Double-stranded ribonucleic acid agents for inhibiting MAPT expression, pharmaceutical compositions, uses thereof, and in vitro method for inhibiting the expression of a MAPT gene in a cell or selectively inhibiting MAPT transcripts containing exon 10 in the cell.
Patent Information
- Application Number
- BR122026019090
- Authority / Receiving Office
- BR · BR
- Patent Type
- Applications
- Publication Date
- 2026-09-08
Smart Images
Figure 00000000_0000_ABST
Description
Double-stranded ribonucleic acid agents for inhibiting MAPT expression, pharmaceutical compositions, uses thereof, and in vitro method for inhibiting the expression of a MAPT gene in a cell or selectively inhibiting MAPT transcripts containing exon 10 in the cell. Separated from BR112022019606-7, filed on March 30, 2021. CROSS-REFERENCE TO RELATED REQUESTS
[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 002.030, filed March 30, 2020, and claims the benefit of U.S. Provisional Application No. 63 / 164.467, filed March 22, 2021. All content of the foregoing applications is hereby incorporated by reference. SEQUENCE LISTING
[0002] This application contains a Sequence Listing that was submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on March 24, 2021, is named A108868_1030WO_SL.txt and is 1,018,753 bytes in size. BACKGROUND OF THE INVENTION
[0003] The gene for microtubule-associated protein tau (MAPT), which encodes Microtubule-Associated Protein Tau (MAPT), a member of the microtubule-associated protein family, is located in the chromosomal region 17q21.31 (base pairs 45,894,382 to 46,028,334 on chromosome 17). The MAPT gene consists of 16 exons. Alternative mRNA splicing gives rise to six MAPT isoforms, with a total of 352–441 amino acids. In three of the six MAPT isoforms, the microtubule-binding domain of MAPT contains three repeated segments, while the corresponding domain contains four repeated segments in the other three MAPT isoforms. Petition 870260076339, dated 07 / 30 / 2026, page 13 / 2173 2 / 505
[0004] MAPT transcripts are differentially expressed throughout the body, predominantly in the central and peripheral nervous systems. Wild-type Tau is involved in microtubule stabilization in neuronal axons, dendritic spine maintenance, and regulation of axonal transport, microtubule dynamics, and cell division. Pathogenic MAPT variants are found in approximately 10% of individuals with primary tauopathy. The variants are primarily equisense mutations and are located in exons 9-13 (microtubule-binding domains), with many affecting the alternative splicing of exon 10.
[0005] Tauopathies are a heterogeneous class of progressive neurodegenerative disorders, pathologically characterized by the presence of tau aggregates in the brain. Phenotypically, tauopathies exhibit variable progression of motor, cognitive, and behavioral deterioration. Tauopathies include, but are not limited to, Alzheimer's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). Tau is an important component of neurofibrillary tangles in the neuronal cytoplasm, a distinctive feature in Alzheimer's disease. Tau aggregation and deposition have also been observed in approximately 50% of the brains of individuals with Parkinson's disease.
[0006] FTD includes, but is not limited to, behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), and corticobasal syndrome (CBS).
[0007] Currently, there are no curative therapies for tauopathies, and treatments aim only to alleviate symptoms and improve the individual's quality of life. Consequently, there is a need for agents that can selectively and efficiently inhibit or adjust the expression of the MAPT gene, so that individuals with a disorder associated with MAPT, for example, Alzheimer's disease, FTD, PSP, or Petition 870260076339, dated 07 / 30 / 2026, p. 14 / 2173 3 / 505 other tauopathy, can be effectively treated. BRIEF SUMMARY OF THE INVENTION
[0008] The present invention provides RNAi compositions that affect RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a MAPT gene. The MAPT gene may be located within a cell, for example, a cell within an individual, such as a human. The use of these iRNAs allows for targeted degradation of mRNAs of the corresponding gene (MAPT gene) in mammals.
[0009] The iRNAs of the invention are designed to target a MAPT gene, for example, a MAPT gene with equivocal and / or deletion mutations in gene exons and with a combination of nucleotide modifications. The iRNAs of the invention inhibit MAPT gene expression by at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%, relative to control levels, and reduce the level of sense- and antisense-containing foci. Without intending to be limited by theory, it is believed that a combination or subcombination of the foregoing properties and specific target sites, or specific modifications in these iRNAs, confers enhanced efficacy, stability, potency, durability, and safety to the iRNAs of the invention.In one aspect, the present invention provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting MAPT expression, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 nucleotides differing by no more than 3 nucleotides from the nucleotide sequence SEQ ID NO: 1 or SEQ ID NO: 3, and the antisense strand comprises at least 15 contiguous nucleotides differing by... Petition 870260076339, dated 07 / 30 / 2026, page 15 / 2173 4 / 505 no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 2 or SEQ ID NO: 4.
[00010] In another aspect, the present invention provides a dsRNA agent for inhibiting MAPT expression, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding Tau, and wherein the complementarity region comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:2 or SEQ ID NO:4.
[00011] In yet another aspect, the present invention provides a dsRNA agent for inhibiting MAPT expression, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding Tau, and wherein the complementarity region comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any of the antisense nucleotide sequences in any of Tables 3-8 and 16-28.
[00012] In one embodiment, the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 512-532, 513-533, 514-534, 515-535, 516-536, 517-537, 518-538, 519-539, 520-540, 1063-1083, 1067-1087, 1072-1092, 1074-1094, 1075-1095, 1125-1145, 1126-1146, 1127-1147, 1129-1149, 1170-1190, 1395-1415, 1905-1925, 1906-1926, 1909-1929, 1911-1931, 1912-1932, 1913-1933, 1914-1934, 1915-1935, 1916-1936, 1919-1939, 1951-1971, 1954-1974, 1958-1978, 2387-2407, 2409-2429, 2410-2430, 2469-2489, 2471-2491, 2472-2492, 2476-2496, 2477-2497, 2478-2498, 2480-2500, 2481-2501, 2482-2502, 2484-2504, 2762-2782, 2764-2784, 2766-2786, 2767-2787, Petition 870260076339, dated 07 / 30 / 2026, page 16 / 2173 5 / 505 2768-2788, 2769-2789, 2819-2839, 2821-2841, 2828-2848, 2943-2963, 2944-2964, 2946-2966, 2947-2967, 3252-3272, 3277-3297, 3280-3300, 3281-3301, 3282-3302, 3284-3304, 3285-3305, 3286-3306, 3331-3351, 3332-3352, 3333-3353, 3334-3354, 3335-3355, 3336-3356, 3338-3358, 3340-3360, 3342-3362, 3343-3363, 3344-3364, 3345-3365, 3346-3366, 3347-3367, 3349-3369, 3350-3370, 3353-3373, 3364-3384, 3366-3386, 3367-3387, 3368-3388, 3369-3389, 3370-3390, 3412-3432, 3414-3434, 3415-3435, 3416-3436, 3417-3437, 3419-3439, 3420-3440, 3424-3444, 3425-3445, 3426-3446, 3427-3447, 3428-3448, 3429-3449, 3430-3450, 3431-3451, 3434-3454, 4132-4152, 4134-4154, 4179-4199, 4182-4202, 4184-4204, 4395-4415, 4425-4445, 4426-4446, 4429-4449, 4469-4489, 4470-4490, 4471-4491, 4472-4492, 4473-4493, 4474-4494, 4569-4589, 4571-4591, 4572-4592, 4596-4616, 4623-4643, 4721-4741, 4722-4742, 4725-4745, 4726-4746, 4766-4786, 4767-4787, 4768-4788, 4769-4789, 4770-4790, 4779-4799, 4805-4825, 4806-4826, 4807-4827, 4808-4828, 4809-4829, 4812-4832, 4813-4833, 4814-4834, 4936-4956, 5072-5092, 5073-5093, 5345-5365, 5346-5366, 5349-5369, 5350-5370, 5351-5371, 5460-5480, 5461-5481, 5463-5483, 5465-5485, 5467-5487, 5468-5488, 5469-5489, 5470-5490, 5471-5491, 5505-5525, 5506-5526, 5507-5527, 5508-5528, 5509-5529, 5511-5531, 5513-5533, 5514-5534, 5541-5561, 5544-5564, 5546-5566, 5547-5567, 5548-5568, 5550-5570, 5551-5571, 5574-5594, 5576-5596, 5614-5634, 521-541, 522-542, 523-543, 524544, 525-545, 526-546, 527-547, 528-548, 529-549, 530-550, 531-551, 532-552, 533-553, 534-554, 535-555, 536-556, 1034-1054, 1035-1055, 1036-1056, 1037-1057, 1038-1058, 1039-1059, 1040-1060, 1041-1061, 1042-1062, 1043-1063, 1044-1064, 1045-1065, 1046-1066, 1047-1067, 1048-1068, 1049-1069, 1050-1070, 1051-1071, 1052-1072, 1053-1073, 1054-1074, 1062-1082, 1064-1084, 1065-1085, 1066-1086, 1068-1088, 1069-1089, 1070-1090, 1071-1091, 1073-1093, 1076-1096, 1077-1097, 1078-1098, 1079-1099, 1080-1100, 1081-1101, 1082-1102, 1128-1148, Petition 870260076339, dated 07 / 30 / 2026, p. 17 / 2173 6 / 505 1129-1149, 1130-1150, 1131-1151, 1132-1152, 1133-1153, 1134-1154, 1135-1155, 1136-1156, 1137-1157, 1138-1158, 1139-1159, 1140-1160, 1141-1161, 1142-1162, 1143-1163, 1144-1164, 1145-1165, 1146-1166, 1147-1167, 1148-1168, 975-995, 976-996, 977-997, 978-998, 979-999, 980-1000, 981-1001, 982-1002, 983-1003, 984-1004, 985-1005, 9861006, 987-1007, 988-1008, 989-1009, 990-1010, 991-1011, 992-1012, 993-1013, 994-1014, 995-1015, 996-1016, 997-1017, 998-1018, 9991019, 1000-1020, 1001-1021, 1002-1022, 1003-1023, 1004-1024, 10051025, 1006-1026, 1007-1027, 1008-1028, 1009-1029, 1010-1030, 10111031, 1012-1032, 1013-1033, 1014-1034, 1015-1035, 1016-1036, 10171037, 1018-1038, 1019-1039, 1020-1040, 1021-1041, 1022-1042, 10231043, 1024-1044, 1025-1045, 1026-1046, 1027-1047, 1028-1048, 10291049, 1030-1050, 1031-1051, 1032-1052, 1033-1053, 1034-1054, 10351055, 1036-1056, 1037-1057, 1038-1058, 1039-1059, 1040-1060, 10411061, 1042-1062, 1043-1063 and 1045-1065 of SEQ ID NO: 3,and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 4.,
[00013] In certain embodiments, the antisense polynucleotides described herein are substantially complementary to a fragment of a MAPT target sequence and comprise a contiguous nucleotide sequence that is complementary, along its entire length, to a fragment of SEQ ID NO: 4 selected from the nucleotide group, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences 520-541, 520-556, 510-534, 512-536, 516-541, 516-540, 520-544, 524-547, 526-551, 529-556, 532-556, 1065-1089, 1068-1095, 1068-1094, 1075-1100, 1076-1100, 1079-1103, 1123-1147, 1127-1151, 1130-1155, 1903-1934, 1903-1930, 1914-1940, 1949-1975, 2470-2497, 294-2965, 3275-3302, 3278-3302, 3329-3353, 3333-3357, 3338-3367, 3338 Petition 870260076339, dated 07 / 30 / 2026, page 18 / 2173 7 / 505 3366, 3348-3390, 3348-3388, 3351-3385, 5507-5562 and 5549-5597 of SEQ ID NO: 3, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 4.
[00014] In one embodiment, the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 977-997, 980-1000, 973-993, 988-1008, 987-1007, 972-992, 979-999, 1001-1021, 976-996, 994-1014, 1002-1022, 978-998, 974-994, 520-540, 521-541, 5464-5484, 1813-1833, 2378-2398, 3242-3262, 5442-5462, 1665-1685, 524-544, 5207-5227, 4670-4690, 3420-3440, 3328-3348, 5409-5429, 5439-5459, 4527-4547, 5441-5461, 5410-5430 and 5446-5466 of SEQ ID NO: 1, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 2.
[00015] In one embodiment, the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-523799.1, AD-523802.1, AD-523795.1, AD-523810.1, AD523809.1, AD-1019331.1, AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD-523824.1, AD-523800.1, AD-523796.1, AD535094.1, AD-535094.1, AD-535095.1, AD-538647.1, AD-535922.1, AD-536317.1, AD-536911.1, AD-538626.1, AD-535864.1,AD523561.1, AD-523565.1, AD-523562.1, AD-526914.1, AD-526394.1, AD-395452.1, AD-525343.1, AD-524274.1, AD-526956.1,AD526986.1, AD-526296.1, AD-526988.1, AD-526957.1, AD-526993.1, AD-1397070.1, AD-1397070.2, AD-1397071.1, AD-1397071.2,AD1397072.1, AD-1397072.2, AD-1397073.1, AD-1397073.2, AD1397074.1, AD-1397074.2, AD-1397075.1, AD-1397075.2, ADPetition 870260076339, dated 07 / 30 / 2026, p. 19 / 2173 8 / 5051397076.1, AD-1397076.2, AD-1397077.1, AD-1397077.2, AD- 1397078.1, AD-1397078.2, AD-1397250.1, AD-1397251.1, AD- 1397252.1, AD-1397253.1, AD-1397254.1, AD-1397255.1, AD- 1397256.1, AD-1397257.1, AD-1397258.1, AD-1397259.1, AD- 1397260.1, AD-1397261.1, AD-1397262.1, AD-1397263.1, AD- 1397264.1, AD-1397265.1, AD-1423242.1, AD-1423243.1, AD- 1423244.1, AD-1423245.1, AD-1423246.1, AD-1423247.1, AD- 1423248.1, AD-1423249.1, AD-1423250.1, AD-1423251.1, AD- 1423252.1, AD-1423253.1, AD-1423254.1, AD-1423255.1, AD- 1423256.1, AD-1423257.1, AD-1423258.1, AD-1423259.1, AD- 1423260.1, AD-1423261.1, AD-1423262.1, AD-1423263.1, AD- 1423264.1, AD-1423265.1, AD-1423266.1, AD-1423267.1, AD- 1423268.1, AD-1423269.1, AD-1423270.1, AD-1423271.1, AD- 1423272.1, AD-1423273.1, AD-1423274.1, AD-1423275.1, AD- 1423276.1, AD-1423277.1, AD-1423278.1, AD-1423279.1, AD- 1423280.1, AD-1423281.1, AD-1423282.1, AD-1423283.1, AD- 1423284.1, AD-1423285.1, AD-1423286.1, AD-1423287.1, AD- 1423288.1, AD-1423289.1, AD-1423290.1, AD-1423291.1, AD- 1423292.1, AD-1423293.1, AD-1423294.1, AD-1423295.1, AD- 1423296.1, AD-1423297.1, AD-1423298.1, AD-1423299.1, AD- 1423300.1, AD-1397266.1, AD-1397266.2, AD-1397267.1, AD- 1423301.1, AD-1397268.1, AD-1397268.2, AD-1397269.1, AD- 1423302.1, AD-1397270.1, AD-1397270.2, AD-1397271.1, AD- 1397271.2, AD-1397272.1, AD-1423303.1, AD-1397273.1, AD- 1423304.1, AD-1397274.1, AD-1423305.1, AD-1397275.1, AD- 1423306.1, AD-1397276.1, AD-1397277.1, AD-1397277.2, AD- 1397278.1, AD-1397279.1, AD-1397280.1, AD-1397281.1, AD- 1397282.1, AD-1397283.1, AD-1397284.1, AD-1397285.1, AD- 1397286.1, AD-1397287.1, AD-1397079.1, AD-1397079.2, AD- 1397288.1, AD-1397289.1, AD-1397290.1, AD-1397080.1, AD-. Petition 870260076339, on 07 / 30 / 2026, page. 20 / 2173 9 / 505 1397080.2, AD-1397291.1, AD-1397292.1, AD-1397293.1, AD- 1397294.1, AD-1397081.1, AD-1397081.2, AD-1397295.1, AD- 1397082.1, AD-1397082.2, AD-1397083.1, AD-1397083.2, AD- 1397296.1, AD-1397297.1, AD-1397298.1, AD-1397299.1, AD- 1397300.1, AD-1397301.1, AD-1397302.1, AD-1397084.1, AD- 1397085.1, AD-1397086.1, AD-1397303.1, AD-1397087.1, AD- 1397087.2, AD-1397304.1, AD-1397305.1, AD-1397306.1, AD- 1397307.1, AD-1397308.1, AD-1397309.1, AD-1397310.1, AD- 1397311.1, AD-1397312.1, AD-1397313.1, AD-1397314.1, AD- 1397315.1, AD-1397316.1, AD-1397317.1, AD-1397318.1, AD- 1397319.1, AD-1397320.1, AD-1397321.1, AD-1397322.1, AD- 1397088.1, AD-1397089.1, AD-1397090.1, AD-1397091.1, AD- 1397092.1, AD-1397093.1, AD-1397094.1, AD-1397095.1, AD- 1397096.1, AD-1397097.1, AD-1397098.1, AD-1397099.1, AD- 1397101.1, AD-1397102.1, AD-1397103.1, AD-1397104.1, AD- 1397105.1, AD-1397106.1, AD-1397107.1, AD-1397108.1, AD- 1397109.1, AD-1397110.1, AD-1397111.1, AD-1397112.1, AD- 1397113.1, AD-1397114.1, AD-1397115.1, AD-1397116.1, AD- 1397117.1, AD-1397118.1, AD-1397119.1, AD-1397120.1, AD- 1397121.1, AD-1397122.1, AD-1397123.1, AD-1397124.1, AD- 1397125.1, AD-1397126.1, AD-1397127.1, AD-1397128.1, AD- 1397129.1, AD-1397130.1, AD-1397131.1, AD-1397132.1, AD- 1397133.1, AD-1397134.1, AD-1397135.1, AD-1397136.1, AD- 1397137.1, AD-1397138.1, AD-1397139.1, AD-1397140.1, AD- 1397141.1, AD-1397142.1, AD-1397143.1, AD-1397144.1, AD- 1397145.1, AD-1397146.1, AD-1397147.1, AD-1397148.1, AD- 1397149.1, AD-1397150.1, AD-1397151.1, AD-1397152.1, AD- 1397153.1, AD-1397154.1, AD-1397155.1, AD-1397156.1, AD- 1397157.1, AD-1397158.1, AD-1397159.1, AD-1397160.1, AD- 1397161.1, AD-1397162.1, AD-1397163.1, AD-1397164.1, AD-. Petition 870260076339, on 07 / 30 / 2026, page. 21 / 2173 10 / 505 1397165.1, AD-1397166.1, AD-1397167.1, AD-1397168.1, AD- 1397169.1, AD-1397170.1, AD-1397171.1, AD-1397172.1, AD- 1397173.1, AD-1397174.1, AD-1397175.1, AD-1397176.1, AD- 1397177.1, AD-1397178.1, AD-1397179.1, AD-1397180.1, AD- 1397181.1, AD-1397182.1, AD-1397183.1 ,AD-1397184.1, AD- 1397185.1, AD-1397186.1, AD-1397187.1, AD-1397188.1, AD- 1397189.1, AD-1397190.1, AD-1397191.1, AD-1397192.1, AD- 1397193.1, AD-1397194.1, AD-1397195.1, AD-1397196.1, AD- 1397197.1, AD-1397198.1, AD-1397199.1, AD-1397200.1, AD- 1397201.1, AD-1397202.1, AD-1397203.1, AD-1397204.1, AD- 1397205.1, AD-1397206.1, AD-1397207.1, AD-1397208.1, AD- 1397209.1, AD-1397210.1, AD-1397211.1, AD-1397212.1, AD- 1397213.1, AD-1397214.1, AD-1397215.1, AD-1397216.1, AD- 1397217.1, AD-1397218.1, AD-1397219.1, AD-1397220.1, AD- 1397221.1, AD-1397222.1, AD-1397223.1, AD-1397224.1, AD- 1397225.1, AD-1397226.1, AD-1397227.1, AD-1397228.1, AD- 1397229.1, AD-1397230.1, AD-1397231.1, AD-1397232.1, AD- 1397233.1, AD-1397234.1, AD-1397235.1, AD-1397236.1, AD- 1397237.1, AD-1397238.1, AD-1397239.1, AD-1397240.1, AD- 1397241.1, AD-1397242.1, AD-1397243.1, AD-1397244.1, AD- 1397245.1, AD-1397246.1, AD-1397247.1, AD-1397248.1, AD- 1397249.1, AD-523565.1, AD-1397072.3, AD-1397073.3, AD- 1397076.3, AD-1397077.3, AD-1397078.3, AD-1397252.2, AD- 1397257.2, AD-1397258.2, AD-1397259.2, AD-1397263.2, AD- 1397264.2, AD-1397309.2, AD-64958.114, AD-393758.4, AD- 1397080.3, AD-1397293.2, AD-1397294.2, AD-1397081.3, AD- 1397083.3, AD-1397298.2, AD-1397299.2, AD-1397084.2, AD- 1397085.2, AD-1397087.3, AD-1397306.2, AD-1397307.2, AD-. 1397308.2, AD-1397088.2, AD-1566238, AD-1566239, AD-1566240, AD-1566241, AD-1566242, AD-1566243, AD-1566244, AD-1566245, Petition 870260076339, on 07 / 30 / 2026, page. 22 / 2173 11 / 505 AD-1566246, AD-1091966, AD-1566255, AD-692906, AD-1566581, AD-1566587, AD-1566635, AD-1566643, AD-1567157, AD-1567167, AD-1567784, AD-1568109, AD-1568148, AD-1568154, AD-1568175, AD-1091965, AD-1566251, AD-1566256, AD-1566575, AD-1566582, AD-1566588, AD-1566638, AD-1566679, AD-1567159, AD-1567199, AD-1567896, AD-1568139, AD-1568150, AD-1568158, AD-692908, AD-1566248, AD-1566252, AD-1566257, AD-1566576, AD-1566583, AD-1566590, AD-1566639, AD-1566861, AD-1567160, AD-1567202, AD-1567897, AD-1568140, AD-1568151, AD-1568161, AD-1568176, AD-1566249, AD-1566253, AD-1566258, AD-1566577, AD-1566584, AD-1566591, AD-1566641, AD-1567153, AD-1567161, AD-1567550, AD-1568105, AD-1568143, AD-1568152, AD-1568172, AD-1569830, AD-1566250, AD-1566254, AD-1566259, AD-1566580, AD-1566586, AD-1566634, AD-1566642, AD-1567154, AD-1567164, AD-1567554, AD-1568108, AD-1568144, AD-1568153, AD-1568174, AD-1569832, AD-1569834, AD-1569835, AD-1569862, AD-1569872, AD-1569890 and AD-1569892.
[00016] In a particular embodiment, the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-523799.1, AD-523802.1, AD-523795.1, AD-523810.1, AD523809.1, AD-1019331.1, AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD-523824.1, AD-523800.1, AD-523796.1,AD535094.1, AD-535094.1, AD-535095.1, AD-538647.1, AD-535922.1, AD-536317.1, AD-536911.1, AD-538626.1, AD-535864.1,AD523561.1, AD-523565.1, AD-523562.1, AD-526914.1, AD-526394.1, AD-395452.1, AD-525343.1, AD-524274.1, AD-526956.1, AD-526986.1, AD-526296.1, AD-526988.1, AD-526957.1 and AD-526993.1. In one embodiment, the antisense tape comprises at least 15 Petition 870260076339, dated 07 / 30 / 2026, page 23 / 2173 12 / 505 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-523799.1, AD523802.1, AD-523795.1, AD-523810.1, AD-523809.1, AD-1019331.1, AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD523824.1, AD-523800.1 and AD-523796.1.
[00017] In some embodiments, the nucleotide sequence of the sense and antisense strand comprises any of the nucleotide sequences of the sense and antisense strand in any of Tables 3-8 and 16-28.
[00018] In one embodiment, the sense strand nucleotide sequence comprises at least 15 contiguous nucleotides corresponding to the sense strand sequence of exon 10 of the MAPT gene presented in SEQ ID NO: 1533 and an antisense strand comprising a sequence complementary to it.
[00019] In one aspect, the present invention provides a dsRNA agent for inhibiting MAPT expression, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 5 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 6.
[00020] In another aspect, the present invention provides a dsRNA agent for inhibiting MAPT expression, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises a region complementary to an mRNA encoding Tau, and wherein the complementary region comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the Petition 870260076339, dated 07 / 30 / 2026, page 24 / 2173 13 / 505 nucleotide sequence of SEQ ID NO:6.
[00021] In yet another aspect, the present invention provides a dsRNA agent for inhibiting MAPT expression, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding Tau, and wherein the complementarity region comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any of the antisense nucleotide sequences in any of Tables 12-13.
[00022] In one embodiment, the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 1065-1085, 1195-1215, 1066-1086, 1068-1088, 705-725, 1067-1087, 4520-4540, 3341-3361, 4515-4535, 5284-5304, 5285-5305, 344-364, 5283-5303, 5354-5374, 2459-2479, 1061-1081, 706-726, 972-992, 45644584, 995-1015, 4546-4566, 968-988, 1127-1147, 4534-4554, 158-178, 4494-4514, 1691-1711, 3544-3564, 198-218, 979-999, 4548-4568, 4551-4571, 543-563, 715-735, 542-562, 352-372, 362-382, 4556-4576, 4547-4567, 4542-4562, 4558-4578, 4549-4569, 5074-5094, 4552-4572, 5073-5093, 5076-5096, 4550-4570 and 2753-2773 of SEQ ID NO: 5, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 6.
[00023] In one embodiment, the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-393758.1, AD-393888.1, AD-393759.1, AD-393761.1, AD393495.1, AD-393760.1, AD-396425.1, AD-395441.1, AD-396420.1, AD-397103.1, AD-397104.1, AD-393239.1, AD-397102.1, AD-Emission 870260076339, of 30 / 07 / 2026, page 25 / 2173 14 / 505 397167.1, AD-394791.1, AD-393754.1, AD-393496.1, AD-393667.1, AD-396467.1, AD-393690.1, AD-396449.1, AD-393663.1,AD393820.1, AD-396437.1, AD-393084.1, AD-396401.1, AD-394296.1, AD-395574.1, AD-393124.1, AD-393674.1, AD-396451.1,AD396454.1, AD-393376.1, AD-393505.1, AD-393375.1, AD-393247.1, AD-393257.1, AD-396459.1, AD-396450.1, AD-396445.1,AD396461.1, AD-396452.1, AD-396913.1, AD-396455.1, AD-396912.1, AD-396915.1, AD-396453.1 and AD-394991.1.
[00024] In one embodiment, the sense strip, the antisense strip, or both the sense strip and the antisense strip described herein are conjugated with one or more lipophilic moieties.
[00025] In one embodiment, the lipophilic moiety is conjugated to one or more internal positions in the double-stranded region of the dsRNA agent.
[00026] In one embodiment, the lipophilic moiety is conjugated via a ligand or carrier.
[00027] In one embodiment, the lipophilicity of the lipophilic moiety, measured by logKow, exceeds 0.
[00028] In one embodiment, the hydrophobicity of the double-stranded RNA agent, measured by the unbound portion in a double-stranded RNA agent plasma protein binding assay, exceeds 0.2.
[00029] In one embodiment, the plasma protein binding assay is an electrophoretic mobility change assay using human serum albumin protein.
[00030] In some embodiments, the dsRNA agent comprises at least one modified nucleotide.
[00031] In one embodiment, no more than five of the nucleotides on the sense strand and no more than five of the nucleotides on the antisense strand in a dsRNA agent of the present invention are unmodified nucleotides.
[00032] In one embodiment, all nucleotides of the sense strand and Petition 870260076339, dated 07 / 30 / 2026, page 26 / 2173 15 / 505 all nucleotides of the antisense strand in the dsRNA agent are modified nucleotides.
[00033] In some embodiments, at least one of the modified nucleotides of the dsRNA agent is selected from the group consisting of a deoxynucleotide, a 3'-terminal deoxythymidine (dT) nucleotide, a 2'-O-methyl modified nucleotide, a 2'-fluorine modified nucleotide, a 2'-deoxy modified nucleotide, a blocking nucleotide, a non-blocking nucleotide, a conformationally restricted nucleotide, an ethyl restricted nucleotide, an abasic nucleotide, a 2'-amino modified nucleotide, a 2'-O-allyl modified nucleotide, a 2'-C-alkyl modified nucleotide, a 2'-hydroxy modified nucleotide, a 2'-methoxyethyl modified nucleotide, a nucleotide modified with 2'-O-alkyl, a morpholino nucleotide, a phosphoramidate, a nucleotide comprising an unnatural base, a tetrahydropyran-modified nucleotide, a 1,5-anhydrohexitol-modified nucleotide, a cyclohexenyl-modified nucleotide,a nucleotide comprising a 5'-phosphorothioate group, a nucleotide comprising a 5'-methylphosphonate group, a nucleotide comprising a 5'-phosphate or 5'-phosphate imitator, a nucleotide comprising vinyl phosphonate, a nucleotide comprising adenosine glycol nucleic acid (GNA), a nucleotide comprising the S-isomer of thymidine glycol nucleic acid (GNA), a nucleotide comprising 2-hydroxymethyltetrahydrofuran-5-phosphate, a nucleotide comprising 2'-deoxythymidine-3'-phosphate, a nucleotide comprising 2'-deoxyguanosine 3'-phosphate and a terminal nucleotide linked to a cholesteryl derivative and a bisdecylamidine group of dodecanoic acid; and combinations thereof.
[00034] In one embodiment, the modified nucleotide of the dsRNA agent is selected from the group consisting of a nucleotide Petition 870260076339, dated 07 / 30 / 2026, page 27 / 2173 16 / 505 modified with 2'-deoxy-2'-fluorine, a nucleotide modified with 2'-deoxy, 3'-terminal deoxythymidine (dT) nucleotides, a blocking nucleotide, an abasic nucleotide, a nucleotide modified with 2'-amino, a nucleotide modified with 2'-alkyl, a morpholino nucleotide, a phosphoramidate and a nucleotide comprising an unnatural base.
[00035] In one embodiment, the modified dsRNA nucleotide comprises a short sequence of 3'-terminal deoxythymidine (dT) nucleotides.
[00036] In one embodiment, the nucleotide modifications of the dsRNA agent are modifications with 2'-O-methyl, GNA, and 2'-fluorine.
[00037] In some embodiments, the dsRNA agent further comprises at least one linkage between the phosphorothioate nucleotides.
[00038] In one embodiment, the dsRNA agent comprises 6-8 linkages between phosphorothioate nucleotides.
[00039] In one embodiment, each strand of dsRNA is no more than 30 nucleotides long.
[00040] In one embodiment, at least one strand of the dsRNA agent comprises a 3' projection of at least 1 nucleotide. In another embodiment, at least one strand of the dsRNA agent comprises a 3' projection of at least 2 nucleotides.
[00041] In some embodiments, the double-stranded region of the dsRNA agent may be 15-30 nucleotide pairs long; 17-23 nucleotide pairs long; 17-25 nucleotide pairs long; 23-27 nucleotide pairs long; 19-21 nucleotide pairs long; or 21-23 nucleotide pairs long.
[00042] In some embodiments, each strand of dsRNA may have 1930 nucleotides; 19-23 nucleotides; or 21-23 nucleotides.
[00043] In one embodiment, one or more lipophilic parts are Petition 870260076339, dated 07 / 30 / 2026, page 28 / 2173 17 / 505 coupled with one or more internal positions on at least one tape, such as by means of a binder or carrier.
[00044] In one embodiment, the internal positions include all positions except the two terminal positions at each end of at least one tape.
[00045] In another embodiment, the internal positions include all positions except the three terminal positions at each end of at least one tape.
[00046] In one embodiment, the internal positions exclude a region of the cleavage site of the sense strand.
[00047] In one embodiment, the internal positions include all positions except positions 9-12, counting from the 5' end of the sense tape.
[00048] In another embodiment, the internal positions include all positions except positions 11-13, counting from the 3' end of the sense tape.
[00049] In one embodiment, the internal positions exclude a region of the cleavage site of the antisense ribbon.
[00050] In one embodiment, the internal positions include all positions except positions 12-14, counting from the 5' end of the antisense tape.
[00051] In one embodiment, the internal positions include all positions except positions 11-13 on the sense tape, counting from the 3' end, and positions 12-14 on the non-sense tape, counting from the 5' end.
[00052] In one embodiment, one or more lipophilic parts are conjugated with one or more of the internal positions selected from the group consisting of positions 4-8 and 13-18 on the sense strip and positions 6-10 and 15-18 on the antisense strip, counting from the 5' end of each strip. Petition 870260076339, dated 07 / 30 / 2026, page 29 / 2173 18 / 505
[00053] In another embodiment, one or more lipophilic parts are conjugated with one or more of the internal positions selected from the group consisting of positions 5, 6, 7, 15 and 17 on the sense strip and positions 15 and 17 on the antisense strip, counting from the 5' end of each strip.
[00054] In one embodiment, internal positions in the double-strand region exclude a region of the sense strand cleavage site.
[00055] In one embodiment, the sense strand is 21 nucleotides long, the antisense strand is 23 nucleotides long, and the lipophilic portion is conjugated to position 21, position 20, position 15, position 1, position 7, position 6, or position 2 of the sense strand or position 16 of the antisense strand.
[00056] In one embodiment, the lipophilic portion is conjugated with position 21, position 20, position 15, position 1, or position 7 of the sense strip.
[00057] In another embodiment, the lipophilic portion is conjugated with position 21, position 20, or position 15 of the sense strip.
[00058] In yet another embodiment, the lipophilic portion is conjugated with position 20 or position 15 of the sense strip.
[00059] In one embodiment, the lipophilic portion is conjugated to position 16 of the antisense strip.
[00060] In one embodiment, the lipophilic part is an aliphatic, alicyclic, or polyalicyclic compound.
[00061] In one embodiment, the lipophilic moiety is selected from the group consisting of lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexianol, hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3-(oleoyl)cholenic acid, dimethoxytritil or phenoxazine. Petition 870260076339, dated 07 / 30 / 2026, page 30 / 2173 19 / 505
[00062] In one embodiment, the lipophilic moiety contains a saturated or unsaturated C4-C30 hydrocarbon chain, and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne.
[00063] In one embodiment, the lipophilic moiety contains a saturated or unsaturated C6-C18 hydrocarbon chain.
[00064] In one embodiment, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain.
[00065] In one embodiment, the saturated or unsaturated C16 hydrocarbon chain is conjugated at position 6, counting from the 5' end of the ribbon.
[00066] In one embodiment, the lipophilic moiety is conjugated by means of a carrier that replaces one or more nucleotides at the internal position(s) or in the double-strand region.
[00067] In one embodiment, the carrier is a cyclic group selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3] dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl and decalinyl; or it is an acyclic moiety based on a serinol backbone or a diethanolamine backbone.
[00068] In one embodiment, the lipophilic moiety is conjugated to the double-stranded RNA agent by means of a ligand containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide, a product of a click reaction, or carbamate linkage.
[00069] In one embodiment, the lipophilic moiety is conjugated with a nucleobase (nitrogenous base), sugar moiety, or linkage between nucleosides.
[00070] In one embodiment, the lipophilic portion or the ligand of Petition 870260076339, dated 07 / 30 / 2026, page 31 / 2173 20 / 505 targeting is conjugated by means of a bioligand selected from the group consisting of DNA, RNA, disulfide, amide, monosaccharides or functionalized oligosaccharides of galactosamine, glucosamine, glucose, galactose, mannose and their combinations.
[00071] In one embodiment, the 3' end of the sense strip is protected by means of an end protection which is a cyclic group having an amine, said cyclic group being selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3] dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl and decalinyl.
[00072] In one embodiment, the dsRNA agent further comprises a targeting ligand that targets a neuronal cell.
[00073] In one embodiment, the dsRNA agent further comprises a targeting ligand that targets a liver cell.
[00074] In one embodiment, the targeting ligand is a GalNAc conjugate.
[00075] In one embodiment, the dsRNA agent further comprises a terminal chiral modification that occurs at the first nucleotide linkage at the 3' end of the antisense strand, having the linking phosphorus atom in the Sp configuration, a terminal chiral modification that occurs at the first nucleotide linkage at the 5' end of the antisense strand, having the linking phosphorus atom in the Rp configuration, and a terminal chiral modification that occurs at the first nucleotide linkage at the 5' end of the sense strand, having the linking phosphorus atom in the Rp or Sp configuration.
[00076] In another embodiment, the dsRNA agent further comprises a terminal chiral modification that occurs in the first and second nucleotide linkages at the 3' end of the antisense strand, having the linking phosphorus atom in the sp configuration, a Petition 870260076339, dated 07 / 30 / 2026, page 32 / 2173 21 / 505 terminal chiral modification that occurs in the first bond between nucleotides at the 5' end of the antisense strand, having the linking phosphorus atom in the Rp configuration, and a terminal chiral modification that occurs in the first bond between nucleotides at the 5' end of the sense strand, having the linking phosphorus atom in the Rp or Sp configuration.
[00077] In yet another embodiment, the dsRNA agent further comprises a terminal chiral modification that occurs at the first, second, and third nucleotide linkages at the 3' end of the antisense strand, having the linking phosphorus atom in the Sp configuration, a terminal chiral modification that occurs at the first nucleotide linkage at the 5' end of the antisense strand, having the linking phosphorus atom in the Rp configuration, and a terminal chiral modification that occurs at the first nucleotide linkage at the 5' end of the sense strand, having the linking phosphorus atom in the Rp or Sp configuration.
[00078] In another embodiment, the dsRNA agent further comprises a terminal chiral modification that occurs at the first and second nucleotide linkages at the 3' end of the antisense strand, having the linking phosphorus atom in the Sp configuration, a terminal chiral modification that occurs at the third nucleotide linkages at the 3' end of the antisense strand, having the linking phosphorus atom in the Rp configuration, a terminal chiral modification that occurs at the first nucleotide linkage at the 5' end of the antisense strand, having the linking phosphorus atom in the Rp configuration, and a terminal chiral modification that occurs at the first nucleotide linkage at the 5' end of the sense strand, having the linking phosphorus atom in the Rp or Sp configuration.
[00079] In another embodiment, the dsRNA agent further comprises a terminal chiral modification that occurs in the first and in Petition 870260076339, dated 07 / 30 / 2026, page 33 / 2173 22 / 505 second bonds between nucleotides at the 3' end of the antisense strand, with the linking phosphorus atom in the sp configuration, a terminal chiral modification that occurs in the first and second bonds between nucleotides at the 5' end of the antisense strand, with the linking phosphorus atom in the rp configuration, and a terminal chiral modification that occurs in the first bond between nucleotides at the 5' end of the sense strand, with the linking phosphorus atom in the rp or sp configuration.
