用于诱导父本UBE3A表达的寡核苷酸制造技术

技术编号:18464282 阅读:243 留言:0更新日期:2018-07-18 15:08
本发明专利技术涉及能够在动物或人神经元中诱导由父本等位基因表达泛素‑蛋白连接酶E3A(UBE3A)的寡核苷酸。寡核苷酸通过与SNORD109B下游的SNHG14长非编码RNA杂交来靶向UBE3A父本等位基因的抑制物。本发明专利技术还涉及用于治疗安吉尔曼综合征(Angelman syndrome)的药物组合物和方法。

Oligonucleotides used to induce the expression of paternal UBE3A

The present invention relates to oligonucleotides capable of inducing ubiquitin protein ligase E3A (UBE3A) expressed by male parent alleles in animal or human neurons. Oligonucleotides target UBE3A male parent alleles by hybridized with SNHG14 long non coding RNA downstream of SNORD109B. The invention also relates to pharmaceutical compositions and methods for the treatment of Angelman's syndrome (Angelman syndrome).

【技术实现步骤摘要】
【国外来华专利技术】用于诱导父本UBE3A表达的寡核苷酸专利
本专利技术涉及与SNORD109B下游的SNHG14互补并杂交的寡核苷酸(寡聚物),其导致诱导动物或人中泛素-蛋白连接酶E3A(UBE3A)的父本表达。本专利技术还涉及用于治疗安吉尔曼综合征(Angelmansyndrome)的药物组合物和方法。
技术介绍
安吉尔曼综合征是由母本遗传染色体15q11.2上的UBE3A基因的缺失或失活引起的神经遗传病。UBE3A基因的父本拷贝通过称为SNHG14(也称为UBE3A-ATS)的UBE3A内源性反义转录物在神经元中经受基因组印记和沉默(Meng等人2012HumMolGenet.Vol.21pp.3001-12)。除神经元之外的其它细胞类型似乎表达来自母本和父本等位基因的UBE3A基因。安吉尔曼综合征的特征在于严重的智力和发育障碍、睡眠障碍、发作(seizures)、急动性运动、脑电图(EEG)异常、频繁的笑声或微笑、以及深度的语言障碍。WO2012/064806公开了通过使用拓扑异构酶抑制剂在细胞中诱导UBE3A表达的方法。该方法可以用于治疗安吉尔曼综合征。其并未公开反义寡核苷酸。WO2014/004572公开了具有靶向小鼠UBE3A-ATS的2’-O-甲氧基乙基-RNA(MOE)修饰的寡核苷酸。所述寡核苷酸仅在小鼠相关测定中进行测试。在MBII-52snoRNA(也称为SNORD115)下游和UBE3A前-mRNA上游的区域,小鼠和人之间不存在保守性。因此,靶向小鼠UBE3A-ATS的寡核苷酸不能转换成将在人中起作用的寡核苷酸。其并未公开靶向人UBE3A-ATS的寡核苷酸。专利技术目的本专利技术鉴定了新型寡核苷酸,其在神经元中诱导人类父本UBE3A表达而不显著影响父本SNORD115、SNORD116和SNRPN转录物的表达。
技术实现思路
本专利技术涉及寡核苷酸,其靶向能够抑制UBE3A表达的核酸并且治疗或预防与UBE3A活性降低有关的疾病(特别是在神经元细胞中)。因此,在本专利技术的第一个方面提供了这样的寡核苷酸,所述寡核苷酸包含长度为10至30个核苷酸的连续核苷酸序列,其与人15号染色体版本GRCh38.p2上对应于位置25278410至25419462的人SNHG14长非编码RNA部分具有至少98%互补性。该区域也类似于SEQIDNO:1。寡核苷酸可以是反义寡核苷酸,优选具有间隔聚体(gapmer)设计。优选地,寡核苷酸能够通过降解、减少或除去UBE3A抑制物(suppressor)(特别是通过减少SNORD109B下游的SNHG14长非编码RNA转录物)来诱导UBE3A的表达(特别是神经元中的父本UBE3A表达)。UBE3A再表达是在不显著影响SNORD115表达的情况下实现的。靶核酸的降解优选通过核酸酶募集实现。在另外的方面,本专利技术提供了包含本专利技术的寡核苷酸和药用稀释剂、载体、盐和/或辅剂的药物组合物。在另外的方面,本专利技术提供了通过将本专利技术的寡核苷酸或组合物以有效量施用至所述细胞以在体内或体外诱导其中父本UBE3A的表达被抑制的靶细胞中的UBE3A表达的方法。在另外的方面,本专利技术提供了用于治疗或预防与UBE3A的体内活性相关的疾病、病症或功能障碍的方法,所述方法包括将治疗或预防有效量的本专利技术的寡核苷酸施用至患有或易感于所述疾病、病症或功能障碍的受试者。