPPTP), 2′-deoxy-propynyl-7-aza-indole-5′-triphosphate (dP7AITP), or 2′-deoxy-allenyl-7-azaindole-5′-triphosphate (dA7AITP).
�Alkyl� refers to a saturated or unsaturated, straight-chain, branched, or cyclic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Typical alkyl groups include, but are not limited to, methyl (�CH3); ethyls such as ethanyl (�CH2CH3), ethenyl (�CH═CH2), ethynyl (�C≡CH); propyls such as propan-1-yl (�CH2CH2CH3), propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl (�CH═CHCH2), prop-1-en-2-yl, prop-2-en-1-yl (�CH2CH═CH2), prop-2-en-2-yl, cycloprop-1-en-1-yl, cycloprop-2-en-1-yl, prop-1-yn-1-yl (�C≡CCH3), prop-2-yn-1-yl (�CH2C≡CH), etc.; butyls such as butan-1-yl (�CH2CH2CH2CH3), butan-2-yl, cyclobutan-1-yl, but-1-en-1-yl (�CH═CH2CH2CH3), but-1-en-2-yl, but-2-en-1-yl (�CH2CH═CH2CH3), but-2-en-2-yl, buta-1,3-dien-1-yl (�CH═CHCH═CH2), buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl (�C≡CCH2CH3), but-1-yn-3-yl, but-3-yn-1-yl (�CH2CH2C≡CH), etc.; and the like. In various embodiments, the alkyl groups are (C1-C6) alkyl and (C1-C3) alkyl.
�Alkoxy� refers to �OR where R is (C1-C6) alkyl.
�Aryloxy� refers to �OR where R is (C6-C20) aryl.
�Alkylaryl� refers to �R�R′ where R is (C1-C6) alkyl and R′ is (C6-C20) aryl.
�Substituted alkyl,� �substituted aryl� and �substituted heteroaryl� refer to alkyl, aryl, and heteroaryl radicals, respectively, in which one or more hydrogen atoms are each independently replaced with another substituent. Typical substituents include, but are not limited to, �X, �R, �O−, �OR, �SR, �S−, �NRR, ═NR, �CX3, �CN, �OCN, �SCN, �NCO, �NCS, �NO, �NO2, ═N2, �N3, �S(O)2O�, �S(O)2OH, �S(O)2R, �P(O)(O−)2, �P(O)(OH)2, �C(O)R, �C(O)X, �C(S)R, �C(O)OR, �C(O)O−, �C(S)OR, �C(O)SR, �C(S)SR, �C(O)NRR, �C(S)NRR and �C(NR)NRR, and the like, where each X is independently a halogen and each R is independently hydrogen, alkyl, aryl, heteroaryl or heterocycle.
The term �nucleotide terminator� or �terminator,� as used herein, refers to an enzymatically-incorporable nucleotide, which does not support incorporation of subsequent nucleotides in a primer extension reaction. A terminator is therefore not an extendable nucleotide. In some embodiments, terminators are those in which the nucleotide is a purine, a 7-deaza-purine, a pyrimidine, a specific nucleotide or nucleotide analog and the sugar moiety is a pentose which includes a 3′-substituent that blocks further synthesis, such as a dideoxynucleotide triphosphate (ddNTP). In some embodiments, substituents that block further synthesis include, but are not limited to, amino, deoxy, halogen, alkoxy and aryloxy groups. Exemplary terminators include, but are not limited to, those in which the sugar-phosphate ester moiety is 3′-(C1-C6)alkylribose-5′-triphosphate, 2′-deoxy-3′-(C1-C6) alkylribose-5′-triphosphate, 2′-deoxy-3′-(C1-C6)alkoxyribose-5-triphosphate, 2′-deoxy-3′-(C5-C14)aryloxyribose-5′-triphosphate, 2′-deoxy-3′-haloribose-5′-triphosphate, 2′-deoxy-3′-aminoribose-5′-triphosphate, 2′,3′-dideoxyribose-5′-triphosphate or 2′,3′-didehydroribose-5′-tri-phosphate. In some embodiments, ddNTPs, such as ddATP, ddCTP, ddGTP, ddITP, and ddTTP, may be used for chain termination.
