IP Library Granted Patent US 12,371,693
Granted Patent B2
US 12,371,693 · App. 18/159,233 · Granted Jul 29, 2025

5-halouracil-modified micrornas and their use in the treatment of cancer

Inventors: Jingfang Ju (East Setauket, NY); Andrew Fesler (Sound Beach, NY)
Assignee: The Research Foundation for The State University of New York
C12N15/1135A61K31/712A61K45/06A61K48/00A61P35/00C07H21/02C12N2310/14C12N2310/141C12N2310/335C12N2310/3533
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Quick Facts
Patent No.
US 12,371,693
App. No.
18/159,233
Granted
Jul 29, 2025
Kind
B2
Abstract

The present disclosure provides nucleic acid compositions that incorporate one or more halouracil molecules. More specifically, the present disclosure reveals that the replacement of uracil nucleotides within a microRNA nucleotide sequence with a 5-halouracil increases the ability of the micro-RNA to inhibit cancer progression and tumorigenesis. As such, the present disclosure provides various nucleic acid (e.g., microRNA) compositions having 5-halouracil molecules incorporated in their nucleic acid sequences and methods for using the same. The present disclosure further provides pharmaceutical compositions comprising the modified nucleic acid compositions, and methods for treating cancers using the same.

Claims (5)

1. A method for treating cancer comprising administering to a subject an effective amount of a double-stranded nucleic acid composition comprising a modified microRNA nucleotide sequence that comprises uracil nucleic acids, wherein all the uracil nucleic acids including the seed region of the modified microRNA nucleotide sequence are 5-fluorouracils to combine the potency of microRNA nucleotide sequence and 5-fluorouracils which is complementary to a B-cell lymphoma 2 (BCL2) nucleotide sequence, wherein said modified microRNA nucleotide sequence binds to the B-cell lymphoma 2 (BCL2) nucleotide sequence that is complementary to miR-129 microRNA nucleotide sequence as set forth in SEQ ID NO: 1 or miR-15a microRNA nucleotide sequence as set forth in SEQ ID NO: 2, wherein said subject has cancer, and progression of said cancer is inhibited, wherein the microRNA comprises miR-129 microRNA or miR-15a microRNA and wherein said subject has a blood cancer.

2. The method of claim 1 , wherein said subject is a human.

3. The method of claim 1 , wherein the nucleic acid composition comprises a modified microRNA nucleotide sequence selected from the group consisting of CU F U F U F U F U F GCGGU F CU F GGGCU F U F GC [SEQ ID NO. 4], U F AGCAGCACAU F AAU F GGU F U F U F GU F G [SEQ ID NO. 6], and combinations thereof.