在另外的方面,本专利技术的寡核苷酸或组合物用于治疗或预防安吉尔曼综合征。附图简述图1:上面的链举例说明了SNORD109B下游的SNHG14转录物(UBE3A-ATS)的区域,其中黑框表示测试的小鼠寡核苷酸的位置。下面的链举例说明了UBE3A编码区,其中黑框表示外显子。外显子1位于160kb左右。将寡核苷酸置于外显子9(位于~97kb)、外显子10(位于~92kb)、外显子13(位于~77kb)和外显子16的5’末端(位于~60kb)的反义区中。图2:其显示实施例2中测试的寡核苷酸在人神经元细胞培养物中诱导UBE3A再表达的能力。与SNORT109B和UBE3A编码区上游的区域之间的人SNHG14长非编码RNA区域(SEQIDNO:1的位置1至55318)互补的寡核苷酸用●非重叠表示。与反义于UBE3A前-mRNA的人SNHG14长非编码RNA区域(SEQIDNO:1的位置55319至141053)互补的寡核苷酸用重叠表示。对人和猕猴(rhesusmonkey)保守的来自表3的寡核苷酸在各图的底部显示为人:猕猴:小鼠之间的保守性用表示。寡核苷酸浓度分别为0.2、1和5μM,如右手侧各图所示。定义寡核苷酸如技术人员通常理解的,如本文所使用的术语“寡核苷酸”定义为包含两个以上共价连接的核苷的分子。这种共价结合的核苷也可以称为核酸分子或寡聚物。寡核苷酸通常通过固相化学合成、随后进行纯化而在实验室中制备。当提及寡核苷酸的序列时,参考共价连接的核苷酸或核苷的核碱基部分或其修饰的序列或顺序。本专利技术的寡核苷酸是人造的,并且是化学合成的,并且通常是纯化的或分离的。本专利技术的寡核苷酸可以包含一个或多个修饰的核苷或核苷酸。反义寡核苷酸如本文所使用的术语“反义寡核苷酸”定义为能够通过与靶核酸杂交(特别是与靶核酸上的连续序列杂交)来调节靶基因表达的寡核苷酸。反义寡核苷酸基本上不是双链的,并且因此不是siRNA。优选地,本专利技术的反义寡核苷酸是单链的。连续核苷酸序列术语“连续核苷酸序列”是指与靶核酸互补的寡核苷酸区域。该术语在本文中与术语“连续核碱基序列”和术语“寡核苷酸基序序列”可互换使用。在一些实施方案中,寡核苷酸的所有核苷酸都存在于连续核苷酸序列中。在一些实施方案中,寡核苷酸包含连续核苷酸序列,并且可以任选地包含另外的一个或多个核苷酸,例如可以用于将官能团连接至连续核苷酸序列的核苷酸接头区域。核苷酸接头区域可以与靶核酸互补或可以不与靶核酸互补。核苷酸核苷酸是寡核苷酸和多核苷酸的结构单元,并且为了本专利技术的目的,其包括天然存在的核苷酸和非天然存在的核苷酸两者。在自然界中,核苷酸(诸如DNA和RNA核苷酸)包含核糖部分、核碱基部分和一个或多个磷酸基团(其不存在于核苷中)。核苷和核苷酸也可以互换地称为“单元”或“单体”。修饰的核苷如本文所使用的术语“修饰的核苷”或“核苷修饰”是指与相当的DNA或RNA核苷相比,通过引入糖部分或(核)碱基部分的一个或多个修饰而被修饰的核苷。在优选的实施方案中,修饰的核苷包含修饰的糖部分。术语修饰的核苷在本文中也可以与术语“核苷类似物”或修饰的“单元”或修饰的“单体”可互换使用。修饰的核苷间连接如技术人员通常理解的,术语“修饰的核苷间连接”定义为本领域技术人员通常理解为除磷酸二酯(PO)连接以外的将两个核苷共价偶联在一起的连接。具有修饰的核苷间连接的核苷酸也称为“修饰的核苷酸”。在一些实施方案中,与磷酸二酯连接相比,修饰的核苷间连接增加了寡核苷酸的核酸酶抗性。对于天然存在的寡核苷酸,核苷间连接包括在相邻核苷之间产生磷酸二酯键的磷酸基团。修饰的核苷间连接对于稳定用于体内使用的寡核苷酸是特别有用的,并且可以用于防止本专利技术的寡核苷酸中的DNA或RNA核苷的区域处的核酸酶切割,例如在间隔聚体寡核苷酸的间隙区域内以及在修饰的核苷的区域中的核酸酶切割。在一个实施方案中,寡核苷酸包含从天然磷本文档来自技高网
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【技术保护点】
1.一种反义寡核苷酸,所述反义寡核苷酸包含长度为10至30个核苷酸的连续核苷酸序列,所述连续核苷酸序列与人15号染色体上的位置25278410至25419462具有至少98%的互补性。

【技术特征摘要】
【国外来华专利技术】2015.11.12 EP 15194367.7;2016.09.19 EP 16189502.41.一种反义寡核苷酸,所述反义寡核苷酸包含长度为10至30个核苷酸的连续核苷酸序列,所述连续核苷酸序列与人15号染色体上的位置25278410至25419462具有至少98%的互补性。2.根据权利要求1所述的寡核苷酸,其中所述连续核苷酸序列与SEQIDNO:1和/或2的靶核酸的区域互补。3.根据权利要求1或2所述的寡核苷酸,其中所述连续核苷酸序列与靶核酸的子序列互补,其中所述子序列选自由表1或2所示的区域组成的组。4.