The term �label� refers to any moiety which can be attached to a molecule and: (i) provides a detectable signal; (ii) interacts with a second label to modify the detectable signal provided by the second label, e.g. FRET (Fluorescent Resonance Energy Transfer); (iii) stabilizes hybridization, e.g., duplex formation; or (iv) provides a member of a binding complex or affinity set, e.g., affinity, antibody/antigen, ionic complexation, hapten/ligand, e.g. biotin/avidin. Labeling can be accomplished using any one of a large number of known techniques employing known labels, linkages, linking groups, reagents, reaction conditions, and analysis and purification methods. Labels include, but are not limited to, light-emitting or light-absorbing compounds which generate or quench a detectable fluorescent, chemiluminescent, or bioluminescent signal (see, e.g., Kricka, L. in Nonisotopic DNA Probe Techniques (1992), Academic Press, San Diego, pp. 3-28). Fluorescent reporter dyes useful for labeling biomolecules include, but are not limited to, fluoresceins (see, e.g., U.S. Pat. Nos. 5,188,934; 6,008,379; and 6,020,481), rhodamines (see, e.g., U.S. Pat. Nos. 5,366,860; 5,847,162; 5,936,087; 6,051,719; and 6,191,278), benzophenoxazines (see, e.g., U.S. Pat. No. 6,140,500), energy-transfer fluorescent dyes, comprising pairs of donors and acceptors (see, e.g., U.S. Pat. Nos. 5,863,727; 5,800,996; and 5,945,526), and cyanines (see, e.g., Kubista, WO 97/45539), as well as any other fluorescent label capable of generating a detectable signal. Examples of fluorescein dyes include, but are not limited to, 6-carboxyfluorescein; 2′,4′,1,4-tetrachlorofluorescein; and 2′,4′,5′,7′,1,4-hexachlorofluorescein. Labels also include, but are not limited to, semiconductor nanocrystals, or quantum dots (see, e.g., U.S. Pat. Nos. 5,990,479 and 6,207,392 B1; Han et al. Nature Biotech. 19: 631-635).
A class of labels are hybridization-stabilizing moieties which serve to enhance, stabilize, or influence hybridization of duplexes, e.g. intercalators, minor-groove binders, and cross-linking functional groups (see, e.g., Blackburn, G. and Gait, M. Eds. �DNA and RNA structure� in Nucleic Acids in Chemistry and Biology, 2nd Edition, (1996) Oxford University Press, pp. 15-81). Yet another class of labels effect the separation or immobilization of a molecule by specific or non-specific capture, for example biotin, digoxigenin, and other haptens (see, e.g., Andrus, A. �Chemical methods for 5′ non-isotopic labeling of PCR probes and primers� (1995) in PCR 2: A Practical Approach, Oxford University Press, Oxford, pp. 39-54). Non-radioactive labeling methods, techniques, and reagents are reviewed in: Non-Radioactive Labelling, A Practical Introduction, Garman, A. J. (1997) Academic Press, San Diego.
A �primer extension product� is produced when one or more nucleotides have been added to a primer in a primer extension reaction. In some embodiments, a primer-extension product includes one type of universal nucleotide. In some embodiments, a primer extension product includes more than one type of universal nucleotide. In some embodiments, a primer extension product is comprised of a 5′ sequence of specific nucleotides followed by one or more universal nucleotides. In some embodiments, the 5′ sequence of specific nucleotides is at least 14 nucleotides in length. A primer extension product may serve as a target nucleic acid template in subsequent extension reactions. A primer extension product may include a terminator.
As used herein, the terms �polynucleotide,� �oligonucleotide,� and �nucleic acid� are used interchangeably and mean single-stranded and double-stranded polymers of nucleotide monomers, including 2′-deoxyribonucleotides (DNA) and ribonucleotides (RNA) linked by internucleotide phosphodiester bond linkages, or internucleotide analogs, and associated counter ions, e.g., H+, NH4 +, trialkylammonium, Mg2+, Na+ and the like. A polynucleotide may be composed entirely of deoxyribonucleotides, entirely of ribonucleotides, or chimeric mixtures thereof. The nucleotide monomer units may comprise any of the nucleotides described herein, including, but not limited to, specific nucleotides, nucleotide analogs, and universal nucleotides. Polynucleotides typically range in size from a few monomeric units, e.g. 5-40 when they are sometimes referred to in the art as oligonucleotides, to several thousands of monomeric nucleotide units. Unless denoted otherwise, whenever a polynucleotide sequence is represented, it will be understood that the nucleotides are in 5′ to 3′ order from left to right and that �A� denotes deoxyadenosine or an analog thereof, �C� denotes deoxycytidine or an analog thereof, �G� denotes deoxyguanosine or an analog thereof, and �T� denotes thymidine or an analog thereof, unless otherwise noted.