[00080] In one embodiment, the dsRNA agent further comprises a phosphate or phosphate mimic at the 5' end of the antisense strand.
[00081] In one embodiment, the phosphate mimic is a 5'-vinyl phosphonate (VP).
[00082] In one embodiment, the base pair at position 1 of the 5' end of the duplex antisense tape is an AU base pair.
[00083] In one embodiment, the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides.
[00084] The present invention also provides cells and pharmaceutical compositions comprising a dsRNA agent of the invention and a lipid formulation.
[00085] The present invention also provides pharmaceutical compositions for inhibiting the expression of a gene encoding MAPT comprising a dsRNA agent of the invention.
[00086] The present invention also provides pharmaceutical compositions for the selective inhibition of MAPT transcripts containing exon 10 comprising a dsRNA agent of the invention.
[00087] In one embodiment, the dsRNA agent is in an unbuffered solution, such as a saline solution or water.
[00088] In another embodiment, the dsRNA agent is in a buffer solution, such as a buffer solution comprising acetate, citrate, prolamine, carbonate or phosphate or any combination thereof. Petition 870260076339, dated 07 / 30 / 2026, page 34 / 2173 23 / 505 of them; or phosphate-buffered saline (PBS).
[00089] In one aspect, the present invention provides a method of inhibiting the expression of a MAPT gene in a cell, the method comprising contacting the cell with a dsRNA agent of the invention, or a pharmaceutical composition of the invention, thereby inhibiting the expression of the MAPT gene in the cell.
[00090] In another aspect, the present invention provides a method comprising the selective inhibition of MAPT transcripts containing exon 10 in a cell, the method comprising contacting the cell with a dsRNA agent of the invention, or a pharmaceutical composition of the invention, thereby selectively degrading MAPT transcripts containing exon 10 in the cell.
[00091] In one form, the cell is inside an individual.
[00092] In one modality, the individual is a human being.
[00093] In one modality, the individual has a disorder associated with MAPT.
[00094] In one modality, the individual has a disorder associated with MAPT that is a neurodegenerative disorder.
[00095] In one form, the individual's neurodegenerative disorder is associated with an abnormality of the Tau protein encoded by the MAPT gene.
[00096] In one embodiment, the abnormality of the Tau protein encoded by the MAPT gene results in the aggregation of Tau in the individual's brain.
[00097] In one modality, the neurodegenerative disorder is a familial disorder.
[00098] In one modality, the neurodegenerative disorder is a sporadic disorder.
[00099] In one modality, the disorder associated with MAPT is selected from the group consisting of tauopathy, disease of Petition 870260076339, dated 07 / 30 / 2026, page 35 / 2173 24 / 505 Alzheimer's disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), semantic primary progressive aphasia (S-PPA), logopenic primary progressive aphasia (L-PPA), frontotemporal dementia with chromosome 17-linked parkinsonism (FTDP-17), Pick's disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle dementia (NFT), FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson's disease, Parkinsonism Post-encephalitic syndrome, Niemann-Pick disease, Huntington's disease, myotonic dystrophy type 1, and Down syndrome (DS). [000100] In some embodiments, cell contact with the dsRNA agent inhibits MAPT expression by at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%, relative to control levels. In one embodiment, the dsRNA agent inhibits MAPT expression by at least about 25%. [000101] In some embodiments, inhibition of MAPT expression decreases serum Tau protein levels in the individual by at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%, relative to control levels. In one embodiment, the dsRNA agent decreases serum Tau protein levels in the individual by at least about 25%. Petition 870260076339, dated 07 / 30 / 2026, page 36 / 2173 25 / 505 [000102] In one aspect, the present invention provides a method of treating an individual with a disorder that would benefit from reduced MAPT expression, comprising administering to the individual a therapeutically effective amount of a dsRNA agent of the invention, or a pharmaceutical composition of the invention, thereby treating the individual with the disorder that would benefit from reduced MAPT expression. [000103] In another aspect, the present invention provides a method of preventing at least one symptom in an individual with a disorder that would benefit from reduced MAPT expression, comprising administering to the individual a prophylactically effective amount of a dsRNA agent of the invention, or a pharmaceutical composition of the invention, thereby preventing at least one symptom in the individual with the disorder that would benefit from reduced MAPT expression. [000104] In one modality, the disorder is a disorder associated with MAPT. [000105] In one form, the disorder is associated with an abnormality of the Tau protein encoded by the MAPT gene. [000106] In one embodiment, the abnormality of the Tau protein encoded by the MAPT gene results in the aggregation of Tau in the individual's brain. [000107] In one embodiment, the disorder associated with MAPT is selected from the group consisting of tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), semantic primary progressive aphasia (PPA-S), logopenic primary progressive aphasia (PPA-L), frontotemporal dementia with chromosome 17-linked parkinsonism (FTDP-17), Pick's disease (PiD), argyrophilic grain disease (AGD), multiple tauopathy Petition 870260076339, dated 07 / 30 / 2026, page 37 / 2173 26 / 505 systems with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle dementia (NFT), FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson's disease, postencephalitic parkinsonism, Niemann-Pick disease, Huntington's disease, myotonic dystrophy type 1, and Down syndrome (DS). [000108] In one modality, the individual is a human being. [000109] In one embodiment, administration of the dsRNA agent of the invention, or of the pharmaceutical composition of the invention, causes a decrease in Tau aggregation in the brain of the individual. [000110] In one embodiment, administering the agent to the individual causes a decrease in the accumulation of Tau. [000111] In one embodiment, the dsRNA agent is administered to the individual at a dose of approximately 0.01 mg / kg to approximately 50 mg / kg. [000112] In another modality, the dsRNA agent is administered to the individual intrathecally. [000113] In yet another embodiment, the dsRNA agent is administered to the individual intracisternally. An illustrative, non-limiting example of intracisternal administration comprises an injection into the cisterna magna (cerebellar medullary cistern) via suboccipital puncture. [000114] In one embodiment, the methods of the invention further comprise determining the MAPT level in (one) sample(s) from the individual. [000115] In one embodiment, the MAPT level in the individual's sample(s) is a level of Tau protein in (a) sample(s) of blood, serum, or cerebrospinal fluid. [000116] In one embodiment, the methods of the invention further comprise administering a therapeutic agent to the individual. Petition 870260076339, dated 07 / 30 / 2026, p. 38 / 2173 27 / 505 additional. [000117] In one aspect, the present invention provides a kit comprising a dsRNA agent of the invention or a pharmaceutical composition of the invention. [000118] In another aspect, the present invention provides a vial comprising a dsRNA agent of the invention or a pharmaceutical composition of the invention. [000119] In yet another aspect, the present invention provides a syringe comprising a dsRNA agent of the invention or a pharmaceutical composition of the invention. [000120] In another aspect, the present invention provides an intrathecal pump comprising a dsRNA agent of the invention or a pharmaceutical composition of the invention. BRIEF SUMMARY OF THE FIGURES [000121] FIG. 1 shows AAV screening in the liver to determine the effect of RNAi compositions on MAPT expression. The vertical axis indicates human MAPT expression in mice dosed with RNAi compositions relative to MAPT expression levels in mice dosed with PBS. [000122] FIG. 2 shows liver AAV screening to determine the effect of selected dsRNA agents in Tables 25-26 on the level of foci containing both sense and antisense in mice expressing human MAPT RNAs. The vertical axis indicates human MAPT expression in mice dosed with RNAi compositions relative to MAPT expression levels in mice dosed with PBS. [000123] FIG. 3 shows AAV screening in the liver to determine the effect of the dsRNA agents selected in Tables 25-26 on the level of foci containing both sense and antisense in mice expressing human MAPT RNAs. The vertical axis Petition 870260076339, dated 07 / 30 / 2026, page 39 / 2173 28 / 505 indicates the expression of human MAPT in mice dosed with RNAi compositions relative to MAPT expression levels in mice dosed with PBS. DETAILED DESCRIPTION OF THE INVENTION [000124] The present invention provides RNAi compositions that affect RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a MAPT gene. The MAPT gene may be located within a cell, for example, a cell within an individual, such as a human being. The use of these iRNAs allows for targeted degradation of mRNAs of the corresponding gene (MAPT gene) in mammals. [000125] The iRNAs of the invention were designed to target a MAPT gene, for example, a MAPT gene with or without nucleotide modifications. The iRNAs of the invention inhibit the expression of the MAPT gene by at least about 25% and reduce the level of sense- and antisense-containing foci. Without intending to be limited by theory, it is believed that a combination or subcombination of the foregoing properties and specific target sites, or specific modifications in these iRNAs, confers on the iRNAs of the invention improved efficacy, stability, potency, durability, and safety. [000126] Consequently, the present invention also provides methods of using the RNAi compositions of the invention to inhibit the expression of a MAPT gene or to treat an individual with a disorder that would benefit from the inhibition or reduction of the expression of a MAPT gene, for example, a MAPT-associated disease, for example, Alzheimer's disease, FTD, PSP or other tauopathy. [000127] The RNAi agents of the invention include an RNA strand (the antisense strand) having a region that is about 30 nucleotides or less in length, for example, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, Petition 870260076339, dated 07 / 30 / 2026, p. 40 / 2173 29 / 505 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23 or 21-22 nucleotides in length, the region of which is substantially complementary to at least part of an mRNA transcript of a MAPT gene, for example, an exon of MAPT. In certain embodiments, the RNAi agents of the invention include an RNA strand (the antisense strand) having a region that is about 21-23 nucleotides in length, the region of which is substantially complementary to at least part of an mRNA transcript of a MAPT gene. [000128] In certain embodiments, the RNAi agents of the invention include an RNA strand (the antisense strand) that may include longer lengths, for example, up to 66 nucleotides, for example, 36-66, 26-36, 25-36, 31-60, 22-43, 27-53 nucleotides in length with a region of at least 19 contiguous nucleotides that is substantially complementary to at least a portion of an mRNA transcript of a MAPT gene. These RNAi agents with the longer antisense strands preferably include a second RNA strand (the sense strand) of 20-60 nucleotides in length, wherein the sense and antisense strands form a duplex of 18-30 contiguous nucleotides. [000129] The use of these RNAi agents allows for the targeted degradation and / or inhibition of mRNAs of a MAPT gene in mammals. Thus, methods and compositions that include these RNAi agents are useful for treating an individual who would benefit from a reduction in the levels or activity of a Tau, such as an individual with a disease associated with MAPT, such as Alzheimer's disease, FTD, PSP, or another tauopathy. [000130] The following detailed description explains how to prepare and use Petition 870260076339, dated 07 / 30 / 2026, p. 41 / 2173 30 / 505 compositions containing RNAi agents to inhibit the expression of a MAPT gene, as well as compositions and methods for treating individuals with diseases and disorders that would benefit from the inhibition or reduction of gene expression. I. Definitions [000131] In order for the present invention to be more easily understood, certain terms are defined first. Furthermore, it should be noted that whenever a value or range of values of a parameter is described, it is intended that the values and ranges intermediate to the described values also form part of this invention. [000132] The articles "um" and "uma" are used in this document to refer to one or more of (i.e., at least one) of the grammatical object of the article. For example, "um elemento" means one element or more than one element, for example, a plurality of elements. [000133] The term including is used in this document to mean, and is used interchangeably with, the phrase including, but not limited to. The term or is used in this document to mean, and is used interchangeably with, the term and / or, unless the context clearly indicates otherwise. [000134] The term "approximately" is used in this document to mean within typical tolerance ranges in the art. For example, "approximately" can be understood as approximately 2 standard deviations from the mean. In certain embodiments, "approximately" means ±10%. In certain embodiments, "approximately" means ±5%. When "approximately" is present before a series of numbers or a range, it is understood that "approximately" can modify each of the numbers in the series or range. [000135] The term "at least" before a number or series of numbers is understood as including the number adjacent to the term "at least" and all subsequent numbers or integers that Petition 870260076339, dated 07 / 30 / 2026, p. 42 / 2173 31 / 505 could logically be included, as is evident from the context. For example, the number of nucleotides in a nucleic acid molecule must be a whole number. For example, at least 18 nucleotides in a 21-nucleotide nucleic acid molecule means that 18, 19, 20, or 21 nucleotides have the indicated property. When "at least" is present before a series of numbers or a range, it is understood that "at least" can modify each of the numbers in the series or range. [000136] As used in this document, "no more than" or "less than" is understood to mean the value adjacent to the phrase and the smaller logical integer values or numbers, as logical from the context, down to zero. For example, a duplex with a projection of no more than 2 nucleotides has a projection of 2, 1, or 0 nucleotides. When "no more than" is present before a series of numbers or a range, it is understood that no more than can modify each of the numbers in the series or range. [000137] As used in this document, the term "at least about," when referring to a measurable value, such as a parameter, a quantity, and the like, shall encompass variations of + / -20%, preferably + / -10%, more preferably + / -5%, and even more preferably + / -1% of the specified value, to the extent that such variations are appropriate to realize in the invention described. For example, inhibition of MAPT gene expression by at least about 25% means that the inhibition of MAPT gene expression can be measured as any value + / -20% of the specified 25%, i.e., 20%, 30%, or any intermediate value between 20-30%. [000138] As used in this document, the control level refers to the expression levels of a gene or the expression level of an RNA molecule or the expression level of one or more proteins or protein subunits in a cell, tissue, or non-cell. Petition 870260076339, dated 07 / 30 / 2026, p. 43 / 2173 32 / 505 modulated or in a system identical to the cell, tissue, or system where the RNAi agents described herein are expressed. The cell, tissue, or system where the RNAi agents are expressed has at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 2-fold, 3-fold, 4-fold, 5-fold or more expression of the gene, RNA, and / or protein described above than that observed in the absence of the RNAi agent. The % difference and / or the number of times difference can be calculated relative to control levels, for example, [expression with RNAi agent - expression without RNAi agent] % difference =------------------------------------------------------------------------------------------ X 100 expression without RNAi agent [000139] As used in this document, detection methods may include determining that the amount of analyte present is below the detection level of the method. [000140] In the event of a conflict between a specified target site and the nucleotide sequence for a sense or antisense strand, the specified sequence takes precedence. [000141] In the event of a conflict between a chemical structure and a chemical name, the chemical structure takes precedence. [000142] The term MAPT gene, also known as DDPAC, FTDP-17, MAPTL, MSTD, MTBT1, MTBT2, PPND, PPP1R103, TAU and microtubule-associated tau protein, refers to the gene that codes for a protein called microtubule-associated tau protein (MAPT). [000143] MAPT mRNA is expressed throughout the body, predominantly in the central nervous system (i.e., the brain and spinal cord) and the peripheral nervous system. Wild-type Tau is Petition 870260076339, dated 07 / 30 / 2026, page 44 / 2173 33 / 505 involved in stabilizing microtubules in neuronal axons, regulating axonal transport and microtubule dynamics, maintaining dendritic spines, and contributing to the integrity of genomic DNA. [000144] Tauopathies are a heterogeneous class of progressive neurodegenerative disorders, pathologically characterized by the presence of Tau aggregates in the brain. Intra- and extracellular neuronal Tau aggregates cause microtubule separation and axonal degeneration, impaired synaptic vesicle release, and the dissemination of tau aggregates among prion-like neurons, called seeding. [000145] Phenotypically, tauopathies exhibit variable progression of motor, cognitive, and behavioral deterioration. Tauopathies include, but are not limited to, Alzheimer's disease, the most common form of presenile dementia that begins primarily with selective memory deterioration and is associated with degeneration of the frontal lobe, temporal lobe (including hippocampus), and parietal lobe of the brain; frontotemporal dementia (FTD), the second most common form of presenile dementia associated with neuronal atrophy of the frontal and temporal lobes, exhibiting a spectrum of behavioral, language, and movement disorders; and progressive supranuclear palsy (PSP), degeneration of the brainstem and basal ganglia, exhibiting gaze dysfunction, extrapyramidal symptoms (parkinsonian symptoms, including limb apraxia, akinesia / bradykinesia, rigidity, and dystonia), and cognitive dysfunction, affecting approximately 20,000 people in the United States. [000146] FTD also includes, but is not limited to, behavioral variant frontotemporal dementia (bvFTD), pathologically associated with progressive atrophy in the prefrontal and anterior temporal lobes, and clinically with alterations in complex thinking, personality and Petition 870260076339, dated 07 / 30 / 2026, page 45 / 2173 34 / 505 behavior, affecting approximately 30,000 people in the United States; primary progressive aphasia - semantic (PPA-S), degeneration of the frontal and temporal lobes associated with difficulty understanding words and effort with names; primary progressive aphasia non-fluent variant (nfvPPA), involving degeneration of the left postfrontal lobe and insula, and exhibiting poor grammar and inability to understand complex sentences, affecting approximately 1,000 people.000 people in the United States; primary progressive aphasia - logopenic (APP-L), degeneration of the left post / calcarine temporal lobe and medial parietal lobe, associated with difficulty retrieving words and frequent pauses; frontotemporal dementia with chromosome 17-linked parkinsonism (FTDP-17), pathologically associated with degeneration of the frontal and temporal lobes and clinically with deterioration of speech and movement; Pick's disease (PiD), degeneration of the frontal and temporal lobes, associated with language and thought difficulties and behavioral changes; FTD with motor neuron disease, involving degeneration of the cortex and motor neurons; and corticobasal syndrome (CBS), degeneration of the posterior frontal and temporal lobes and basal ganglia [i.e., corticobasal degeneration (CBD)], exhibiting extrapyramidal symptoms (similar to those in Parkinson's disease and PSP) and cognitive dysfunction, affecting approximately 2,000 people in the United States.MAPT mutations are reported in approximately 10% of individuals with bvFTD, nfvPPA, CBS, and PSP, respectively. MAPT is an important component of neurofibrillary tangles in the neuronal cytoplasm, a distinctive feature in Alzheimer's disease. MAPT aggregation and deposition have also been observed in approximately 50% of the brains of individuals with Parkinson's disease. Tau involvement is indicated in the pathogenesis of other diseases, including, but not limited to, argyrophilic grain disease (AGD), multisystem tauopathy with pre-dementia. Petition 870260076339, dated 07 / 30 / 2026, page 46 / 2173 35 / 505 senile (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle dementia (NFT), FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), postencephalitic parkinsonism, Niemann-Pick disease, Huntington's disease, myotonic dystrophy type 1, and Down syndrome (DS). [000147] The MAPT gene consists of 16 exons (E1-E16). Alternative mRNA splicing of E2, E3, and E10 gives rise to six tau isoforms (352-441 amino acids). E1, E4, E5, E7, E9, E11, E12, and E13 are constitutively spliced exons. E6 and E8 are not transcribed in the human brain. E4a is expressed only in the peripheral nervous system. E0 (part of the promoter) and E14 are non-coding exons. [000148] Pathogenic variants in MAPT are found in approximately 10% of individuals with primary tauopathy. The variants are primarily equivocal senses and are located in exons 9-13 (microtubule-binding domains), with many affecting the alternative splicing of exon 10. Examples of coding region mutations include R5H and R5L in E1; K257T, I260V, L266V, G272V, and G273R in E9; N279K, L284L, ΔN296, N296N, N296H, ΔN298, P301L, P301S, P301T, G303V, G304S, S305I, S305N and S305S in E10; L315R, K317M, S320F, P332S in E11; G335S, G335V, Q336R, V337M, E342V, S352L, S356T, V363I, P364S, G366R, and K369I in E12; G389R, R406W, and T427M in E13 of the MAPT gene. MAPT (tau) null (- / -) humans are likely nonviable. MAPT heterozygous (+ / -) humans have obscure or unknown phenotypes. Humans with MAPT overexpression (+ / + / +) are associated with early-onset dementia, FTD, PSP, and CBD. [000149] Each of the six MAPT (tau) protein isoforms contains three or four repeat segments (R1, R2, R3, and R4) in its microtubule-binding domain. Each repeat has 31 or 32 Petition 870260076339, dated 07 / 30 / 2026, page 47 / 2173 36 / 505 amino acids in length. The splicing of E9, E10, E11, and E12 gives rise to R1, R2, R3, and R4, respectively, from the repeat segments in the microtubule-binding domain of MAPT. Three MAPT (tau) isoforms, in which E10 is inserted, contain four repeat segments (4R), while the other three MAPT isoforms, in which E10 is removed, contain three repeat segments (3R). [000150] The translation of E2 and E3 gives rise to segments N1 and N2, respectively. The alternative splicing of E2 and E3 gives rise to the tau isoforms 0N (E2 and E3 are removed, resulting in no N segments), 1N (E2 is inserted and E3 is removed, resulting in one N segment), and 2N (E2 and E3 are inserted, resulting in two N segments). Thus, the six MAPT(tau) isoforms resulting from the alternative splicing are 2N4R, 1N4R, 0N4R, 2N3R, 1N3R, and 0N3R. [000151] In healthy individuals, 3R and 4R MAPT transcript isoforms exist in a 1:1 ratio. The 3R / 4R isoform ratio is skewed in disease states, and the ratio predicts the type of tau aggregate. Aggregation of four-repeat tau into filaments is characteristic of PSP, CBD, argyrophilic grain disease (AGD), multisystem tauopathy with presarenile dementia (MSTD), and white matter tauopathy with globular glial inclusions (FTD with GGIs), which belong to the FTD spectrum (4R tauopathy). In contrast, in Pick's disease, three-repeat tau predominates in neuronal inclusions (3R tauopathy). In Alzheimer's disease, or other neurodegenerative diseases with neurofibrillary tangles (NFT dementia), both the three- and four-repeat tau isoforms compose the neurofibrillary lesions (3 / 4R tauopathy). FTLD with MAPT mutations can be 3R, 4R, or 3 / 4R tauopathy. [000152] FTD with motor neuron disease is associated with FTLD-TDP43 and FTLD-FUS pathology. It is associated with mutations Petition 870260076339, dated 07 / 30 / 2026, p. 48 / 2173 37 / 505 genetics of C9ORF72, FUS, TARDBP and VCP. [000153] bvFTD is associated with FTLD-Tau (3R) and FTLD-TDP43 pathology. Ten percent of cases involve the MAPT mutation. It is associated with the genetic mutations of C9ORF72, GRN, and VCP. [000154] PPA-S can be sporadic. It is associated with FTLD-TDP43 pathology. [000155] nfvPPA is associated with FTLD-Tau (4R) pathology, Alzheimer's disease, and FTLD-TDP43, in order of significance. Ten percent of cases involve the MAPT mutation. nfvPPA is also associated with GRN mutations. [000156] PPA-L can be sporadic. It is associated with Alzheimer's disease pathology and FTLD-Tau, in order of significance. [000157] CBS is associated with FTLD-Tau (4R) pathology and Alzheimer's disease, in order of significance. Ten percent of cases are associated with the MAPT mutation. The remaining cases may be sporadic. [000158] PSP involves FTLD-Tau (4R) pathology. Ten percent of cases are associated with the MAPT mutation. The remaining cases may be sporadic. [000159] Tauopathy generally begins between the ages of 60 and 80 and affects the remaining life expectancy by 6 to 10 years. Tauopathies are phenotypically heterogeneous, with varying degrees of motor, cognitive, and behavioral impairment. In particular, the progression of motor symptoms is variable. [000160] Currently, there are no approved disease-modifying therapies for tauopathies. Available treatments aim only to alleviate symptoms and improve the individual's quality of life as the disease progresses. Drugs in preclinical or clinical development include active and passive immunotherapies; inhibitors of O-deglycosylation, aggregation, kinases, acetylation, caspases or Petition 870260076339, dated 07 / 30 / 2026, page 49 / 2173 38 / 505 tau expression; phosphatase activators; microtubule stabilizers; and modulators of autophagy or proteosomal degradation. Biomarkers and tests used in clinical trials to assess tauopathy include threonine 181-phosphorylated tau protein (pTau), total tau protein (tTau), neurofilament light chain (NfL), and volumetric MRI (vMRI). [000161] Illustrative nucleotide and amino acid sequences of MAPT can be found, for example, in GenBank Accession No. NM_016841.4 (MAPT variant from Homo sapiens 4, SEQ ID NO: 1, reverse complement, SEQ ID NO: 2); GenBank Accession No. NM_005910 (MAPT variant from Homo sapiens 2, SEQ ID NO: 3, reverse complement, SEQ ID NO: 4); GenBank Accession No. NM_001038609.2 (MAPT from Mus musculus, SEQ ID NO: 5; reverse complement, SEQ ID NO: 6); GenBank Accession No.: XM_005584540.1 (MAPT variant from Macaca fascicularis X13, SEQ ID NO: 7, reverse complement, SEQ ID NO: 8); GenBank Accession Number: XM_008768277.2 (MAPT of Rattus norvegicus, variant X7, SEQ ID NO: 9, reverse complement, SEQ ID NO: 10) and GenBank Accession Number: XM_005624183.3 (MAPT variant of Canis lupus X23, SEQ ID NO: 11, reverse complement, SEQ ID NO: 12). [000162] The nucleotide sequence of the genomic region of the human chromosome that harbors the MAPT gene can be found, for example, in the Genome Reference Consortium Human Build 38 (also referred to as Human Genome build 38 or GRCh38), available in GenBank. The nucleotide sequence of the genomic region of human chromosome 17 that harbors the MAPT gene can also be found, for example, in GenBank Accession No. NC_000017.11, corresponding to nucleotides 45894382-46028334 of human chromosome 17. The nucleotide sequence of the human MAPT gene can be found, for example, in GenBank Accession No. NG_007398.2 Petition 870260076339, dated 07 / 30 / 2026, page 50 / 2173 39 / 505 [000163] Other examples of MAPT sequences can be found in publicly available databases, for example, GenBank, OMIM and UniProt. [000164] Additional information about MAPT can be found, for example, on the NCBI website which refers to gene 100128977. The term MAPT, as used in this document, also refers to variations of the MAPT gene, including variants provided in the clinical variant database, for example, on the NCBI clinical variant website which refers to the term mapt. [000165] All the content of each of the previous GenBank Accession Numbers and Genes database numbers is incorporated into this document by reference as of the filing date of this application. [000166] As used in this document, the target sequence refers to a contiguous portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a MAPT gene, including mRNA that is a product of RNA processing of a primary transcription product (e.g., MAPT mRNA resulting from alternative splicing). In one embodiment, the target portion of the sequence will be at least long enough to serve as a substrate for RNAi-directed cleavage at, or near, that portion of the nucleotide sequence of an mRNA molecule formed during the transcription of a MAPT gene. [000167] The target sequence is approximately 15-30 nucleotides long. For example, the target sequence could be approximately 15-30 nucleotides, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, Petition 870260076339, dated 07 / 30 / 2026, page 51 / 2173 40 / 505 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23 or 21-22 nucleotides in length. In certain embodiments, the target sequence is 19-23 nucleotides long, optionally 21-23 nucleotides long. Intermediate ranges and lengths between the ranges and lengths described above are also considered to be part of the invention. [000168] As used in this document, the term strand comprising a sequence refers to an oligonucleotide comprising a chain of nucleotides that is described by the sequence referred to, using standard nucleotide nomenclature. G, C, A, T, and U generally represent a nucleotide containing guanine, cytosine, adenine, thymidine, and uracil as a base, respectively, in the context of a modified or unmodified nucleotide. However, it will be understood that the term ribonucleotide or nucleotide may also refer to a modified nucleotide, as also detailed below, or a substituent moiety (see, for example, Table 1). Those skilled in the art are well aware that guanine, cytosine, adenine, thymidine, and uracil can be substituted for other moieties without substantially altering the base-pairing properties of an oligonucleotide comprising a nucleotide containing such a substitution moiety.For example, without limitation, a nucleotide comprising inosine as its base may base-pair with nucleotides containing adenine, cytosine, or uracil. Consequently, nucleotides containing uracil, guanine, or adenine may be substituted in the dsRNA nucleotide sequences presented in the invention by a nucleotide containing, for example, inosine. In another example, adenine and cytosine, anywhere in the oligonucleotide, may be substituted by guanine and uracil, respectively, to form the GU Wobble base-pairing with mRNA. Petition 870260076339, dated 07 / 30 / 2026, page 52 / 2173 41 / 505 target. Sequences containing such replacement parts are suitable for the compositions and methods presented in the invention. [000169] The terms RNAi, RNAi agent, RNA interference agent, RNA interference agent, as used interchangeably herein, refer to an agent containing RNA, as defined herein, that mediates the targeted cleavage of an RNA transcript via an RNA-induced silencing complex (RISC). RNA interference (RNAi) is a process that directs the degradation of a specific mRNA sequence. RNAi modulates, for example, inhibits, the expression of MAPT in a cell, for example, a cell within an individual, such as a mammalian individual. [000170] In one embodiment, an RNAi agent of the invention includes a single-stranded RNAi that interacts with a target RNA sequence, for example, a MAPT target mRNA sequence, to guide the cleavage of the target RNA. Without wanting to be limited by theory, it is believed that the long double-stranded RNA, introduced into cells, is broken down into short double-stranded interfering RNAs (siRNAs), comprising a sense strand and an antisense strand, by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease III type enzyme, processes this dsRNA into short interfering RNAs of 19-23 base pairs, with characteristic two-base 3' projections (Bernstein, et al., (2001) Nature 409:363). These siRNAs are then incorporated into an RNA-induced silencing complex (RISC), where one or more helicases unwind the siRNA duplex, allowing the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). After binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). So, in one aspect, the Petition 870260076339, dated 07 / 30 / 2026, p. 53 / 2173 42 / 505 The invention relates to a single-stranded RNA (ssRNA) (the antisense strand of an siRNA duplex) generated within a cell that promotes the formation of a RISC complex to effect the silencing of the target gene, i.e., a MAPT gene. Consequently, the term siRNA is also used in this document to refer to an RNAi as described above. [000171] In another embodiment, the RNAi agent may be a single-stranded RNA that is introduced into a cell or organism to inhibit a target mRNA. Single-stranded RNAi agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. Single-stranded siRNAs are generally 15-30 nucleotides long and are chemically modified. The design and testing of single-stranded RNAs are described in U.S. Patent No. 8,101,348 and in Lima et al., (2012) Cell 150:883894, the entire contents of each of which are hereby incorporated by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150:883-894. [000172] In another embodiment, an RNAi agent for use in the compositions and methods of the invention is a double-stranded RNA and is referred to herein as a double-stranded RNAi agent, double-stranded RNA (dsRNA) molecule, dsRNA agent, or dsRNA. The term dsRNA refers to a complex of ribonucleic acid molecules having a duplex structure comprising two antiparallel and substantially complementary nucleic acid strands, referred to as having sense and antisense orientations relative to a target RNA, i.e., a MAPT gene. In some embodiments of the invention, a double-stranded RNA (dsRNA) triggers the degradation of a target RNA, for example, an mRNA, through a mechanism of Petition 870260076339, dated 07 / 30 / 2026, p. 54 / 2173 43 / 505 post-transcriptional gene silencing, referred to in this document as RNA interference or RNAi. [000173] In general, a dsRNA molecule may include ribonucleotides, but, as described in detail in this document, each or both strands may also include one or more non-ribonucleotides, for example, a deoxyribonucleotide, a modified nucleotide. Furthermore, as used in this descriptive report, an RNAi agent may include ribonucleotides with chemical modifications; an RNAi agent may include substantial modifications in multiple nucleotides. As used in this document, the term modified nucleotide refers to a nucleotide having, independently, a modified sugar moiety, a modified nucleotide linkage, or a modified nucleobase. Thus, the term modified nucleotide encompasses substitutions, additions, or removal of, for example, a functional group or atom, in the nucleoside linkages, sugar moieties, or nucleobases.Suitable modifications for use in the agents of the invention include all types of modifications described herein or known in the art. Any such modifications, as used in an siRNA-type molecule, are covered by the RNAi agent for the purposes of this descriptive report and claims. [000174] In certain embodiments of the present invention, the inclusion of a deoxynucleotide, if present, within an RNAi agent may be considered as constituting a modified nucleotide. [000175] The duplex region can have any length that allows specific degradation of a desired target RNA via a RISC pathway and can vary from approximately 15-36 base pairs in length, for example, approximately 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36 base pairs in length, such as approximately 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15Petition 870260076339, dated 07 / 30 / 2026, page 55 / 2173 44 / 505 24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21- 30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23 or 21-22 base pairs of length. In certain embodiments, the duplex region has 1921 base pairs of length, for example, 21 base pairs of length. The bands and lengths intermediate to the bands and lengths described above are also considered to be part of the invention. [000176] The two strands that form the duplex structure may be different parts of a larger RNA molecule, or they may be separate RNA molecules. When the two strands are part of a larger molecule and are therefore linked by an unbroken chain of nucleotides between the 3' end of one strand and the 5' end of the other strand forming the duplex structure, the linking RNA strand is referred to as a hairpin loop. A hairpin loop may comprise at least one unpaired nucleotide. In some embodiments, the hairpin loop may comprise at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 23 or more unpaired nucleotides or nucleotides not oriented toward the dsRNA target site. In some embodiments, the hairpin loop may have 10 or fewer nucleotides. In some forms, the hairpin loop may have 8 or fewer unpaired nucleotides.In some embodiments, the hairpin loop may have 4-10 unpaired nucleotides. In some embodiments, the hairpin loop may have 4-8 nucleotides. [000177] When the two substantially complementary strands of a dsRNA are composed of separate RNA molecules, these molecules do not need to, but can, be covalently linked. Petition 870260076339, dated 07 / 30 / 2026, page 56 / 2173 45 / 505 In certain embodiments where the two strands are covalently linked by means other than an unbroken chain of nucleotides between the 3' end of one strand and the 5' end of the other strand forming the duplex structure, the linking structure is referred to as a linker (although it should be noted that certain other structures, defined elsewhere in this document, may also be referred to as a linker). RNA strands may have an equal or different number of nucleotides. The maximum number of base pairs is the number of nucleotides in the shorter dsRNA strand less any projections present in the duplex. In addition to the duplex structure, an RNAi may comprise one or more nucleotide projections. In one embodiment of the RNAi agent, at least one strand comprises a 3' projection of at least 1 nucleotide.In another embodiment, at least one strand comprises a 3' projection of at least 2 nucleotides, for example, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, or 15 nucleotides. In other embodiments, at least one strand of the RNAi agent comprises a 5' projection of at least 1 nucleotide. In certain embodiments, at least one strand comprises a 5' projection of at least 2 nucleotides, for example, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, or 15 nucleotides. Still in other embodiments, both the 3' and 5' ends of a strand of the RNAi agent comprise a projection of at least 1 nucleotide. [000178] In one embodiment, an RNAi agent of the invention is a dsRNA, each strand of which independently comprises 19-23 nucleotides, which interacts with a target RNA sequence, for example, a target mRNA sequence of MAPT, to direct the cleavage of the target RNA. [000179] In some embodiments, an iRNA of the invention is a 24-30 nucleotide dsRNA that interacts with a target RNA sequence, for example, a target mRNA sequence of MAPT, to Petition 870260076339, dated 07 / 30 / 2026, p. 57 / 2173 46 / 505 to guide the cleavage of the target RNA. [000180] As used in this document, the term nucleotide projection refers to at least