根据权利要求1-3所述的寡核苷酸,其中所述寡核苷酸包含选自由以下组成的组的序列:SEQIDNO:4,5,6,7,8,9,10,11,12,13,14,15,16,17,1819,20,21,22,23,23,24,25,26,26,27,28,29,30,31,31,32,33,34,35,36,37,38,39,40,41,42,43,44,44,45,45,46,47,48,49,50,51,52,53,53,54,54,55,56,57,58,59,60,61,62,63,64,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,79,80,81,8283,84,85,86,87,88,89,90,91,92,93,94,95,95,96,96,96,97,98,99,100,101,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,281,282,283,284,285,286,287,288,289,290,291,292,293,294,295,296,297,298,299,300,301,302,303,304,304,305,306,307,308,309,310,311,312,313,314,315,316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,347,348,349,350,351,352,353,354,355,356,357,358,359,360,361,362,363,364,365,366,367,368,369,370,371,372,373,374,375,376,377,378,379,380,381,382,383,384,385,386,387,388,389,390,391,392,393,394,395,396,397,398,399,400,401,402,403,404,405,406,407,408,409,410,411,412,413,414,415,416,417,418,419,420,421,422,423,424,425,426,427,428,429,430,431,432,433,434,435,436,437,438,439,440,441,442,443,444,445,446,447,448,449,450,451,452,453,454,455,456,457,458,459,460,461,462,463,464,465,466,467,468,469,470,471,472,473,474,475,476,477,478,479,480,481,482,483,484,485,486,487,488,489,490,491,492,493,494,495,496,497,498,499,500,501,502,503,504,505,506,507,508,509,510,511,512,513,514,515,516,517,518,519,520,521,522,523,524,525,526,527,528,529,530,531,532,533,534,535,536,537,538,539,540,541,542,543,544,545,546,547,548,549,550,551,552,553,554,555,556,557,558,559,560,561,562,563,564,565,566,567,568,569,570,571,572,573,574,575,576,577,578,579,580,581,582,583,584,585,586,587,588,589,590,591,592,593,594,595,596,596,597,598,599,600,601,602,603,604,605,606,607,608,609,610,611,612,613,614,615,616,617,618,619,620,621,622,623,624,625,626,627,628,629,630,631,632,633,634,635,636,637,638,639,640,641,642,643,644,645,646,647,648,649,650,651,652,653,654,655,656,657,658,659,660,661,662,663,664,665,666,667,668,669,670,671,672,673,674,675,676,677,678,679,680,681,682,683,684,685,686,687,688,689,690,691,692,693,694,695,696,697,698,699,700,702,703,704,705,706,707,708,709,710,711,712,713,714,715,716,717,718,719,719,720,721,722,723,724,725,726,727,728,729,730,731,732,733,734,735,736,737,738,739,740,741,742,743,744,745,746,747,748,749,750,751,752,754,755,756,757,758,759,760,761,762,763,764,765,766,767,768,769,770,772,773,774,775,776,777,778,779,780,781,782,783,784,785,786,787,788,789,790,791,792,793,794,795,796,797,798,799,800,801,802,803,804,805,806,807,808,809,810,811,812,813,814,815,816,817和818。