4. The method of claim 1 , wherein said nucleic acid composition is administered to the subject by injection.

5. The method of claim 4 , wherein said nucleic acid composition is injected intravenously or intraperitoneal.

Continuity (6)
Division 16176137 · Oct 31, 2018
Continuation In Part PCTUS2017059011 · Oct 30, 2017
Provisional Application 62464491 · Feb 28, 2017
Provisional Application 62422298 · Nov 15, 2016
Provisional Application 62415740 · Nov 1, 2016
Related Publication 20230365972A1 · Nov 16, 2023
References Cited (346)
US 8748098B2 · Hernando et al. · 2014 [cited by applicant]
US 8846631B2 · Marcusson et al. · 2014 [cited by applicant]
US 8980854B2 · Boll et al. · 2015 [cited by applicant]
US 8993533B2 · Collard et al. · 2015 [cited by applicant]
US 9084770B2 · Tachas et al. · 2015 [cited by applicant]
US 9238838B2 · Markel et al. · 2016 [cited by applicant]
US 9243296B2 · Chajut et al. · 2016 [cited by applicant]
US 9255267B2 · Mendell et al. · 2016 [cited by applicant]
US 9333218B2 · Wang et al. · 2016 [cited by applicant]
US 9487781B2 · Yerushalmi · 2016 [cited by applicant]
US 9528110B2 · Collard et al. · 2016 [cited by applicant]
US 9611477B2 · Collard et al. · 2017 [cited by applicant]
US 9611478B2 · Kelnar et al. · 2017 [cited by applicant]
US 9714423B2 · Collard et al. · 2017 [cited by applicant]
US 9878050B2 · Rana · 2018 [cited by applicant]
US 9902995B2 · Collard et al. · 2018 [cited by applicant]
US 9920369B2 · Collard et al. · 2018 [cited by applicant]
US 9932585B2 · Bassell et al. · 2018 [cited by applicant]
US 9988690B2 · Hoshen et al. · 2018 [cited by applicant]
US 9993567B2 · Feinstein · 2018 [cited by applicant]
US 10053696B2 · Chen et al. · 2018 [cited by applicant]
US 10087443B2 · Schaefer · 2018 [cited by applicant]
US 10100315B2 · Collard et al. · 2018 [cited by applicant]
US 10201556B2 · van Haastert et al. · 2019 [cited by applicant]
US 10221413B2 · Collard et al. · 2019 [cited by applicant]
US 10253320B2 · Collard et al. · 2019 [cited by applicant]
US 10301627B2 · Bennett et al. · 2019 [cited by applicant]
US 10337011B2 · Collard et al. · 2019 [cited by applicant]
US 10443055B2 · Pandolfi et al. · 2019 [cited by applicant]
US 10487327B2 · Collard et al. · 2019 [cited by applicant]
US 10709729B2 · Zhang et al. · 2020 [cited by applicant]
US 10961271B2 · Lee et al. · 2021 [cited by applicant]
US 11033570B2 · Yu et al. · 2021 [cited by applicant]
US 11058709B1 · Spector et al. · 2021 [cited by applicant]
US 11236337B2 · Ju et al. · 2022 [cited by applicant]
US 11713462B2 · Grossman et al. · 2023 [cited by applicant]
US 11744846B2 · Murray et al. · 2023 [cited by applicant]
US 20050261217A1 · Dobie et al. · 2005 [cited by applicant]
US 20050261218A1 · Esau et al. · 2005 [cited by applicant]
US 20070072204A1 · Hannon et al. · 2007 [cited by applicant]
US 20070259349A1 · Bentwich et al. · 2007 [cited by applicant]
US 20070259350A1 · Bentwich et al. · 2007 [cited by applicant]
US 20070259352A1 · Bentwich et al. · 2007 [cited by applicant]
US 20080076674A1 · Litman et al. · 2008 [cited by applicant]
US 20080182237A1 · Bentwich et al. · 2008 [cited by applicant]
US 20090136957A1 · Ivanovska et al. · 2009 [cited by applicant]
US 20090137504A1 · Echwald et al. · 2009 [cited by applicant]
US 20090163435A1 · Bader et al. · 2009 [cited by applicant]
US 20090253780A1 · Takeshita et al. · 2009 [cited by applicant]
US 20100105760A1 · Collard et al. · 2010 [cited by applicant]
US 20100113284A1 · Aristarkhov et al. · 2010 [cited by applicant]
US 20100113560A1 · Lieberman et al. · 2010 [cited by applicant]
US 20100184830A1 · Croce et al. · 2010 [cited by applicant]
US 20100227909A1 · Cleary et al. · 2010 [cited by applicant]
US 20100279292A1 · Marsh et al. · 2010 [cited by applicant]
US 20100286234A1 · Elmen et al. · 2010 [cited by applicant]
US 20100311815A1 · Chinnaiyan et al. · 2010 [cited by applicant]
US 20110071215A1 · Pass et al. · 2011 [cited by applicant]
US 20110105583A1 · Cleary et al. · 2011 [cited by applicant]
US 20110118337A1 · Chau et al. · 2011 [cited by applicant]