one unpaired nucleotide projecting from the duplex structure of an RNAi agent, for example, a dsRNA. For example, when a 3' end of one strand of a dsRNA extends beyond the 5' end of the other strand, or vice versa, there is a nucleotide projection. A dsRNA may comprise a projection of at least one nucleotide; alternatively, the projection may comprise at least two nucleotides, at least three nucleotides, at least four nucleotides, at least five nucleotides, or more. A nucleotide projection may comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide / nucleoside. The projection(s) may be on the sense strand, the antisense strand, or any combination thereof.Furthermore, the nucleotide(s) of a projection may be present on the 5' end, the 3' end, or both ends of an antisense or sense strand of a dsRNA. [000181] In one embodiment, the antisense strand of a dsRNA has a projection of 1-10 nucleotides, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, at the 3' end or the 5' end. In another embodiment, the sense strand of a dsRNA has a projection of 1-10 nucleotides, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, at the 3' end or the 5' end. In another embodiment, one or more of the nucleotides in the projection are replaced by a thiophosphate nucleoside. [000182] In certain embodiments, the antisense strand of a dsRNA has a projection of 1-10 nucleotides, for example, 0-3, 1-3, 2-4, 2-5, 4-10, 5-10, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides, at the 3' end or at the 5' end. In one embodiment, the sense strand of a dsRNA has a projection of 1-10 nucleotides, for example, 1, Petition 870260076339, dated 07 / 30 / 2026, page 58 / 2173 47 / 505 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides, at the 3' end or at the 5' end. In another embodiment, one or more of the nucleotides in the projection are replaced by a thiophosphate nucleoside. [000183] In certain embodiments, the projection on the sense strand or the antisense strand may include extended lengths greater than 10 nucleotides, for example, 1-30 nucleotides, 2-30 nucleotides, 10-30 nucleotides, or 10-15 nucleotides in length. In certain embodiments, an extended projection is on the sense strand of the duplex. In certain embodiments, an extended projection is present on the 3' end of the sense strand of the duplex. In certain embodiments, an extended projection is present on the 5' end of the sense strand of the duplex. In certain embodiments, an extended projection is on the antisense strand of the duplex. In certain embodiments, an extended projection is present on the 3' end of the antisense strand of the duplex. In certain embodiments, an extended projection is present on the 5' end of the antisense strand of the duplex. In certain embodiments, one or more of the nucleotides in the projection are replaced by a thiophosphate nucleoside.In certain modalities, the projection includes a self-complementary part, so that the projection is able to form a hairpin structure that is stable under physiological conditions. [000184] The terms "untapped" or "untapped-terminated," as used in this document in reference to a dsRNA, mean that there are no unpaired nucleotides or nucleotide analogs at a given terminal end of a dsRNA, i.e., no nucleotide projection. One or both ends of a dsRNA may be untapped. When both ends of a dsRNA are untapped, the dsRNA is said to be untapped-terminated. To be clear, an untapped-terminated dsRNA is a dsRNA that is without the ends at both ends, i.e., without a nucleotide projection at either end of the molecule. In most cases Petition 870260076339, dated 07 / 30 / 2026, p. 59 / 2173 48 / 505 times, this molecule will be double-stranded along its entire length. [000185] The term antisense strand or guide strand refers to the strand of an RNAi agent, for example, a dsRNA, that includes a region that is substantially complementary to a target sequence, for example, a MAPT mRNA. [000186] As used in this document, the term complementarity region refers to the region on the antisense strand that is substantially complementary to a sequence, for example, a target sequence, for example, a MAPT nucleotide sequence, as defined in this document. Where the complementarity region is not fully complementary to the target sequence, mismatches may be in the internal or terminal regions of the molecule. In general, the most tolerated mismatches are in the terminal regions, for example, within 5, 4, 3, or 2 nucleotides of the 5' or 3' end of the RNAi agent. In some embodiments, a double-stranded RNA agent of the invention includes a mismatch of nucleotides in the antisense strand.In some embodiments, the antisense strand of the double-stranded RNA agent of the invention includes no more than 4 mismatches with the target mRNA, for example, the antisense strand includes 4, 3, 2, 1, or 0 mismatches with the target mRNA. In some embodiments, the double-stranded RNA agent of the antisense strand of the invention includes no more than 4 mismatches with the sense strand, for example, the antisense strand includes 4, 3, 2, 1, or 0 mismatches with the sense strand. In some embodiments, a double-stranded RNA agent of the invention includes a nucleotide mismatch in the sense strand. In some embodiments, the sense strand of the double-stranded RNA agent of the invention includes no more than 4 mismatches with the antisense strand, for example, the sense strand includes 4, 3, 2, 1, or 0 mismatches with the antisense strand. In some... Petition 870260076339, dated 07 / 30 / 2026, p. 60 / 2173 In 49 / 505 embodiments, the nucleotide mismatch is, for example, within 5, 4, or 3 nucleotides from the 3' end of the iRNA. In another embodiment, the nucleotide mismatch is, for example, at the 3' terminal nucleotide of the iRNA agent. In some embodiments, the mismatch(es) is / are not in the seed region. [000187] Thus, an RNAi agent as described herein may contain one or more mismatches with the target sequence. In one embodiment, an RNAi agent as described herein contains no more than 3 mismatches (i.e., 3, 2, 1, or 0 mismatches). In one embodiment, an RNAi agent as described herein contains no more than 2 mismatches. In one embodiment, an RNAi agent as described herein contains no more than 1 mismatch. In one embodiment, an RNAi agent as described herein contains 0 mismatches. In certain embodiments, if the antisense strand of the RNAi agent contains mismatches with the target sequence, the mismatch may optionally be restricted to be within the last 5 nucleotides of the 5' or 3' end of the complementarity region.For example, in such embodiments, for a 23-nucleotide RNAi agent, the strand that is complementary to a region of a MAP gene generally does not contain any mismatch within the central 13 nucleotides. The methods described in this document or methods known in the art can be used to determine whether an RNAi agent containing a mismatch with a target sequence is effective in inhibiting the expression of a MAPT gene. For example, Jackson et al. (Nat. Biotechnol. 2003;21: 635-637) described an expression profiling study where the expression of a small set of genes with sequence identity to the MAPK14 siRNA was analyzed. Petition 870260076339, dated 07 / 30 / 2026, page 61 / 2173 50 / 505 only in 12-18 nt of the sense strand, was negatively regulated with kinetics similar to MAPK14. Similarly, Lin et al., (Nucleic Acids Res. 2005; 33(14): 4527-4535), using qPCR and reporter assays, showed that a 7 nt complementation between an siRNA and a target is sufficient to cause mRNA target degradation. Consideration of the effectiveness of RNAi agents with mismatch pairings in inhibiting the expression of a MAPT gene is important, especially if the particular complementarity region in a MAPT gene is known to have polymorphic sequence variation within the population. [000188] As used in this document, substantially all nucleotides are modified, are largely, but not entirely, modified and may include no more than 5, 4, 3, 2 or 1 unmodified nucleotide. [000189] The term sense strand or passenger strand, as used herein, refers to the strand of an RNAi agent that includes a region that is substantially complementary to a region of the antisense strand, as that term is defined herein. [000190] As used in this document, the term cleavage region refers to a region that is located immediately adjacent to the cleavage site. The cleavage site is the site on the target where cleavage occurs. In some embodiments, the cleavage region comprises three bases on each end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage region comprises two bases on each end of, and immediately adjacent to, the cleavage site. In some embodiments, the cleavage site occurs specifically at the site bound by nucleotides 10 and 11 of the antisense strand, and the cleavage region comprises nucleotides 11, 12, and 13. [000191] As used in this document, and unless otherwise indicated. Petition 870260076339, dated 07 / 30 / 2026, page 62 / 2173 51 / 505 Conversely, the term complementary, when used to describe a first nucleotide sequence in relation to a second nucleotide sequence, refers to the ability of an oligonucleotide or polynucleotide comprising the first nucleotide sequence to hybridize and form a duplex structure, under certain conditions, with an oligonucleotide or polynucleotide comprising the second nucleotide sequence, as will be understood by those skilled in the art. Such conditions may be, for example, stringent conditions, including, but not limited to, 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50°C or 70°C for 12-16 hours, followed by washing (see, for example, Molecular Cloning: A Laboratory Manual, Sambrook, et al. (1989) Cold Spring Harbor Laboratory Press).As used in this document, stringent conditions or stringent hybridization conditions refer to the conditions under which an antisense compound will hybridize with its target sequence, but with a minimum number of other sequences. Stringent conditions are sequence-dependent and will differ under different circumstances, and the stringent conditions under which antisense compounds hybridize with a target sequence are determined by the nature and composition of the antisense compounds and the assays being investigated. Other conditions, such as physiologically relevant conditions as they may be found within an organism, may be applied. The expert will be able to determine the most appropriate set of conditions for a complementarity test of two sequences according to the final application of the hybridized nucleotides. [000192] Complementary sequences within an RNAi agent, for example, within a dsRNA as described in this document, include oligonucleotide or polynucleotide base pairing comprising a first nucleotide sequence with Petition 870260076339, dated 07 / 30 / 2026, page 63 / 2173 52 / 505 an oligonucleotide or polynucleotide comprising a second nucleotide sequence along the entire length of one or both nucleotide sequences. Such sequences may be referred to herein as fully complementary with respect to each other. However, where a first sequence is referred to herein as substantially complementary with respect to a second sequence, the two sequences may be fully complementary or may form one or more, but generally no more than 5, 4, 3 or 2, base pairs that are mismatched after hybridization to a duplex of up to 30 base pairs.In some embodiments, the substantially complementary sequences described herein comprise a contiguous nucleotide sequence that is at least about 80% complementary, along its entire length, to the equivalent region of the MAPT target sequence, such as about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% complementary. However, when two oligonucleotides are designed to form, after hybridization, one or more single-stranded projections, such projections should not be considered erroneous pairings with respect to the determination of complementarity.For example, a dsRNA comprising an oligonucleotide of 21 nucleotides in length and another oligonucleotide of 23 nucleotides in length, wherein the longer oligonucleotide comprises a 21-nucleotide sequence that is fully complementary to the shorter oligonucleotide, may still be referred to as fully complementary for the purposes described herein. [000193] The complementary sequences, as used in this document, may also include, or be formed entirely from, non-Watson-Crick base pairs or base pairs Petition 870260076339, dated 07 / 30 / 2026, page 64 / 2173 53 / 505 formed from non-natural and modified nucleotides, insofar as the above requirements regarding their ability to hybridize are met. Such non-Watson-Crick base pairs include, but are not limited to, Wobble or Hoogstein G:U base pairing. [000194] The terms complementary, fully complementary and substantially complementary contained herein may be used in relation to base pairing between the sense strand and the antisense strand of a dsRNA or between the antisense strand of an RNAi agent and a target sequence, as will be understood from the context of their use. [000195] As used in this document, a polynucleotide that is substantially complementary to at least part of a messenger RNA (mRNA) refers to a polynucleotide that is substantially complementary to a contiguous part of the mRNA of interest (e.g., an mRNA encoding Tau). For example, a polynucleotide is complementary to at least part of a MAPT mRNA if the sequence is substantially complementary to an unbroken part of an mRNA encoding Tau. [000196] Therefore, in some embodiments, the antisense polynucleotides described in this document are fully complementary to the MAPT target sequence. In other embodiments, the antisense polynucleotides described herein are substantially complementary to the MAPT target sequence and comprise a contiguous nucleotide sequence that is at least 80% complementary, along its entire length, to the equivalent nucleotide sequence region of any of the SEQ ID NOs: 1, 3, 5, 7, 9 and 11, or a fragment of any of the SEQ ID NOs: 1, 3, 5, 7, 9 and 11, as approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98% or approximately 99% complementary. Petition 870260076339, dated 07 / 30 / 2026, p. 65 / 2173 54 / 505 [000197] In some embodiments, the antisense polynucleotides described herein are substantially complementary to a fragment of a MAPT target sequence and comprise a contiguous nucleotide sequence that is at least 80% complementary, along its entire length, to a fragment of SEQ ID NO: 1 selected from the nucleotide group 977-997, 980-1000, 973-993, 988-1008, 987-1007, 972-992, 979-999, 1001-1021, 976-996, 994-1014, 1002-1022, 978-998, 974-994, 981-1001, 9951015, 1003-1023, 989-1009, 1031-1051, 975-995, 983-1003, 992-1012, 982-1002, 1236-1256, 1023-1043, 986-1006, 1014-1034, 1237-1257, 1030-1050, 997-1017, 1009-1029, 1013-1033, 1027-1047, 998-1018, 1026-1046, 1022-1042, 1065-1085, 1025-1045, 1017-1037, 1006-1026, 1000-1020, 984-1004, 1010-1030, 1064-1084, 1016-1036, 993-1013, 1033-1053, 971-991, 1008-1028, 1032-1052, 1015-1035, 1063-1083, 1020-1040, 985-1005, 999-1019, 1004-1024, 1024-1044, 1104-1124, 990-1010, 1005-1025, 1021-1041, 1028-1048, 996-1016, 1011-1031, 991-1011, 1018-1038, 1228-1248, 1230-1250, 1029-1049, 1019-1039, 1012-1032, 1062-1082, 1231-1251, 1229-1249, 1226-1246, 1227-1247, 975-997, 978-1000, 971-993, 986-1008, 985-1007, 977-999, 999-1021, 974-996, 992-1014, 1000-1022, 976-998, 972-994, 979-1001, 9931015, 1001-1023, 987-1009, 1029-1051, 973-995, 981-1003, 990-1012, 980-1002, 1234-1256, 1021-1043, 984-1006, 1012-1034, 1235-1257, 1028-1050, 995-1017, 1007-1029,1011-1033, 1025-1047, 996-1018, 1024-1046, 1020-1042, 1063-1085, 1023-1045, 1015-1037, 1004-1026, 998-1020, 982-1004, 1008-1030, 1062-1084, 1014-1036, 991-1013, 1031-1053, 1006-1028, 1030-1052, 1013-1035, 1018-1040, 983-1005, 997-1019, 1002-1024, 1022-1044, 988-1010, 1003-1025, 1019-1041, 1026-1048, 994-1016, 1009-1031, 989-1011, 1016-1038, 1226-1248, 1228-1250, 1027-1049, 1017-1039, 1010-1032 1229-1251, 1227-1249, 1224-1246 and 1225-1247 of SEQ ID NO: 1, such as about 85%, about Petition 870260076339, dated 07 / 30 / 2026, p. 66 / 2173 55 / 505 of 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98% or approximately 99% complementary. Intermediate ranges to the ranges described above are also considered to be part of the invention. [000198] In some embodiments, the antisense polynucleotides described herein are substantially complementary to a fragment of a MAPT target sequence and comprise a contiguous nucleotide sequence that is at least 80% complementary, along its entire length, to a fragment of SEQ ID NO: 1 selected from the nucleotide group 520-540, 521-541, 5464-5484, 1813-1833, 2378-2398, 3242-3262, 5442-5462, 1665-1685, 1816-1836, 4667-4687, 3183-3203, 3422-3442, 3326-3346, 2379-2399, 3338-3358, 5446-5466, 5440-5460, 5410-5430, 3246-3266, 3181-3201, 2297-2317, 2380-2400, 3328-3348, 5460-5480, 3184-3204, 3420-3440, 3321-3341, 4529-4549, 5473-5493, 5466-5486, 5439-5459, 5369-5389, 4528-4548, 3338-3358, 4670-4690, 3421-3441, 2298-2318, 5444-5464, 5448-5468, 3337-3357, 5415-5435, 3340-3360, 3318-3338, 5207-5227, 1812-1832, 5409-5429, 4629-4649, 4628-4648, 3344-3364, 1809-1829, 5443-5463, 3244-3264, 3180-3200, 3327-3347, 4522-4542, 2667-2687, 4668-4688, 4083-4103,5445-5465, 2294-2314, 4842-4862, 5438-5458, 4084-4104, 2668-2688, 4526-4546, 4521-4541, 5459-5479, 3188-3208, 5467-5487, 5441-5461, 4519-4539, 4669-4689, 5450-5470, 3341-3361, 5458-5478, 4520-4540, 4329-4349, 4525-4545, 4524-4544, 5208-5228 5305-5325, 4475-4495, 2666-2686, 4086-4106, 4523-4543, 4527-4547, 4085-4105, 5259-5279, 518-540, 519-541, 5462-5484, 1811-1833, 2376-2398, 3240-3262, 5440-5462, 1663-1685, 1814-1836, 4665-4687, 3181-3203, 3420-3442, 3324-3346, 2377-2399, 3336-3358 54445466, 5438-5460, 5408-5430, 3244-3266, 3179-3201, 2295-2317, 2378-2400, 3326-3348, 5458-5480, 3182-3204, 3418-3440, 3319-3341, 4527-4549, 5471-5493, 5464-5486, 5437-5459, 5367-5389, 4526-4548, 4668, Petition 870260076339, dated 07 / 30 / 2026, p. 67 / 2173 56 / 505 4690, 3419-3441, 2296-2318, 5442-5464, 5446-5468, 3335-3357, 5413-5435, 3338-3360, 3316-3338, 1810-1832, 5407-5429, 4627-4649, 4626-4648, 3342-3364, 1807-1829, 5441-5463, 3242-3264, 3178-3200, 3325-3347, 4520-4542, 2665-2687, 4666-4688, 4081-4103 5443-5465, 22922314, 4840-4862, 5436-5458, 4082-4104, 2666-2688, 4524-4546, 45194541, 5457-5479, 3186-3208, 5465-5487, 5439-5461, 4517-4539, 46674689, 5448-5470, 3339-3361, 5456-5478, 4518-4540, 4327-4349, 45234545, 4522-4544, 5206-5228, 5303-5325, 4473-4495, 2664-2686, 40844106, 4521-4543, 4525-4547, 4083-4105 and 5257-5279 of SEQ ID NO: 1, as approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98% or approximately 99% complementary. Intermediate ranges to the ranges described above are also considered to be part of the invention. [000199] In some embodiments, the antisense polynucleotides described herein are substantially complementary to a fragment of a MAPT target sequence and comprise a contiguous nucleotide sequence that is at least 80% complementary, along its entire length, to a fragment of SEQ ID NO: 1 selected from the nucleotide group 520-540, 524-544, 521-541, 5207-5227, 4670-4690, 3420-3440, 3328-3348, 1665-1685, 5409-5429, 5439-5459, 4527-4547, 5441-5461, 5410-5430, 5446-5466, 5467-5487, 5369-5389, 3421-3441, 5442-5462, 2379-2399, 47154735, 5464-5484, 3244-3264, 5440-5460, 1812-1832, 3181-3201, 33273347, 5448-5468, 4529-4549, 2378-2398, 4668-4688, 5438-5458, 54655485, 3326-3346, 3180-3200, 5458-5478, 3321-3341, 3338-3358, 3188-3208, 2294-2314, 4628-4648, 5415-5435, 5459-5479, 3184-3204, 2375-2395, 3422-3442, 3246-3266, 3337-3357, 2297-2317, 4528-4548, 318-33203, 5450-5470, 5444-5464, 5466-5486, 2380-2400, 3242-3262, 4520-4540, 5445-5465, 3318-33381816-1836, 5443-5463, 5460-5480, 4842, Petition 870260076339, dated 07 / 30 / 2026, p. 68 / 2173 57 / 505 4862, 3338-3358, 1809-1829, 3423-3443, 4720-4740, 5259-5279, 40844104, 1813-1833, 4522-4542, 4822-4842, 4523-4543, 2298-2318, 45214541,4086-4106, 4524-4544, 2668-2688, 4667-4687, 4083-4103, 40854105, 4629-4649, 4329-4349, 2667-2687, 4475-4495, 3344-3364, 46694689, 3340-3360, 4519-4539, 2666-2686, 5208-5228, 4526-4546, 45254545, 3341-3361, 518-540, 522-544, 519-541, 4668-4690, 3418-3440, 3326-3348, 1663-1685, 5407-5429, 5437-5459, 4525-4547, 5439-5461, 5408-5430, 5444-5466, 5465-5487, 5367-5389, 3419-3441, 5440-5462, 2377-2399, 4713-4735, 5462-5484, 3242-3264, 5438-5460, 1810-1832, 3179-3201, 3325-3347, 5446-5468, 4527-4549, 2376-2398, 4666-4688, 5436-5458, 5463-5485, 3324-3346, 3178-3200, 5456-5478, 3319-3341, 3336-3358, 3186-3208, 2292-2314, 4626-4648, 5413-5435, 5457-5479, 3182-3204, 2373-2395, 3420-3442, 3244-3266, 3335-3357, 2295-2317, 4526-4548, 3181-3203, 5448-5470, 5442-5464, 5464-5486, 2378-2400, 3240-3262, 4518-4540, 5443-5465, 3316-3338, 1814-1836, 5441-5463, 5458-5480,4840-4862, 1807-1829, 3421-3443, 4718-4740, 5257-5279, 4082-4104, 1811-1833, 4520-4542, 4820-4842, 4521-4543, 2296-2318, 4519-4541, 4084-4106, 4522-4544, 2666-2688, 4665-4687, 4081-4103, 4083-4105, 4627-4649, 4327-4349, 2665-2687, 4473-4495, 3342-3364, 4667-4689, 3338-3360, 4517-4539, 2664-2686, 5206-5228, 4524-4546, 4523-4545 and 3339-3361 of SEQ ID NO: 1, as approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98% or approximately 99% complementary. Intermediate ranges to the ranges described above are also considered to be part of the invention. [000200] In some embodiments, the antisense polynucleotides described in this document are substantially complementary to a fragment of a MAPT target sequence and comprise a contiguous nucleotide sequence that is at least 80% complementary, along its entire length, to a SEQ fragment. Petition 870260076339, dated 07 / 30 / 2026, p. 69 / 2173 58 / 505 ID NO: 1 selected from the nucleotide group 977-997, 9801000, 973-993, 988-1008, 987-1007, 972-992, 979-999, 1001-1021, 976-996, 994-1014, 1002-1022, 978-998, 974-994, 520-540, 521-541, 5464-5484, 1813-1833, 2378-2398, 3242-3262, 5442-5462, 1665-1685, 524-544, 5207-5227, 4670-4690, 3420-3440, 3328-3348, 5409-5429, 5439-5459, 4527-4547, 5441-5461, 5410-5430 and 5446-5466 of SEQ ID NO: 1, as approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98% or approximately 99% complementary. Intermediate ranges to the ranges described above are also considered to be part of the invention. [000201] In some embodiments, the antisense polynucleotides described herein are substantially complementary to a fragment of a MAPT target sequence and comprise a contiguous nucleotide sequence that is at least 80% complementary, along its entire length, to a fragment of SEQ ID NO: 3 selected from the nucleotide group 512-532, 513-533, 514-534, 515-535, 516-536, 517-537, 518-538, 519-539, 520-540, 1063-1083, 1067-1087, 1072-1092, 1074-1094, 1075-1095, 1125-1145, 1126-1146, 1127-1147, 1129-1149, 1170-1190, 1395-1415, 1905-1925, 1906-1926, 1909-1929, 1911-1931, 1912-1932, 1913-1933, 1914-1934, 1915-1935, 1916-1936, 1919-1939, 1951-1971, 1954-1974, 1958-1978, 2387-2407, 2409-2429, 2410-2430, 2469-2489, 2471-2491, 2472-2492, 2476-2496, 2477-2497, 2478-2498, 2480-2500, 2481-2501, 2482-2502, 2484-2504, 2762-2782, 2764-2784, 2766-2786, 2767-2787, 2768-2788, 2769-2789, 2819-2839, 2821-2841, 2828-2848, 2943-2963, 2944-2964, 2946-2966,2947-2967, 3252-3272, 3277-3297, 3280-3300, 3281-3301, 3282-3302, 3284-3304, 3285-3305, 3286-3306, 3331-3351, 3332-3352, 3333-3353, 3334-3354, 3335-3355, 3336-3356, 3338-3358, 3340-3360, 3342-3362, 3343-3363, 3344-3364, 3345-3365, 3346-3366, 3347-3367 Petition 870260076339, dated 07 / 30 / 2026, p. 70 / 2173 59 / 505 3349-3369, 3350-3370, 3353-3373, 3364-3384, 3366-3386, 3367-3387 3368-3388, 3369-3389, 3370-3390, 3412-3432, 3414-3434, 3415-3435, 3416-3436, 3417-3437, 3419-3439, 3420-3440, 3424-3444, 3425-3445, 3426-3446, 3427-3447, 3428-3448, 3429-3449, 3430-3450, 3431-3451, 3434-3454, 4132-4152, 4134-4154, 4179-4199, 4182-4202, 4184-4204, 4395-4415, 4425-4445, 4426-4446, 4429-4449, 4469-4489, 4470-4490, 4471-4491, 4472-4492, 4473-4493, 4474-4494, 4569-4589, 4571-4591, 4572-4592, 4596-4616, 4623-4643, 4721-4741, 4722-4742, 4725-4745, 4726-4746, 4766-4786, 4767-4787, 4768-4788, 4769-4789, 4770-4790, 4779-4799, 4805-4825, 4806-4826, 4807-4827, 4808-4828, 4809-4829, 4812-4832, 4813-4833, 4814-4834, 4936-4956, 5072-5092, 5073-5093, 5345-5365, 5346-5366, 5349-5369, 5350-5370, 5351-5371, 5460-5480, 5461-5481, 5463-5483, 5465-5485, 5467-5487, 5468-5488, 5469-5489, 5470-5490, 5471-5491, 5505-5525, 5506-5526, 5507-5527, 5508-5528, 5509-5529, 5511-5531, 5513-5533, 5514-5534, 5541-5561, 5544-5564, 5546-5566, 5547-5567, 5548-5568, 5550-5570, 5551-5571, 5574-5594, 5576-5596, 5614-5634, 521-541, 522-542, 523-543, 524-544, 525-545, 526-546, 527-547, 528-548, 529-549, 530-550, 531-551, 532-552, 533553, 534-554, 535-555, 536-556, 1034-1054, 1035-1055, 1036-1056, 1037-1057, 1038-1058, 1039-1059, 1040-1060, 1041-1061, 1042-1062, 1043-1063, 1044-1064, 1045-1065, 1046-1066, 1047-1067, 1048-1068, 1049-1069, 1050-1070, 1051-1071, 1052-1072, 1053-1073, 1054-1074, 1062-1082, 1064-1084, 1065-1085, 1066-1086, 1068-1088, 1069-1089, 1070-1090, 1071-1091, 1073-1093, 1076-1096, 1077-1097, 1078-1098, 1079-1099, 1080-1100, 1081-1101, 1082-1102, 1128-1148, 1129-1149, 1130-1150, 1131-1151, 1132-1152, 1133-1153, 1134-1154, 1135-1155, 1136-1156, 1137-1157, 1138-1158, 1139-1159, 1140-1160, 1141-1161, 1142-1162, 1143-1163, 1144-1164, 1145-1165, 1146-1166, 1147-1167, 1148-1168, 975-995, 976-996, 977-997, 978-998, 979-999, 980-1000, 981-1001, 982-1002, 983-1003, 984-1004, 985-1005, 986-1006, 987 Petition 870260076339, dated 07 / 30 / 2026, p. 71 / 2173 60 / 505 1007, 988-1008, 989-1009, 990-1010, 991-1011, 992-1012, 993-1013, 994-1014, 995-1015, 996-1016, 997-1017, 998-1018, 999-1019, 1000-1020, 1001-1021, 1002-1022, 1003-1023, 1004-1024, 1005-1025, 1006-1026, 1007-1027, 1008-1028, 1009-1029, 1010-1030, 1011-1031, 1012-1032, 1013-1033, 1014-1034, 1015-1035, 1016-1036, 1017-1037, 1018-1038, 1019-1039, 1020-1040, 1021-1041, 1022-1042, 1023-1043, 1024-1044, 1025-1045, 1026-1046, 1027-1047, 1028-1048, 1029-1049, 1030-1050, 1031-1051, 1032-1052 1033-1053, 1034-1054, 1035-1055, 1036-1056, 1037-1057, 1038-1058, 1039-1059, 1040-1060, 1041-1061, 1042-1062, 1043-1063 and 1045-1065 of SEQ ID NO: 3, as approximately 85%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98% or approximately 99% complementary. Intermediate ranges to the ranges described above are also considered to be part of the invention. [000202] In some modalities,The antisense polynucleotides described in this document are substantially complementary to a fragment of a MAPT target sequence and comprise a contiguous nucleotide sequence that is at least 80% complementary, along its entire length, to a fragment of SEQ ID NO: 5 selected from the nucleotide group 1065-1085, 1195-1215, 1066-1086, 1068-1088, 705-725, 1067-1087, 4520-4540, 3341-3361, 4515-4535, 5284-5304, 5285-5305, 344-364, 5283-5303, 5354-5374, 2459-2479. 1061-1081, 706-726, 972-992, 4564-4584, 995-1015, 4546-4566, 968-988, 1127-1147, 4534-4554, 158-178, 449-4514, 1691-1711, 3544-3564, 198-218, 979-999, 4548-4568, 4551-4571, 543-563, 715-735, 542-562, 352-372, 362-382, 4556-4576, 4547-4567 4542-4562, 4558-4578, 4549-4569, 5074-5094, 4552-4572, 50735093, 5076-5096, 4550-4570 and 2753-2773 of SEQ ID NO: 5, such as about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about, Petition 870260076339, dated 07 / 30 / 2026, p. 72 / 2173 61 / 505 of 98% or approximately 99% complementary. Intermediate ranges to the ranges described above are also considered to be part of the invention. [000203] In other embodiments, the antisense polynucleotides described herein are substantially complementary to the MAPT target sequence and comprise a contiguous nucleotide sequence that is at least about 80% complementary, along its entire length, to any of the sense strand nucleotide sequences in any of Tables 3-8, 12-13, and 16-28, or a fragment of any of the sense strand nucleotide sequences in any of Tables 3-8, 12-13, and 16-28, such as about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% complementary. [000204] In one embodiment, an RNAi agent of the invention includes a sense strand that is substantially complementary to an antisense polynucleotide which, in turn, is equal to a MAPT target sequence and wherein the sense strand polynucleotide comprises a contiguous nucleotide sequence that is at least about 80% complementary, along its entire length, to the equivalent nucleotide sequence region of SEQ ID NOs: 1, 3, 5, 7, 9 and 11, or a fragment of any of the SEQ ID NOs: 1, 3, 5, 7, 9 and 11, such as about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% complementary.In some embodiments, an iRNA of the invention includes a sense strand that is substantially complementary to an antisense polynucleotide which, in turn, is complementary to a MAPT target sequence, and wherein the sense strand polynucleotide comprises a contiguous nucleotide sequence that is at least about 80% complementary throughout its entire length. Petition 870260076339, dated 07 / 30 / 2026, p. 73 / 2173 62 / 505 length, to any of the nucleotide sequences of the antisense strand in any of Tables 3-8, 12-13 and 16-28, or a fragment of any of the nucleotide sequences of the antisense strand in any of Tables 3-8 and 16-28, such as about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or 100% complementary. 000205 AD-1019331.1, AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD523824.1, AD-523800.1, AD-523796.1, AD-523803.1, AD-523817.1, AD-523825.1, AD-523811.1, AD-523854.1, AD-523797.1,AD523805.1, AD-523814.1, AD-523804.1, AD-1019356.1, AD-523846.1, AD-523808.1, AD-523835.1, AD-1019357.1, AD-523853.1,AD523819.1, AD-523830.1, AD-523834.1, AD-523850.1, AD-523820.1, AD-523849.1, AD-523845.1, AD-393758.3, AD-523848.1,AD523840.1, AD-523828.1, AD-523822.1, AD-523806.1, AD-523831.1, AD-393757.1, AD-523839.1, AD-523815.1, AD-523856.1,AD1019330.1, AD-523829.1, AD-523855.1, AD-523836.1, AD-1019329.1, AD-523843.1, AD-523807.1, AD-523821.1, AD-523826.1,AD523847.1, AD-523786.1, AD-523812.1, AD-523827.1, AD-523844.1, AD-523851.1, AD-523818.1, AD-523832.1, AD-523813.1,AD523841.1, AD-1019352.1, AD-1019354.1, AD-523852.1, AD-523842.1, AD-523833.1, AD-1019328.1, AD-1019355.1, AD-1019353.1,AD1019350.1 and AD-1019351.1. In particular modes, the sense and antisense tapes are selected from any of the duplexes AD-523799.1, AD-523802.1, AD-523795.1, AD-523810.1, AD523809.1, AD-1019331.1, AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD-523824.1, AD-523800.1 and AD-523796.1. Petition 870260076339, dated 07 / 30 / 2026, page 74 / 2173 63 / 505 [000206] In certain modes, the sense and antisense tapes are selected from any of the duplexes AD-535094.1, AD535094.1, AD-535095.1, AD-538647.1, AD-535922.1, AD-536317.1, AD-536911.1, AD-538626.1, AD-535864.1, AD-535925.1, AD538012.1, AD-536872.1, AD-536954.1, AD-536964.1, AD-536318.1 AD-536976.1, AD-538630.1, AD-538624.1, AD-538594.1, AD536915.1, AD-536870.1, AD-536236.1, AD-536319.1, AD-536966.1 AD-538643.1, AD-536873.1, AD-536952.1, AD-536959.1, AD537921.1, AD-538652.1, AD-538649.1, AD-538623.1, AD-538573.1 AD-537920.1, AD-536939.1, AD-538015.1, AD-536953.1, AD536237.1, AD-538628.1, AD-538632.1, AD-536975.1, AD-538599.1 AD-536978.1, AD-536956.1, AD-538571.1, AD-535921.1, AD538593.1, AD-537974.1, AD-537973.1, AD-536982.1, AD-535918.1 AD-538627.1, AD-536913.1, AD-536869.1, AD-536965.1,AD537914.1, AD-536504.1, AD-538013.1, AD-537579.1, AD-538629.1, AD-536233.1, AD-538141.1, AD-538622.1, AD-537580.1,AD536505.1, AD-537918.1, AD-537913.1, AD-538642.1, AD-536877.1, AD-538650.1, AD-538625.1, AD-537911.1, AD-538014.1,AD538634.1, AD-536979.1, AD-538641.1, AD-537912.1, AD-537761.1, AD-537917.1, AD-537916.1, AD-538432.1, AD-538529.1,AD537867.1, AD-536503.1, AD-537582.1, AD-537915.1, AD-537919.1, AD-537581.1 and AD-538483.1. In particular modes, the sense and antisense tapes are selected from any of the duplexes AD-535094.1, AD-535094.1, AD-535095.1, AD-538647.1, AD535922.1, AD-536317.1, AD-536911.1, AD-538626.1 and AD-535864.1. [000207] In certain embodiments, the sense and antisense tapes are selected from any of the duplexes AD-523561.1, AD523565.1, AD-523562.1, AD-526914.1, AD-526394.1, AD-395452.1, AD-525343.1, AD-524274.1, AD-526956.1, AD-526986.1, AD526296.1, AD-526988.1, AD-526957.1, AD-526993.1, AD-527013.1, Petition 870260076339, dated 07 / 30 / 2026, page 75 / 2173 64 / 505 AD-526936.1, AD-395453.1, AD-526989.1, AD-524719.1, AD526423.1, AD-527010.1, AD-525305.1, AD-526987.1, AD-524331.1 AD-525266.1, AD-525342.1, AD-526995.1, AD-526298.1,AD524718.1, AD-526392.1, AD-526985.1, AD-527011.1, AD-525341.1, AD-525265.1, AD-527004.1, AD-525336.1, AD-525353.1, AD525273.1, AD-524638.1, AD-526350.1, AD-526962.1, AD-527005.1, AD-525269.1, AD-524715.1, AD-395454.1, AD-525307.1,AD525352.1, AD-524641.1, AD-526297.1, AD-525268.1, AD-526997.1, AD-526991.1, AD-527012.1, AD-524720.1, AD-525303.1,AD526289.1, AD-526992.1, AD-525333.1, AD-524335.1, AD-526990.1, AD-527006.1, AD-526505.1, AD-525309.1, AD-524328.1, AD395455.1, AD-526428.1, AD-526847.1, AD-525957.1, AD-524332.1 AD-526291.1, AD-526485.1, AD-526292.1, AD-524642.1,AD526290.1, AD-525959.1, AD-526293.1, AD-524899.1, AD-526391.1, AD-525956.1, AD-525958.1, AD-526351.1, AD-526138.1,AD524898.1, AD-526244.1, AD-525359.1, AD-526393.1, AD-525355.1, AD-526288.1, AD-524897.1, AD-526796.1, AD-526295.1, AD-526294.1 and AD-525356.1. In particular modes, the sense and antisense tapes are selected from any of the duplexes AD523561.1, AD-523565.1, AD-523562.1, AD-526914.1, AD-526394.1, AD-395452.1, AD-525343.1, AD-524274.1, AD-526956.1, AD526986.1, AD-526296.1, AD-526988.1, AD-526957.1 and AD-526993.1. [000208] In certain modes, the sense and antisense tapes are selected from any of the duplexes AD-393758.1, AD393888.1, AD-393759.1, AD-393761.1, AD-393495.1, AD-393760.1, AD-396425.1, AD-395441.1, AD-396420.1, AD-397103.1,AD397104.1, AD-393239.1, AD-397102.1, AD-397167.1, AD-394791.1, AD-393754.1, AD-393496.1, AD-393667.1, AD-396467.1,AD393690.1, AD-396449.1, AD-393663.1, AD-393820.1, AD-396437.1, AD-393084.1, AD-396401.1, AD-394296.1, AD-395574.1,AD Petition 870260076339, dated 07 / 30 / 2026, page 76 / 2173 65 / 505 393124.1, AD-393674.1, AD-396451.1, AD-396454.1, AD-393376.1, AD-393505.1, AD-393375.1, AD-393247.1, AD-393257.1, AD396459.1, AD-396450.1, AD-396445.1, AD-396461.1, AD-396452.1, AD-396913.1, AD-396455.1, AD-396912.1, AD-396915.1, AD-396453.1 and AD-394991.1. [000209] In one embodiment, the sense and antisense tapes are selected from either of the AD-1397070.1, AD- duplexes. 1397070.2, AD-1397071.1, AD-1397071.2, AD-1397072.1, AD- 1397072.2, AD-1397073.1, AD-1397073.2, AD-1397074.1, AD- 1397074.2, AD-1397075.1, AD-1397075.2, AD-1397076.1, AD- 1397076.2, AD-1397077.1, AD-1397077.2, AD-1397078.1, AD- 1397078.2, AD-1397250.1, AD-1397251.1, AD-1397252.1, AD- 1397253.1, AD-1397254.1, AD-1397255.1, AD-1397256.1, AD- 1397257.1, AD-1397258.1, AD-1397259.1, AD-1397260.1, AD- 1397261.1, AD-1397262.1, AD-1397263.1, AD-1397264.1, AD- 1397265.1, AD-1423242.1, AD-1423243.1, AD-1423244.1, AD- 1423245.1, AD-1423246.1, AD-1423247.1, AD-1423248.1, AD- 1423249.1, AD-1423250.1, AD-1423251.1, AD-1423252.1, AD- 1423253.1, AD-1423254.1, AD-1423255.1, AD-1423256.1, AD- 1423257.1, AD-1423258.1, AD-1423259.1, AD-1423260.1, AD- 1423261.1, AD-1423262.1, AD-1423263.1, AD-1423264.1, AD- 1423265.1, AD-1423266.1, AD-1423267.1, AD-1423268.1, AD- 1423269.1, AD-1423270.1, AD-1423271.1, AD-1423272.1, AD- 1423273.1, AD-1423274.1, AD-1423275.1, AD-1423276.1, AD- 1423277.1, AD-1423278.1, AD-1423279.1, AD-1423280.1, AD- 1423281.1, AD-1423282.1, AD-1423283.1, AD-1423284.1, AD- 1423285.1, AD-1423286.1, AD-1423287.1, AD-1423288.1, AD- 1423289.1, AD-1423290.1, AD-1423291.1, AD-1423292.1, AD- 1423293.1, AD-1423294.1, AD-1423295.1, AD-1423296.1, AD- 1423297.1, AD-1423298.1, AD-1423299.1, AD-1423300.1, AD-. Petition 870260076339, on 07 / 30 / 2026, page. 77 / 2173 66 / 505 1397266.1, AD-1397266.2, AD-1397267.1, AD-1423301.1, AD- 1397268.1, AD-1397268.2, AD-1397269.1, AD-1423302.1, AD- 1397270.1, AD-1397270.2, AD-1397271.1, AD-1397271.2, AD- 1397272.1, AD-1423303.1, AD-1397273.1, AD-1423304.1, AD- 1397274.1, AD-1423305.1, AD-1397275.1, AD-1423306.1, AD- 1397276.1, AD-1397277.1, AD-1397277.2, AD-1397278.1, AD- 1397279.1, AD-1397280.1, AD-1397281.1, AD-1397282.1, AD- 1397283.1, AD-1397284.1, AD-1397285.1, AD-1397286.1, AD- 1397287.1, AD-1397079.1, AD-1397079.2, AD-1397288.1, AD- 1397289.1, AD-1397290.1, AD-1397080.1, AD-1397080.2, AD- 1397291.1, AD-1397292.1, AD-1397293.1, AD-1397294.1, AD- 1397081.1, AD-1397081.2, AD-1397295.1, AD-1397082.1, AD- 1397082.2, AD-1397083.1, AD-1397083.2, AD-1397296.1, AD- 1397297.1, AD-1397298.1, AD-1397299.1, AD-1397300.1, AD- 1397301.1, AD-1397302.1, AD-1397084.1, AD-1397085.1, AD- 1397086.1, AD-1397303.1, AD-1397087.1, AD-1397087.2, AD- 1397304.1, AD-1397305.1, AD-1397306.1, AD-1397307.1, AD- 1397308.1, AD-1397309.1, AD-1397310.1, AD-1397311.1, AD- 1397312.1, AD-1397313.1, AD-1397314.1, AD-1397315.1, AD- 1397316.1, AD-1397317.1, AD-1397318.1, AD-1397319.1, AD- 1397320.1, AD-1397321.1, AD-1397322.1, AD-1397088.1, AD- 1397089.1, AD-1397090.1, AD-1397091.1, AD-1397092.1, AD- 1397093.1, AD-1397094.1, AD-1397095.1, AD-1397096.1, AD- 1397097.1, AD-1397098.1, AD-1397099.1, AD-1397101.1, AD- 1397102.1, AD-1397103.1, AD-1397104.1, AD-1397105.1, AD- 1397106.1, AD-1397107.1, AD-1397108.1, AD-1397109.1, AD- 1397110.1, AD-1397111.1, AD-1397112.1, AD-1397113.1, AD- 1397114.1, AD-1397115.1, AD-1397116.1, AD-1397117.1, AD- 1397118.1, AD-1397119.1, AD-1397120.1, AD-1397121.1, AD- 1397122.1, AD-1397123.1, AD-1397124.1, AD-1397125.1, AD-. Petition 870260076339, on 07 / 30 / 2026, page. 78 / 2173 67 / 505 1397126.1, AD-1397127.1, AD-1397128.1, AD-1397129.1, AD- 1397130.1, AD-1397131.1, AD-1397132.1, AD-1397133.1, AD- 1397134.1, AD-1397135.1, AD-1397136.1, AD-1397137.1, AD- 1397138.1, AD-1397139.1, AD-1397140.1, AD-1397141.1, AD- 1397142.1, AD-1397143.1, AD-1397144.1, AD-1397145.1, AD- 1397146.1, AD-1397147.1, AD-1397148.1, AD-1397149.1, AD- 1397150.1, AD-1397151.1, AD-1397152.1, AD-1397153.1, AD- 1397154.1, AD-1397155.1, AD-1397156.1, AD-1397157.1, AD- 1397158.1, AD-1397159.1, AD-1397160.1, AD-1397161.1, AD- 1397162.1, AD-1397163.1, AD-1397164.1, AD-1397165.1, AD- 1397166.1, AD-1397167.1, AD-1397168.1, AD-1397169.1, AD- 1397170.1, AD-1397171.1, AD-1397172.1, AD-1397173.1, AD- 1397174.1, AD-1397175.1, AD-1397176.1, AD-1397177.1, AD- 1397178.1, AD-1397179.1, AD-1397180.1, AD-1397181.1, AD- 1397182.1, AD-1397183.1 ,AD-1397184.1, AD-1397185.1, AD- 1397186.1, AD-1397187.1, AD-1397188.1, AD-1397189.1, AD- 1397190.1, AD-1397191.1, AD-1397192.1, AD-1397193.1, AD- 1397194.1, AD-1397195.1, AD-1397196.1, AD-1397197.1, AD- 1397198.1, AD-1397199.1, AD-1397200.1, AD-1397201.1, AD- 1397202.1, AD-1397203.1, AD-1397204.1, AD-1397205.1, AD- 1397206.1, AD-1397207.1, AD-1397208.1, AD-1397209.1, AD- 1397210.1, AD-1397211.1, AD-1397212.1, AD-1397213.1, AD- 1397214.1, AD-1397215.1, AD-1397216.1, AD-1397217.1, AD- 1397218.1, AD-1397219.1, AD-1397220.1, AD-1397221.1, AD- 1397222.1, AD-1397223.1, AD-1397224.1, AD-1397225.1, AD- 1397226.1, AD-1397227.1, AD-1397228.1, AD-1397229.1, AD- 1397230.1, AD-1397231.1, AD-1397232.1, AD-1397233.1, AD- 1397234.1, AD-1397235.1, AD-1397236.1, AD-1397237.1, AD- 1397238.1, AD-1397239.1, AD-1397240.1, AD-1397241.1, AD- 1397242.1, AD-1397243.1, AD-1397244.1, AD-1397245.1, AD-. Petition 870260076339, on 07 / 30 / 2026, page. 79 / 2173 68 / 505 1397246.1, AD-1397247.1, AD-1397248.1, AD-1397249.1, AD523565.1, AD-1397072.3, AD-1397073.3, AD-1397076.3, AD1397077.3, AD-1397078.3, AD-1397252.2, AD-1397257.2, AD1397258.2, AD-1397259.2, AD-1397263.2, AD-1397264.2, AD1397309.2, AD-64958.114, AD-393758.4, AD-1397080.3, AD1397293.2 AD-1397294.2, AD-1397081.3, AD-1397083.3, AD1397298.2, AD-1397299.2, AD-1397084.2, AD-1397085.2, AD1397087.3, AD-1397306.2, AD-1397307.2, AD-1397308.2 e AD1397088.2. [000210] In one embodiment, at least partial suppression of MAPT gene expression is assessed by a reduction in the amount of MAPT mRNA, for example, sense mRNA, antisense mRNA, total MAPT mRNA, which can be isolated from, or detected in, a first cell or group of cells in which a MAPT gene is transcribed and which has been treated so that MAPT gene expression is inhibited, compared with a second cell or group of cells substantially identical to the first cell or group of cells, but which has not been treated in this way (control cells). The degree of inhibition can be expressed in terms of: (mRNA in control cells) - (mRNA in treated cells) X 100 mRNA in control cells [000211] The phrase "contact a cell with an RNAi agent, such as a dsRNA," as used in this document, includes contact with a cell by any possible means. Contact of a cell with an RNAi agent includes contact of a cell in vitro with the RNAi agent or