5.根据权利要求1-4所述的寡核苷酸,所述寡核苷酸包含一个或多个修饰的核苷。6.根据权利要求5所述的寡核苷酸,其中所述一个或多个修饰的核苷是2’糖修饰的核苷。7.根据权利要求6所述的寡核苷酸,其中一个或多个所述2’糖修饰的核苷独立地选自由以下组成的组:2’-O-烷基-RNA、2’-O-甲基-RNA、2’-烷氧基-RNA、2’-O-甲氧基乙基-RNA、2’-氨基-DNA、2’-氟-DNA、阿糖基核酸(ANA)、2’-氟-ANA和LNA核苷。8.根据权利要求5至7中任一项所述的寡核苷酸,其中所述一个或多个修饰的核苷是LNA核苷。9.根据权利要求1-8中任一项所述的寡核苷酸,其中所述寡核苷酸包含至少一个修饰的核苷间连接。10.根据权利要求9所述的寡核苷酸,其中所述连续核苷酸序列内的所述核苷间连接是硫代磷酸酯核苷间连接。11.根据权利要求1-10所述的寡核苷酸,其中所述寡核苷酸能够募集RNA酶H。12.根据权利要求11所述的寡核苷酸,其中所述寡核苷酸是间隔聚体。13.根据权利要求11或12所述的寡核苷酸,其中所述寡核苷酸是式5’-F-G-F’-3’的间隔聚体,其中区域F和F’独立地包含1-7个修饰的核苷,并且G是能够募集RNA酶H的6至16个核苷的区域。14.根据权利要求1-13中任一项所述的寡核苷酸,其中所述寡核苷酸选自由以下组成的组:CMPIDNO:4_1,4_2,5_1,5_2,6_1,6_2,7_1,7_2,8_1,9_1,10_1,11_1,11_2,12_1,12_2,13_1,13_2,14_1,15_1,16_1,17_1,17_2,18_1,18_2,19_1,19_2,20_1,21_1,22_1,23_1,23_2,24_1,25_1,26_1,26_2,27_1,28_1,28_2,29_1,29_2,30_1,31_1,31_2,32_1,33_1,34_1,34_2,34_3,34_4,34_5,34_6,34_7,35_1,35_2,36_1,37_1,38_1,38_2,38_3,38_4,38_5,38_6,39_1,39_2,39_3,39_4,39_5,40_1,40_2,40_3,40_4,40_5,40_6,40_7,40_8,41_1,42_1,43_1,44_1,44_2,45_1,45_2,46_1,47_1,48_1,48_2,48_3,48_4,48_5,48_6,48_7,49_1,50_1,51_1,52_1,53_1,53_2,54_1,54_2,54_3,55_1,55_2,56_1,57_1,58_1,58_2,58_3,59_1,59_2,60_1,60_2,60_3,61_1,62_1,63_1,64_1,64_2,65_1,66_1,67_1,68_1,69_1,69_2,69_3,70_1,70_2,70_3,71_1,72_1,72_2,73_1,73_2,73_3,74_1,74_2,75_1,75_2,76_1,77_1,77_2,77_3,78_1,79_1,79_2,79_3,80_1,80_2,80_3,81_1,82_1,82_2,83_1,83_2,84_1,84_2,85_1,85_2,86_1,87_1,88_1,88_2,89_1,90_1,91_1,92_1,93_1,94_1,95_1,95_2,96_1,96_2,96_3,97_1,97_2,97_3,97_4,98_1,98_2,98_3,99_1,99_2,99_3,99_4,100_1,100_2,100_3,101_1,101_2,101_3,101_4,102_1,102_2,102_3,102_4,103_1,103_2,103_3,103_4,104_1,104_2,104_3,105_1,105_2,105_3,105_4,106_1,106_2,106_3,106_4,107_1,107_2,107_3,107_4,108_1,108_2,108_3,108_4,109_1,109_2,109_3,109_4,110_1,110_2,111_1,111_2,111_3,112_1,112_2,113_1,114_1,115_1,116_1,117_1,118_1,119_1,120_1,120_2,121_1,122_1,123_1,124_1,125_1,126_1,126_2,127_1,128_1,128_2,128_3,128_4,129_1,129_2,130_1,131_1,