wherein each B is independently the base moiety of a nucleotide, e.g., a purine, a 7-deazapurine, a pyrimidine, a specific nucleotide, or a universal nucleotide; each m defines the length of the respective nucleic acid and can range from zero to thousands, tens of thousands, or even more; each R is independently selected from the group comprising hydrogen, hydroxyl, halogen, �R″, �OR″, and �NR″R″, where each R″ is independently (C1-C6) alkyl or (C5-C14) aryl, or two adjacent Rs may be taken together to form a bond such that the ribose sugar is 2′,3′-didehydroribose, and each R′ may be independently hydroxyl or
The terms �nucleic acid,� �polynucleotide,� and �oligonucleotide� may also include nucleic acid analogs, polynucleotide analogs, and oligonucleotide analogs. The terms �nucleic acid analog,� �polynucleotide analog,� and �oligonucleotide analog� are used interchangeably and, as used herein, refer to a polynucleotide that contains at least one nucleotide analog and/or at least one phosphate ester analog and/or at least one pentose sugar analog. Also included within the definition of polynucleotide analogs are polynucleotides in which the phosphate ester and/or sugar phosphate ester linkages are replaced with other types of linkages, such as N-(2-aminoethyl)-glycine amides and other amides (see, e.g., Nielsen et al., 1991, Science 254: 1497-1500; WO 92/20702; U.S. Pat. Nos. 5,719,262; 5,698,685); morpholinos (see, e.g., U.S. Pat. Nos. 5,698,685; 5,378,841; 5,185,144); carbamates (see, e.g., Stirchak & Summerton, 1987, J. Org. Chem. 52: 4202); methylene(methylimino) (see, e.g., Vasseur et al., 1992, J. Am. Chem. Soc. 114: 4006); 3′-thioformacetals (see, e.g., Jones et al., 1993, J. Org. Chem. 58: 2983); sulfamates (see, e.g., U.S. Pat. No. 5,470,967); 2-aminoethylglycine, commonly referred to as PNA (see, e.g., Buchardt, WO 92/20702; Nielsen (1991) Science 254:1497-1500); and others (see, e.g., U.S. Pat. No. 5,817,781; Frier & Altman, 1997, Nucl. Acids Res. 25:4429 and the references cited therein). Phosphate ester analogs include, but are not limited to, (i) C1-C4 alkylphosphonate, e.g. methylphosphonate; (ii) phosphoramidate; (iii) C1-C6 alkyl-phosphotriester; (iv) phosphorothioate; and (v) phosphorodithioate.
The term �variant� as used herein refers to any alteration of a protein, including, but not limited to, changes in amino acid sequence, substitutions of one or more amino acids, addition of one or more amino acids, deletion of one or more amino acids, and alterations to the amino acids themselves. In some embodiments, the changes involve conservative amino acid substitutions. Conservative amino acid substitution may involve replacing one amino acid with another that has, e.g., similar hydrophobicity, hydrophilicity, charge, or aromaticity. In some embodiments, conservative amino acid substitutions may be made on the basis of similar hydropathic indices. A hydropathic index takes into account the hydrophobicity and charge characteristics of an amino acid, and in some embodiments, may be used as a guide for selecting conservative amino acid substitutions. The hydropathic index is discussed, e.g., in Kyte et al., J. Mol. Biol., 157:105-131 (1982). It is understood in the art that conservative amino acid substitutions may be made on the basis of any of the aforementioned characteristics.
Alterations to the amino acids may include, but are not limited to, glycosylation, methylation, phosphorylation, biotinylation, and any covalent and noncovalent additions to a protein that do not result in a change in amino acid sequence. �Amino acid� as used herein refers to any amino acid, natural or normatural, that may be incorporated, either enzymatically or synthetically, into a polypeptide or protein.
In some such embodiments, one or both of R6 and R7 comprises a phosphoramidite. In some embodiments, R5 and R6 are the same or different, and are independently selected from the group consisting of H, halogen groups, �R, �OR, and �NR2, where each R is independently H, C1-C6 alkyl or C5-C14 aryl, and R7 is selected from the group consisting of H, Cl, F, �R′, �OR′, �NR′2 or halogen groups, where each R′ is independently H, monophosphate, diphosphate, triphosphate, C1-C6 alkyl or C5-C14 aryl.
It is to be understood that the above-described syntheses are merely representative approaches that may be modified in numerous ways, as will be appreciated by those of ordinary skill in the art. All manner of chemical transformations and reagents known in the art are contemplated for use in accordance with various embodiments�including but not limited to those described in treatises such as Comprehensive Organic Transformations, 2nd Edition by Richard C. Larock (Wiley-VCH, New York, 1999), Advanced Organic Chemistry Part B: Reactions and Synthesis by Francis A. Carey and Richard J. Sundberg (Kluwer Academic/Plenum Publishers, 2001), Some Modem Methods of Organic Synthesis, 3rd Edition by W. Carruthers (Cambridge, 1987), Protective Groups in Organic Synthesis, 3rd Edition by Theodora W. Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., 1999), and March's Advanced Organic Chemistry, 5th Edition by Michael B. Smith and Jerry March (John Wiley & Sons, Inc., 2001), and references cited therein.
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