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(12) United States Patent (10) Patent No.: US 7,786.292 B2 Karelson Et Al

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(12) United States Patent (10) Patent No.: US 7,786.292 B2 Karelson Et Al USOO7786292B2 (12) United States Patent (10) Patent No.: US 7,786.292 B2 Karelson et al. (45) Date of Patent: Aug. 31, 2010 (54) ANTISENSE AGENTS COMBINING 5,118,800 A 6/1992 Smith et al. STRONGLY BOUND BASE-MODIFIED 5,118,802 A 6/1992 Smith et al. OLGONUCLEOTDE AND ARTIFICAL 5,130,302 A 7/1992 Spielvogel et al. NUCLEASE 5,134,066 A 7/1992 Rogers et al. 5,138,045 A 8, 1992 Cook et al. 5,166,315 A 11/1992 Summerton et al. (75) Inventors: Mati Karelson, Tartumaa (EE); Mart 5,175.273 A 12/1992 Bischofberger et al. Saarma, Helsinki (FI); Mehis Pilv, 5,177,196 A 1/1993 Meyer, Jr. et al. Tallinn (EE) 5,185,444 A 2, 1993 Summerton et al. 5,188,897 A 2f1993 Suhadolnik et al. (73) Assignee: Baltic Technology Development, Ltd., 5,194.599 A 3, 1993 Froehler et al. Tallinn (EE) 5,213,804 A 5/1993 Martin et al. 5,214,134 A 5/1993 Weis et al. (*) Notice: Subject to any disclaimer, the term of this 5,214,136 A 5/1993 Lin et al. patent is extended or adjusted under 35 5,216,141 A 6/1993 Benner U.S.C. 154(b) by 0 days. 5,218, 105 A 6/1993 Cook et al. 5,227,170 A 7, 1993 Sullivan 5,235,033. A 8, 1993 Summerton et al. (21) Appl. No.: 11/742,384 5.245,022 A 9, 1993 Weis et al. 5,254,469 A 10/1993 Warren, III et al. (22) Filed: Apr. 30, 2007 5,258,506 A 11/1993 Urdea et al. 5,262,536 A 11/1993 Hobbs, Jr. (65) Prior Publication Data 5,264.221 A 11/1993 Tagawa et al. US 2007/O25983O A1 Nov. 8, 2007 5,264,423 A 11/1993 Cohen et al. 5,264,562 A 11/1993 Matteucci Related U.S. Application Data (Continued) (60) Provisional application No. 60/797,448, filed on May 3, 2006. FOREIGN PATENT DOCUMENTS EP O 680969 11, 1995 (51) Int. Cl. C7H 2L/04 (2006.01) C7H 2L/00 (2006.01) (Continued) A6 IK3I/70 (2006.01) OTHER PUBLICATIONS (52) U.S. Cl. .................... 536/24.5:536/23.1536/25.3: Delehanty et al., “RNA hydrolysis and inhibition of translation by a 514744 Co (III)-cyclen complex.” RNA. 11: 831-6 (2005). (58) Field of Classification Search ....................... None Hicke et al., “Tumor targeting by an aptamer.” J. Nucl. Med. 47: See application file for complete search history. 668-78 (2006). Hjelstuen et al., “Comparative evaluation of 99mTc-MAG2 (56) References Cited oligonucleotides with phophodiester or phosphorothioate back bones: preparation, stability and biodistribution.” Journal of Labeled U.S. PATENT DOCUMENTS Compounds and Radiopharmaceuticals. 42: 737-60 (1999). 3,687,808 A 8, 1972 Merigan et al. Mardirossian et al. In vivo hybridization of Technetium-99m-la 4,426,330 A 1, 1984 Sears beled peptide nucleic acid (PNA).J. Nucl. Med. 38:907-13 (1997). 4,469,863. A 9, 1984 Ts'o et al. Roivainen et al., “68Ga-labeled oligonucleotides for in vivo imaging 4476,301 A 10, 1984 Imbach et al. with PET. J. Nucl. Med. 45: 347-55 (2004). 