contact of a cell in vivo with the RNAi agent. Contact may be made directly or indirectly. Thus, for example, the RNAi agent may be brought into physical contact with the cell by the individual performing the method or, alternatively, the RNAi agent may be placed in a situation that will allow or cause it to... Petition 870260076339, dated 07 / 30 / 2026, page 80 / 2173 69 / 505 then contact the cell. [000212] In vitro cell contact can be achieved, for example, by incubating the cell with the RNAi agent. In vivo cell contact can be achieved, for example, by injecting the RNAi agent into or near the tissue where the cell is located, or by injecting the RNAi agent into another area, for example, the central nervous system (CNS), optionally via intrathecal, intravitreal, intracisternal or other injection, or into the bloodstream or subcutaneous space, so that the agent subsequently reaches the tissue where the cell to be contacted is located. For example, the RNAi agent may contain or be linked to a linker, for example, a lipophilic part(s), as described below and in more detail, for example, in PCT / US2019 / 031170, which is incorporated herein by reference, that directs or stabilizes the RNAi agent at a site of interest, for example, the CNS. Combinations of in vitro and in vivo contact methods are also possible.For example, a cell can also be contacted in vitro with an RNAi agent and subsequently transplanted into an individual. [000213] In one embodiment, contact of a cell with an RNAi agent includes introducing or distributing the RNAi agent into the cell, facilitating or effecting uptake or absorption into the cell. Uptake or absorption of an RNAi agent can occur through diffusive or active cellular processes without assistance, or by assistive agents or devices. Introduction of an RNAi agent into a cell can be in vitro or in vivo. For example, for in vivo introduction, an RNAi agent can be injected into a tissue site or administered systemically. In vitro introduction into a cell includes methods known in the art, such as electroporation and lipofection. Other approaches are described below or are known in the art. Petition 870260076339, dated 07 / 30 / 2026, page 81 / 2173 70 / 505 [000214] The term lipophilic or lipophilic moiety refers broadly to any compound or chemical moiety with an affinity for lipids. One way to characterize the lipophilicity of the lipophilic moiety is by the octanol-water partition coefficient, logKow, where Kow is the ratio of the concentration of a chemical in the octanol phase to its concentration in the aqueous phase of a biphasic system at equilibrium. The octanol-water partition coefficient is a property of a substance measured in the laboratory. However, it can also be predicted using coefficients assigned to the structural components of a chemical, which are calculated using first-principles or empirical methods (see, for example, Tetko et al., J. Chem. Inf. Comput. Sci. 41:140721 (2001), which is incorporated herein by reference in its entirety).It provides a thermodynamic measure of a substance's tendency to prefer a non-aqueous or non-oily medium over water (i.e., its hydrophilic / lipophilic balance). In principle, a chemical substance is lipophilic when its logKow exceeds 0. Typically, the lipophilic moiety has a logKow that exceeds 1, exceeds 1.5, exceeds 2, exceeds 3, exceeds 4, exceeds 5, or exceeds 10. For example, the logKow of 6-aminohexanol is predicted to be approximately 0.7. Using the same method, the logKow of N-(hexan-6-ol) cholesterol carbamate is predicted to be 10.7. [000215] The lipophilicity of a molecule can change in relation to the functional group it carries. For example, adding a hydroxyl group or an amine group to the end of a lipophilic moiety can increase or decrease the value of the partition coefficient (e.g., logKow) of the lipophilic moiety. [000216] Alternatively, the hydrophobicity of the double-stranded RNAi agent, conjugated with one or more lipophilic moieties, can be measured by its protein-binding characteristics. For example, in Petition 870260076339, dated 07 / 30 / 2026, p. 82 / 2173 71 / 505 In certain embodiments, the unbound portion in the plasma protein binding assay of the double-stranded RNAi agent can be determined to correlate positively with the relative hydrophobicity of the double-stranded RNAi agent, which can then correlate positively with the silencing activity of the double-stranded RNAi agent. [000217] In one embodiment, the determined plasma protein binding assay is an electrophoretic mobility change assay (EMSA) using human serum albumin protein. An illustrative protocol of this binding assay is illustrated in detail, for example, in PCT / US2019 / 031170. In short, duplexes were incubated with human serum albumin and the unbound portion was determined. The illustrative assay protocol includes duplexes at a stock concentration of 10 μM, diluted to a final concentration of 0.5 μM (total volume of 20 μL) containing 0, 20, or 90% serum in 1x PBS. Samples can be mixed, centrifuged for 30 seconds, and then incubated at room temperature for 10 minutes.Once the incubation step is complete, 4 μL of 6x EMSA Gel Loading Solution can be added to each sample, centrifuged for 30 seconds, and 12 μL of each sample can be loaded onto a 10% BioRad 26-well PAGE (polyacrylamide gel electrophoresis). The gel can be run for 1 hour at 100 volts. After the run is complete, the gel is removed from the casing and washed in 50 mL of 10% TBE (Tris base, boric acid, and EDTA). Once the wash is complete, 5 μL of SYBR Gold can be added to the gel, which is then incubated at room temperature for 10 minutes, and the gel washed again in 50 mL of 10% TBE. In this illustrative essay, a Gel Doc XR+ gel documentation system can be used to read the gel, using the following parameters: the definition of the imaging application for SYBR Gold, the definition of the size for the Bio-Rad criterion gel, the definition of... Petition 870260076339, dated 07 / 30 / 2026, page 83 / 2173 72 / 505 exposure as automatic for intense bands, saturated highlight pixels can be changed to one and the color is set to gray. Detection, molecular weight analysis, and output can be disabled. Once a clean image of the gel is obtained, Image Lab 5.2 can be used to process the image. Pathways and bands can be manually defined to measure band intensity. The band intensities of each sample can be normalized to PBS to obtain the unbound siRNA portion. From this measurement, the relative hydrophobicity can be determined. The hydrophobicity of the double-stranded RNAi agent, measured by the unbound siRNA portion in the binding assay, exceeds 0.15, exceeds 0.2, exceeds 0.25, exceeds 0.3, exceeds 0.35, exceeds 0.4, exceeds 0.45, or exceeds 0.5 for an increased in vivo siRNA distribution. [000218] Consequently, the conjugation of the lipophilic parts with the internal position(s) of the double-stranded RNAi agent provides ideal hydrophobicity for enhanced siRNA distribution in vivo. [000219] The term lipid nanoparticle or LNP is a vesicle comprising a lipid layer that encapsulates a pharmaceutically active molecule, such as a nucleic acid molecule, for example, an RNAi agent or a plasmid from which an RNAi agent is transcribed. LNPs are described, for example, in US Patents Nos. 6,858,225, 6,815,432, 8,158,601 and 8,058,069, the entire contents of which are incorporated herein by reference. [000220] As used in this document, an individual is an animal, such as a mammal, including a primate (such as a human being, a non-human primate, for example, a monkey and a chimpanzee) or a non-primate (such as a rat or a mouse). In a preferred embodiment, the individual is a human being, such as a human being. Petition 870260076339, dated 07 / 30 / 2026, page 84 / 2173 73 / 505 A human being treated or evaluated for a disease, disorder, or condition that would benefit from reduced MAPT expression; a human being at risk for a disease, disorder, or condition that would benefit from reduced MAPT expression; a human being with a disease, disorder, or condition that would benefit from reduced MAPT expression; or a human being treated for a disease, disorder, or condition that would benefit from reduced MAPT expression, as described herein. In some embodiments, the individual is a female human being. In other embodiments, the individual is a male human being. In one embodiment, the individual is an adult individual. In one embodiment, the individual is a pediatric individual. In another embodiment, the individual is a juvenile individual, that is, an individual under 20 years of age. [000221] As used in this document, the terms treatment or treatment refer to a beneficial or desired outcome, including, but not limited to, relief or improvement of one or more signs or symptoms associated with MAPT gene expression or Tau production in MAPT-associated diseases such as Alzheimer's disease, FTD, PSP, or other tauopathies. Treatment may also mean prolonged survival compared to the survival expected in the absence of treatment. [000222] The term "minor," in the context of the MAPT level in an individual or of a disease marker or symptom, refers to a statistically significant decrease in that level. The decrease may be, for example, at least 10%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more. In certain modalities, a decrease is at least 20%. In certain modalities, the decrease is at least 50% in a disease marker, for example, the level of foci containing sense or antisense and / or the level of abnormal dipeptide repeat protein, for example, a decrease Petition 870260076339, dated 07 / 30 / 2026, page 85 / 2173 74 / 505 of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more. In some modalities, a decrease is at least about 25% in a disease marker, for example, the expression level of the Tau protein and / or gene is decreased by, for example, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95%. Lower, in the context of the MAPT level in an individual, is preferably down to a level accepted as within the normal range for an individual without such a disorder. In certain modalities, the smaller the decrease, the smaller the difference between the level of a marker or symptom for an individual suffering from a disease and a level accepted within the normal range for an individual, for example, the level of decrease in body weight between an obese individual and an individual with a weight accepted within the normal range. [000223] As used in this document, prevention or avoidance, when used in reference to a disease, disorder or condition thereof that would benefit from a reduction in the expression of a MAPT gene or in the production of a Tau, refers to a reduction in the probability that an individual will develop a symptom associated with such disease, disorder or condition, for example, a symptom of a disease associated with MAPT. The inability to develop a disease, disorder or condition, or the reduction in the development of a symptom associated with such disease, disorder or condition (for example, by at least about 10%, on a clinically accepted scale for such disease or disorder), or the delayed display of symptoms (for example, by days, weeks, months or years) is considered effective prevention. [000224] As used in this document, the term MAPT-associated disease or MAPT-associated disorder or tauopathy Petition 870260076339, dated 07 / 30 / 2026, p. 86 / 2173 75 / 505 includes any disease or disorder that would benefit from a reduction in MAPT expression and / or activity. Illustrative MAPT-associated diseases include Alzheimer's disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), semantic primary progressive aphasia (S-PPA), logopenic primary progressive aphasia (L-PPA), frontotemporal dementia with chromosome 17-linked parkinsonism (FTDP-17), Pick's disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD) with GGIs, FTLD with MAPT mutations, neurofibrillary tangle dementia (NFT), FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), and... corticobasal degeneration (CBD), progressive supranuclear palsy (PSP),Parkinson's disease, post-encephalitic parkinsonism, Niemann-Pick disease, Huntington's disease, myotonic dystrophy type 1, and Down syndrome (DS). [000225] A therapeutically effective amount, as used herein, is intended to include the amount of an RNAi agent that, when administered to an individual with a MAPT-associated disease, is sufficient to effect treatment of the disease (e.g., by decreasing, improving, or maintaining existing disease or one or more symptoms of the disease). The therapeutically effective amount may vary depending on the RNAi agent, how the agent is administered, the disease and its severity, and the history, age, weight, family history, genetic makeup, types of prior or concurrent treatments, if any, and other individual characteristics of the individual being treated. [000226] A prophylactically effective quantity, as used in this document, is intended to include the quantity of an agent of Petition 870260076339, dated 07 / 30 / 2026, page 87 / 2173 76 / 505 RNAi that, when administered to an individual with a MAPT-associated disorder, is sufficient to prevent or improve the disease or one or more symptoms of the disease. Disease improvement includes slowing the course of the disease or reducing the severity of further disease development. The prophylactically effective amount may vary depending on the RNAi agent, how the agent is administered, the degree of risk of the disease, and the history, age, weight, family history, genetic makeup, types of prior or concurrent treatments, if any, and other individual characteristics of the individual being treated. [000227] A therapeutically effective amount or a prophylactically effective amount also includes an amount of an RNAi agent that produces some desired local or systemic effect at a reasonable benefit / risk ratio applicable to any treatment. An RNAi agent used in the methods of the present invention may be administered in an amount sufficient to produce a reasonable benefit / risk ratio applicable to such treatment. [000228] The phrase pharmaceutically acceptable is used in this document to refer to compounds, materials, compositions or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human subjects and animal subjects, without toxicity, irritation, excessive allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio. [000229] The phrase "pharmaceutically acceptable vehicle," as used herein, means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid feedstock, diluent, excipient, manufacturing aid (for example, lubricant, talc, magnesium, calcium, or zinc stearate, or steric acid), or solvent encapsulation material, involved in a feedstock or Petition 870260076339, dated 07 / 30 / 2026, page 88 / 2173 77 / 505 transport the compound in question from one organ, or part of the body, to another organ, or part of the body. Each vehicle must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the individual being treated. Some examples of materials that can serve as pharmaceutically acceptable vehicles include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) lubricating agents, such as magnesium stearate, sodium lauryl sulfate, and talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;(10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffer solutions; (21) polyesters, polycarbonates or polyanhydrides; (22) bulking agents, such as polypeptides and amino acids; (23) serum components, such as serum albumin, HDL and LDL; and (22) other compatible non-toxic substances used in pharmaceutical formulations.; [000230] The term sample, as used in this document, includes a collection of fluids, cells, or similar tissues isolated from an individual, as well as the fluids, cells, or tissues present in an individual. Examples of biological fluids include blood, serum and serous fluids, plasma, cerebrospinal fluid, Petition 870260076339, dated 07 / 30 / 2026, page 89 / 2173 78 / 505 ocular fluids, lymph, urine, saliva, and the like. Tissue samples may include samples of tissues, organs, or localized regions. For example, samples may be derived from particular organs, parts of organs, or fluids or cells within those organs. In certain embodiments, samples may be derived from the brain (e.g., whole brain or certain brain segments, e.g., striatum, or certain cell types in the brain, such as neurons and glial cells (astrocytes, oligodendrocytes, microglial cells)). In some embodiments, a sample derived from an individual refers to blood taken from the individual or plasma or serum derived from them. In other embodiments, a sample derived from an individual refers to brain tissue (or subcomponents thereof) or retinal tissue (or subcomponents thereof) derived from the individual. [000231] The substituted term refers to the substitution of one or more hydrogen radicals in a given structure by the radical of a specified substituent, including, but not limited to: alkyl, alkenyl, alkynyl, aryl, heterocyclyl, halo, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understood that the substituent can also be substituted. [000232] The term alkyl refers to non-aromatic hydrocarbon chains, saturated and unsaturated, which may be a linear chain or a branched chain, containing the indicated number of carbon atoms (these include, without limitation, propyl, allyl or propargyl). Petition 870260076339, dated 07 / 30 / 2026, p. 90 / 2173 79 / 505 which may optionally be inserted with N, O or S. For example, (C1-C6) alkyl means a radical with 1 to 6 carbon atoms in a linear or branched arrangement. (C1-C6) alkyl includes, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl and hexyl. In certain embodiments, a lipophilic part of the present invention may include a C6-C18 alkyl hydrocarbon chain. [000233] The term alkylene refers to a linear or branched, aliphatic, saturated, optionally substituted divalent hydrocarbon radical having a specified number of carbon atoms. For example, (C1-C6) alkylene means a divalent saturated aliphatic radical with 1-6 carbon atoms in a linear arrangement, for example, [(CH2)n], where n is an integer from 1 to 6. “(C1-C6) alkylene” includes methylene, ethylene, propylene, butylene, pentylene, and hexylene. Alternatively, (C1-C6) alkylene means a saturated divalent radical with 1-6 carbon atoms in a branched arrangement, for example: [(CH2CH2CH2CH2CH(CH3)], [(CH2CH2CH2CH2C(CH3)2], [(CH2C(CH3)2CH(CH3))], and the like. The term alkylenedioxo refers to a divalent species of the structure —O—R—O—, where R represents an alkylene. [000234] The term mercapto refers to an -SH radical. The term thioalkoxy refers to an -S-alkyl radical. [000235] The term halo refers to any fluorine, chlorine, bromine, or iodine radical. Halogen and halo are used interchangeably in this document. [000236] As used in this document, the term cycloalkyl means a non-aromatic hydrocarbon ring group, saturated or unsaturated, having from 3 to 14 carbon atoms, unless otherwise specified. For example, (C3-C10)cycloalkyl means a hydrocarbon radical of a cyclic, aliphatic, saturated hydrocarbon ring having 3-10 members. Examples of groups Petition 870260076339, dated 07 / 30 / 2026, page 91 / 2173 80 / 505 Cycloalkyl groups include, but are not limited to, cyclopropyl, methylcyclopropyl, 2,2-dimethylcyclobutyl, 2-ethylcyclopentyl, cyclohexyl, etc. Cycloalkyl groups may include multiple spiro or fused rings. The cycloalkyl groups are optionally mono-, di-, tri-, tetra-, or penta-substituted at any position, as permitted by normal valence. [000237] As used in this document, the term alkenyl refers to a non-aromatic, linear or branched hydrocarbon radical containing at least one carbon-carbon double bond and having from 2 to 10 carbon atoms, unless otherwise specified. Up to five carbon-carbon double bonds may be present in such groups. For example, C2-C6 alkenyl is defined as an alkenyl radical having from 2 to 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, and cyclohexenyl. The linear, branched, or cyclic portion of the alkenyl group may contain double bonds and is optionally mono-, di-, tri-, tetra-, or penta-substituted at any position, as permitted by normal valence. The term cycloalkenyl means a monocyclic hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon double bond. [000238] As used in this document, the term alkynyl refers to a linear or branched hydrocarbon radical containing from 2 to 10 carbon atoms, unless otherwise specified, and containing at least one carbon-carbon triple bond. Up to 5 carbon-carbon triple bonds may be present. Thus, C2-C6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, and 2-butynyl. The linear or branched portion of the alkynyl group may contain triple bonds, as permitted by normal valence, and may optionally be mono-, di-, tri-, tetra-, or penta-substituted at any position, as permitted by normal valence. Petition 870260076339, dated 07 / 30 / 2026, p. 92 / 2173 81 / 505 [000239] As used in this document, alkoxy or alkoxyl refers to an alkyl group as defined above, with the indicated number of carbon atoms linked via an oxygen bridge. For example, a (C1-C3)alkoxy includes methoxy, ethoxy, and propoxy. For example, a (C1-C6)alkoxy is intended to include the C1, C2, C3, C4, C5, and C6 alkoxy groups. For example, a (C1-C8)alkoxy is intended to include the C1, C2, C3, C4, C5, C6, C7, and C8 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy. Alkylthio means an alkyl radical linked through a sulfur bonding atom. The terms alkylamino or aminoalkyl mean an alkyl radical linked through an NH bond. Dialkylamino means two alkyl radicals linked through a nitrogen bonding atom.Amino groups can be unsubstituted, monosubstituted, or disubstituted. In some embodiments, the two alkyl radicals are the same (e.g., N,N-dimethylamino). In some embodiments, the two alkyl radicals are different (e.g., N-ethyl-N-methylamino). [000240] As used in this document, aryl or aromatic means any stable monocyclic or polycyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, indanyl, and biphenyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, the linkage is understood to be through the aromatic ring. Aryl groups are optionally mono-, di-, tri-, tetra-, or penta-substituted at any position, as permitted by normal valence. The term arylalkyl or the term aralkyl refers to alkyl substituted by an aryl. The term arylalkoxy refers to an aryl-substituted alkoxy. [000241] Hetero refers to the substitution of at least one atom Petition 870260076339, dated 07 / 30 / 2026, p. 93 / 2173 82 / 505 of carbon, in a ring system, by at least one heteroatom selected from N, S, and O. Hetero also refers to the substitution of at least one carbon atom in an acyclic system. A hetero ring system or a hetero acyclic system may have, for example, 1, 2, or 3 carbon atoms substituted by a heteroatom. [000242] As used in this document, the term heteroaryl represents a stable monocyclic or polycyclic ring of up to 7 atoms in each ring, in which at least one ring is aromatic and contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S.Examples of heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinolinyl, quinoxalinyl, pyrazolyl, indoyl, benzotriazolyl, furanyl, tienyl, benzothienyl, benzofuranyl, benzimidazolonyl, benzoxazolonyl, quinolinyl, isoquinolinyl, dihydroisoindolonyl, imidazopyridinyl, isoindolonyl, indazolyl, oxazolyl, oxadiazolyl, isoxazolyl, indoyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline. A heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and a ring is non-aromatic or does not contain heteroatoms, the linkage is understood to be through the aromatic ring or through the ring containing heteroatoms. Heteroaryl groups are optionally mono-, di-, tri-, tetra-, or penta-substituted at any position, as permitted by normal valence. [000243] As used in this document, the term heterocycle, heterocyclic or heterocyclyl means an aromatic or non-aromatic heterocycle of 3 to 14 members, containing 1 to 4 heteroatoms selected from the group consisting of O, N and S, including polycyclic groups. As used in this document, the term heterocyclic is also considered synonymous with the terms heterocycle and heterocyclyl and is understood to also have the same characteristics. Petition 870260076339, dated 07 / 30 / 2026, page 94 / 2173 83 / 505 definitions presented in this document. A heterocycline includes the heteroaryls mentioned above, as well as their dihydro and tetrahydro analogs. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naftpyridinyl, oxadiazolyl, oxo-oxazolidinyl, oxazolyl, oxazoline, oxopiperazinyl, oxopyrrolidinyl, oxomorpholinyl, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyridinonyl, pyrimidyl, pyrimidinonyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroiso-oxazolyl, dihydroisothiazolyl, dihydro-oxadiazolyl, dihydro-oxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dioxythiomorpholinyl, methylenedioxybenzoyl, tetrahydrofuranyl and tetrahydrothienyl, and their N-oxides. The attachment of a heterocyclyl substituent can occur through a carbon atom or through a heteroatom. Heterocyclyl groups are optionally mono-, di-, tri-, tetra- or penta-substituted at any position.as permitted by normal valence. [000244] A heterocycloalkyl group refers to a cycloalkyl residue in which one to four of the carbons are replaced by a heteroatom, such as oxygen, nitrogen, or sulfur. Examples of Petition 870260076339, dated 07 / 30 / 2026, p. 95 / 2173 84 / 505 heterocycles whose radicals are heterocyclyl groups include tetrahydropyran, morpholine, pyrrolidine, piperidine, thiazolidine, oxazole, oxazoline, isoxazole, dioxane, tetrahydrofuran and the like. [000245] The term heteroaryl refers to a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic aromatic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N or S (e.g., carbon atoms and 1-3, 1-6 or 1-9 heteroatoms of N, O or S if monocyclic, bicyclic or tricyclic, respectively), wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted by a substituent. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl and the like. The term heteroarylalkyl or the term heteroaralkyl refers to an alkyl substituted by a heteroaryl. The term heteroarylalkoxy refers to an alkoxy substituted by a heteroaryl. [000246] The term cycloalkyl, as used in this document, includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, for example, 3 to 8 carbons and, for example, 3 to 6 carbons, wherein the cycloalkyl group may additionally be optionally substituted. Cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. [000247] The term acyl refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclocarbonyl or heteroarylcarbonyl substituent, any of which may also be substituted by substituents. [000248] As used herein, keto refers to any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl group, as defined herein Petition 870260076339, dated 07 / 30 / 2026, p. 96 / 2173 85 / 505 document, linked via a carbonyl bridge. [000249] Examples of keto groups include, but are not limited to, alkanoyl (e.g., acetyl, propionyl, butanoyl, pentanoyl, hexanoyl), alkenoyl (e.g., acryloyl), alkynyl (e.g., ethinoyl, propinoyl, butinoyl, pentinoyl, hexanoyl), arylyl (e.g., benzoyl), heteroaryl (e.g., pyrroloyl, imidazolyl, quinolinoyl, pyridinoyl). [000250] As used in this document, alkoxycarbonyl refers to any alkoxy group, as defined above, linked via a carbonyl bridge (i.e., -C(O)O-alkyl). Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-propoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, or n-pentoxycarbonyl. [000251] As used in this document, aryloxycarbonyl refers to any aryl group, as defined in this document, connected via an oxycarbonyl bridge (i.e., -C(O)Oaryl). Examples of aryloxycarbonyl groups include, but are not limited to, phenoxycarbonyl and naphthyloxycarbonyl. [000252] As used herein, heteroaryloxycarbonyl refers to any heteroaryl group, as defined herein, linked via an oxycarbonyl bridge (i.e., -C(O)O-heteroaryl). Examples of heteroaryloxycarbonyl groups include, but are not limited to, 2-pyridyloxycarbonyl, 2-oxazolyloxycarbonyl, 4-thiazolyloxycarbonyl, or pyrimidinyloxycarbonyl. [000253] The term oxo refers to an oxygen atom, which forms a carbonyl group when bonded to carbon, an N-oxide when bonded to nitrogen, and a sulfoxide or sulfone when bonded to sulfur. [000254] Those skilled in the art would readily understand and consider that the compounds and compositions described herein may have certain atoms (for example, N, O, or S atoms) in a Petition 870260076339, dated 07 / 30 / 2026, p. 97 / 2173 86 / 505 protonated or deprotonated state, depending on the environment in which the compound or composition is placed. Consequently, as used in the present document, the structures described herein consider that certain functional groups, such as, for example, OH, SH or NH, can be protonated or deprotonated. The invention in the present document is intended to cover the compounds and compositions described, regardless of their protonation state based on the pH of the environment, as would be readily understood by those skilled in the art. II. RNAi Agents of the Invention [000255] RNAi agents that inhibit the expression of a MAPT gene are described in this document. In one embodiment, the RNAi agent includes double-stranded ribonucleic acid (dsRNA) molecules to inhibit the expression of a MAPT gene in a cell, such as a cell within an individual, for example, a mammal, such as a human with a MAPT-associated disease, for example, Alzheimer's disease, FTD, PSP, or another tauopathy. The dsRNA includes an antisense strand with a complementarity region that is complementary to at least part of an mRNA formed in the expression of a MAPT gene. The complementarity region is about 15-30 nucleotides or less in length.Upon contact with a cell expressing the MAPT gene, the RNAi agent inhibits the expression of the MAPT gene (e.g., a human gene, a primate gene, a non-primate gene) by at least 25%, or more, as described herein, when compared to a similar cell not contacted with the RNAi agent or an RNAi agent not complementary to the MAPT gene. MAPT gene expression can be tested, for example, by a PCR-based or branched DNA (bDNA)-based method, or by a protein-based method, such as immunofluorescence analysis, using, for example, [methods]. Petition 870260076339, dated 07 / 30 / 2026, page 98 / 2173 87 / 505 example, western blotting or flow cytometry techniques. In one embodiment, the knockdown level (reduced expression) is tested in BE(2)-C cells using an assay method provided in Example 1 below. In some embodiments, the knockdown level is tested in primary mouse hepatocytes. In some embodiments, the knockdown level is tested in Neuro-2a cells. [000256] A dsRNA includes two RNA strands that are complementary and hybridize to form a duplex structure under the conditions in which the dsRNA will be used. One strand of a dsRNA (the antisense strand) includes a region of complementarity that is substantially complementary and, in general, fully complementary to a target sequence. The target sequence may be derived from the sequence of an mRNA formed during the expression of a MAPT gene. The other strand (the sense strand) includes a region that is complementary to the antisense strand, so that the two strands hybridize and form a duplex structure when combined under appropriate conditions. As described elsewhere in this document and as known in the art, the complementary sequences of a dsRNA may also be contained as self-complementary regions of a single nucleic acid molecule, as opposed to being in separate oligonucleotides. [000257] In general, the duplex structure has 15 to 30 base pairs in length, for example, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23 or 21-22 base pairs of length. In certain preferred embodiments, the duplex structure has 18 to 25 base pairs of length, for example, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, Petition 870260076339, dated 07 / 30 / 2026, page 99 / 2173 88 / 505 19-20, 20-25, 20-24, 20-23, 20-22, 20-21, 21-25, 21-24, 21-23, 21-22 22-25, 22-24, 22-23, 23-25, 23-24 or 24-25 base length pairs, for example, 19-21 base length pairs. Intermediate ranges and lengths between the ranges and lengths described above are also considered part of the invention. [000258] Similarly, the region of complementarity to the target sequence is 15 to 30 nucleotides long, for example, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23 or 21-22 nucleotides in length, for example, 1923 nucleotides in length or 21-23 nucleotides in length. Intermediate ranges and lengths between the ranges and lengths described above are also considered part of the invention. [000259] In some embodiments, the duplex structure is 19 to 30 base pairs long. Similarly, the region of complementarity to the target sequence is 19 to 30 nucleotides long. [000260] In some embodiments, the dsRNA is 15 to 23 nucleotides long, 19 to 23 nucleotides long, or 25 to 30 nucleotides long. In general, the dsRNA is long enough to serve as a substrate for the Dicer enzyme. For example, it is well known in the art that dsRNAs longer than about 2,123 nucleotides can serve as substrates for Dicer. As those skilled in the art will also recognize, the region of an RNA targeted for cleavage will most often be part of a larger RNA molecule, frequently an mRNA molecule. When Petition 870260076339, dated 07 / 30 / 2026, p. 100 / 2173 89 / 505 relevant, a portion of an mRNA target is a contiguous sequence of an mRNA target of sufficient length to allow it to be a substrate for RNAi-directed cleavage (i.e., cleavage via a RISC pathway). [000261] One skilled in the art will also recognize that the duplex region is a primary functional part of a dsRNA, for example, a duplex region of about 15 to 36 base pairs, for example, 15-36, 15-35, 15-34, 15-33, 15-32, 15-31, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23 or 21-22 base pairs, for example, 19-21 base pairs. Thus, in one embodiment, up to the point that it becomes processed into a functional duplex, for example, 15-30 base pairs, which targets a desired RNA for cleavage, an RNA molecule or a complex of RNA molecules having a duplex region larger than 30 base pairs is a dsRNA. Thus, someone skilled in the art will recognize that, in one embodiment, a miRNA is a dsRNA. In another embodiment, a dsRNA is not a naturally occurring miRNA. In yet another embodiment, an RNAi agent useful for targeting MAPT expression is not generated in the target cell by cleavage of a larger dsRNA. [000262] A dsRNA as described herein may also include one or more single-stranded nucleotide projections, for example, 1, 2, 3, or 4 nucleotides. A nucleotide projection may comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide / nucleoside. The projection(s) may be on the sense strand, the antisense strand, or any combination thereof. In addition, the nucleotide(s) of a projection may Petition 870260076339, dated 07 / 30 / 2026, page 101 / 2173 90 / 505 must be present on the 5' end, the 3' end, or both ends of an antisense or sense strand of a dsRNA. [000263] A dsRNA can be synthesized by standard methods known in the art. The double-stranded RNAi compounds of the invention can be prepared using a two-step procedure. First, the individual strands of the double-stranded RNA molecule are prepared separately. Then, the component strands are annealed. The individual strands of the siRNA compound can be prepared using organic synthesis in solution phase or solid phase or both. Organic synthesis offers the advantage that oligonucleotide strands comprising non-natural or modified nucleotides can be easily prepared. Similarly, the single-stranded oligonucleotides of the invention can be prepared using organic synthesis in solution phase or solid phase or both. [000264] In one aspect, a dsRNA of the invention includes at least two nucleotide sequences, a sense sequence and an antisense sequence. The sense strand sequence for MAPT can be selected from the group of sequences provided in any of Tables 3-8, 12-13, and 16-28, and the corresponding antisense nucleotide sequence of the sense strand can be selected from the group of sequences in any of Tables 3-8, 12-13, and 16-28. In this aspect, one of the two sequences is complementary to the other of the two sequences, with one of the sequences being substantially complementary to a sequence of an mRNA generated in the expression of a MAPT gene.Therefore, in this respect, a dsRNA will include two oligonucleotides, where one oligonucleotide is described as the sense strand (passenger strand) in any of Tables 3-8, 12-13, and 16-28, and the second oligonucleotide is described as the corresponding antisense strand (guide strand) of the sense strand in any of Tables 3-8, 12-13, and 16-28. Petition 870260076339, dated 07 / 30 / 2026, page 102 / 2173 91 / 505 [000265] In one embodiment, the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 512-532, 513-533, 514-534, 515-535, 516-536, 517-537, 518-538, 519-539, 520-540, 1063-1083, 1067-1087, 1072-1092, 1074-1094, 1075-1095, 1125-1145, 1126-1146, 1127-1147, 1905-1925, 1906-1926, 1909-1929, 1914-1934, 1915-1935, 1916-1936, 1958-1978, 2387-2407, 2409-2429, 2472-2492, 2476-2496, 2477-2497, 2482-2502, 2484-2504, 2762-2782, 2768-2788, 2769-2789, 2819-2839, 2944-2964, 2946-2966, 2947-2967, 3281-3301, 3282-3302, 3284-3304, 3332-3352, 3333-3353, 3334-3354, 3340-3360, 3342-3362, 3343-3363, 3347-3367, 3349-3369, 3350-3370, 3367-3387, 3368-3388, 3369-3389, 3415-3435, 3416-3436, 3417-3437, 3425-3445, 3426-3446, 3427-3447, 3431-3451, 3434-3454, 4132-4152, 4184-4204, 4395-4415, 4425-4445, 4470-4490, 4471-4491, 4472-4492, 4571-4591, 4572-4592, 4596-4616, 4725-4745, 4726-4746, 4766-4786, 4770-4790, 4779-4799, 4805-4825, 4809-4829, 4812-4832, 4813-4833, 5073-5093, 5345-5365, 5346-5366, 5460-5480, 5461-5481, 5463-5483, 5469-5489, 5470-5490, 5471-5491, 1129-1149, 1170-1190, 1395-1415, 1911-1931, 1912-1932, 1913-1933, 1919-1939, 1951-1971, 1954-1974, 2410-2430, 2469-2489, 2471-2491, 2478-2498, 2480-2500, 2481-2501, 2764-2784, 2766-2786, 2767-2787, 2821-2841, 2828-2848, 2943-2963, 3252-3272 3277-3297, 3280-3300, 3285-3305, 3286-3306, 3331-3351, 3335-3355, 3336-3356, 3338-3358, 3344-3364, 3345-3365, 3346-3366, 3353-3373, 3364-3384, 3366-3386, 3370-3390, 3412-3432, 3414-3434, 3419-3439, 3420-3440, 3424-3444, 3428-3448, 3429-3449, 3430-3450, 4134-4154, 4179-4199, 4182-4202, 4426-4446, 4429-4449, 4469-4489, 4473-4493, 4474-4494, 4569-4589, 4623-4643, 4721-4741, 4722-4742, 4767-4787, 4768-4788, 4769-4789, 4806-4826, 4807-4827, 4808-4828, 4814-4834, 4936-4956, 5072-5092, 5349-5369, 5350-5370, 5351-5371, 5465-5485, 5467-5487, 5468-5488, 5505-5525, 5506-5526, 5507-5527, Petition 870260076339, dated 07 / 30 / 2026, p. 103 / 2173 92 / 505 5508-5528, 5509-5529, 5511-5531,5513-5533, 5514-5534, 5541-5561, 5544-5564, 5546-5566, 5547-5567, 5548-5568, 5550-5570, 5551-5571, 5574-5594, 5576-5596, 5614-5634, 521-541, 522-542, 523-543, 524544, 525-545, 526-546, 527-547, 528-548, 529-549, 530-550, 531-551, 532-552, 533-553, 534-554, 535-555, 536-556, 1034-1054, 1035-1055, 1036-1056, 1037-1057, 1038-1058, 1039-1059, 1040-1060, 1041-1061, 1042-1062, 1043-1063, 1044-1064, 1045-1065, 1046-1066, 1047-1067, 1048-1068, 1049-1069, 1050-1070, 1051-1071, 1052-1072, 1053-1073, 1054-1074, 1062-1082, 1064-1084, 1065-1085, 1066-1086, 1068-1088, 1069-1089, 1070-1090, 1071-1091, 1073-1093, 1076-1096, 1077-1097, 1078-1098, 1079-1099, 1080-1100, 1081-1101, 1082-1102, 1128-1148, 1129-1149, 1130-1150, 1131-1151, 1132-1152, 1133-1153, 1134-1154, 1135-1155, 1136-1156, 1137-1157, 1138-1158, 1139-1159, 1140-1160, 1141-1161, 1142-1162, 1143-1163, 1144-1164, 1145-1165, 1146-1166, 1147-1167, 1148-1168, 975-995, 976-996, 977-997, 978-998, 979-999, 980-1000,981-1001, 982-1002, 983-1003, 984-1004, 985-1005, 986-1006, 987-1007, 988-1008, 989-1009, 990-1010, 991-1011, 992-1012, 993-1013, 994-1014, 995-1015, 996-1016, 997-1017, 998-1018, 999-1019, 1000-1020, 1001-1021, 1002-1022, 1003-1023, 1004-1024, 1005-1025, 1006-1026, 1007-1027, 1008-1028, 1009-1029, 1010-1030, 1011-1031, 1012-1032, 1013-1033, 1014-1034, 1015-1035, 1016-1036, 1017-1037, 1018-1038, 1019-1039, 1020-1040, 1021-1041, 1022-1042, 1023-1043, 1024-1044, 1025-1045, 1026-1046, 1027-1047, 1028-1048, 1029-1049, 1030-1050, 1031-1051, 1032-1052, 1033-1053, 1034-1054, 1035-1055, 1036-1056, 1037-1057, 1038-1058, 1039-1059, 1040-1060, 1041-1061, 1042-1062, 1043-1063 and 1045-1065 of SEQ ID NO: 3, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 4. [000266] In certain embodiments, the antisense polynucleotides described in this document are substantially complementary to Petition 870260076339, dated 07 / 30 / 2026, p. 104 / 2173 93 / 505 a fragment of a MAPT target sequence and comprise a contiguous nucleotide sequence that is at least 80% complementary, along its entire length, to a fragment of SEQ ID NO: 4 selected from the nucleotide group, wherein the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 520-541, 520-556, 510-534, 512-536, 516-541, 516-540, 520-544, 524-547, 526-551, 529-556, 532-556, 1065-1089, 1068-1095, 1068-1094, 1075-1100, 1076-1100, 1079-1103, 1123-1147, 1127-1151, 1130-1155, 1903-1934, 1903-1930, 1914-1940, 1949-1975, 2470-2497, 2941-2965, 3275-3302, 3278-3302, 3329-3353, 3333-3357, 3338-3367, 3338-3366, 3348-3390, 3348-3388, 3351-3385, 5507-5562 and 5549-5597 of SEQ ID NO: 3, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 4. In some embodiments,The antisense polynucleotides described herein are substantially complementary to a fragment of a MAPT target sequence and comprise a complementary contiguous nucleotide sequence, along its entire length, to a fragment of SEQ ID NO: 4 selected from the nucleotide group, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences 520-541, 520-556, 510-534, 512-536, 516-541, 516-540, 520-544, 524-547, 526-551, 529-556, 532-556, 1065-1089. 