132_1,132_2,132_3,133_1,133_2,133_3,133_4,134_1,134_2,135_1,135_2,136_1,137_1,138_1,139_1,140_1,141_1,142_1,143_1,144_1,145_1,145_2,146_1,146_2,147_1,148_1,149_1,150_1,150_2,151_1,152_1,153_1,154_1,155_1,156_1,157_1,158_1,159_1,160_1,161_1,162_1,163_1,164_1,165_1,166_1,167_1,168_1,169_1,169_10,169_11,169_12,169_13,169_14,169_15,169_16,169_17,169_18,169_19,169_2,169_20,169_21,169_22,169_23,169_24,169_25,169_26,169_27,169_28,169_29,169_3,169_30,169_31,169_32,169_33,169_34,169_35,169_36,169_37,169_38,169_39,169_4,169_40,169_41,169_42,169_43,169_44,169_45,169_46,169_47,169_48,169_49,169_5,169_50,169_51,169_52,169_53,169_54,169_55,169_56,169_57,169_6,169_7,169_8,169_9,169_58,169_59,169_60,169_61,169_62,170_1,171_1,172_1,173_1,174_1,175_1,176_1,177_1,178_1,179_1,180_1,181_1,182_1,183_1,184_1,185_1,186_1,187_1,188_1,189_1,190_1,191_1,192_1,193_1,194_1,195_1,196_1,197_1,198_1,199_1,200_1,201_1,202_1,203_1,204_1,205_1,206_1,207_1,208_1,208_2,208_3,208_4,208_5,208_6,208_7,209_1,209_10,209_2,209_3,209_4,209_5,209_6,209_7,209_8,209_9,210_1,211_1,212_1,213_1,214_1,215_1,216_1,217_1,218_1,219_1,220_1,221_1,222_1,223_1,224_1,225_1,226_1,227_1,228_1,229_1,230_1,231_1,232_1,233_1,234_1,235_1,236_1,236_10,236_11,236_12,236_13,236_14,236_15,236_16,236_2,236_3,236_4,236_5,236_6,236_7,236_8,236_9,236_17,236_18,236_19,236_20,236_21,237_1,237_10,237_11,237_12,237_13,237_14,237_15,237_16,237_2,237_3,237_4,237_5,237_6,237_7,237_8,237_9,237_17,237_18,237_19,237_20,237_21,238_1,239_1,239_10,239_11,239_12,239_13,239_14,239_15,239_16,239_2,239_3,239_4,239_5,239_6,239_7,239_8,239_9,239_17,239_18,239_19,239_20,239_21,240_1,241_1,241_10,241_2,241_3,241_4,241_5,241_6,241_7,241_8,241_9,241_11,241_12,241_13,241_14,241_15,242_1,243_1,244_1,244_2,244_3,244_4,244_5,245_1,246_1,247_1,248_1,249_1,250_1,251_1,252_1,253_1,254_1,255_1,256_1,257_1,258_1,259_1,260_1,261_1,262_1,263_1,264_1,265_1,266_1,267_1,268_1,269_1,270_1,271_1,272_1,273_1,274_1,275_1,276_1,277_1,278_1,279_1,280_1,281_1,282_1,283_1,284_1,285_1,285_2,285_3,285_4,285_5,285_6,285_7,285_8,285_9,285_10,285_11,286_1,287_1,288_1,289_1,290_1,291_1,292_1,293_1,294_1,295_1,296_1,297_1,298_1,299_1,300_1,301_1,