4,534,899 A 8, 1985 Sears 4,587,044 A 5, 1986 Miller et al. (Continued) 4,605,735 A 8/1986 Miyoshi et al. 4,667,025 A 5/1987 Miyoshi et al. Primary Examiner Tracy Vivlemore 4,762,779 A 8, 1988 Snitman (74) Attorney, Agent, or Firm—Marshall, Gerstein & Borun 4,789,737 A 12/1988 Miyoshi et al. LLP 4,824.941 A 4, 1989 Gordon et al. 4,828,979 A 5, 1989 Klevan et al. (57) ABSTRACT 4,835,263. A 5/1989 Nguyen et al. 4,845,205 A 7/1989 Huynh Dinh et al. The present invention provides compounds having a chelat 4,876,335 A 10, 1989 Yamane et al. ing moiety and an oligonucleotide sequence wherein the oli 4,904,582 A 2, 1990 Tullis gonucleotide includes one or more modified nucleobases, 4,948,882 A 8, 1990 Ruth Such as hydroxynucleobases. The disclosed compounds are 4,958,013 A 9/1990 Letsinger Suitable for antisense therapy. The chelating moiety can be 4,981,957 A 1/1991 Lebleu et al. complexed to an ion of a lanthanide metal. These compounds 5,013,556 A 5, 1991 Woodle et al. are efficient translation inhibitors of nucleic acids and have 5,023,243 A 6, 1991 Tullis 5,034,506 A 7, 1991 Summerton et al. increased binding affinity for target nucleic acids. The inven 5,082,830 A 1/1992 Brakel et al. tion also includes compositions and methods of using these 5,108,921 A 4, 1992 Low et al. compositions as antisense therapy. 5,109,124 A 4, 1992 Ramachandran et al. 5, 112,963 A 5, 1992 Pieles et al. 37 Claims, 2 Drawing Sheets US 7,786.292 B2 Page 2 U.S. PATENT DOCUMENTS 5,565,555 A 10, 1996 Froehler et al. 5,567,810 A 10/1996 Weis et al. 5,264,564 A 1 1/1993 Matteucci 5,567,811 A 10/1996 Misiura et al. 5,272,250 A 12/1993 Spielvogel et al. 5,571,799 A 1 1/1996 Tkachuk et al. 5,276,019 A 1/1994 Cohen et al. 5,574,142 A 1 1/1996 Meyer, Jr. et al. 5,278.302 A 1/1994 Caruthers et al. 5,576.427 A 11/1996 Cook et al. 5,286,717 A 2f1994 Cohen et al. 5,578,717. A 1 1/1996 Urdea et al. 5,292,873 A 3, 1994 Rokita et al. 5,578,718 A 11/1996 Cook et al. 5,317,098 A 5/1994 Shizuya et al. 5,580,575 A 12/1996 Unger et al. 5,319,080 A 6, 1994 Leumann 5,580,731 A 12/1996 Chang et al. 5,321,131 A 6/1994 Agrawal et al. 5,583,020 A 12/1996 Sullivan 5,354,844. 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A 10/1995 Cook et al. 5,623,070 A 4, 1997 Cook et al. 5,462,854 A 10, 1995 Coassin et al. 5,625,050 A 4/1997 Beaton et al. 5,466,677 A 11/1995 Baxter et al. 5,627,053 A 5/1997 USman et al. 5,466,786 A 1 1/1995 Buhr et al. 5,633,360 A 5/1997 Bischofberger et al. 5,469,854. A 1 1/1995 Unger et al. 5,639,873. A 6/1997 Barascut et al. 5,470,967 A 1 1/1995 Huie et al. 5,645,985 A 7/1997 Froehler et al. 5,476,925 A 12/1995 Letsinger et al. 5,646,265 A 7, 1997 McGee 5,484.908 A 1/1996 Froehler et al. 5,646.269 A 7/1997 Matteucci et al. 5,486,603 A 1, 1996 Buhr 5,658,873. A 8, 1997 BertSch-Frank et al. 5,489,677 A 2/1996 Sanghviet al. 5,663,312 A 9, 1997 Chaturvedulla 5,502,177 A 3, 1996 Matteucci et al. 5,670,633. A 9, 1997 Cook et al. 5,510.475 A 4, 1996 Agrawal et al.
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