1068-1095, 1068-1094, 1075-1100, 1076-1100, 1079-1103, 1123-1147, 1127-1151, 1130-1155, 1903-1934, 1903-1930, 1914-1940, 1949-1975, 2470-2497, 2941-2965, 3275-3302, 3278-3302, 3329-3353, 3333-3357, 3338-3367, 3338-3366, 3348-3390, 3348-3388, 3351-3385, 5507-5562 and 5549-5597 of SEQ ID NO: 3,and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 4., Petition 870260076339, dated 07 / 30 / 2026, page 105 / 2173 94 / 505 [000267] In one embodiment, the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 977-997, 980-1000, 973-993, 988-1008, 987-1007, 972-992, 979-999, 1001-1021, 976-996, 994-1014, 1002-1022, 978-998, 974-994, 520-540, 521-541, 5464-5484, 1813-1833, 2378-2398, 3242-3262, 5442-5462, 1665-1685, 524-544, 5207-5227, 4670-4690, 3420-3440, 3328-3348, 5409-5429, 5439-5459, 4527-4547, 5441-5461, 5410-5430 and 5446-5466 of SEQ ID NO: 1, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 2. [000268] In one embodiment, the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-523799.1, AD-523802.1, AD-523795.1, AD-523810.1, AD523809.1, AD-1019331.1, AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD-523824.1, AD-523800.1, AD-523796.1, AD535094.1, AD-535094.1, AD-535095.1, AD-538647.1, AD-535922.1, AD-536317.1, AD-536911.1, AD-538626.1, AD-535864.1,AD523561.1, AD-523565.1, AD-523562.1, AD-526914.1, AD-526394.1, AD-395452.1, AD-525343.1, AD-524274.1, AD-526956.1,AD526986.1, AD-526296.1, AD-526988.1, AD-526957.1, AD-526993.1, AD-1397070.1, AD-1397070.2, AD-1397071.1, AD-1397071.2, AD- 1397072.1, AD-1397072.2, AD-1397073.1, AD-1397073.2, AD- 1397074.1, AD-1397074.2, AD-1397075.1, AD-1397075.2, AD- 1397076.1, AD-1397076.2, AD-1397077.1, AD-1397077.2, AD- 1397078.1, AD-1397078.2, AD-1397250.1, AD-1397251.1, AD- 1397252.1, AD-1397253.1, AD-1397254.1, AD-1397255.1, AD- 1397256.1, AD-1397257.1, AD-1397258.1, AD-1397259.1, AD- Petition 870260076339, on 07 / 30 / 2026, page. 106 / 2173 95 / 505 1397260.1, AD-1397261.1, AD-1397262.1, AD-1397263.1, AD- 1397264.1, AD-1397265.1, AD-1423242.1, AD-1423243.1, AD- 1423244.1, AD-1423245.1, AD-1423246.1, AD-1423247.1, AD- 1423248.1, AD-1423249.1, AD-1423250.1, AD-1423251.1, AD- 1423252.1, AD-1423253.1, AD-1423254.1, AD-1423255.1, AD- 1423256.1, AD-1423257.1, AD-1423258.1, AD-1423259.1, AD- 1423260.1, AD-1423261.1, AD-1423262.1, AD-1423263.1, AD- 1423264.1, AD-1423265.1, AD-1423266.1, AD-1423267.1, AD- 1423268.1, AD-1423269.1, AD-1423270.1, AD-1423271.1, AD- 1423272.1, AD-1423273.1, AD-1423274.1, AD-1423275.1, AD- 1423276.1, AD-1423277.1, AD-1423278.1, AD-1423279.1, AD- 1423280.1, AD-1423281.1, AD-1423282.1, AD-1423283.1, AD- 1423284.1, AD-1423285.1, AD-1423286.1, AD-1423287.1, AD- 1423288.1, AD-1423289.1, AD-1423290.1, AD-1423291.1, AD- 1423292.1, AD-1423293.1, AD-1423294.1, AD-1423295.1, AD- 1423296.1, AD-1423297.1, AD-1423298.1, AD-1423299.1, AD- 1423300.1, AD-1397266.1, AD-1397266.2, AD-1397267.1, AD- 1423301.1, AD-1397268.1, AD-1397268.2, AD-1397269.1, AD- 1423302.1, AD-1397270.1, AD-1397270.2, AD-1397271.1, AD- 1397271.2, AD-1397272.1, AD-1423303.1, AD-1397273.1, AD- 1423304.1, AD-1397274.1, AD-1423305.1, AD-1397275.1, AD- 1423306.1, AD-1397276.1, AD-1397277.1, AD-1397277.2, AD- 1397278.1, AD-1397279.1, AD-1397280.1, AD-1397281.1, AD- 1397282.1, AD-1397283.1, AD-1397284.1, AD-1397285.1, AD- 1397286.1, AD-1397287.1, AD-1397079.1, AD-1397079.2, AD- 1397288.1, AD-1397289.1, AD-1397290.1, AD-1397080.1, AD- 1397080.2, AD-1397291.1, AD-1397292.1, AD-1397293.1, AD- 1397294.1, AD-1397081.1, AD-1397081.2, AD-1397295.1, AD- 1397082.1, AD-1397082.2, AD-1397083.1, AD-1397083.2, AD- 1397296.1, AD-1397297.1, AD-1397298.1, AD-1397299.1, AD-. Petition 870260076339, on 07 / 30 / 2026, page. 107 / 2173 96 / 505 1397300.1, AD-1397301.1, AD-1397302.1, AD-1397084.1, AD- 1397085.1, AD-1397086.1, AD-1397303.1, AD-1397087.1, AD- 1397087.2, AD-1397304.1, AD-1397305.1, AD-1397306.1, AD- 1397307.1, AD-1397308.1, AD-1397309.1, AD-1397310.1, AD- 1397311.1, AD-1397312.1, AD-1397313.1, AD-1397314.1, AD- 1397315.1, AD-1397316.1, AD-1397317.1, AD-1397318.1, AD- 1397319.1, AD-1397320.1, AD-1397321.1, AD-1397322.1, AD- 1397088.1, AD-1397089.1, AD-1397090.1, AD-1397091.1, AD- 1397092.1, AD-1397093.1, AD-1397094.1, AD-1397095.1, AD- 1397096.1, AD-1397097.1, AD-1397098.1, AD-1397099.1, AD- 1397101.1, AD-1397102.1, AD-1397103.1, AD-1397104.1, AD- 1397105.1, AD-1397106.1, AD-1397107.1, AD-1397108.1, AD- 1397109.1, AD-1397110.1, AD-1397111.1, AD-1397112.1, AD- 1397113.1, AD-1397114.1, AD-1397115.1, AD-1397116.1, AD- 1397117.1, AD-1397118.1, AD-1397119.1, AD-1397120.1, AD- 1397121.1, AD-1397122.1, AD-1397123.1, AD-1397124.1, AD- 1397125.1, AD-1397126.1, AD-1397127.1, AD-1397128.1, AD- 1397129.1, AD-1397130.1, AD-1397131.1, AD-1397132.1, AD- 1397133.1, AD-1397134.1, AD-1397135.1, AD-1397136.1, AD- 1397137.1, AD-1397138.1, AD-1397139.1, AD-1397140.1, AD- 1397141.1, AD-1397142.1, AD-1397143.1, AD-1397144.1, AD- 1397145.1, AD-1397146.1, AD-1397147.1, AD-1397148.1, AD- 1397149.1, AD-1397150.1, AD-1397151.1, AD-1397152.1, AD- 1397153.1, AD-1397154.1, AD-1397155.1, AD-1397156.1, AD- 1397157.1, AD-1397158.1, AD-1397159.1, AD-1397160.1, AD- 1397161.1, AD-1397162.1, AD-1397163.1, AD-1397164.1, AD- 1397165.1, AD-1397166.1, AD-1397167.1, AD-1397168.1, AD- 1397169.1, AD-1397170.1, AD-1397171.1, AD-1397172.1, AD- 1397173.1, AD-1397174.1, AD-1397175.1, AD-1397176.1, AD- 1397177.1, AD-1397178.1, AD-1397179.1, AD-1397180.1, AD-. Petition 870260076339, on 07 / 30 / 2026, page. 108 / 2173 97 / 505 1397181.1, AD-1397182.1, AD-1397183.1 ,AD-1397184.1, AD- 1397185.1, AD-1397186.1, AD-1397187.1, AD-1397188.1, AD- 1397189.1, AD-1397190.1, AD-1397191.1, AD-1397192.1, AD- 1397193.1, AD-1397194.1, AD-1397195.1, AD-1397196.1, AD- 1397197.1, AD-1397198.1, AD-1397199.1, AD-1397200.1, AD- 1397201.1, AD-1397202.1, AD-1397203.1, AD-1397204.1, AD- 1397205.1, AD-1397206.1, AD-1397207.1, AD-1397208.1, AD- 1397209.1, AD-1397210.1, AD-1397211.1, AD-1397212.1, AD- 1397213.1, AD-1397214.1, AD-1397215.1, AD-1397216.1, AD- 1397217.1, AD-1397218.1, AD-1397219.1, AD-1397220.1, AD- 1397221.1, AD-1397222.1, AD-1397223.1, AD-1397224.1, AD- 1397225.1, AD-1397226.1, AD-1397227.1, AD-1397228.1, AD- 1397229.1, AD-1397230.1, AD-1397231.1, AD-1397232.1, AD- 1397233.1, AD-1397234.1, AD-1397235.1, AD-1397236.1, AD- 1397237.1, AD-1397238.1, AD-1397239.1, AD-1397240.1, AD- 1397241.1, AD-1397242.1, AD-1397243.1, AD-1397244.1, AD- 1397245.1, AD-1397246.1, AD-1397247.1, AD-1397248.1, AD- 1397249.1, AD-523565.1, AD-1397072.3, AD-1397073.3, AD- 1397076.3, AD-1397077.3, AD-1397078.3, AD-1397252.2, AD- 1397257.2, AD-1397258.2, AD-1397259.2, AD-1397263.2, AD- 1397264.2, AD-1397309.2, AD-64958.114, AD-393758.4, AD- 1397080.3, AD-1397293.2, AD-1397294.2, AD-1397081.3, AD- 1397083.3, AD-1397298.2, AD-1397299.2, AD-1397084.2, AD- 1397085.2, AD-1397087.3, AD-1397306.2, AD-1397307.2, AD-. 1397308.2, AD-1397088.2, AD-1566238, AD-1566239, AD-1566240, AD-1566241, AD-1566242, AD-1566243, AD-1566244, AD-1566245, AD-1566246, AD-1091965, AD-1566248, AD-1566249, AD-1566250, AD-1091966, AD-1566251, AD-1566252, AD-1566253, AD-1566254, AD-1566255, AD-1566256, AD-1566257, AD-1566258, AD-1566259, AD-692906, AD-1566575, AD-1566576, AD-1566577, AD-1566580, Petition 870260076339, on 07 / 30 / 2026, page. 109 / 2173 98 / 505 AD-1566581, AD-1566582, AD-1566583, AD-1566584, AD-1566586, AD-1566587, AD-1566588, AD-1566590, AD-1566591, AD-1566634, AD-1566635, AD-1566638, AD-1566639, AD-1566641, AD-1566642, AD-1566643, AD-1566679, AD-1566861, AD-1567153, AD-1567154, AD-1567157, AD-1567159, AD-1567160, AD-1567161, AD-1567164, AD-1567167, AD-1567199, AD-1567202, AD-1567550, AD-1567554, AD-1567784, AD-1567896, AD-1567897, AD-1568105, AD-1568108, AD-1568109, AD-1568139, AD-1568140, AD-1568143, AD-1568144, AD-1568148, AD-1568150, AD-1568151, AD-1568152, AD-1568153, AD-1568154, AD-1568158, AD-1568161, AD-1568172, AD-1568174, AD-1568175, AD-692908, AD-1568176, AD-1569830, AD-1569832, AD-1569834, AD-1569835, AD-1569862, AD-1569872, AD-1569890 e AD-1569892. [000269] In a particular embodiment, the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-523799.1, AD-523802.1, AD-523795.1, AD-523810.1, AD523809.1, AD-1019331.1, AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD-523824.1, AD-523800.1, AD-523796.1,AD535094.1, AD-535094.1, AD-535095.1, AD-538647.1, AD-535922.1, AD-536317.1, AD-536911.1, AD-538626.1, AD-535864.1,AD523561.1, AD-523565.1, AD-523562.1, AD-526914.1, AD-526394.1, AD-395452.1, AD-525343.1, AD-524274.1, AD-526956.1, AD-526986.1, AD-526296.1, AD-526988.1, AD-526957.1 and AD-526993.1. In one embodiment, the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-523799.1, AD-523802.1, AD-523795.1, AD-523810.1, AD-523809.1, AD-1019331.1, Petition 870260076339, dated 07 / 30 / 2026, page 110 / 2173 99 / 505 AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD523824.1, AD-523800.1 and AD-523796.1. [000270] In some embodiments, the present invention provides a dsRNA agent for inhibiting MAPT expression, wherein the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding Tau, and wherein the complementarity region comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any of the antisense nucleotide sequences in any of Tables 12-13. [000271] In one embodiment, the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 1065-1085, 1195-1215, 1066-1086, 1068-1088, 705-725, 1067-1087, 4520-4540, 3341-3361, 4515-4535, 5284-5304, 5285-5305, 344-364, 5283-5303, 5354-5374, 2459-2479, 1061-1081, 706-726, 972-992, 4564-4584, 995-1015, 4546-4566, 968-988, 1127-1147, 4534-4554, 158-178, 4494-4514, 1691-1711, 3544-3564, 198-218, 979-999, 4548-4568, 4551-4571, 543-563, 715-735, 542-562, 352-372, 362-382, 4556-4576, 4547-4567, 4542-4562, 4558-4578, 4549-4569, 5074-5094, 4552-4572, 5073-5093, 5076-5096, 4550-4570 and 2753-2773 of SEQ ID NO: 5, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 6. [000272] In one embodiment, the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-393758.1, AD-393888.1, AD-393759.1, AD-393761.1, AD393495.1, AD-393760.1, AD-396425.1, AD-395441.1, AD-396420.1, Petition 870260076339, dated 07 / 30 / 2026, page 111 / 2173 100 / 505 AD-397103.1, AD-397104.1, AD-393239.1, AD-397102.1,AD397167.1, AD-394791.1, AD-393754.1, AD-393496.1, AD-393667.1, AD-396467.1, AD-393690.1, AD-396449.1, AD-393663.1,AD393820.1, AD-396437.1, AD-393084.1, AD-396401.1, AD-394296.1, AD-395574.1, AD-393124.1, AD-393674.1, AD-396451.1,AD396454.1, AD-393376.1, AD-393505.1, AD-393375.1, AD-393247.1, AD-393257.1, AD-396459.1, AD-396450.1, AD-396445.1,AD396461.1, AD-396452.1, AD-396913.1, AD-396455.1, AD-396912.1, AD-396915.1, AD-396453.1 and AD-394991.1. [000273] In one embodiment, the nucleotide sequence of the sense strand comprises at least 15 contiguous nucleotides corresponding to the sense strand sequence of exon 10 of the MAPT gene presented in SEQ ID NO.: 1533 and an antisense strand comprising a sequence complementary to it. [000274] In one embodiment, the substantially complementary dsRNA sequences are contained on separate oligonucleotides. In another embodiment, the substantially complementary dsRNA sequences are contained on a single oligonucleotide. [000275] It will be understood that, although the sequences in Tables 68, 13, 17, 19, 21, 23, 26 and 28 are described as modified or conjugated sequences, the RNA of the RNAi agent of the invention, for example, a dsRNA of the invention, may comprise any of the sequences presented in any of Tables 3-8, 12-13 and 16-28, which are unmodified, unconjugated, or modified or conjugated differently from what is described therein. For example, although the sense strands of the agents of the invention may be conjugated with a GalNAc ligand, these agents may be conjugated with a portion that directs distribution to the CNS, for example, a C16 ligand, as described herein. In one embodiment, the lipophilic portion contains a saturated C16 hydrocarbon chain. Petition 870260076339, dated 07 / 30 / 2026, p. 112 / 2173 101 / 505 or unsaturated (e.g., a C16 alkyl or linear alkenyl). A lipophilic linker may be included at any of the positions provided in this application. In some embodiments, the lipophilic moiety is conjugated with a nucleobase, sugar moiety, or linkage between the nucleosides of the double-stranded iRNA agent. For example, a C16 linker may be conjugated through the 2'-oxygen of a ribonucleotide, as shown in the following structure: * where * signifies a linkage to an adjacent nucleotide and B is a nucleobase or a nucleobase analogue, optionally where B is adenine, guanine, cytosine, thymine or uracil. The design and synthesis of the ligands and monomers provided in this document are described, for example, in PCT publications Nos. WO2019 / 217459, WO2020 / 132227 and WO2020 / 257194, the contents of which are incorporated herein by reference in their entirety. [000276] In some embodiments, the double-stranded RNA agent further comprises a phosphate or phosphate mimic at the 5' end of the antisense strand. In one embodiment, the phosphate mimic is a 5'-vinyl phosphonate (VP). In some embodiments, the 5' end of the antisense strand of the double-stranded RNA agent does not contain a 5'-vinyl phosphonate (VP). [000277] Those skilled in the art are well aware that dsRNAs having a duplex structure of about 20 to 23 base pairs, for example, 21 base pairs, have been hailed as particularly effective in inducing RNA interference (Elbashir et al., (2001) EMBO J., 20:6877-6888). However, others have found that the structures Petition 870260076339, dated 07 / 30 / 2026, page 113 / 2173 Shorter or longer RNA duplexes (102 / 505) may also be effective (Chu and Rana (2007) RNA 14:1714-1719; Kim et al. (2005) Nat Biotech 23:222-226). In the embodiments described above, by virtue of the nature of the oligonucleotide sequences provided herein, the dsRNAs described herein may include at least one strand of a minimum length of 21 nucleotides. It can reasonably be expected that shorter duplexes, only a few nucleotides shorter at one or both ends, may be similarly effective compared to the dsRNAs described above.Consequently, dsRNAs having a sequence of at least 15, 16, 17, 18, 19, 20 or more contiguous nucleotides, derived from one of the sequences provided in this document and differing in their ability to inhibit the expression of a MAPT gene by at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95% inhibition, relative to a control level, of a dsRNA comprising the complete sequence, using the in vitro assay with, for example, A549 cells and a concentration of 10 nM of the RNA agent and the PCR assay, as provided in the examples contained herein, are considered to be within the scope of the present invention. In some embodiments, the inhibition of a dsRNA comprising the complete sequence was measured using the in vitro assay with primary mouse hepatocytes. [000278] In addition, the RNAs described herein identify (one) site(s) in a MAPT transcript that is / are susceptible to RISC-mediated cleavage. As such, the present invention further provides RNAi agents that target within this / these site(s). As used herein, an agent is said to... Petition 870260076339, dated 07 / 30 / 2026, page 114 / 2173 103 / 505 RNAi targets within a particular location of an RNA transcript if the RNAi agent promotes cleavage of the transcript anywhere within that particular location. Such an RNAi agent will generally include at least about 15 contiguous nucleotides, preferably at least 19 nucleotides, from one of the sequences provided herein linked to additional nucleotide sequences taken from the region contiguous to the selected sequence in a MAPT gene. III. Modified RNAi Agents of the Invention [000279] In one embodiment, the RNA of the RNAi agent of the invention, for example, a dsRNA, is unmodified and does not comprise, for example, chemical modifications or conjugations known in the art and described herein. In preferred embodiments, the RNA of an RNAi agent of the invention, for example, a dsRNA, is chemically modified to increase stability or other beneficial characteristics. In certain embodiments of the invention, substantially all nucleotides of an RNAi agent of the invention are modified. In other embodiments of the invention, all nucleotides of an RNAi agent of the invention are modified. The RNAi agents of the invention in which substantially all nucleotides are modified are largely, but not entirely, modified and may include no more than 5, 4, 3, 2 or unmodified nucleotides.In other embodiments of the invention, the RNAi agents of the invention may include no more than 5, 4, 3, 2, or 1 modified nucleotide. [000280] The nucleic acids presented in the invention can be synthesized or modified by methods well established in the art, such as those described in Current Protocols in Nucleic Acid Chemistry, Beaucage, SL et al. (Eds.), John Wiley & Sons, Inc., New York, NY, USA, which is hereby incorporated by reference. The modifications Petition 870260076339, dated 07 / 30 / 2026, p. 115 / 2173 104 / 505 include, for example, end modifications, such as 5' end modifications (phosphorylation, conjugation, reverse linkages) or 3' end modifications (conjugation, DNA nucleotides, reverse linkages, etc.); base modifications, such as substitution with stabilizing bases, destabilizing bases, or bases that pair with an expanded repertoire of pairs, base removal (abasic nucleotides) or conjugated bases; sugar modifications (e.g., at the 2' or 4' position) or sugar substitution; or backbone modifications, including modification or substitution of phosphodiester bonds. Specific examples of RNAi agents useful in the embodiments described herein include, but are not limited to, RNAs containing modified or unlinked backbones between natural nucleosides.RNAs having modified backbones include, among others, those that lack a phosphorus atom in the backbone. For the purposes of this descriptive report, and as sometimes mentioned in the art, modified RNAs that lack a phosphorus atom in their backbone between nucleosides may also be considered as oligonucleosides. In some embodiments, a modified RNAi agent will have a phosphorus atom in its backbone between nucleosides. [000281] Modified RNA backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates, including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates, including 3'-aminophosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters and boranephosphates having normal 3'-5' linkages, analogs linked in 2'-5' of these and those with inverted polarity in which adjacent pairs of units of Petition 870260076339, dated 07 / 30 / 2026, p. 116 / 2173 105 / 505 nucleosides are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'. Various salts, mixed salts, and free acid forms are also included. In some embodiments of the invention, the dsRNA agents of the invention are in a free acid form. In other embodiments of the invention, the dsRNA agents of the invention are in a salt form. In one embodiment, the dsRNA agents of the invention are in a sodium salt form. In certain embodiments, when the dsRNA agents of the invention are in the sodium salt form, sodium ions will be present in the agent as counter-ions for substantially all phosphodiester and / or phosphorothiotate groups present in the agent. Agents in which substantially all phosphodiester and / or phosphorothioate linkages have a sodium counter-ion include no more than 5, 4, 3, 2, or 1 phosphodiester and / or phosphorothioate linkage without a sodium counter-ion.In some embodiments, when the dsRNA agents of the invention are in the form of a sodium salt, sodium ions will be present in the agent as counter-ions for all phosphodiester and / or phosphorothiotate groups present in the agent. [000282] Representative U.S. patents teaching the preparation of the aforementioned phosphorus-containing bonds include, but are not limited to, U.S. Patents Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,195; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,316; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,625,050; 6,028,188; 6,124,445; 6,160,109; 6,169,170; 6,172,209; 6,239,265; 6,277,603; 6,326,199; 6,346,614; 6,444,423; 6,531,590; 6,534,639; 6,608,035; 6,683,167; 6,858,715; 6,867,294; 6,878,805; 7,015,315; 7,041,816; 7,273,933; 7,321,029; and US Patrol RE39464, the entire contents of each of which are incorporated herein by reference. [000283] Modified RNA main strands that do not include Petition 870260076339, dated 07 / 30 / 2026, p. 117 / 2173 106 / 505 a phosphorus atom in them have main chains that are formed by linkages between short-chain alkyl or cycloalkyl nucleosides, mixed heteroatoms and linkages between alkyl or cycloalkyl nucleosides, or one or more linkages between short-chain heteroatomic or heterocyclic nucleosides. These include those with morpholino linkages (formed, in part, from the sugar portion of a nucleoside); siloxane main chains; sulfide, sulfoxide and sulfone main chains; formacetyl and thioformacetyl main chains; methylene formacetyl and thioformacetyl main chains; alkene-containing main chains; sulfamate main chains; methyleneimino and methylenehydrazino main chains; sulfonate and sulfonamide main chains; amide main chains; and others with mixed parts of N, O, S and CH2 components. [000284] Representative U.S. patents teaching the preparation of the aforementioned oligonucleosides include, but are not limited to, U.S. Patents Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,645,62; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; and 5,677,439, the entire content of each of which is hereby incorporated into this document by reference. [000285] In other embodiments, suitable RNA mimics are considered for use in RNAi agents, wherein both the sugar and the linkage between the nucleosides, i.e., the backbone of the nucleotide units, are replaced by alternative groups. The base units are retained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an RNA mimic that has been shown to possess excellent properties of Petition 870260076339, dated 07 / 30 / 2026, pp. 118 / 2173 107 / 505 hybridization, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar backbone of an RNA is replaced by an amide-containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are linked directly or indirectly to the aza nitrogen atoms of the amide portion of the backbone. Representative US patents teaching the preparation of PNA compounds include, but are not limited to, US Patents Nos. 5,539,082; 5,714,331; and 5,719,262, the entire content of each of which is hereby incorporated by reference. Additional PNA compounds suitable for use in the RNAi agents of the invention are described, for example, in Nielsen et al., Science, 1991, 254, 1497-1500.[000286] Some embodiments presented in the invention include RNAs with phosphorothioate backbones and oligonucleosides with heteroatom backbones and, in particular, --CH2--NH-CH2-, --CH2--N(CH3)--O--CH2-- [known as a methylene (methylimino) or MMI backbone], --CH2--O--N(CH3)--CH2--, --CH2-N(CH3)--N(CH3)--CH2-- and --N(CH3)--CH2---- [where the native phosphodiester backbone is represented as --O--P--O-CH2--] of U.S. Patent No. 5,489,677 mentioned above, and the amide structures of U.S. Patent No. 5,602,240 referenced above. In some embodiments, the RNAs presented in this document have the morpholino backbone structures of US5,034,506 mentioned above. [000287] Modified RNAs may also contain one or more substituted sugar moieties. RNAi agents, for example, dsRNAs, presented in this document may include one of the following at the 2' position: OH; F; O-, S- or N-alkyl; O-, S- or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein alkyl, alkenyl and alkynyl may be C1 to C10 alkyl or C2 to C10 substituted or unsubstituted alkenyl and alkynyl. Appropriate modifications Petition 870260076339, dated 07 / 30 / 2026, p. 119 / 2173 Illustrative examples include O[(CH2)nO]mCH3, O(CH2).nOCH3, O(CH2)nNH2, O(CH2)nCH3, O(CH2)nONH2, and O(CH2)nON[(CH2)nCH3)]2, where neither are from 1 to about 10. In other embodiments, dsRNAs include one of the following at the 2' position: C1 to C10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleavage group, a reporter group, an intercalator, a group for to improve the pharmacokinetic properties of an RNAi agent or a group to improve the pharmacodynamic properties of an RNAi agent, and other substituents with similar properties. In some embodiments, the modification includes a 2'-methoxyethoxy (2'-O--CH2CH2OCH3, also known as 2'-O(2-methoxyethyl) or 2'-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78:486504), i.e., an alkoxy-alkoxy group.Another illustrative modification is 2'-dimethylamino-oxyethoxy, that is, an O(CH2)2ON(CH3)2 group, also known as 2'-DMAOE, as described in the examples below, and 2'-dimethylaminoethoxyethoxy (also known in the art as 2'-O-dimethylaminoethoxyethyl or 2'-DMAEOE), that is, 2'-O--CH2-O-CH2--N(CH2)2. Other illustrative modifications include: 5'-Me-2'-F nucleotides, 5'-Me-2'-OMe nucleotides, 5'-Me-2'-deoxynucleotides (both the R and S isomers in these three families); 2'-alkoxyalkyl; and 2'NMA (N-methylacetamide). [000288] Other modifications include 2'-methoxy (2'-OCH3), 2'-aminopropoxy (2'-OCH2CH2CH2NH2), 2'-O-hexadecyl, and 2'-fluorine (2'-F). Similar modifications can also be made at other positions on the RNA of an RNAi agent, particularly at the 3' position of the sugar over the 3'-terminal nucleotide or in dsRNAs linked at 2'-5' and at the 5' position of the 5'-terminal nucleotide. RNAi agents may also have sugar mimics, such as cyclobutyl moieties in place of the sugar. Petition 870260076339, dated 07 / 30 / 2026, pp. 120 / 2173 109 / 505 of pentofuranosyl sugar. Representative US patents teaching the preparation of such modified sugar structures include, but are not limited to, US Pats. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920, some of which are jointly owned with the present application. The entire content of each of the foregoing is hereby incorporated by reference herein. [000289] An RNAi agent of the invention may also include modifications or substitutions of nucleobases (often referred to in the art simply as bases). As used in this document, unmodified or natural nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U).Modified nucleobases include other synthetic and natural nucleobases, such as 5-methylcytosine (5-me-C), 5-hydroxymethylcytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyyl anal and other 8-substituted adenines and guanines. 5-halo, particularly 5-bromo, 5-trifluoromethyl and other uracils and cytosines substituted at 5,7-methylguanine and 7-methyladenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-da-azaadenine and 3-deazaadenine. Other nucleobases include those described in US Pat. No. 3,687.808, those described in Modified Nucleosides in Biochemistry, Biotechnology and Medicine, Herdewijn, P. ed. WileyVCH, 2008; those described in The Concise Encyclopedia Of Polymer. Petition 870260076339, dated 07 / 30 / 2026, pp. 121 / 2173 110 / 505 Science And Engineering, pages 858-859, Kroschwitz, J. L, ed. John Wiley & Sons, 1990, those described by Englisch et al., (1991) Angewandte Chemie, International Edition, 30:613, and those described by Sanghvi, Y S., Chapter 15, dsRNA Research and Applications, pages 289-302, Crooke, ST and Lebleu, B., Ed., CRC Press, 1993. Some of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds presented in the invention. These include pyrimidines substituted at 5,6-azapyrimidines and purines substituted at N-2, N-6 and O-6, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-Methylcytosine substitutions have been shown to increase the stability of the nucleic acid duplex at 0.6-1.2 °C (Sanghvi, YS, Crooke, ST and Lebleu, B., Eds., dsRNA Research and Applications, CRC Press, Boca Raton, 1993, pp.276-278) and are illustrative base substitutions, even more particularly when combined with the 2'-O-methoxyethyl sugar modifications. [000290] Representative U.S. Patents teaching the preparation of some of the above-mentioned modified nucleobases, as well as other modified nucleobases, include, but are not limited to, U.S. Patents Nos. 3,687,808, 4,845,205; 5,130,30;. 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121 5,596,091; 5,614,617; 5,681,941; 5,750,692; 6,015,886; 6,147,200; 6,166,197; 6,222,025; 6,235,887; 6,380,368; 6,528,640; 6,639,062; 6,617,438; 7,045,610; 7,427,672; and 7,495,088, the entire content of each of which is hereby incorporated into this document by reference. [000291] An RNAi agent of the invention can also be modified to include one or more blocked nucleic acids (LNA). A blocked nucleic acid is a nucleotide with a modified ribose moiety, where the ribose moiety comprises an extra bridge that Petition 870260076339, dated 07 / 30 / 2026, p. 122 / 2173 111 / 505 links the carbons at 2' and 4'. This structure effectively “locks” the ribose in the 3'-endo structural conformation. The addition of blocked nucleic acids to siRNAs has been shown to increase siRNA stability in serum and reduce off-target effects (Elmen, J. et al., (2005) Nucleic Acids Research 33(1):439-447; Mook, OR. et al., (2007) Mol Canc Ther 6(3):833-843; Grunweller, A. et al., (2003) Nucleic Acids Research 31(12):3185-3193). [000292] An RNAi agent of the invention can also be modified to include one or more bicyclic sugar moieties. A bicyclic sugar is a furanosyl ring modified by bridging two atoms. A bicyclic nucleoside (BNA) is a nucleoside with a sugar moiety comprising a bridge linking two carbon atoms of the sugar ring, thus forming a bicyclic ring system. In certain embodiments, the bridge links the 4' carbon and the 2' carbon of the sugar ring. Thus, in some embodiments, an agent of the invention may include one or more blocked nucleic acids (LNAs). A blocked nucleic acid is a nucleotide with a modified ribose moiety, wherein the ribose moiety comprises an extra bridge linking the 2' and 4' carbons. In other words, an LNA is a nucleotide comprising a bicyclic sugar moiety comprising a 4'-CH2-O-2' bridge. This structure effectively blocks ribose in the 3'-endo structural conformation.The addition of blocked nucleic acids to siRNAs has been shown to increase siRNA stability in serum and reduce off-target effects (Elmen, J. et al., (2005) Nucleic Acids Research 33(1):439-447; Mook, OR. et al., (2007) Mol Canc Ther 6(3):833-843; Grunweller, A. et al., (2003) Nucleic Acids Research 31(12):3185-3193). Examples of bicyclic nucleosides for use in the polynucleotides of the invention include, without limitation, nucleosides comprising a bridge between the 4' and 2' ribosyl ring atoms. In certain embodiments, the agents... Petition 870260076339, dated 07 / 30 / 2026, p. 123 / 2173 112 / 505 antisense polynucleotides of the invention include one or more bicyclic nucleosides comprising a 4' to 2' bridge. Examples of such 4' to 2' bridged bicyclic nucleosides include, but are not limited to, 4'-(CH2)—O-2' (LNA); 4'-(CH2)—S-2'; 4'(CH2)2—O-2' (ENA); 4'-CH(CH3)—O-2' (also referred to as restricted ethyl or cEt) and 4'-CH(CH2OCH3)—O-2' (and analogs thereof; see, for example, U.S. Pat. No. 7,399,845); 4'-C(CH3)(CH3)—O-2' (and its analogs; see, for example, U.S. Patent No. 8,278,283); 4'-CH2—N(OCH3)-2' (and its analogues; see, for example, US Patent No. 8,278,425); 4'-CH2—O—N(CH3)-2' (see, for example, US Patent Publication No. 2004 / 0171570); 4'-CH2—N(R)—O-2', wherein R is H, C1-C12 alkyl, or a protecting group (see, for example, US Pat. No. 7,427,672); 4'-CH2—C(H)(CH3)-2' (see, for example, Chattopadhyaya et al., J. Org. Chem., 2009, 74, 118-134); and 4'-CH2—C(=CH2)-2' (and its analogues; see, for example, US Patent No. 8,278,426).All the content from each of the previous sections is hereby incorporated into this document by reference. [000293] Additional representative U.S. Patents and U.S. Patent Publications teaching the preparation of blocked nucleic acid nucleotides include, but are not limited to, the following: U.S. Patents Nos. 6,268,490; 6,525,191; 6,670,461; 6,770,748; 6,794,499; 6,998,484; 7,053,207; 7,034,133; 7,084,125; 7,399,845; 7,427,672; 7,569,686; 7,741,457; 8,022,193; 8,030,467; 8,278,425; 8,278,426; 8,278,283; US 2008 / 0039618; and US 2009 / 0012281, the entire content of each of which is hereby incorporated into this document by reference. [000294] Any of the above bicyclic nucleosides can be prepared having one or more stereochemical sugar configurations, including, for example, α-L-ribofuranose and β-D-ribofuranose (see WO 99 / 14226). Petition 870260076339, dated 07 / 30 / 2026, pp. 124 / 2173 113 / 505 [000295] An RNAi agent of the invention can also be modified to include one or more restricted ethyl nucleotides. As used herein, a restricted ethyl nucleotide or cEt is a blocked nucleic acid comprising a bicyclic sugar moiety comprising a 4'-CH(CH3)-O-2' bridge. In one embodiment, a restricted ethyl nucleotide is in the S conformation, referred to herein as S-cEt. [000296] An RNAi agent of the invention may also include one or more conformationally restricted nucleotides (CRNs). CRNs are nucleotide analogs with a linker connecting the C2' and C4' carbons of ribose or the C3' and -C5' carbons of ribose. CRNs lock the ribose ring into a stable conformation and increase the hybridization affinity to mRNA. The linker is of sufficient length to place the oxygen in an ideal position for stability and affinity, resulting in less contraction of the ribose ring. [000297] Representative publications that teach the preparation of some of the CRNs mentioned above include, but are not limited to, US 2013 / 0190383; and WO 2013 / 036868, the entire content of each of which is hereby incorporated into this document by reference. [000298] In some embodiments, an RNAi agent of the invention comprises one or more monomers that are UNA (unblocked nucleic acid) nucleotides. UNA is an unblocked acyclic nucleic acid in which any of the sugar bonds have been removed, forming an unblocked sugar residue. In one example, UNA also comprises a monomer with the C1'-C4' bonds having been removed (i.e., the carbon-oxygen-carbon covalent bond between carbons C1' and C4'). In another example, the C2'C3' bond (i.e., the carbon-carbon covalent bond between carbons C2' and C3') of the sugar has been removed (see Nuc. Acids Symp. Series, 52, 133). Petition 870260076339, dated 07 / 30 / 2026, page 125 / 2173 114 / 505 134 (2008) and Fluiter et al., Mol. Biosyst., 2009, 10, 1039, incorporated herein by reference). [000299] Representative US publications that teach the preparation of UNA include, but are not limited to, US8,314,227; and US Patent Publications Nos. 2013 / 0096289; 2013 / 0011922; and 2011 / 0313020, all the content of each of them being incorporated into this document by reference. [000300] An RNAi agent of the invention may also include one or more cyclohexene nucleic acids or (CeNA). CeNAs are nucleotide analogs with a substitution of the furanose portion of DNA for a cyclohexene ring. The incorporation of cyclohexenyl nucleosides into a DNA strand increases the stability of a DNA / RNA hybrid. CeNA is stable against degradation in serum and a CeNA / RNA hybrid is capable of activating E. coli RNase H, resulting in cleavage of the RNA strand (see Wang et al., Am. Chem. Soc. 2000, 122, 36, 8595-8602, hereby incorporated by reference). [000301] Potentially stabilizing modifications at the ends of RNA molecules may include N-(acetylaminocaproyl)4-hydroxyprolinol (Hyp-C6-NHAc), N-(caproyl-4-hydroxyprolinol (HypC6), N-(acetyl-4-hydroxyprolinol (Hyp-NHAc), thymidine-2'-O-deoxythymidine (ether), N-(aminocaproyl)-4-hydroxyprolinol (Hyp-C6-amino), 2-docosanoyl-uridine-3-phosphate, the inverted base dT (idT), and others. The invention for this modification can be found in WO 2011 / 005861. [000302] Other modifications of an RNAi agent of the invention include a 5' phosphate or 5' phosphate mimic, for example, a 5' terminal phosphate or phosphate mimic on the antisense strand of an RNAi agent. Suitable phosphate mimics are described, for example, in US 2012 / 0157511, the full contents of which are incorporated herein by reference. A. Modified RNAi Agents Comprising Reasons for the Invention Petition 870260076339, dated 07 / 30 / 2026, pp. 126 / 2173 115 / 505 [000303] In certain aspects of the invention, the double-stranded RNAi agents of the invention include agents with chemical modifications, as described, for example, in WO 2013 / 075035, the entire content of which is incorporated herein by reference. As shown herein and in WO 2013 / 075035, a superior result can be obtained by introducing one or more motifs of three identical modifications on three consecutive nucleotides in a sense or antisense strand of an RNAi agent, particularly at, or near, the cleavage site. In some embodiments, the sense and antisense strands of the RNAi agent may otherwise be completely modified. The introduction of these motifs disrupts the modification pattern, if present, of the sense or antisense strand. The RNAi agent may optionally be conjugated with a lipophilic linker, for example, a C16 linker, on the sense strand.The RNAi agent can optionally be modified with a nucleic acid (S)-glycol (GNA) modification, for example, on one or more residues of the antisense strand. The resulting RNAi agents exhibit superior gene silencing activity. [000304] Consequently, the invention provides double-stranded RNAi agents capable of inhibiting the expression of a target gene (i.e., a MAPT gene) in vivo. The RNAi agent comprises a sense strand and an antisense strand. Each strand of the RNAi agent can be 15-30 nucleotides long. For example, each strand may be 1630 nucleotides long, 17-30 nucleotides long, 25-30 nucleotides long, 27-30 nucleotides long, 17-23 nucleotides long, 17-21 nucleotides long, 17-19 nucleotides long, 19-25 nucleotides long, 19-23 nucleotides long, 19-21 nucleotides long, 21-25 nucleotides long, or 21-23 nucleotides long. In certain embodiments, each strand is 19... (Petition 870260076339, dated 07 / 30 / 2026, page 127 / 2173) 116 / 505 nucleotides in length. [000305] The sense strand and the antisense strand typically form a duplex double-stranded RNA (dsRNA), also referred to in this document as an RNAi agent. The duplex region of an RNAi agent can be 15-30 nucleotide pairs long. For example, the duplex region can be 16-30 nucleotide pairs long, 17-30 nucleotide pairs long, 27-30 nucleotide pairs long, 17-23 nucleotide pairs long, 17-21 nucleotide pairs long, 17-19 nucleotide pairs long, 19-25 nucleotide pairs long, 19-23 nucleotide pairs long, 19-21 nucleotide pairs long, 21-25 nucleotide pairs long, or 21-23 nucleotide pairs long. In another example, the duplex region is selected from nucleotides 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27 in length.In preferred embodiments, the duplex region is 19-21 nucleotide pairs long. [000306] In one embodiment, the RNAi agent may contain one or more projection regions or capping groups at the 3' end, the 5' end, or both ends of one or both strands. The projection may be 1-6 nucleotides long, for example, 2-6 nucleotides long, 1-5 nucleotides long, 2-5 nucleotides long, 1-4 nucleotides long, 2-4 nucleotides long, 1-3 nucleotides long, 2-3 nucleotides long, or 1-2 nucleotides long. In preferred embodiments, the nucleotide projection region is 2 nucleotides long. The projections can be the result of one ribbon being longer than the other, or the result of two ribbons of the same length being staggered.The projection may form a mismatch with the target mRNA, or it may be complementary to the sequences of the target genes, or it may be something else. Petition 870260076339, dated 07 / 30 / 2026, p. 128 / 2173 117 / 505 sequence. The first and second tapes can also be joined, for