302_1,303_1,304_1,304_10,304_2,304_3,304_4,304_5,304_6,304_7,304_8,304_9,304_11,304_12,304_13,304_14,304_15,305_1,306_1,307_1,308_1,309_1,310_1,311_1,312_1,313_1,314_1,315_1,316_1,317_1,318_1,319_1,320_1,321_1,322_1,323_1,324_1,325_1,326_1,327_1,328_1,329_1,330_1,331_1,332_1,333_1,334_1,335_1,336_1,337_1,338_1,339_1,340_1,341_1,342_1,343_1,344_1,345_1,346_1,347_1,348_1,349_1,350_1,351_1,352_1,353_1,354_1,355_1,356_1,357_1,358_1,359_1,360_1,361_1,361_10,361_2,361_3,361_4,361_5,361_6,361_7,361_8,361_9,362_1,362_10,362_2,362_3,362_4,362_5,362_6,362_7,362_8,362_9,363_1,364_1,365_1,366_1,367_1,368_1,369_1,370_1,371_1,372_1,373_1,374_1,375_1,376_1,377_1,378_1,379_1,380_1,381_1,382_1,383_1,384_1,385_1,386_1,387_1,388_1,389_1,390_1,391_1,392_1,393_1,394_1,395_1,396_1,397_1,398_1,399_1,400_1,401_1,402_1,403_1,404_1,405_1,406_1,407_1,408_1,409_1,410_1,411_1,412_1,413_1,414_1,415_1,416_1,417_1,418_1,419_1,420_1,421_1,422_1,423_1,424_1,425_1,425_10,425_2,425_3,425_4,425_5,425_6,425_7,425_8,425_9,426_1,427_1,428_1,429_1,430_1,431_1,432_1,433_1,434_1,435_1,436_1,437_1,438_1,439_1,440_1,441_1,442_1,443_1,444_1,445_1,446_1,447_1,448_1,449_1,450_1,451_1,452_1,453_1,454_1,455_1,456_1,457_1,458_1,459_1,460_1,461_1,462_1,463_1,464_1,465_1,466_1,467_1,468_1,469_1,470_1,471_1,472_1,473_1,474_1,475_1,476_1,477_1,478_1,479_1,480_1,481_1,482_1,483_1,484_1,485_1,486_1,487_1,488_1,489_1,490_1,491_1,492_1,493_1,494_1,495_1,496_1,497_1,498_1,499_1,500_1,501_1,502_1,503_1,504_1,505_1,506_1,507_1,508_1,509_1,510_1,511_1,512_1,513_1,514_1,515_1,516_1,517_1,518_1,519_1,520_1,521_1,522_1,523_1,524_1,525_1,526_1,527_1,528_1,529_1,530_1,531_1,532_1,533_1,534_1,535_1,536_1,537_1,538_1,539_1,540_1,541_1,542_1,543_1,544_1,545_1,546_1,547_1,548_1,549_1,550_1,551_1,552_1,553_1,554_1,555_1,556_1,557_1,558_1,559_1,560_1,561_1,562_1,563_1,564_1,565_1,566_1,567_1,568_1,569_1,570_1,570_2,570_3,570_4,570_5,570_6,570_7,570_8,570_9,570_10,570_11,570_12,570_13,570_14,571_1,571_2,571_3,571_4,571_5,571...

【专利技术属性】
技术研发人员:韦罗妮卡·科斯塔马伊·黑特耶恩马里乌斯·赫纳拉维·姚高希亚马斯·奥波尔·詹森克里斯托弗·帕奇吕克·彼泽森索伦·韦斯特高·拉斯穆森
申请(专利权)人:豪夫迈·罗氏有限公司
类型:发明
国别省市:瑞士,CH

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