example, by additional bases to form a staple or by other binders that are not bases. [000307] In one embodiment, the nucleotides in the RNAi agent projection region may each independently be a modified or unmodified nucleotide, including, but not limited to, modified with 2'-sugar, such as 2-F, 2'-O-methyl, thymidine (T), and any combination thereof. [000308] For example, TT can be a sequence projecting to either end on any strand. The projection can form a mismatch with the target mRNA, or it can be complementary to the sequences of the genes that are targets, or it can be another sequence altogether. [000309] The 5' or 3' projections on the sense strand, the antisense strand, or both strands of the RNAi agent can be phosphorylated. In some embodiments, the projection region(s) contain(s) two nucleotides with a phosphorothioate between the two nucleotides, where the two nucleotides may be the same or different. In one embodiment, the projection is present at the 3' end of the sense strand, the antisense strand, or both strands. In one embodiment, this 3' projection is present on the antisense strand. In one embodiment, this 3' projection is present on the sense strand. [000310] The RNAi agent may contain only a single projection, which can strengthen the RNAi's interference activity without affecting its overall stability. For example, the single-stranded projection may be located at the 3' terminal end of the sense strand or, alternatively, at the 3' terminal end of the antisense strand. RNAi may also have a blunt end, located at the 5' end of the antisense strand (or at the 3' end of the sense strand) or vice versa. In general, the antisense strand of RNAi has a nucleotide projection at the 3' end and the 5' end is blunt. Although undesirable Petition 870260076339, dated 07 / 30 / 2026, page 129 / 2173 118 / 505 being limited by theory, the asymmetrical blunt end at the 5' end of the antisense tape and the projection at the 3' end of the antisense tape favor the loading of the guide tape in the RISC process. [000311] In one embodiment, the RNAi agent has two blunt ends and is 19 nucleotides long, wherein the sense strand contains at least one motif of three 2'-F modifications on three consecutive nucleotides, at positions 7, 8, 9 from the 5' end. The antisense strand contains at least one motif of three 2'-O-methyl modifications on three consecutive nucleotides, at positions 11, 12, 13 from the 5' end. [000312] In another embodiment, the RNAi agent has two blunt ends and is 20 nucleotides long, wherein the sense strand contains at least one motif of three 2'-F modifications on three consecutive nucleotides, at positions 8, 9, 10 from the 5' end. The antisense strand contains at least one motif of three 2'-O-methyl modifications on three consecutive nucleotides, at positions 11, 12, 13 from the 5' end. [000313] In yet another embodiment, the RNAi agent has two blunt ends and is 21 nucleotides long, wherein the sense strand contains at least one motif of three 2'-F modifications on three consecutive nucleotides, at positions 9, 10, 11 from the 5' end. The antisense strand contains at least one motif of three 2'-O-methyl modifications on three consecutive nucleotides, at positions 11, 12, 13 from the 5' end. [000314] In one embodiment, the RNAi agent comprises a 21-nucleotide sense strand and a 23-nucleotide antisense strand, wherein the sense strand contains at least one motif of three 2'-F modifications on three consecutive nucleotides, at positions 9, 10, 11 from the 5' end; the antisense strand contains at least one motif of Petition 870260076339, dated 07 / 30 / 2026, page 130 / 2173 119 / 505 Three 2'-O-methyl modifications on three consecutive nucleotides, at positions 11, 12, 13 from the 5' end, wherein one end of the RNAi agent is blunt, while the other end comprises a 2-nucleotide projection. Preferably, the 2-nucleotide projection is at the 3' end of the antisense strand. When the 2-nucleotide projection is at the 3' end of the antisense strand, there may be two phosphorothioate nucleotide linkages between the three terminal nucleotides, wherein two of the three nucleotides are the projection nucleotides and the third nucleotide is a paired nucleotide close to the projection nucleotide. In one embodiment, the RNAi agent additionally has two phosphorothioate nucleotide linkages between the three terminal nucleotides at both the 5' end of the sense strand and the 5' end of the antisense strand.In one embodiment, each nucleotide in the sense and antisense strands of the RNAi agent, including the nucleotides that are part of the motifs, are modified nucleotides. In another embodiment, each residue is independently modified with a 2'-O-methyl or 3'-fluorine group, for example, in an alternate motif. Optionally, the RNAi agent further comprises a linker (e.g., a lipophilic linker, optionally a C16 linker). [000315] In one embodiment, the RNAi agent comprises a sense strand and an antisense strand, wherein the sense strand is 25-30 nucleotide residues long, in which, from the 5' terminal nucleotide (position 1), positions 1 to 23 of the first strand comprise at least 8 ribonucleotides; the antisense strand is 36-66 nucleotide residues long and, from the 3' terminal nucleotide, comprises at least 8 ribonucleotides in positions paired with positions 1-23 of the sense strand to form a duplex; wherein at least the 3' terminal nucleotide of the antisense strand is not paired with the sense strand and up to 6 consecutive 3' terminal nucleotides are not. Petition 870260076339, dated 07 / 30 / 2026, pp. 131 / 2173 120 / 505 paired with the sense strand, thus forming a 3' single-stranded projection of 1-6 nucleotides; wherein the 5' end of the antisense strand comprises 10-30 consecutive nucleotides, which are not paired with the sense strand, thus forming a 5' single-stranded projection of 10-30 nucleotides; wherein at least the 5'-terminal and 3'-terminal nucleotides of the sense strand are base-paired with the nucleotides of the antisense strand, when the sense and antisense strands are aligned for maximum complementarity, thus forming a substantially duplex region between the sense and antisense strands; and the antisense strand is sufficiently complementary to a target RNA along at least 19 ribonucleotides of antisense strand length to reduce the expression of the target gene when the double-stranded nucleic acid is introduced into a mammalian cell;and wherein the sense strand contains at least one motif of three 2'-F modifications on three consecutive nucleotides, where at least one of the motifs occurs at, or near, the cleavage site. The antisense strand contains at least one motif of three 2'-O-methyl modifications on three consecutive nucleotides, at, or near, the cleavage site. [000316] In one embodiment, the RNAi agent comprises sense and antisense strands, wherein the RNAi agent comprises a first strand with a length that is at least 25 and at most 29 nucleotides and a second strand with a length that is at most 30 nucleotides with at least one motif of three 2'O-methyl modifications on three consecutive nucleotides, at positions 11, 12, 13 from the 5' end; wherein the 3' end of the first strand and the 5' end of the second strand form a blunt end and the second strand is 1-4 nucleotides longer at its 3' end than the first strand, wherein the duplex region is at least 25 nucleotides long, and the second strand is sufficiently Petition 870260076339, dated 07 / 30 / 2026, page 132 / 2173 121 / 505 complementary to a target mRNA, along at least 19 nucleotides of second-strand length, to reduce target gene expression when the RNAi agent is introduced into a mammalian cell, and wherein cleavage of the RNAi agent with the dicer preferably results in an siRNA comprising the 3' end of the second strand, thus reducing target gene expression in the mammal. Optionally, the RNAi agent further comprises a linker. [000317] In one embodiment, the sense strand of the RNAi agent contains at least one motif of three identical modifications on three consecutive nucleotides, where one of the motifs occurs at the cleavage site on the sense strand. [000318] In one embodiment, the antisense strand of the RNAi agent may also contain at least one motif of three identical modifications on three consecutive nucleotides, where one of the motifs occurs at, or near, the cleavage site on the antisense strand. [000319] For an RNAi agent with a duplex region of 17-23 nucleotides in length, the cleavage site of the antisense strand is typically around positions 10, 11, and 12 from the 5' end. Thus, motifs of three identical modifications can occur at positions 9, 10, 11; positions 10, 11, 12; positions 11, 12, 13; positions 12, 13, 14; or positions 13, 14, 15 of the antisense strand, counting from the 1st nucleotide from the 5' end of the antisense strand or counting from the 1st paired nucleotide within the duplex region from the 5' end of the antisense strand. The cleavage site on the antisense strand can also change according to the length of the RNAi duplex region from the 5' end. [000320] The sense strand of the RNAi agent may contain at least one motif of three identical modifications on three consecutive nucleotides at the strand's cleavage site; and the antisense strand may have at least one motif of three identical modifications on three nucleotides. Petition 870260076339, dated 07 / 30 / 2026, pp. 133 / 2173 122 / 505 consecutive nucleotides at, or near, the cleavage site of the strand. When the sense strand and the antisense strand form a dsRNA duplex, the sense strand and the antisense strand may be aligned so that a motif of three nucleotides on the sense strand and a motif of three nucleotides on the antisense strand have at least one nucleotide overlap, that is, at least one of the three nucleotides of the motif on the sense strand forms a base pair with at least one of the three nucleotides of the motif on the antisense strand. Alternatively, at least two nucleotides may overlap, or all three nucleotides may overlap. [000321] In one embodiment, the sense strand of the RNAi agent may contain more than one motif of three identical modifications at three consecutive nucleotides. The first motif may occur at, or near, the cleavage site of the strand, and the other motifs may be a wing modification. The term wing modification, in this document, refers to a motif that occurs elsewhere on the strand that is separate from the motif at, or near, the cleavage site of the same strand. The wing modification is adjacent to the first motif or is separated by at least one or more nucleotides. When the motifs are immediately adjacent to each other, then the chemistries of the motifs are distinct from each other, and when the motifs are separated by one or more nucleotides, then the chemistries may be the same or different. Two or more wing modifications may be present.For example, when two extension modifications are present, each extension modification may occur at one end relative to the first motif, which is at, or near, the cleavage site, or on either side of the primary motif. [000322] Like the sense strand, the antisense strand of the RNAi agent can contain more than one motif of three identical modifications in three Petition 870260076339, dated 07 / 30 / 2026, page 134 / 2173 123 / 505 consecutive nucleotides, with at least one of the motifs occurring at, or near, the cleavage site of the strand. This antisense strand may also contain one or more extensional modifications in an alignment similar to the extensional modifications that may be present on the sense strand. [000323] In one embodiment, the modification in the extension over the sense strand or the antisense strand of the RNAi agent typically does not include the first or the two terminal nucleotides at the 3' end, at the 5' end, or at both ends of the strand. [000324] In another embodiment, the modification in the extension over the sense strand or the antisense strand of the RNAi agent typically does not include the first or both paired nucleotides within the duplex region at the 3' end, at the 5' end, or at both ends of the strand. [000325] When the sense strand and the antisense strand of the RNAi agent each contain at least one extension modification, the extension modifications may occur on the same end of the duplex region and have an overlap of one, two, or three nucleotides. [000326] When the sense strand and the antisense strand of the RNAi agent each contain at least two extension modifications, the sense strand and the antisense strand may be aligned so that two modifications, each from one strand, occur at one end of the duplex region, having an overlap of one, two, or three nucleotides; two modifications, each from one strand, occur at the other end of the duplex region, having an overlap of one, two, or three nucleotides; two modifications from one strand occur on each side of the main motif, having an overlap of one, two, or three nucleotides in the duplex region. [000327] In one embodiment, the RNAi agent comprises erroneous pairing(s) with the target, within the duplex, or its Petition 870260076339, dated 07 / 30 / 2026, page 135 / 2173 124 / 505 combinations. Erroneous pairing can occur in the projection region or the duplex region. The basis pair can be classified based on its propensity to promote dissociation or fusion (e.g., in the free energy of association or dissociation of a particular pairing, the simplest approach is to examine the pairs on an individual pair basis, although analysis by nearest neighbor or similar can also be used). In terms of dissociation promotion: A:U is preferred to G:C; G:U is preferred to G:C; and I:C is preferred to G:C (I=inosine). Erroneous pairings, for example, non-canonical or different pairings (as described elsewhere in this document), are preferred to canonical pairings (A:T, A:U, G:C); and pairings that include a universal basis are preferred to canonical pairings. [000328] In one embodiment, the RNAi agent comprises at least one of the first 1, 2, 3, 4, or 5 base pairs within the 5' end duplex regions of the antisense strand, independently selected from the group of: A:U, G:U, I:C, and pairs with erroneous pairings, for example, non-canonical or different pairings or pairings that include a universal base, to promote dissociation of the antisense strand at the 5' end of the duplex. [000329] In one embodiment, the nucleotide at position 1 within the 5' end duplex region of the antisense strand is selected from the group consisting of A, dA, dU, U, and dT. Alternatively, at least one of the first 1, 2, or 3 base pairs within the 5' end duplex region of the antisense strand is an AU base pair. For example, the first base pair within the 5' end duplex region of the antisense strand is an AU base pair. [000330] In another embodiment, the nucleotide at the 3' end of the sense strand is deoxythymine (dT). In another embodiment, the nucleotide at the 3' end of the antisense strand is deoxythymine (dT). In a Petition 870260076339, dated 07 / 30 / 2026, page 136 / 2173 In the 125 / 505 modality, there is a short sequence of deoxythymine nucleotides, for example, two dT nucleotides on the 3' end of the sense or antisense strand. [000331] In one embodiment, the sense tape sequence can be represented by formula (I): 5' np-Na-(XX )i-Nb-Y Y -Nb-(Z )j-Na-nq 3' (I) where: iej are, each independently, 0 or 1; small are, each independently, 0-6; Each Na independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; Each Nb independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; Each np and nq independently represents a nucleotide in the projection; where Nb and Y do not have the same modification; and XXX, YYY, and ZZZ each independently represent a motif of three identical modifications in three consecutive nucleotides. Preferably, YYY is all nucleotides modified with 2'-F. [000332] In one embodiment, Na or Nb comprises alternating pattern modifications. [000333] In one embodiment, the YYY motif occurs at, or near, the cleavage site of the sense strand. For example, when the RNAi agent has a duplex region of 17-23 nucleotides in length, the YYY motif may occur at or in the vicinity of the cleavage site (e.g., it may occur at positions 6, 7, 8, 7, 8, 9, 8, 9, 10, 9, 10, 11, 10, 11, 12 or 11, 12, 13) of the sense strand, counting from Petition 870260076339, dated 07 / 30 / 2026, page 137 / 2173 126 / 505 of the 1st nucleotide, starting from the 5' end; or optionally, counting starting at the 1st paired nucleotide within the duplex region, from the 5' end. [000334] In one embodiment, i is 1 and j is 0, or i is 0 and j is 1, or both i and j are 1. The sense tape can therefore be represented by the following formulas: 5' np-Na-YYY-Nb-ZZZ-Na-nq 3' (Ib); 5' np-Na-XXX-Nb-YYY-Na-nq 3' (Ic); or 5' np-Na-XXX-Nb-YYY-Nb-ZZZ-Na-nq 3' (Id). [000335] When the sense strand is represented by the formula (Ib), Nb represents an oligonucleotide sequence comprising 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. [000336] Each Na independently can represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. [000337] When the sense strand is represented as formula (Ic), Nb represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na can independently represent an oligonucleotide sequence comprising 2-20, 2-15 or 2-10 modified nucleotides. [000338] When the sense strand is represented as formula (Id), each Nb independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-5, 0-4, 0-2, or 0 modified nucleotides. Preferably, Nb is 0, 1, 2, 3, 4, 5, or 6. Each Na can independently represent an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. [000339] Each of X, Y, and Z can be equal to or different from one another. [000340] In other forms, i is 0 and j is 0, and the sense strip can be represented by the formula: 5' np-Na-YYY-Na-nq 3' (Ia). Petition 870260076339, dated 07 / 30 / 2026, page 138 / 2173 127 / 505 [000341] When the sense strand is represented by the formula (Ia), each Na independently can represent an oligonucleotide sequence comprising 2-20, 2-15 or 2-10 modified nucleotides. [000342] In one embodiment, the antisense strand sequence of RNAi can be represented by formula (II): 5' nq-Na'-(Z'Z'Z')k-Nb'-YW-Nb'-(X'X'X')l-N'a-np' 3' (II) where: kel are, each independently, 0 or 1; p' eq' are, each independently, 0-6; Each Na' independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; each Nb' independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; Each np' and nq' independently represents a nucleotide in the projection; where Nb' and Y' do not have the same modification; X'X'X', Y'Y'Y', and Z'Z'Z' each independently represent a motif of three identical modifications in three consecutive nucleotides. [000343] In one embodiment, Na' or Nb' comprises alternating pattern modifications. [000344] The Y'Y'Y' motif occurs at, or near, the cleavage site of the antisense strand. For example, when the RNAi agent has a duplex region of 17-23 nucleotides in length, the Y'Y'Y' motif may occur at positions 9, 10, 11; 10, 11, 12; 11, 12, 13; 12, 13, 14; or 13, 14, 15 of the antisense strand, with counting starting from the 1st nucleotide from the 5' end; or optionally, counting starting from the 1st paired nucleotide within the duplex region, from the Petition 870260076339, dated 07 / 30 / 2026, page 139 / 2173 128 / 505 end 5'. Preferably, the Y'Y'Y' motif occurs in positions 11, 12, 13. [000345] In one embodiment, the Y'Y'Y' motif is all nucleotides modified with 2'-OMe. [000346] In one embodiment, k is 1 and el is 0, or k is 0 and el is 1, or both kel are 1. [000347] The nonsense tape can therefore be represented by the following formulas: 5' nq'-Na'-Z'Z'Z'-Nb'-Y'W-Na'-np' 3' (IIb); 5' nq'-Na'-Y'Y'Y'-Nb'-X'X'X'-np' 3' (IIc); or 5' nq'-Na'-Z'Z'Z'-Nb'-Y'Y'Y'-Nb'-X'X'X'-Na'-np' 3' (IId). [000348] When the antisense strand is represented by formula (IIb), Nb' represents an oligonucleotide sequence comprising 010, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2, or 0 modified nucleotides. Each Na' independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. [000349] When the antisense strand is represented as formula (IIc), Nb' represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na' independently represents an oligonucleotide sequence comprising 2-20, 2-15 or 2-10 modified nucleotides. [000350] When the antisense strand is represented as formula (IId), each Nb' independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2, or 0 modified nucleotides. Each Na' independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. Preferably, Nb is 0, 1, 2, 3, 4, 5, or 6. [000351] In other modes, k is 0 and el is 0 and the nonsense tape can be represented by the formula: 5' np'-Na'-Y'Y'Y'- Na'-nq' 3' (Ia). Petition 870260076339, dated 07 / 30 / 2026, pp. 140 / 2173 129 / 505 [000352] When the antisense strand is represented as formula (lla), each Na' independently represents an oligonucleotide sequence comprising 2-20, 2-15 or 2-10 modified nucleotides. [000353] Each of X', Y' and Z' can be the same or different from each other. [000354] Each nucleotide of the sense and antisense strands can be independently modified with LNA, HNA, CeNA, 2'-methoxyethyl, 2'-O-methyl, 2'-O-allyl, 2'-C-allyl, 2'-hydroxyl, or 2'-fluorine. For example, each nucleotide of the sense and antisense strands is independently modified with 2'-O-methyl or 2'-fluorine. Each X, Y, Z, X', Y', and Z', in particular, can represent a 2'-O-methyl modification or a 2'-fluorine modification. [000355] In one embodiment, the RNAi agent sense strand may contain the YYY motif occurring at positions 9, 10, and 11 of the strand when the duplex region is 21 nt long, counting from the 1st nucleotide from the 5' end or, optionally, counting from the 1st paired nucleotide within the duplex region from the 5' end; and Y represents the 2'-F modification. The sense strand may additionally contain the XXX motif or the ZZZ motifs as extension modifications at the opposite end of the duplex region; and XXX and ZZZ each independently represent a 2'-OMe modification or a 2'-F modification. [000356] In one embodiment, the antisense strand may contain the Y'Y'Y' motif occurring at positions 11, 12, 13 of the strand, counting from the 1st nucleotide, from the 5' end, or optionally, counting from the 1st paired nucleotide within the duplex region, from the 5' end; and Y' represents the 2'-O-methyl modification. The antisense strand may additionally contain the X'X'X' motif or the Z'Z'Z' motifs as extension modifications at the end. Petition 870260076339, dated 07 / 30 / 2026, pp. 141 / 2173 130 / 505 opposite of the duplex region; and X'X'X' and Z'Z'Z', each independently, represent a 2'-OMe modification or a 2'-F modification. [000357] The sense strip, represented by any of the formulas (Ia), (Ib), (Ic) and (Id) mentioned above, forms a duplex with an antisense strip that is represented by any of the formulas (IIa), (IIb), (IIc) and (IId), respectively. [000358] Consequently, the RNAi agents for use in the methods of the invention may comprise a sense strand and an antisense strand, each strand having 14 to 30 nucleotides, the RNAi duplex represented by formula (III): sense: 5' np -Na-(XXX)i -Nb- YYY -Nb -(ZZZ)j-Na-nq 3' antisense: 3' np'-Na'-(X'X'X')k-Nb'-Y'Y'Y'-Nb'-(Z'Z'Z')l-Na'-nq' 5' (III) where: i, j, kel are, each independently, 0 or 1; p, p', qeq' are, each independently, 0-6; Each Na and Na' independently represents an oligonucleotide sequence comprising 0-25 modified nucleotides, each sequence comprising at least two differently modified nucleotides; Each Nb and Nb' independently represents an oligonucleotide sequence comprising 0-10 modified nucleotides; where each np', np, nq' and nq, each of which may or may not be present, independently represents a nucleotide of the projection; and XXX, YYY, ZZZ, X'X'X', Y'Y'Y', and Z'Z'Z', each independently, represent a motif of three identical modifications in three consecutive nucleotides. [000359] In one embodiment, i is 0 and j is 0; or i is 1 and j is 0; or i is 0 and j Petition 870260076339, dated 07 / 30 / 2026, pp. 142 / 2173 131 / 505 is 1; or both iej are 0; or both iej are 1. In another way, k is 0 el is 0; or k is 1 el is 0; k is 0 el is 1; or both kel are 0; or both kel are 1. [000360] Illustrative combinations of the sense strand and antisense strand forming an RNAi duplex include the formulas below: 5' np- Na-Y YY -Na-nq 3' 3' np'-Na'-Y'Y'Y' -Na'nq' 5' (IIIa) 5' np -Na -YYY -Nb -ZZZ -Na-nq 3' 3' np'-Na'-Y'Y'Y'-Nb'-Z'Z'Z'-Na'nq' 5' (IIIb) 5' np-Na- XXX -Nb -YYY - Na-nq 3' 3' np'-Na'-X'X'X'-Nb'-Y'Y'Y'-Na'-nq' 5' (IIIc) 5' np -Na -XXX -Nb-Y YY -Nb- ZZZ -Na-nq 3' 3' np'-Na'-X'X'X'-Nb'-Y'Y'Y'-Nb'-Z'Z'Z'-Na-nq' 5' (IIId) [000361] When the RNAi agent is represented by formula (IIIa), each Na independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. [000362] When the RNAi agent is represented by the formula (IIIb), each Nb independently represents an oligonucleotide sequence comprising 1-10, 1-7, 1-5, or 1-4 modified nucleotides. Each Na independently represents an oligonucleotide sequence comprising 2-20, 2-15, or 2-10 modified nucleotides. [000363] When the RNAi agent is represented as formula (IIIc), each Nb, Nb' independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na independently represents an oligonucleotide sequence comprising 2-20, 2-15 or 2-10 modified nucleotides. [000364] When the RNAi agent is represented as a formula Petition 870260076339, dated 07 / 30 / 2026, pp. 143 / 2173 132 / 505 (IIId), each Nb, Nb' independently represents an oligonucleotide sequence comprising 0-10, 0-7, 0-10, 0-7, 0-5, 0-4, 0-2 or 0 modified nucleotides. Each Na, Na' independently represents an oligonucleotide sequence comprising 2-20, 2-15 or 210 modified nucleotides. Each of Na, Na', Nb and Nb' independently comprises alternating pattern modifications. [000365] In one embodiment, when the RNAi agent is represented by formula (IIId), the Na modifications are 2'-O-methyl or 2'-fluorine modifications. In another embodiment, when the RNAi agent is represented by formula (IIId), the Na modifications are 2'-O-methyl or 2'-fluorine modifications and np' >0 and at least one np' is linked to a neighboring nucleotide via a phosphorothioate linkage. In yet another embodiment, when the RNAi agent is represented by formula (IIId), the Na modifications are 2'-O-methyl or 2'-fluorine modifications, np' >0 and at least one np' is linked to a neighboring nucleotide via a phosphorothioate linkage, and the sense strand is conjugated with one or more C16 (or related) moieties linked through a bivalent or trivalent branched ligand (described below).In another embodiment, when the RNAi agent is represented by formula (IIId), the Na modifications are 2'-O-methyl or 2'-fluorine modifications, np' >0 and at least one np' is linked to a neighboring nucleotide via a phosphorothioate linkage, the sense strand comprises at least one phosphorothioate linkage and the sense strand is conjugated with one or more lipophilic moieties, for example, of C16 (or related), optionally linked via a bivalent or trivalent branched linker. [000366] In one embodiment, when the RNAi agent is represented by formula (IIIa), the Na modifications are 2'O-methyl or 2'-fluorine modifications, np' >0 and at least one np' is linked to a neighboring nucleotide via a phosphorothioate linkage, the sense strand comprises at least one phosphorothioate linkage, and the sense strand is conjugated with a Petition 870260076339, dated 07 / 30 / 2026, p. 144 / 2173 133 / 505 or more lipophilic parts, for example, of C16 (or related), linked through a branched bivalent or trivalent ligand. [000367] In one embodiment, the RNAi agent is a multimer containing at least two duplexes represented by formulas (III), (IIIa), (IIIb), (IIIc) and (IIId), wherein the duplexes are linked by a linker. The linker may be cleavable or non-cleavable. Optionally, the multimer further comprises a linker. Each of the duplexes may be directed to the same gene or two different genes; or each of the duplexes may be directed to the same gene at two different target sites. [000368] In one embodiment, the RNAi agent is a multimer containing three, four, five, six or more duplexes represented by formulas (III), (IIIa), (IIIb), (IIIc) and (IIId), wherein the duplexes are linked by a linker. The linker may be cleavable or non-cleavable. Optionally, the multimer further comprises a linker. Each of the duplexes may be directed to the same gene or two different genes; or each of the duplexes may be directed to the same gene at two different target sites. [000369] In one embodiment, two RNAi agents represented by formulas (III), (IIIa), (IIIb), (IIIc) and (IIId) are linked to each other at the 5' end, and at one or both 3' ends, and are optionally conjugated with a linker. Each of the agents may be directed to the same gene or two different genes; or each of the agents may be directed to the same gene at two different save sites. [000370] Several publications describe multimeric RNAi agents that can be used in the methods of the invention. Such publications include WO2007 / 091269, WO2010 / 141511, WO2007 / 117686, WO2009 / 014887 and WO2011 / 031520; and US 7858769, the entire content of each of which is hereby incorporated herein. Petition 870260076339, dated 07 / 30 / 2026, pp. 145 / 2173 134 / 505 document by reference. [000371] In certain embodiments, the compositions and methods of the invention include a vinyl phosphonate (VP) modification of an RNAi agent as described in this document. In illustrative embodiments, a vinyl phosphonate of the invention has the following structure: Ox THE [000372] A vinyl phosphonate of the present invention can be linked to the antisense or sense strand of a dsRNA of the invention. In certain embodiments, a vinyl phosphonate of the present invention is optionally linked to the antisense strand of a dsRNA at the 5' end of the antisense strand of the dsRNA. The dsRNA agent may comprise a phosphorus-containing group at the 5' end of the sense or antisense strand. The phosphorus-containing group at the 5' end may be 5'-end phosphate (5'-P), 5'-end phosphorothioate (5'-PS), 5'-end phosphorodithioate (5'-PS2), 5'-end vinyl phosphonate (5VP), 5'-end methyl phosphonate (MePhos), or 5'-deoxy-5'-C-malonyl. When the phosphorus-containing group at the 5' end is vinyl phosphonate at the 5' end (5'-VP), the 5'-VP may be the 5'-E-VP isomer (i.e., trans-vinyl phosphate), the cis-vinyl phosphate isomer, or mixtures thereof. [000373] For example, when the phosphate mimic is a 5'-vinyl phosphonate (VP), the 5'-terminal nucleotide may have the following structure, Petition 870260076339, dated 07 / 30 / 2026, pp. 146 / 2173 135 / 505 where * indicates the location of the bond at the 5' position of the adjacent nucleotide; R is hydrogen, hydroxyl, methoxy, or fluorine (for example, hydroxyl); and B is a nucleobase or a modified nucleobase, optionally where B is adenine, guanine, cytosine, thymine, or uracil. [000374] Vinyl phosphate modifications are also considered for the compositions and methods of the present invention. An illustrative vinyl phosphate structure is: O - P - OH I OH i. Thermally Destabilizing Modifications [000375] In certain embodiments, a dsRNA molecule can be optimized for RNA interference by incorporating thermally destabilizing modifications in the seed region of the antisense strand (i.e., at positions 2-9 of the 5' end of the antisense strand) to reduce or inhibit off-target gene silencing. dsRNAs with an antisense strand comprising at least one thermally destabilizing duplex modification within the first 9 nucleotide positions, counting from the 5' end of the antisense strand, have been found to reduce off-target gene silencing activity. Consequently, in some embodiments, the antisense strand comprises at least one (e.g., one, two, three, four, five, or more) thermally destabilizing duplex modification within the first 9 nucleotide positions of the 5' region of the antisense strand.In some embodiments, one or more thermally destabilizing duplex modifications are located at positions 2-9, or preferably at positions 4-8, of the 5' end of the tape. Petition 870260076339, dated 07 / 30 / 2026, pp. 147 / 2173 136 / 505 antisense. In some other embodiments, the thermally destabilizing duplex modification(s) is / are located at position 6, 7, or 8 of the 5' end of the antisense strand. In still other embodiments, the thermally destabilizing duplex modification is located at position 7 of the 5' end of the antisense strand. The term thermally destabilizing modification(s) includes the modification(s) that would result in a dsRNA with a lower overall melting temperature (Tm) (preferably a Tm one, two, three, or four degrees lower than the Tm of the dsRNA without such modification(s)). In some embodiments, the thermally destabilizing duplex modification is located at position 2, 3, 4, 5, or 9 of the 5' end of the antisense strand. [000376] Thermally destabilizing modifications may include, but are not limited to, abasic modification; mismatch pairing with the opposite nucleotide on the opposite strand; and sugar modification, such as a 2'-deoxy modification or an acyclic nucleotide, for example, unblocked nucleic acids (UNA) or glycol nucleic acid (GNA). [000377] The basic modifications exemplified include, but are not limited to, the following: Where R = H, Me, Et or OMe; R' = H, Me, Et or OMe; R = H, Me, Et or OMe Petition 870260076339, dated 07 / 30 / 2026, pp. 148 / 2173 137 / 505 Mod2 (Basic Spacer 2-OMe) Mod3 (3'-OMe) Mod4 (5'-Me) X = OMe, F Mod3 (Hyp-spacer) where B is a modified or unmodified nucleobase. [000378] The sugar modifications exemplified include, but are not limited to, the following: 2'-deoxy nucleic glycol acid R = H, OH, O-alkyl nucleic acid unlocked nucleic glycol acid R = H, OH, O-alkyl R = H, OH, O-alkyl unlocked nucleic acid R = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R' = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R” = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R”' = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R”” = H, OH, CH3, CH2CH3, O-alkyl, NH2, NHMe, NMe2 R = H, methyl, ethyl where B is a modified or unmodified nucleobase. [000379] In some embodiments, the thermally destabilizing modification of the duplex is selected from the group consisting of: Petition 870260076339, dated 07 / 30 / 2026, pp. 149 / 2173 138 / 505 where B is a modified or unmodified nucleobase and the asterisk above each structure represents R, S, or racemic. [000380] The term acyclic nucleotide refers to any nucleotide with an acyclic ribose sugar, for example, where any of the linkages between the carbons of the ribose (e.g., C1'-C2', C2'-C3', C3'-C4', C4'-O4', or C1'-O4') is absent or at least one of the carbons of the ribose or oxygen (e.g., C1', C2', C3', C4', or O4') is, independently or in combination, absent from the nucleotide. In some forms, the acyclic nucleotide is II I, B, or B, where B is a modified or unmodified nucleobase, R1 and R2 are independently H, halogen, OR3, or alkyl; and R3 is H, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or sugar). The acyclic derivative provides greater flexibility of the main chain without affecting the pairings. Petition 870260076339, dated 07 / 30 / 2026, pages 150 / 2173 139 / 505 Watson-Crick. The acyclic nucleotide can be linked via a 2'-5' or 3'-5' linkage. [000381] The term 'GNA' refers to nucleic acid glycol, which is a polymer similar to DNA or RNA, but differing in the composition of its backbone, as it is composed of repeating units of glycerol linked by phosphodiester bonds: [000382] The thermally destabilizing modification of the duplex can be the mismatch pairings (i.e., non-complementary base pairs) between the thermally destabilizing nucleotide and the opposite nucleotide on the opposite strand, within the dsRNA duplex. Illustrative mismatch base pairs include G:G, G:A, G:U, G:T, A:A, A:C, C:C, C:U, C:T, U:U, T:T, U:T, or a combination thereof. Other mismatch base pairings known in the art are also amenable to the present invention. A mismatch pairing can occur between nucleotides that are naturally occurring nucleotides or modified nucleotides, i.e., the mismatch base pairing can occur between the nucleobases of the respective nucleotides, regardless of modifications to the ribose sugars of the nucleotides. In certain embodiments, the dsRNA molecule contains at least one nucleobase in the mismatch that is a 2'-deoxy nucleobase; for example, the 2'-deoxy nucleobase is on the sense strand. [000383] In some embodiments, the thermally destabilizing modification of the duplex in the seed region of the antisense strand includes nucleotides with impaired WC H-bonding to the base. Petition 870260076339, dated 07 / 30 / 2026, pages 151 / 2173 140 / 505 complementary information about the target mRNA, such as: [000384] Further examples of abasic nucleotide modifications, acyclic nucleotides (including UNA and GNA) and mismatch modifications have been described in detail in WO 2011 / 133876, which is hereby incorporated by reference in its entirety. [000385] Thermally destabilizing modifications may also include a universal base with reduced or abolished capacity to form hydrogen bonds with opposing bases, and phosphate modifications. [000386] In some embodiments, the thermally destabilizing modification of the duplex includes nucleotides with non-canonical bases, such as, but not limited to, nucleobase modifications with impaired or completely abolished ability to form hydrogen bonds with bases on the opposite strand. These nucleobase modifications were evaluated for destabilization of the central region of the dsRNA duplex as described in WO 2010 / 0011895, which is hereby incorporated by reference in its entirety. Illustrative nucleobase modifications are: Petition 870260076339, dated 07 / 30 / 2026, pp. 152 / 2173 141 / 505 inosine nebularine 2-aminopurine 4-Fluoro-6-methylbenzimidazole 4-Methylbenzimidazole 2,4-difluorotoluene 5-nitroindole 3-nitropyrrole [000387] In some embodiments, the thermally stabilizing modification of the duplex in the seed region of the antisense strand includes one or more α-nucleotides complementary to the base on the target mRNA, such as: the'' R where R is H, OH, OCH3, F, NH2, NHMe, nme2 or O-alkyl. [000388] Illustrative phosphate modifications known to decrease the thermal stability of dsRNA duplexes, compared to natural phosphodiester bonds, are: 1 0 0 I ό 1 0 1 0 1 0 O=P-SH I o=p-ch3 o=p-ch2-cooh O=PR IO=P-NH-R IO=POR I 1 0 1 o 1 0 1 O 1 1 1 O 1 1 1 O 1 1 1 R = alkyl 1 1 1 [000389] The alkyl group for R can be a C1-Ce alkyl group. Specific alkyl groups for R include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl. [000390] As those skilled in the art will recognize, given that the functional role of nucleobases is to define the specificity of an RNAi agent of the invention, while nucleobase modifications can be performed in various ways, as described in Petition 870260076339, dated 07 / 30 / 2026, pages 153 / 2173 142 / 505 of this document, for example, to introduce destabilizing modifications in an RNAi agent of the invention, for example, for the purpose of increasing the effect on the target relative to the effect off the target, the range of modifications available and generally present in the RNAi agents of the invention tends to be much greater for non-nucleobase modifications, for example, modifications with sugar groups or phosphate backbones of polyribonucleotides. Such modifications are described in more detail in other sections of the present invention and are expressly considered for RNAi agents of the invention having native nucleobases or modified nucleobases as described above or elsewhere in this document. [000391] In addition to the antisense strand comprising a thermally destabilizing modification, dsRNA may also comprise one or more stabilizing modifications. For example, dsRNA may comprise at least two (e.g., two, three, four, five, six, seven, eight, nine, ten, or more) stabilizing modifications. Without limitation, all stabilizing modifications may be present on a strand. In some embodiments, both the sense and antisense strands comprise at least two stabilizing modifications. The stabilizing modification may occur at any nucleotide on the sense strand or the antisense strand. For example, the stabilizing modification may occur at each nucleotide on the sense strand or the antisense strand; each stabilizing modification may occur in an alternating pattern on the sense strand or the antisense strand; or the sense strand or the antisense strand comprises both stabilizing modifications in an alternating pattern.The alternating pattern of stabilizing modifications on the sense tape may be the same as or different from the antisense tape, and the alternating pattern of stabilizing modifications on the sense tape may have a modification relative to the alternating pattern. Petition 870260076339, dated 07 / 30 / 2026, pages 154 / 2173 143 / 505 of the stabilizing modifications on the antisense tape. [000392] In some embodiments, the antisense tape comprises at least two (for example, two, three, four, five, six, seven, eight, nine, ten or more) stabilizing modifications. Without limitation, a stabilizing modification on the antisense tape may be present in any position. In some embodiments, the antisense tape comprises stabilizing modifications at positions 2, 6, 8, 9, 14 and 16 from the 5' end. In some other embodiments, the antisense tape comprises stabilizing modifications at positions 2, 6, 14 and 16 from the 5' end. In some other embodiments, the antisense tape comprises stabilizing modifications at positions 2, 14 and 16 from the 5' end. [000393] In some embodiments, the antisense strand comprises at least one stabilizing modification adjacent to the destabilizing modification. For example, the stabilizing modification may be the nucleotide at the 5' end or the 3' end of the destabilizing modification, i.e., at position -1 or +1 from the position of the destabilizing modification. In some embodiments, the antisense strand comprises a stabilizing modification at each 5' end and 3' end of the destabilizing modification, i.e., positions -1 and +1 from the position of the destabilizing modification. [000394] In some embodiments, the antisense tape comprises at least two stabilizing modifications at the 3' end of the destabilizing modification, that is, at positions +1 and +2 from the position of the destabilizing modification. [000395] In some embodiments, the sense tape comprises at least two (for example, two, three, four, five, six, seven, eight, nine, ten or more) stabilizing modifications. Without limitation, a stabilizing modification on the sense tape may be present in any position. In some embodiments, the sense tape comprises Petition 870260076339, dated 07 / 30 / 2026, pp. 155 / 2173 144 / 505 stabilizing modifications at positions 7, 10, and 11 from the 5' end. In some other embodiments, the sense tape comprises stabilizing modifications at positions 7, 9, 10, and 11 from the 5' end. In some embodiments, the sense tape comprises stabilizing modifications at positions opposite or complementary to positions 11, 12, and 15 of the antisense tape, counting from the 5' end of the antisense tape. In some other embodiments, the sense tape comprises stabilizing modifications at positions opposite or complementary to positions 11, 12, 13, and 15 of the antisense tape, counting from the 5' end of the antisense tape. In some embodiments, the sense tape comprises a block of two, three, or four stabilizing modifications. [000396] In some embodiments, the sense tape does not comprise a stabilizing modification in the opposite or complementary position to the thermally destabilizing duplex modification in the antisense tape. [000397] Illustrative thermally stabilizing modifications include, but are not limited to, 2'-fluorine modifications. Other thermally stabilizing modifications include, but are not limited to, LNA. [000398] In some embodiments, the dsRNA of the invention comprises at least four (for example, four, five, six, seven, eight, nine, ten or more) 2'-fluorine nucleotides. Without limitation, all 2'-fluorine nucleotides may be present on one strand. In some embodiments, both the sense and antisense strands comprise at least two 2'-fluorine nucleotides. The 2'-fluorine modification may occur on any nucleotide of the sense strand or the antisense strand. For example, the 2'-fluorine modification may occur on each nucleotide on the sense strand or the antisense strand; each 2'-fluorine modification may occur in an alternating pattern on the sense strand or the antisense strand; or the sense strand or the antisense strand comprises both 2'-fluorine modifications. Petition 870260076339, dated 07 / 30 / 2026, pages 156 / 2173 145 / 505 fluoride in an alternating pattern. The alternating pattern of 2'-fluoride modifications on the sense strip may be the same as or different from the antisense strip, and the alternating pattern of 2'-fluoride modifications on the sense strip may have an offset relative to the alternating pattern of 2'-fluoride modifications on the antisense strip. [000399] In some embodiments, the antisense strand comprises at least two (e.g., two, three, four, five, six, seven, eight, nine, ten, or more) 2'-fluorine nucleotides. Without limitation, a 2'-fluorine modification in the antisense strand may be present at any position. In some embodiments, the antisense comprises 2'-fluorine nucleotides at positions 2, 6, 8, 9, 14, and 16 from the 5' end. In some other embodiments, the antisense comprises 2'-fluorine nucleotides at positions 2, 6, 14, and 16 from the 5' end. Still in some other embodiments, the antisense comprises 2'-fluorine nucleotides at positions 2, 14, and 16 from the 5' end. [000400] In some embodiments, the antisense strand comprises at least one 2'-fluorine nucleotide adjacent to the destabilizing modification. For example, the 2'-fluorine nucleotide may be the nucleotide at the 5' end or the 3' end of the destabilizing modification, i.e., at position -1 or +1 from the position of the destabilizing modification. In some embodiments, the antisense strand comprises a 2'-fluorine nucleotide at each of the 5' and 3' ends of the destabilizing modification, i.e., positions -1 and +1 from the position of the destabilizing modification. [000401] In some embodiments, the antisense strand comprises at least two 2'-fluoronucleotides at the 3' end of the destabilizing modification, that is, at positions +1 and +2 from the position of the destabilizing modification. [000402] In some forms, the sense tape comprises at least two (for example, two, three, four, five, six, seven, eight, nine, Petition 870260076339, dated 07 / 30 / 2026, pages 157 / 2173 146 / 505 ten or more) 2'-fluorine nucleotides. Without limitation, a 2'-fluorine modification on the sense strand may be present at any position. In some embodiments, the antisense strand comprises 2'-fluorine nucleotides at positions 7, 10, and 11 from the 5' end. In some other embodiments, the sense strand comprises 2'-fluorine nucleotides at positions 7, 9, 10, and 11 from the 5' end. In some embodiments, the sense strand comprises 2'-fluorine nucleotides at positions opposite or complementary to positions 11, 12, and 15 of the antisense strand, counting from the 5' end of the antisense strand. In some other embodiments, the sense strand comprises 2'-fluoronucleotides in positions opposite or complementary to positions 11, 12, 13, and 15 of the antisense strand, counting from the 5' end of the antisense strand. In some embodiments, the sense strand comprises a block of two, three, or four 2'-fluoronucleotides. [000403] In some embodiments, the sense strand does not comprise a 2'-fluoronucleotide in the opposite or complementary position to the thermally destabilizing duplex modification in the antisense strand. [000404] In some embodiments, the dsRNA molecule of the invention comprises a 21-nucleotide (nt) sense strand and a 23-nucleotide (nt) antisense strand, wherein the antisense strand contains at least one thermally destabilizing nucleotide, wherein the at least one thermally destabilizing nucleotide occurs in the seed region of the antisense strand (i.e., at positions 2-9 of the 5' end of the antisense strand), wherein one end of the dsRNA is blunt, while the other end comprises a 2 nt projection, and wherein the dsRNA optionally further has at least one (for example, one, two, three, four, five, six or all seven) of the following features: (i) antisense comprises 2, 3, 4, 5 or 6 2'-fluorine modifications; (ii) the antisense strand comprises 1, 2, 3, 4 or 5 linkages between phosphorothioate nucleotides; (iii) the sense strand is conjugated with a Petition 870260076339, dated 07 / 30 / 2026, pp. 158 / 2173 147 / 505 linker; (iv) the sense strand comprises 2, 3, 4, or 5 2'-fluorine modifications; (v) the sense strand comprises 1, 2, 3, 4, or 5 phosphorothioate nucleotide linkages; (vi) the dsRNA comprises at least four 2'-fluorine modifications; and (vii) the dsRNA comprises a blunt end at the 5' end of the antisense strand. Preferably, the 2 nt projection is at the 3' end of the antisense strand. [000405] In some embodiments, the dsRNA molecule of the invention comprises a sense strand and an antisense strand, wherein: the sense strand is 25-30 nucleotide residues long, wherein from the 5' terminal nucleotide (position 1), positions 1 to 23 of said sense strand comprise at least 8 ribonucleotides; the antisense strand is 36-66 nucleotide residues long and, from the 3' terminal nucleotide, at least 8 ribonucleotides in positions paired with positions 1-23 of the sense strand to form a duplex; wherein at least the 3' terminal nucleotide of the antisense strand is not paired with the sense strand, and up to 6 consecutive 3' terminal nucleotides are not paired with the sense strand, thus forming a 3' single-stranded projection of 1-6 nucleotides; wherein the 5' end of the antisense strand comprises 10-30 consecutive nucleotides that are not paired with the sense strand, thus forming a 5' single-stranded projection of 10-30 nucleotides;wherein at least the nucleotides at the 5' and 3' ends of the sense strand are base-paired with the nucleotides of the antisense strand, when the sense and antisense strands are aligned for maximum complementarity, thereby forming a substantially duplex region between the sense and antisense strands; and the antisense strand is sufficiently complementary to a target RNA along at least 19 ribonucleotides of antisense strand length to reduce the expression of the target gene when said double-stranded nucleic acid is introduced into a mammalian cell; and wherein the antisense strand contains at least one nucleotide; Petition 870260076339, dated 07 / 30 / 2026, pp. 159 / 2173 148 / 505 thermally destabilizing, where at least one thermally destabilizing nucleotide is in the seed region of the antisense strand (i.e., at positions 2-9 of the 5' end of the antisense strand).For example, the thermally destabilizing nucleotide occurs between positions opposite or complementary to positions 14-17 of the 5' end of the sense strand and wherein the dsRNA optionally also has at least one (e.g., one, two, three, four, five, six, or all seven) of the following features: (i) the antisense comprises 2, 3, 4, 5, or 6 2'-fluorine modifications; (ii) the antisense comprises 1, 2, 3, 4, or 5 linkages between phosphorothioate nucleotides; (iii) the sense strand is conjugated with a ligand; (iv) the sense strand comprises 2, 3, 4, or 5 2'-fluorine modifications; (v) the sense strand comprises 1, 2, 3, 4, or 5 linkages between phosphorothioate nucleotides; and (vi) the dsRNA comprises at least four 2'-fluorine modifications; and (vii) the dsRNA comprises a duplex region of 12-30 nucleotide pairs in length. [000406] In some embodiments, the dsRNA molecule of the invention comprises a sense strand and an antisense strand, wherein said dsRNA molecule comprises a sense strand with a length that is at least 25 and at most 29 nucleotides and an antisense strand with a length that is at most 30 nucleotides, wherein the sense strand comprises a modified nucleotide that is susceptible to enzymatic degradation at position 11 from the 5' end, wherein the 3' end of said sense strand and the 5' end of said antisense strand form a blunt end and said antisense strand is 1-4 nucleotides longer at its 3' end than the sense strand, wherein the duplex region is at least 25 nucleotides long, and said antisense strand is sufficiently complementary to a target mRNA along at least 19 nt of said antisense strand length, to reduce the expression of target gene Petition 870260076339, dated 07 / 30 / 2026, pp. 160 / 2173149 / 505 where said dsRNA molecule is introduced into a mammalian cell, and wherein cleavage of said dsRNA by dicer preferably results in an siRNA comprising said 3' end of said antisense strand, thereby reducing target gene expression in mammals, wherein the antisense strand contains at least one thermally destabilizing nucleotide, wherein the at least one thermally destabilizing nucleotide is in the seed region of the antisense strand (i.e., at positions 2-9 of the 5' end of the antisense strand), and wherein the dsRNA optionally further has at least one (e.g., one, two, three, four, five, six, or all seven) of the following features: (i) the antisense comprises 2, 3, 4, 5, or 6 2'-fluorine modifications; (ii) the antisense strand comprises 1, 2, 3, 4, or 5 linkages between phosphorothioate nucleotides; (iii) the sense strand is conjugated with a ligand; (iv) the sense strand comprises 2, 3, 4, or 5 2'-fluorine modifications;(v) the sense strand comprises 1, 2, 3, 4, or 5 linkages between phosphorothioate nucleotides; and (vi) the dsRNA comprises at least four 2'-fluorine modifications; and (vii) the dsRNA has a duplex region 12–29 nucleotide pairs in length. [000407] In some embodiments, each nucleotide in the sense and antisense strands of the dsRNA molecule can be modified. Each nucleotide can be modified with an equal or different modification, which may include one or more alterations of one or both of the non-binding phosphate oxygens or of one or more of the binding phosphate oxygens; an alteration of a constituent of the ribose sugar, for example, of the 2' hydroxyl group in the ribose sugar; a wholesale substitution of the phosphate moiety with dephospho ligands; a modification or substitution of a naturally occurring base; and a substitution or modification of the ribose-phosphate backbone. [000408] Because nucleic acids are polymers of subunits, many of the modifications occur at a position that is repeated within Petition 870260076339, dated 07 / 30 / 2026, pages 161 / 2173 150 / 505 of a nucleic acid, for example, a modification of a base, or a phosphate group, or a non-bonding O of a phosphate group. In some cases, the modification will occur at all positions in question in the nucleic acid, however, in many cases, it will not. By way of example, a modification may occur only at a 3' or 5' terminal position, it may occur only in a terminal region, for example, at a position on a terminal nucleotide or in the last 2, 3, 4, 5 or 10 nucleotides of a strand. A modification may occur in a double-stranded region, a single-stranded region, or in both. A modification may occur only in the double-stranded region of an RNA or it may occur only in a single-stranded region of an RNA.For example, a phosphorothioate modification at a non-bonding O position can occur at only one or both ends, it can occur only in a terminal region, for example, at a position on a terminal nucleotide or in the last 2, 3, 4, 5, or 10 nucleotides of a strand, or it can occur in both double-stranded and single-stranded regions, particularly at the ends. The 5' end or ends can be phosphorylated. [000409] It may be possible, for example, to increase stability, include particular bases in the projections, or include modified nucleotides or nucleotide substitutes in the single-strand projections, for example, in a 5' or 3' projection, or in both. For example, it may be desirable to include purine nucleotides in the projections. In some embodiments, all or some of the bases in a 3' or 5' projection may be modified, for example, with a modification described in this document. The modifications may include, for example, the use of modifications at the 2' position of the ribose sugar with modifications that are known in the art, for example, the use of deoxyribonucleotides modified with 2'-deoxy-2'-fluorine (2'-F) or 2'O-methyl instead of the nucleobase ribosugar, and modifications in the group Petition 870260076339, dated 07 / 30 / 2026, pages 162 / 2173 151 / 505 phosphate, for example, phosphorothioate modifications. The projections do not need to be homologous to the target sequence. [000410] In some embodiments, each residue of the sense and antisense strands is independently modified with blocked nucleic acid (LNA), unblocked nucleic acid (UNA), cyclohexene nucleic acid (CeNA), 2'-methoxyethyl, 2'-O-methyl, 2'-O-allyl, 2'-C-allyl, 2'-deoxy, or 2'-fluorine. The strands may contain more than one modification. In some embodiments, each residue of the sense and antisense strands is independently modified with 2'-O-methyl or 2'-fluorine. It should be understood that these modifications are in addition to at least one thermally destabilizing duplex modification present in the antisense strand. [000411] At least two different modifications are typically present on the sense strand and the antisense strand. These two modifications may be 2'-deoxy, 2'-O-methyl, or 2'-fluorine modifications, acyclic nucleotides, or others. In some embodiments, the sense strand and the antisense strand each comprise two differently modified nucleotides selected from 2'-O-methyl or 2'-deoxy. In some embodiments, each residue of the sense and antisense strands is independently modified with a 2'-O-methyl nucleotide, a 2'-deoxy nucleotide, a 2'-deoxy-2'-fluoronucleotide, a 2'-ON-methylacetamide (2'-O-NMA) nucleotide, a 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) nucleotide, a 2'-O-aminopropyl (2'-O-AP) nucleotide, or a 2'-ara-F nucleotide. Again, it should be understood that these modifications are in addition to at least one thermally destabilizing duplex modification present in the antisense strand. [000412] In some embodiments, the dsRNA molecule of the invention comprises alternating pattern modifications, particularly in the B1, B2, B3, B1', B2', B3', B4' regions. The term alternating motif or alternating pattern, as used in this document, refers to Petition 870260076339, dated 07 / 30 / 2026, pp. 163 / 2173 152 / 505 refers to a motif with one or more modifications, each modification occurring on alternating nucleotides of a strand. The alternating nucleotide may refer to one for every other nucleotide or one for every three nucleotides, or a similar pattern. For example, if A, B, and C each represent a type of nucleotide modification, the alternating motif could be ABABABABABABAB, AABBAABBAABB, AABAABAABAAB, AAABAAABAAAB, AAABBBAAABBB, or ABCABCABCABC, etc. [000413] The type of modifications contained in the alternating motif can be the same or different. For example, if A, B, C, D each represent a type of nucleotide modification, the alternating pattern, that is, the modifications in each other nucleotide, can be the same, but each sense strand or antisense strand can be selected from several possible modifications within the alternating motif, such as ABABAB., ACACAC., BDBDBD. or CDCDCD. etc. [000414] In some embodiments, the dsRNA molecule of the invention comprises the modification pattern for the alternate motif on the sense strand relative to the modification pattern for the alternate motif on the displaced antisense strand. The displacement may be such that the modified nucleotide group of the sense strand corresponds to a differently modified nucleotide group of the antisense strand and vice versa. For example, when the sense strand is paired with the antisense strand in the dsRNA duplex, the alternate motif on the sense strand may start with ABABAB from 5'-3' of the strand and the alternate motif on the antisense strand may start with BABABA from 3'-5' of the strand within the duplex region.As another example, the alternating motif on the sense tape might start with AABBAABB from 5'-3' of the tape and the alternating motif on the antisense tape might start with BBAABBAA from 3'-5' of the tape within the duplex region, so that there is a complete or partial offset of the modification patterns between the two. Petition 870260076339, dated 07 / 30 / 2026, pp. 164 / 2173 153 / 505 sense tape and anti-sense tape. [000415] The dsRNA molecule of the invention may further comprise at least one linkage between methyl phosphorothioate or phosphonate nucleotides. The modification of the linkage between methyl phosphorothioate or phosphonate nucleotides may occur at any nucleotide of the sense strand or the antisense strand or both, at any position on the strand. For example, the modification of the linkage between nucleotides may occur at each nucleotide on the sense strand or the antisense strand; each modification of the linkage between nucleotides may occur in an alternating pattern on the sense strand or the antisense strand; or the sense strand or the antisense strand may comprise both modifications of the linkage between nucleotides in an alternating pattern.The alternating pattern of nucleotide linkage modification on the sense strand may be the same as or different from that of the antisense strand, and the alternating pattern of nucleotide linkage modification on the sense strand may be offset from the alternating pattern of nucleotide linkage modification on the antisense strand. [000416] In some embodiments, the dsRNA molecule comprises a modification of the phosphorothioate or methyl phosphonate nucleotide linkage in the projection region. For example, the projection region comprises two nucleotides having a phosphorothioate or methyl phosphonate nucleotide linkage between the two nucleotides. Modifications of the nucleotide linkage can also be made to link the projection nucleotides to terminal paired nucleotides within the duplex region. For example, at least 2, 3, 4, or all of the projection nucleotides may be linked via the phosphorothioate or methyl phosphonate nucleotide linkage, and optionally, there may be additional phosphorothioate or methyl phosphonate nucleotide linkages linking the projection nucleotide to a paired nucleotide that is adjacent to the projection nucleotide. Petition 870260076339, dated 07 / 30 / 2026, pages 165 / 2173 154 / 505 projection. For example, there may be at least two phosphorothioate nucleotide linkages between the three terminal nucleotides, where two of the three nucleotides are projection nucleotides and the third is a nucleotide paired close to the projection nucleotide. Preferably, these three terminal nucleotides may be at the 3' end of the antisense strand. [000417] In some embodiments, the sense strand of the dsRNA molecule comprises 1-10 blocks of two to ten linkages between phosphorothioate or methyl phosphonate nucleotides, separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 linkages between phosphate nucleotides, wherein one of the linkages between phosphorothioate or methyl phosphonate nucleotides is placed in any position in the oligonucleotide sequence and said sense strand is paired with an antisense strand comprising any combination of linkages between phosphorothioate, methyl phosphonate and phosphate nucleotides or an antisense strand comprising a linkage of phosphorothioate or methyl phosphonate or phosphate. [000418] In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of two phosphorothioate or methyl phosphonate nucleotide bonds, separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 phosphate nucleotide bonds, wherein one of the phosphorothioate or methyl phosphonate nucleotide bonds is placed in any position in the oligonucleotide sequence and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methyl phosphonate and phosphate nucleotide bonds or an antisense strand comprising a phosphorothioate or methyl phosphonate or phosphate bond. [000419] In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of three bonds between nucleotides. Petition 870260076339, dated 07 / 30 / 2026, pages 166 / 2173 155 / 505 of phosphorothioate or methyl phosphonate, separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 phosphate nucleotide bonds, wherein one of the bonds between the phosphorothioate or methyl phosphonate nucleotides is placed in any position in the oligonucleotide sequence and said antisense strand is paired with a sense strand comprising any combination of bonds between the phosphorothioate, methyl phosphonate and phosphate nucleotides or an antisense strand comprising a phosphorothioate or methyl phosphonate or phosphate bond. [000420] In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of four bonds between phosphorothioate or methyl phosphonate nucleotides, separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 bonds between phosphate nucleotides, wherein one of the bonds between phosphorothioate or methyl phosphonate nucleotides is placed in any position in the oligonucleotide sequence and said antisense strand is paired with a sense strand comprising any combination of bonds between phosphorothioate, methyl phosphonate and phosphate nucleotides or an antisense strand comprising a phosphorothioate or methyl phosphonate or phosphate bond. [000421] In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of five phosphorothioate or methyl phosphonate nucleotide bonds, separated by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 phosphate nucleotide bonds, wherein one of the phosphorothioate or methyl phosphonate nucleotide bonds is placed in any position in the oligonucleotide sequence and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methyl phosphonate and phosphate nucleotide bonds or an antisense strand comprising a phosphorothioate or methyl phosphonate or phosphate bond. Petition 870260076339, dated 07 / 30 / 2026, pages 167 / 2173 156 / 505 [000422] In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of six phosphorothioate or methyl phosphonate nucleotide bonds, separated by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 phosphate nucleotide bonds, wherein one of the phosphorothioate or methyl phosphonate nucleotide bonds is placed in any position in the oligonucleotide sequence and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methyl phosphonate and phosphate nucleotide bonds or an antisense strand comprising a phosphorothioate or methyl phosphonate or phosphate bond. [000423] In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of seven phosphorothioate or methyl phosphonate nucleotide bonds, separated by 1, 2, 3, 4, 5, 6, 7 or 8 phosphate nucleotide bonds, wherein one of the phosphorothioate or methyl phosphonate nucleotide bonds is placed in any position in the oligonucleotide sequence and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methyl phosphonate and phosphate nucleotide bonds or an antisense strand comprising a phosphorothioate or methyl phosphonate or phosphate bond. [000424] In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of eight phosphorothioate or methyl phosphonate nucleotide bonds, separated by 1, 2, 3, 4, 5 or 6 phosphate nucleotide bonds, wherein one of the phosphorothioate or methyl phosphonate nucleotide bonds is placed in any position in the oligonucleotide sequence and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methyl phosphonate and phosphate nucleotide bonds or an antisense strand comprising a phosphorothioate or methyl phosphonate or phosphate bond. Petition 870260076339, dated 07 / 30 / 2026, pages 168 / 2173 157 / 505 [000425] In some embodiments, the antisense strand of the dsRNA molecule comprises two blocks of nine phosphorothioate or methyl phosphonate nucleotide bonds, separated by 1, 2, 3, or 4 phosphate nucleotide bonds, wherein one of the phosphorothioate or methyl phosphonate nucleotide bonds is placed in any position in the oligonucleotide sequence and said antisense strand is paired with a sense strand comprising any combination of phosphorothioate, methyl phosphonate, and phosphate nucleotide bonds or an antisense strand comprising a phosphorothioate or methyl phosphonate or phosphate bond. [000426] In some embodiments, the dsRNA molecule of the invention further comprises one or more modifications of the linkage between phosphorothioate or methyl phosphonate nucleotides within 1-10 of the terminal positions of the sense or antisense strand. For example, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides may be linked by the linkage between phosphorothioate or methyl phosphonate nucleotides at one end or both ends of the sense or antisense strand. [000427] In some embodiments, the dsRNA molecule of the invention further comprises one or more modifications of the linkage between phosphorothioate or methyl phosphonate nucleotides in positions 1-10 of the inner duplex regions of each sense or antisense strand. For example, at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 nucleotides may be linked by the linkage between phosphorothioate or methyl phosphonate nucleotides in positions 8-16 of the duplex region, counting from the 5' end of the sense strand; the dsRNA molecule may optionally further comprise one or more modifications of the linkage between phosphorothioate or methyl phosphonate nucleotides in terminal positions 1-10. [000428] In some embodiments, the dsRNA molecule of Petition 870260076339, dated 07 / 30 / 2026, pp. 169 / 2173 The invention further comprises one to five modifications of the bond between phosphorothioate or methyl phosphonate nucleotides at positions 15 and one to five modifications of the bond between phosphorothioate or methyl phosphonate nucleotides at positions 18-23 of the sense strand (counting from the 5' end), and one to five modifications of the bond between phosphorothioate or methyl phosphonate nucleotides at positions 1 and 2 and one to five at positions 18-23 of the antisense strand (counting from the 5' end). [000429] In some embodiments, the dsRNA molecule of the invention further comprises a modification of the linkage between phosphorothioate nucleotides at positions 1-5 and a modification of the linkage between phosphorothioate or methyl phosphonate nucleotides at positions 18-23 of the sense strand (counting from the 5' end), and a modification of the linkage between phosphorothioate nucleotides at position 1 or 2 and two modifications of the linkage between phosphorothioate or methyl phosphonate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000430] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the linkage between phosphorothioate nucleotides at positions 1-5 and one modification of the linkage between phosphorothioate nucleotides at positions 18-23 of the sense strand (counting from the 5' end), and one modification of the linkage between phosphorothioate nucleotides at position 1 or 2 and two modifications of the linkage between phosphorothioate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000431] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the phosphorothioate nucleotide linkage at positions 1-5 and two modifications of the phosphorothioate nucleotide linkage at positions 18-23 of the sense strand (counting from the 5' end), and a modification of the linkage Petition 870260076339, dated 07 / 30 / 2026, pages 170 / 2173 159 / 505 between phosphorothioate nucleotides at position 1 or 2 and two modifications of the bond between phosphorothioate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000432] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the linkage between phosphorothioate nucleotides at positions 1-5 and two modifications of the linkage between phosphorothioate nucleotides at positions 18-23 of the sense strand (counting from the 5' end), and one modification of the linkage between phosphorothioate nucleotides at position 1 or 2 and one modification of the linkage between phosphorothioate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000433] In some embodiments, the dsRNA molecule of the invention further comprises a modification of the linkage between phosphorothioate nucleotides at positions 1-5 and a modification of the linkage between phosphorothioate nucleotides at positions 18-23 of the sense strand (counting from the 5' end), and two modifications of the linkage between phosphorothioate nucleotides at positions 1 and 2 and two modifications of the linkage between phosphorothioate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000434] In some embodiments, the dsRNA molecule of the invention further comprises a modification of the linkage between phosphorothioate nucleotides at positions 1-5 and one at positions 18-23 of the sense strand (counting from the 5' end), and two modifications of the linkage between phosphorothioate nucleotides at positions 1 and 2 and a modification of the linkage between phosphorothioate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000435] In some embodiments, the dsRNA molecule of the invention further comprises a modification of the linkage between the phosphorothioate nucleotides at positions 1-5 (counting from the 5' end) of the sense strand and two modifications of the linkage between the Petition 870260076339, dated 07 / 30 / 2026, pp. 171 / 2173 160 / 505 phosphorothioate nucleotides at positions 1 and 2 and a modification of the linkage between the phosphorothioate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000436] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the linkage between phosphorothioate nucleotides at positions 1-5 (counting from the 5' end) of the sense strand and one modification of the linkage between phosphorothioate nucleotides at position 1 or 2 and two modifications of the linkage between phosphorothioate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000437] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the phosphorothioate nucleotide linkage at positions 1-5 and one at positions 18-23 of the sense strand (counting from the 5' end), and two modifications of the phosphorothioate nucleotide linkage at positions 1 and 2 and one modification of the phosphorothioate nucleotide linkage at positions 18-23 of the antisense strand (counting from the 5' end). [000438] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the phosphorothioate nucleotide linkage at positions 1-5 and one modification of the phosphorothioate nucleotide linkage at positions 18-23 of the sense strand (counting from the 5' end), and two modifications of the phosphorothioate nucleotide linkage at positions 1 and 2 and two modifications of the phosphorothioate nucleotide linkage at positions 18-23 of the antisense strand (counting from the 5' end). [000439] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the linkage between phosphorothioate nucleotides at positions 1-5 and a modification of the linkage between phosphorothioate nucleotides at positions 18-23 of the sense strand (counting from the 5' end), and a modification of the linkage Petition 870260076339, dated 07 / 30 / 2026, pages 172 / 2173 161 / 505 between phosphorothioate nucleotides at position 1 or 2 and two modifications of the bond between phosphorothioate nucleotides at positions 18-23 of the antisense strand (counting from the 5' end). [000440] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the linkage between phosphorothioate nucleotides at positions 1 and 2 and two modifications of the linkage between phosphorothioate nucleotides at positions 20 and 21 of the sense strand (counting from the 5' end), and one modification of the linkage between phosphorothioate nucleotides at position 1 and one at position 21 of the antisense strand (counting from the 5' end). [000441] In some embodiments, the dsRNA molecule of the invention further comprises a modification of the linkage between phosphorothioate nucleotides at position 1 and a modification of the linkage between phosphorothioate nucleotides at position 21 of the sense strand (counting from the 5' end), and two modifications of the linkage between phosphorothioate nucleotides at positions 1 and 2 and two modifications of the linkage between phosphorothioate nucleotides at positions 20 and 21 of the antisense strand (counting from the 5' end). [000442] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the linkage between phosphorothioate nucleotides at positions 1 and 2 and two modifications of the linkage between phosphorothioate nucleotides at positions 21 and 22 of the sense strand (counting from the 5' end), and one modification of the linkage between phosphorothioate nucleotides at position 1 and one modification of the linkage between phosphorothioate nucleotides at position 21 of the antisense strand (counting from the 5' end). [000443] In some embodiments, the dsRNA molecule of the invention further comprises a modification of the linkage between phosphorothioate nucleotides at position 1 and a modification of the linkage between phosphorothioate nucleotides at position 21 of the sense strand (counting Petition 870260076339, dated 07 / 30 / 2026, pages 173 / 2173 162 / 505 from the 5' end), and two modifications of the bond between phosphorothioate nucleotides at positions 1 and 2 and two modifications of the bond between phosphorothioate nucleotides at positions 21 and 22 of the antisense strand (counting from the 5' end). [000444] In some embodiments, the dsRNA molecule of the invention further comprises two modifications of the phosphorothioate nucleotide linkage at positions 1 and 2 and two modifications of the phosphorothioate nucleotide linkage at positions 22 and 23 of the sense strand (counting from the 5' end), and one modification of the phosphorothioate nucleotide linkage at position 1 and one modification of the phosphorothioate nucleotide linkage at position 21 of the antisense strand (counting from the 5' end). [000445] In some embodiments, the dsRNA molecule of the invention further comprises a modification of the linkage between phosphorothioate nucleotides at position 1 and a modification of the linkage between phosphorothioate nucleotides at position 21 of the sense strand (counting from the 5' end), and two modifications of the linkage between phosphorothioate nucleotides at positions 1 and 2 and two modifications of the linkage between phosphorothioate nucleotides at positions 23 and 23 of the antisense strand (counting from the 5' end). [000446] In some embodiments, the compound of the invention comprises a pattern of chiral centers in the main chain. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 5 linkages between nucleotides in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 6 linkages between nucleotides in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 7 linkages between nucleotides in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain Petition 870260076339, dated 07 / 30 / 2026, pages 174 / 2173 163 / 505 comprises at least 8 linkages between nucleotides in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 9 linkages between nucleotides in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 10 linkages between nucleotides in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 11 linkages between nucleotides in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 12 linkages between nucleotides in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 13 linkages between nucleotides in the sp configuration.In some embodiments, a common pattern of chiral centers in the main chain comprises at least 14 nucleotide linkages in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 15 nucleotide linkages in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 16 nucleotide linkages in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 17 nucleotide linkages in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 18 nucleotide linkages in the sp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises at least 19 nucleotide linkages in the sp configuration.In some embodiments, a common pattern of chiral centers in the main chain comprises no more than 8 nucleotide linkages in the Rp configuration. In some embodiments, a common pattern of centers... Petition 870260076339, dated 07 / 30 / 2026, pages 175 / 2173 164 / 505 chiral centers of the main chain comprise no more than 7 linkages between nucleotides in the Rp configuration. In some embodiments, a common pattern of chiral centers of the main chain comprises no more than 6 linkages between nucleotides in the Rp configuration. In some embodiments, a common pattern of chiral centers of the main chain comprises no more than 5 linkages between nucleotides in the Rp configuration. In some embodiments, a common pattern of chiral centers of the main chain comprises no more than 4 linkages between nucleotides in the Rp configuration. In some embodiments, a common pattern of chiral centers of the main chain comprises no more than 3 linkages between nucleotides in the Rp configuration. In some embodiments, a common pattern of chiral centers of the main chain comprises no more than 2 linkages between nucleotides in the Rp configuration.In some embodiments, a common pattern of chiral centers in the main chain comprises no more than 1 linkage between nucleotides in the Rp configuration. In some embodiments, a common pattern of chiral centers in the main chain comprises no more than 8 linkages between ...
Claims
1. Double-stranded ribonucleic acid (dsRNA) agent for inhibiting MAPT expression, characterized in that the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises a region complementary to an mRNA encoding Tau and the complementary region comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the SEQ ID NOs: 1629, 1807, 2523, 2699, 3269, 3327, 3459, 3637, 1637, 1815, 2572, 2748, 3254, 3312, 3482, 3660, 1638, 1816, 2577, 2753, 3257, 3315, 3485, 3663, 88, 238, 93, or 243 or any of the antisense nucleotide sequences in any of Tables 3-8 and 16-28.
2. dsRNA agent, according to claim 1, characterized in that: (a) the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 514-534, 1067-1087, 1072-1092, 512-532, 513-533, 515-535, 516-536, 517-537, 518-538, 519-539, 520-540, 1063-1083, 1074-1094, 1075-1095, 1125-1145, 1126-1146, 1127-1147, 1129-1149, 1170-1190, 1395-1415, 1905-1925, 1906-1926, 1909-1929, 1911-1931, 1912-1932, 1913-1933, 1914-1934, 1915-1935, 1916-1936, 1919-1939, 1951-1971, 1954-1974, 1958-1978, 2387-2407, 2409-2429, 2410-2430, 2469-2489, 2471-2491, 2472-2492 2476-2496, 2477-2497, 2478-2498, 2480-2500, 2481-2501, 2482-2502, 2484-2504, 2762-2782, 2764-2784, 2766-2786, 2767-2787, 2768-2788, 2769-2789, 2819-2839, 2821-2841, 2828-2848, 2943-2963, 2944-2964, 2946-2966, 2947-2967, 3252-3272, 3277-3297, 3280-3300, 3281-3301, 3282-3302, 3284-3304, 3285-3305, 3286-3306, 3331-3351, 3332-3352,3333-3353, 3334-3354, 3335-3355, 3336-3356, 3338-3358, 3340-3360, Petition 870260076339, dated 07 / 30 / 2026, p. 518 / 2173 2 / 22 3342-3362, 3343-3363, 3344-3364, 3345-3365, 3346-3366, 3347-3367, 3349-3369, 3350-3370, 3353-3373, 3364-3384, 3366-3386, 3367-3387, 3368-3388, 3369-3389, 3370-3390, 3412-3432, 3414-3434, 3415-3435, 3416-3436, 3417-3437, 3419-3439, 3420-3440, 3424-3444, 3425-3445, 3426-3446, 3427-3447, 3428-3448, 3429-3449, 3430-3450, 3431-3451, 3434-3454, 4132-4152, 4134-4154, 4179-4199, 4182-4202, 4184-4204, 4395-4415, 4425-4445, 4426-4446, 4429-4449, 4469-4489, 4470-4490, 4471-4491, 4472-4492, 4473-4493, 4474-4494, 4569-4589, 4571-4591, 4572-4592, 4596-4616, 4623-4643, 4721-4741, 4722-4742, 4725-4745, 4726-4746, 4766-4786, 4767-4787, 4768-4788, 4769-4789, 4770-4790, 4779-4799, 4805-4825, 4806-4826, 4807-4827, 4808-4828, 4809-4829, 4812-4832, 4813-4833, 4814-4834, 4936-4956, 5072-5092, 5073-5093, 5345-5365, 5346-5366, 5349-5369, 5350-5370, 5351-5371, 5460-5480, 5461-5481,5463-5483, 5465-5485, 5467-5487, 5468-5488, 5469-5489, 5470-5490, 5471-5491, 5505-5525, 5506-5526, 5507-5527, 5508-5528, 5509-5529, 5511-5531, 5513-5533, 5514-5534, 5541-5561, 5544-5564, 5546-5566, 5547-5567, 5548-5568, 5550-5570, 5551-5571, 5574-5594, 5576-5596, 5614-5634, 521-541, 522-542, 523-543, 524-544, 525-545, 526-546, 527-547, 528-548, 529-549, 530-550, 531-551, 532-552, 533553, 534-554, 535-555, 536-556, 1034-1054, 1035-1055, 1036-1056, 1037-1057, 1038-1058, 1039-1059, 1040-1060, 1041-1061, 1042-1062, 1043-1063, 1044-1064, 1045-1065, 1046-1066, 1047-1067, 1048-1068, 1049-1069, 1050-1070, 1051-1071, 1052-1072, 1053-1073, 1054-1074, 1062-1082, 1064-1084, 1065-1085, 1066-1086, 1068-1088, 1069-1089, 1070-1090, 1071-1091, 1073-1093, 1076-1096, 1077-1097, 1078-1098, 1079-1099, 1080-1100, 1081-1101, 1082-1102, 1128-1148, 1129-1149, 1130-1150, 1131-1151, 1132-1152, 1133-1153, 1134-1154, 1135-1155, 1136-1156, 1137-1157, 1138-1158, 1139-1159, 1140-1160, 1141-1161, 1142-1162, 1143-1163,1144-1164, 1145-1165, 1146-1166, 1147-1167, 1148-1168, 975-995, 976-996, 977-997, 978-998, 979-999, 980-1000, Petition 870260076339, dated 07 / 30 / 2026, p. 519 / 2173 3 / 22 981-1001, 982-1002, 983-1003, 984-1004, 985-1005, 986-1006, 987-1007, 988-1008, 989-1009, 990-1010, 991-1011, 992-1012, 993-1013, 994-1014, 995-1015, 996-1016, 997-1017, 998-1018, 999-1019, 1000-1020, 1001-1021, 1002-1022, 1003-1023, 1004-1024, 1005-1025, 1006-1026, 1007-1027, 1008-1028, 1009-1029, 1010-1030, 1011-1031, 1012-1032, 1013-1033, 1014-1034, 1015-1035, 1016-1036, 1017-1037, 1018-1038, 1019-1039, 1020-1040, 1021-1041, 1022-1042, 1023-1043, 1024-1044, 1025-1045 1026-1046, 1027-1047, 1028-1048, 1029-1049, 10301050, 1031-1051, 1032-1052, 1033-1053, 1034-1054, 1035-1055, 10361056, 1037-1057, 1038-1058, 1039-1059, 1040-1060, 1041-1061, 10421062, 1043-1063 and 1045-1065 of SEQ ID NO: 3,and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 4; and / or (b) the sense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences 510-534, 512-536, 1065-1089, 1068-1095, 1068-1094, 520-541, 520-556, 516-541, 516-540, 520-544, 524-547, 526-551, 529-556, 532-556, 1075-1100, 1076-1100, 1079-1103, 1123-1147, 1127-1151, 1130-1155, 1903-1934, 19031930, 1914-1940, 1949-1975, 2470-2497, 2941-2965, 3275-3302, 32783302, 3329-3353, 3333-3357, 3338-3367, 3338-3366, 3348-3390, 33483388, 3351-3385, 5507-5562 and 5549-5597 of SEQ ID NO: 3,and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 4; and / or (c) the sense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences 977-997, 980-1000, 973-993, 988-1008, 987-1007, 972-992, 979-999, 1001-1021, 976-996, 994-1014, 1002-1022, 978-998, 974-994, 520-540, 521-541, 5464-5484, 1813-1833, 2378-2398, 3242-3262, 5442-5462, 1665-1685, 524 Petition 870260076339, dated 07 / 30 / 2026, page 520 / 2173 4 / 22 544, 5207-5227, 4670-4690, 3420-3440, 3328-3348, 5409-5429, 5439-5459, 4527-4547, 5441-5461, 5410-5430 and 5446-5466 of SEQ ID NO: 1,and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 2; and / or (d) the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a duplex selected from the group consisting of AD-1397072.1, AD-1566240, AD-523799.1, AD-1019331.1, AD-1397080.1, AD-1397081.1, AD-1566576, AD-1566581, AD-523802.1, AD-523795.1, AD-523810.1, AD-523809.1, AD-523801.1, AD-523823.1, AD-523798.1, AD-523816.1, AD-523824.1, AD-523800.1, AD-523796.1, AD-535094.1, AD-535094.1, AD-535095.1, AD-538647.1,AD535922.1, AD-536317.1, AD-536911.1, AD-538626.1, AD-535864.1, AD-523561.1, AD-523565.1, AD-523562.1, AD-526914.1,AD526394.1, AD-395452.1, AD-525343.1, AD-524274.1, AD-526956.1, AD-526986. 1, AD-526296.1, AD-526988.1, AD-526957.1, AD- 526993.1, AD-1397070.1, AD-1397071.1, AD-1397073.1, AD- 1397074.1, AD-1397075.1, AD-1397076.1,AD-1397077.1, AD- 1397078.1, AD-1397250.1, AD-1397251.1, AD-1397252.1, AD- 1397253.1, AD-1397254.1, AD-1397255.1, AD-1397256.1, AD- 1397257.1, AD-1397258.1, AD-1397259.1, AD-1397260.1, AD- 1397261.1, AD-1397262.1, AD-1397263.1, AD-1397264.1, AD- 1397265.1, AD-1423242.1, AD-1423243.1, AD-1423244.1, AD- 1423245.1, AD-1423246.1, AD-1423247.1, AD-1423248.1, AD- 1423249.1, AD-1423250.1, AD-1423251.1, AD-1423252.1, AD- 1423253.1, AD-1423254.1, AD-1423255.1, AD-1423256.1, AD- 1423257.1, AD-1423258.1, AD-1423259.1, AD-1423260.1, AD- 1423261.1, AD-1423262.1, AD-1423263.1, AD-1423264.1, AD- 1423265.1, AD-1423266.1, AD-1423267.1, AD-1423268.1, AD- Petit 870260076339, on 07 / 30 / 2026, pág. 521 / 2173 5 / 22 1423269.1, AD-1423270.1, AD-1423271.1, AD-1423272.1, AD- 1423273.1, AD-1423274.1, AD-1423275.1, AD-1423276.1, AD- 1423277.1, AD-1423278.1, AD-1423279.1, AD-1423280.1, AD- 1423281.1, AD-1423282.1, AD-1423283.1, AD-1423284.1, AD- 1423285.1, AD-1423286.1, AD-1423287.1, AD-1423288.1, AD- 1423289.1,AD-1423290.1, AD-1423291.1, AD-1423292.1, AD- 1423293.1, AD-1423294.1, AD-1423295.1, AD-1423296.1, AD- 1423297.1, AD-1423298.1, AD-1423299.1, AD-1423300.1, AD- 1397266.1, AD-1397266.2, AD-1397267.1, AD-1423301.1, AD- 1397268.1, AD-1397269.1, AD-1423302.1, AD-1397270.1, AD- 1397271.1, AD-1397272.1, AD-1423303.1, AD-1397273.1, AD- 1423304.1, AD-1397274.1, AD-1423305.1, AD-1397275.1, AD- 1423306.1, AD-1397276.1, AD-1397277.1, AD-1397278.1, AD- 1397279.1, AD-1397280.1, AD-1397281.1, AD-1397282.1, AD- 1397283.1, AD-1397284.1, AD-1397285.1, AD-1397286.1, AD- 1397287.1, AD-1397079.1, AD-1397288.1, AD-1397289.1, AD- 1397290.1, AD-1397291.1, AD-1397292.1, AD-1397293.1, AD- 1397294.1, AD-1397295.1, AD-1397082.1, AD-1397083.1, AD- 1397296.1, AD-1397297.1, AD-1397298.1, AD-1397299.1, AD- 1397300.1, AD-1397301.1, AD-1397302.1, AD-1397084.1, AD- 1397085.1, AD-1397086.1, AD-1397303.1, AD-1397087.1, AD- 1397304.1, AD-1397305.1, AD-1397306.1, AD-1397307.1, AD- 1397308.1, AD-1397309.1, AD-1397310.1,AD-1397311.1, AD- 1397312.1, AD-1397313.1, AD-1397314.1, AD-1397315.1, AD- 1397316.1, AD-1397317.1, AD-1397318.1, AD-1397319.1, AD- 1397320.1, AD-1397321.1, AD-1397322.1, AD-1397088.1, AD- 1397089.1, AD-1397090.1, AD-1397091.1, AD-1397092.1, AD- 1397093.1, AD-1397094.1, AD-1397095.1, AD-1397096.1, AD- 1397097.1, AD-1397098.1, AD-1397099.1, AD-1397101.1, AD- 1397102.1, AD-1397103.1, AD-1397104.1, AD-1397105.1, AD- Petition 870260076339, on 07 / 30 / 2026, page. 522 / 2173 6 / 22 1397106.1, AD-1397107.1, AD-1397108.1, AD-1397109.1, AD- 1397110.1, AD-1397111.1, AD-1397112.1, AD-1397113.1, AD- 1397114.1, AD-1397115.1, AD-1397116.1, AD-1397117.1, AD- 1397118.1, AD-1397119.1, AD-1397120.1, AD-1397121.1, AD- 1397122.1, AD-1397123.1, AD-1397124.1, AD-1397125.1, AD- 1397126.1, AD-1397127.1, AD-1397128.1, AD-1397129.1, AD- 1397130.1, AD-1397131.1, AD-1397132.1, AD-1397133.1, AD- 1397134.1, AD-1397135.1, AD-1397136.1, AD-1397137.1, AD- 1397138.1, AD-1397139.1, AD-1397140.1, AD-1397141.1, AD- 1397142.1,AD-1397143.1, AD-1397144.1, AD-1397145.1, AD- 1397146.1, AD-1397147.1, AD-1397148.1, AD-1397149.1, AD- 1397150.1, AD-1397151.1, AD-1397152.1, AD-1397153.1, AD- 1397154.1, AD-1397155.1, AD-1397156.1, AD-1397157.1, AD- 1397158.1, AD-1397159.1, AD-1397160.1, AD-1397161.1, AD- 1397162.1, AD-1397163.1, AD-1397164.1, AD-1397165.1, AD- 1397166.1, AD-1397167.1, AD-1397168.1, AD-1397169.1, AD- 1397170.1, AD-1397171.1, AD-1397172.1, AD-1397173.1, AD- 1397174.1, AD-1397175.1, AD-1397176.1, AD-1397177.1, AD- 1397178.1, AD-1397179.1, AD-1397180.1, AD-1397181.1, AD- 1397182.1, AD-1397183.1, AD-1397184.1, AD-1397185.1, AD- 1397186.1, AD-1397187.1, AD-1397188.1, AD-1397189.1, AD- 1397190.1, AD-1397191.1, AD-1397192.1, AD-1397193.1, AD- 1397194.1, AD-1397195.1, AD-1397196.1, AD-1397197.1, AD- 1397198.1, AD-1397199.1, AD-1397200.1, AD-1397201.1, AD- 1397202.1, AD-1397203.1, AD-1397204.1, AD-1397205.1, AD- 1397206.1, AD-1397207.1, AD-1397208.1, AD-1397209.1, AD- 1397210.1, AD-1397211.1, AD-1397212.1,AD-1397213.1, AD- 1397214.1, AD-1397215.1, AD-1397216.1, AD-1397217.1, AD- 1397218.1, AD-1397219.1, AD-1397219.1, AD-139,2217. AD-1397221.1, AD- 1397222.1, AD-1397223.1, AD-1397224.1, AD-1397225.1, AD- Petition 870260076339, of 30 / 07 / 2026, p. 523 / 2173 7 / 22 1397226.1, AD-1397227.1, AD-1397228.1, AD-1397229.1, AD1397230.1, AD-1397231.1, AD-1397232.1, AD-1397233.1,AD1397234.1, AD-1397235.1, AD-1397236.1, AD-1397237.1,AD1397238.1, AD-1397239.1, AD-1397239.1,AD-1397240.1, AD-1397241.1,AD1397242.1, AD-1397243.1, AD-1397244.1, AD-1397245.1,AD1397246.1, AD-1397247.1, AD-1397248,AD-1397242.1,AD-1397246.1 523565.1, AD-1566238, AD-1566239, AD-1566241, AD-1566242, AD1566243, AD-1566244, AD-1566245, AD-1566246, AD-1566245, AD-1566246, AD-1566245, AD-1946,866 AD-1566249, AD-1566250, AD-1091966, AD-1566251, AD1566252, AD-1566253, AD-1566254, AD-1566255, AD-1566256, AD-1566256,566 AD-1566258, AD-1566259, AD-692906, AD-1566575, AD1566577, AD-1566580, AD-1566582, AD-1566583, AD-1566584, AD-1566583, AD-1566584, AD-156656,78666 AD-1566588, AD-1566590, AD-1566591, AD1566634,AD-1566635, AD-1566638, AD-1566639, AD-1566641, AD1566642, AD-1566643, AD-1566679, AD-1566861, AD-1567153, AD1567154, AD-1567157, AD-1567159, AD-1567160, AD-1567161, AD1567164, AD-1567167, AD-1567199, AD-1567202, AD-1567550, AD1567554, AD-1567784, AD-1567896, AD-1567897, AD-1568105, AD1568108, AD-1568109, AD-1568139, AD-1568140, AD-1568143, AD1568144, AD-1568148, AD-1568150, AD-1568151, AD-1568152, AD1568153, AD-1568154, AD-1568158, AD-1568161, AD-1568172, AD1568174, AD-1568175, AD-692908, AD-1568176, AD-1569830, AD1569832, AD-1569834, AD-1569835, AD-1569862, AD-1569872,AD1569890 and AD-1569892; and / or (e) the sense and antisense strand nucleotide sequence comprises any of the sense and antisense strand nucleotide sequences in any of Tables 3-8 and 16-28; and / or (f) the sense strand nucleotide sequence comprises at least 15 contiguous nucleotides corresponding to the exon 10 sense strand sequence of the MAPT gene presented in SEQ ID No.: 1533 Petition 870260076339, dated 07 / 30 / 2026, p. 524 / 2173 8 / 22 and an antisense strand comprising a sequence complementary to it.
3. Double-stranded ribonucleic acid (dsRNA) agent for inhibiting MAPT expression, characterized in that the dsRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding Tau and wherein the complementarity region comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from SEQ ID NO: 1346 or 1442 or any of the antisense nucleotide sequences in any of Tables 12-13.
4. dsRNA agent according to claim 3, characterized in that (a) the sense strand comprises at least 15 contiguous nucleotides differing in no more than three nucleotides from any of the nucleotide sequences 1067-1087, 1065-1085, 1195-1215, 1066-1086, 1068-1088, 705-725, 4520-4540, 3341-3361, 4515-4535, 5284-5304, 5285-5305, 344-364, 5283-5303, 5354-5374, 2459-2479, 1061-1081, 706-726, 972-992, 4564-4584, 995-1015, 4546-4566, 968-988, 1127-1147, 4534-4554, 158-178, 4494-4514, 1691-1711, 3544-3564, 198-218, 979-999, 4548-4568, 4551-4571, 543-563, 715-735, 542-562, 352-372, 362-382, 4556-4576, 4547-4567, 4542-4562 4558-4578, 4549-4569, 5074-5094, 4552-4572, 5073-5093, 5076-5096, 4550-4570 and 2753-2773 of SEQ ID NO: 5, and the antisense strand comprises at least 15 contiguous nucleotides of the corresponding nucleotide sequence of SEQ ID NO: 6;and / or (b) the antisense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any of the nucleotide sequences of the antisense strand of a Petition 870260076339, dated 07 / 30 / 2026, page 1. 525 / 2173 9 / 22 duplex selected from the group consisting of AD-393760.1, AD393758.1, AD-393888.1, AD-393759.1, AD-393761.1, AD-393495.1, AD-396425.1, AD-395441.1, AD-396420.1, AD-397103.1, AD397104.1, AD-393239.1, AD-397102.1, AD-397167.1, AD-394791.1, AD-393754.1, AD-393496.1, AD-393667.1, AD-396467.1, AD393690.1, AD-396449.1, AD-393663.1, AD-393820.1, AD-396437.1, AD-393084.1, AD-396401.1, AD-394296.1, AD-395574.1,AD393124.1, AD-393674.1, AD-396451.1, AD-396454.1, AD-393376.1, AD-393505.1, AD-393375.1, AD-393247.1, AD-393257.1,AD396459.1, AD-396450.1, AD-396445.1, AD-396461.1, AD-396452.1, AD-396913.1, AD-396455.1, AD-396912.1, AD-396915.1, AD-396453.1 and AD-394991.1.; 5. dsRNA agent, according to any one of claims 1 to 4, characterized in that the sense strand, the antisense strand, or both the sense and antisense strands are conjugated with one or more lipophilic moieties.
6. dsRNA agent, according to claim 5, characterized in that one or more lipophilic parts are conjugated to one or more internal positions in the double-stranded region of the dsRNA agent, and / or one or more lipophilic parts are conjugated via a ligand or carrier, and / or the lipophilicity of one or more lipophilic parts, measured by logKow, exceeds 0.
7. dsRNA agent, according to any one of claims 1 to 6, characterized in that the hydrophobicity of the double-stranded RNA agent, measured by the unbound portion in a plasma protein binding assay of the double-stranded RNA agent, exceeds 0.2, optionally wherein the plasma protein binding assay is a Petition 870260076339, dated 07 / 30 / 2026, page 526 / 2173 10 / 22 electrophoretic mobility change assay using human serum albumin protein.
8. dsRNA agent, according to any one of claims 1 to 7, characterized in that the dsRNA agent comprises at least one modified nucleotide, optionally in which no more than five of the sense strand nucleotides and no more than five of the antisense strand nucleotides are unmodified nucleotides, or in which all sense strand nucleotides and all antisense strand nucleotides are modified nucleotides, and / or in which at least one of the modified nucleotides is selected from the group consisting of a deoxynucleotide, a 3'-terminal deoxythymidine (dT) nucleotide, a 2'-O-methyl-modified nucleotide, a 2'-fluorine-modified nucleotide, a 2'-deoxy-modified nucleotide, a blocking nucleotide, an unblocking nucleotide, a nucleotide conformationally restricted, a restricted ethyl nucleotide, an abasic nucleotide, a nucleotide modified with 2'-amino, a nucleotide modified with 2'-allyl,a nucleotide modified with 2'-C-alkyl, a nucleotide modified with 2'-hydroxy, a nucleotide modified with 2'-methoxyethyl, a nucleotide modified with 2'-O-alkyl, a morpholino nucleotide, a phosphoramidate, a nucleotide comprising an unnatural base, a nucleotide modified with tetrahydropyran, a nucleotide modified with 1,5-anhydrohexitol, a nucleotide modified with cyclohexenyl, a nucleotide comprising a 5'-phosphorothioate group, a nucleotide comprising a 5'-methylphosphonate group, a nucleotide comprising a 5'-phosphate or 5'-phosphate mimic, a nucleotide comprising vinyl phosphonate, a nucleotide comprising adenosine glycol nucleic acid (GNA), a nucleotide comprising the S isomer of thymidine-glycol nucleic acid (GNA), a nucleotide comprising 2-hydroxymethyl-tetrahydrofuran-5-phosphate, a nucleotide comprising 2'-deoxythymidine-3'-phosphate, Petition 870260076339, dated 07 / 30 / 2026, page 527 / 2173 11 / 22a nucleotide comprising 2'-deoxyguanosine-3'-phosphate and a terminal nucleotide linked to a cholesteryl derivative and a bisdecylamide group of dodecanoic acid; and combinations thereof, optionally wherein the modified nucleotide is selected from the group consisting of a nucleotide modified with 2'-deoxy-2'-fluorine, a nucleotide modified with 2'-deoxy, 3'-terminal deoxythymidine (dT) nucleotides, a blocking nucleotide, an abasic nucleotide, a nucleotide modified with 2'-amino, a nucleotide modified with 2'-alkyl, a morpholino nucleotide, a phosphoramidate and a nucleotide comprising an unnatural base, or wherein the modified nucleotide comprises a short sequence of 3'-terminal deoxythymidine (dT) nucleotides, or wherein the modifications in the nucleotides are modifications with 2'-O-methyl, GNA and 2'-fluorine.
9. dsRNA agent, according to any one of claims 1 to 8, characterized in that it further comprises at least one linkage between phosphorothioate nucleotides, optionally wherein the dsRNA agent comprises 6-8 linkages between phosphorothioate nucleotides; and / or 10. dsRNA agent, according to any one of claims 1 to 9, characterized in that each strand is no more than 30 nucleotides long; and / or in that at least one strand comprises a 3' projection of at least 1 nucleotide; and / or in that at least one strand comprises a 3' projection of at least 2 nucleotides; and / or in that the double-stranded region is 15 to 30 nucleotide pairs long, optionally in that the double-stranded region is 17-23, 17-25, 23-27, 19-21, or 21-23 nucleotide pairs long; and / or in which each strand has 19-30, 19-23, or 21-23 nucleotides.
11. dsRNA agent, according to any one of claims 5 to 10, characterized in that: (a) one or more lipophilic moieties are conjugated to one or more internal positions on at least one strand in the double-stranded region of the dsRNA agent, optionally wherein one or more lipophilic moieties are conjugated to one or more internal positions on at least one strand by means of a linker or carrier, optionally (i) wherein the one or more internal positions include all positions except the two or three terminal positions at each end of at least one strand; and / or (ii) wherein the one or more internal positions exclude a region of the cleavage site of the sense strand, optionally wherein the one or more internal positions include all positions except positions 9-12, counting from the 5' end of the sense strand, or wherein the one or more internal positions include all positions except positions 11-13,counting from the 3' end of the sense tape; and / or (iii) where one or more internal positions exclude a region of the cleavage site of the antisense tape, optionally where the internal positions include all positions except positions 12-14, counting from the 5' end of the antisense tape; and / or (iv) where one or more internal positions include all positions except positions 11-13 on the sense tape, Petition 870260076339, dated 07 / 30 / 2026, page 529 / 2173 13 / 22 counting from the 3' end, and positions 12-14 on the antisense tape, counting from the 5' end; and / or (b) one or more lipophilic portions are conjugated with one or more of the internal positions selected from the group consisting of positions 4-8 and 13-18 on the sense strip, and positions 6-10 and 15-18 on the antisense strip, counting from the 5' end of each strip,optionally wherein one or more lipophilic parts are conjugated with one or more of the internal positions selected from the group consisting of positions 5, 6, 7, 15 and 17 on the sense strand and positions 15 and 17 on the antisense strand, counting from the 5' end of each strand; and / or (c) one or more internal positions in the double-strand region exclude a region of the cleavage site of the sense strand; and / or (d) the sense strand is 21 nucleotides long, the antisense strand is 23 nucleotides long, and one or more lipophilic moieties are conjugated to position 21, position 20, position 15, position 1, position 7, position 6, or position 2 of the sense strand or position 16 of the antisense strand, optionally wherein one or more lipophilic moieties are conjugated to position 21, position 20, position 15, position 1, or position 7 of the sense strand,or wherein one or more lipophilic parts are conjugated to position 16 of the antisense strip; and / or (and) one or more lipophilic parts are an aliphatic, alicyclic or polyalicyclic compound, optionally wherein one or more lipophilic parts are selected from the group consisting of lipid, cholesterol, retinoic acid, cholic acid, adamantane acetic acid, 1-pyrenebutyric acid, dihydrotestosterone, 1,3-bis-O(hexadecyl)glycerol, geranyloxyhexianol, Petition 870260076339, dated 07 / 30 / 2026, page. 530 / 2173 14 / 22 hexadecylglycerol, borneol, menthol, 1,3-propanediol, heptadecyl group, palmitic acid, myristic acid, O3-(oleoyl)lithocholic acid, O3(oleoyl)cholenic acid, dimethoxytrityl or phenoxazine, or wherein one or more lipophilic moieties contain a saturated or unsaturated C4-C30 hydrocarbon chain and an optional functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne,optionally wherein one or more lipophilic parts contain a saturated or unsaturated C6-C18 hydrocarbon chain, or wherein one or more lipophilic parts contain a saturated or unsaturated C16 hydrocarbon chain, optionally wherein the saturated or unsaturated C16 hydrocarbon chain is conjugated at position 6, counting from the 5' end of the strand; and / or (f) one or more lipophilic moieties are conjugated by means of a carrier that replaces one or more nucleotides at one or more internal position(s) or in the double-strand region, optionally wherein the carrier is a cyclic group selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3] dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl,tetrahydrofuranyl and decalinyl; or is an acyclic moiety based on a serinol backbone or a diethanolamine backbone, or wherein one or more lipophilic moieties are conjugated with the double-stranded RNA agent by means of a linker containing an ether, thioether, urea, carbonate, amine, amide, maleimidathioether, disulfide, phosphodiester, sulfonamide, a product of a click reaction or carbamate linkage; and / or Petition 870260076339, 07 / 30 / 2026, p. 531 / 2173 15 / 22 (g) one or more lipophilic moieties are conjugated with a nucleobase, sugar moiety or linkage between nucleosides; and / or (h) one or more lipophilic parts or the targeting ligand is conjugated via a biocleavable ligand selected from the group consisting of DNA, RNA, disulfide, amide, monosaccharides or oligosaccharides functionalized with galactosamine, glucosamine, glucose, galactose, mannose,and combinations thereof; and / or (i) the 3' end of the sense strand is protected by an end shield which is a cyclic group having an amine, said cyclic group being selected from the group consisting of pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, [1,3] dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, tetrahydrofuranyl and decalinyl; and / or (j) the dsRNA agent further comprises a targeting ligand that targets a neuronal cell or a liver cell, optionally wherein the targeting ligand is a GalNAc conjugate.
12. dsRNA agent, according to any one of claims 1 to 11, characterized in that it further comprises (i) a terminal chiral modification occurring at the first nucleotide linkage at the 3' end of the antisense strand, having the linking phosphorus atom in the sp configuration, a terminal chiral modification occurring at the first nucleotide linkage at the 5' end of the antisense strand, having the linking phosphorus atom in the rp configuration, and a terminal chiral modification occurring at the first nucleotide linkage at the 5' end of the sense strand, having the Petition 870260076339, dated 07 / 30 / 2026, page 1. 532 / 2173 16 / 22 linking phosphorus atom in the Rp configuration or in the Sp configuration, or (ii) a terminal chiral modification that occurs in the first and second nucleotide bonds at the 3' end of the antisense strand, having the linking phosphorus atom in the Sp configuration,a terminal chiral modification that occurs at the first nucleotide bond at the 5' end of the antisense strand, having the linking phosphorus atom in the Rp configuration, and a terminal chiral modification that occurs at the first nucleotide bond at the 5' end of the sense strand, having the linking phosphorus atom in the Rp or Sp configuration, or (iii) a terminal chiral modification that occurs at the first, second, and third nucleotide bonds at the 3' end of the antisense strand, having the linking phosphorus atom in the Sp configuration, a terminal chiral modification that occurs at the first nucleotide bond at the 5' end of the antisense strand, having the linking phosphorus atom in the Rp configuration, and a terminal chiral modification that occurs at the first nucleotide bond at the 5' end of the sense strand, having the linking phosphorus atom in the Rp or Sp configuration,or (iv) a terminal chiral modification that occurs in the first and second nucleotide bonds at the 3' end of the antisense strand, having the linking phosphorus atom in the sp configuration, a terminal chiral modification that occurs in the third nucleotide bonds at the 3' end of the antisense strand, having the linking phosphorus atom in the rp configuration, a terminal chiral modification that occurs in the first nucleotide bond at the 5' end of the antisense strand, having the linking phosphorus atom in the rp configuration, and Petition 870260076339, dated 07 / 30 / 2026, p. 533 / 2173 17 / 22 a terminal chiral modification that occurs in the first nucleotide bond at the 5' end of the sense strand, having the linking phosphorus atom in the Rp or Sp configuration, or (v) a terminal chiral modification that occurs in the first and second nucleotide bonds at the 3' end of the antisense strand, having the linking phosphorus atom in the Sp configuration,a terminal chiral modification that occurs in the first and second nucleotide bonds at the 5' end of the antisense strand, having the linking phosphate atom in the Rp configuration, and a terminal chiral modification that occurs in the first nucleotide bond at the 5' end of the sense strand, having the linking phosphate atom in the Rp or Sp configuration.
13. dsRNA agent, according to any one of claims 1 to 12, characterized in that it further comprises a phosphate or phosphate mimic at the 5' end of the antisense strand, optionally wherein the phosphate mimic is a 5'-vinyl phosphonate (VP); and / or wherein the base pair at position 1 of the 5' end of the antisense strand of the duplex is an AU base pair; and / or wherein the sense strand has a total of 21 nucleotides and the antisense strand has a total of 23 nucleotides.
14. Pharmaceutical composition, characterized in that it comprises the dsRNA agent, as defined in any one of claims 1 to 13.
15. Pharmaceutical composition according to claim 14, characterized in that (a) it comprises a lipid formulation; and / or (b) it selectively inhibits MAPT transcripts containing exon 10; and / or Petition 870260076339, dated 07 / 30 / 2026, page 534 / 2173 18 / 22 (c) the dsRNA agent is in an unbuffered solution, optionally wherein the unbuffered solution is saline or water; and / or (d) said dsRNA agent is in a buffer solution, optionally wherein the buffer solution comprises acetate, citrate, prolamine, carbonate or phosphate or any combination thereof, or wherein the buffer solution is a phosphate-buffered saline (PBS).
16. Use of the dsRNA agent, as defined in any one of claims 1 to 13, or of the pharmaceutical composition, as defined in claim 14 or 15, characterized in that it is used in the manufacture of a medicament or kit to inhibit the expression of a MAPT gene in a cell or to selectively inhibit MAPT transcripts containing exon 10 in the cell.
17. Use according to claim 16, characterized in that the cell is inside an individual.
18. Use, according to claim 16 or 17, characterized in that the individual is a human being, and / or in that the individual has a disorder associated with MAPT, optionally in that the disorder associated with MAPT is a neurodegenerative disorder, optionally in that the neurodegenerative disorder is associated with an abnormality of the Tau protein encoded by the MAPT gene, optionally in that the abnormality of the Tau protein encoded by the MAPT gene results in the aggregation of Tau in the individual's brain, and / or in that the neurodegenerative disorder is a familial disorder. Petition 870260076339, dated 07 / 30 / 2026, p. 535 / 2173 19 / 22 or a sporadic disorder, and / or in which the disorder associated with MAPT is selected from the group consisting of tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), semantic primary progressive aphasia (PPA-S),Primary progressive aphasia - logopenic (PPA-L), frontotemporal dementia with chromosome 17-linked parkinsonism (FTDP-17), Pick's disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle dementia (NFT), FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson's disease, postencephalitic parkinsonism, Niemann-Pick disease, Huntington's disease, myotonic dystrophy type 1, and Down syndrome (DS).
19. Use, according to any one of claims 16 to 18, characterized in that cell contact with the dsRNA agent inhibits MAPT expression by at least 25%; and / or in that inhibition of MAPT expression decreases the serum Tau protein level in the individual by at least 25%.
20. Use of the dsRNA agent, as defined in any one of claims 1 to 13, or of the pharmaceutical composition, as defined in claim 14 or 15, characterized in that it is in the manufacture of a medicament or kit to treat an individual with a disorder that would benefit from reduced expression of the MAPT gene, or in the manufacture of a medicament to prevent at least one symptom in the individual with the disorder that would benefit from reduced expression of the MAPT gene, wherein said medicament or kit is formulated to be administered to the individual with a therapeutically effective amount of the dsRNA agent or pharmaceutical composition.
21. Use according to claim 20, characterized in that: (a) the disorder is associated with an abnormality of the Tau protein encoded by the MAPT gene, optionally wherein the abnormality of the Tau protein encoded by the MAPT gene results in the aggregation of Tau in the brain of the individual, and / or wherein the disorder is selected from the group consisting of tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA), primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), frontotemporal dementia with chromosome 17-linked parkinsonism (FTDP-17), Pick's disease (PiD), argyrophilic grain disease (AGD), multisystem tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle dementia (NFT),FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson's disease, postencephalitic parkinsonism, Niemann-Pick disease, Huntington's disease, myotonic dystrophy type 1 and Down syndrome (DS); and / or (b) the individual is a human being, optionally in which the medicine or kit causes a decrease in Tau aggregation in the individual's brain; and / or (c) the dsRNA agent or pharmaceutical composition is formulated in the medicine or kit to be administered to the individual at a dose of approximately 0.01 mg / kg to approximately 50 mg / kg of the dsRNA agent; and / or. (d) the dsRNA agent or pharmaceutical composition is formulated in the medicine or kit to be administered to the individual intrathecally or intracisternally; and / or (e) the use further comprises determining the MAPT level in a sample(s) from the individual,optionally where the MAPT level in the individual's sample(s) is a Tau protein level in (one) cerebrospinal fluid sample(s); and / or (f) the use further comprises the administration to the individual of an additional therapeutic agent.
22. In vitro method for inhibiting the expression of a MAPT gene in a cell or selectively inhibiting MAPT transcripts containing exon 10 in the cell, characterized in that it comprises contacting the cell with the dsRNA agent, as defined in any one of claims 1 to 13, or the pharmaceutical composition, as defined in claim 14 or 15, thereby inhibiting the expression of the MAPT gene or selectively degrading MAPT transcripts containing exon 10 in the cell.
23. In vitro method, according to claim 22, characterized in that the cell was isolated from an individual, optionally wherein the individual is a human being, and / or the individual has a MAPT-associated disorder, optionally wherein the MAPT-associated disorder is a neurodegenerative disorder, optionally wherein the neurodegenerative disorder is associated with an abnormality of the Tau protein encoded by the MAPT gene, optionally Petition 870260076339, dated 07 / 30 / 2026, p. 538 / 2173 22 / 22 mind in which the abnormality of the Tau protein encoded by the MAPT gene results in the aggregation of Tau in the individual's brain, and / or in which the neurodegenerative disorder is a familial or sporadic disorder, and / or in which the MAPT-associated disorder is selected from the group consisting of tauopathy, Alzheimer's disease, frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), non-fluent variant primary progressive aphasia (nfvPPA),Primary progressive aphasia - semantic (PPA-S), primary progressive aphasia - logopenic (PPA-L), frontotemporal dementia with chromosome 17-linked parkinsonism (FTDP-17), Pick's disease (PiD), argyrophilic grain disease (AGD), multiple system tauopathy with presenile dementia (MSTD), white matter tauopathy with globular glial inclusions (FTLD with GGIs), FTLD with MAPT mutations, neurofibrillary tangle dementia (NFT), FTD with motor neuron disease, amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Parkinson's disease, postencephalitic parkinsonism, Niemann-Pick disease, Huntington's disease, myotonic dystrophy type 1, and Down syndrome (DS).
24. In vitro method, according to claim 22 or 23, characterized in that contact of the cell with the dsRNA agent inhibits MAPT expression by at least 25%; and / or inhibition of MAPT expression decreases the serum Tau protein level in the individual by at least 25%.