US 20110166200A1 · Zhang et al. · 2011 [cited by applicant]
US 20110166201A1 · Ju et al. · 2011 [cited by applicant]
US 20110172293A1 · Fish et al. · 2011 [cited by applicant]
US 20110263514A1 · Rana · 2011 [cited by applicant]
US 20110269814A1 · Manoharan et al. · 2011 [cited by applicant]
US 20110301226A1 · Mendell et al. · 2011 [cited by applicant]
US 20120087992A1 · Ju et al. · 2012 [cited by applicant]
US 20120093789A1 · Srivastava et al. · 2012 [cited by applicant]
US 20120177599A1 · Pass et al. · 2012 [cited by applicant]
US 20120184603A1 · Litman et al. · 2012 [cited by applicant]
US 20120202981A1 · Lee et al. · 2012 [cited by applicant]
US 20120207723A1 · He et al. · 2012 [cited by applicant]
US 20120238618A1 · Elmen et al. · 2012 [cited by applicant]
US 20120264131A1 · Goel et al. · 2012 [cited by applicant]
US 20120322743A1 · Hernando et al. · 2012 [cited by applicant]
US 20130085077A1 · Croce et al. · 2013 [cited by applicant]
US 20130109628A1 · Wang et al. · 2013 [cited by applicant]
US 20130123138A1 · Pass et al. · 2013 [cited by applicant]
US 20140088300A1 · Schmitz, Sr. et al. · 2014 [cited by applicant]
US 20140256789A1 · Oren et al. · 2014 [cited by applicant]
US 20140336241A1 · Chajut et al. · 2014 [cited by applicant]
US 20140363469A1 · Meyers · 2014 [cited by applicant]
US 20150087607A1 · Marcussen et al. · 2015 [cited by applicant]
US 20150133525A1 · Collard et al. · 2015 [cited by applicant]
US 20150159159A1 · Anderson et al. · 2015 [cited by applicant]
US 20150167007A1 · Collard et al. · 2015 [cited by applicant]
US 20150225725A1 · Collard et al. · 2015 [cited by applicant]
US 20150337305A1 · Bennett · 2015 [cited by examiner]
US 20150337332A1 · Ruohoa-Baker · 2015 [cited by applicant]
US 20150376711A1 · Michot · 2015 [cited by applicant]
US 20160002640A1 · Collard et al. · 2016 [cited by applicant]
US 20160010092A1 · Collard et al. · 2016 [cited by applicant]
US 20160017331A1 · Chung et al. · 2016 [cited by applicant]
US 20160090636A1 · Ju et al. · 2016 [cited by applicant]
US 20160312301A1 · Lee et al. · 2016 [cited by applicant]
US 20160376598A1 · Lee et al. · 2016 [cited by applicant]
US 20170015999A1 · Yerushalmi · 2017 [cited by applicant]
US 20170081666A1 · Yao · 2017 [cited by applicant]
US 20170182177A1 · Rana · 2017 [cited by applicant]
US 20170211074A1 · Chen et al. · 2017 [cited by applicant]
US 20180066260A1 · Collard et al. · 2018 [cited by applicant]
US 20180195067A1 · Pandolfi et al. · 2018 [cited by applicant]
US 20180207191A1 · Lancaster et al. · 2018 [cited by applicant]
US 20180221393A1 · Peled et al. · 2018 [cited by applicant]
US 20180320175A1 · Lee et al. · 2018 [cited by applicant]
US 20190062754A1 · Ju et al. · 2019 [cited by applicant]
US 20190112665A1 · Hoshen et al. · 2019 [cited by applicant]
US 20190247418A1 · Pavel et al. · 2019 [cited by applicant]
US 20190330632A1 · Anand et al. · 2019 [cited by applicant]
US 20200140859A1 · Pandolfi et al. · 2020 [cited by applicant]
US 20200354719A1 · Ju et al. · 2020 [cited by applicant]
US 20210324383A1 · Jaffee et al. · 2021 [cited by applicant]
US 20220090076A1 · Ju et al. · 2022 [cited by applicant]
US 20220145304A1 · Ju et al. · 2022 [cited by applicant]
US 20220275374A1 · Ruiz Echevarria et al. · 2022 [cited by applicant]
AU 2009228393B2 · 2014 [cited by applicant]
CA 2583375C · 2013 [cited by applicant]
CN 103476931A · 2013 [cited by applicant]
CN 110290794A · 2019 [cited by applicant]
CN 113573736A · 2021 [cited by applicant]
EP 2090665A2 · 2009 [cited by applicant]
EP 2152722A2 · 2010 [cited by applicant]
EP 2370582A2 · 2011 [cited by applicant]
EP 2296669B1 · 2012 [cited by applicant]
EP 2471956A1 · 2012 [cited by applicant]
EP 1978986B1 · 2013 [cited by applicant]
EP 2183393B1 · 2014 [cited by applicant]
EP 2569432B1 · 2017 [cited by applicant]
EP 2872634B1 · 2018 [cited by applicant]
EP 2113567B1 · 2019 [cited by applicant]
EP 3736022A2 · 2020 [cited by applicant]
EP 3800256A1 · 2021 [cited by applicant]
JP 2008519606A · 2008 [cited by applicant]
JP 2009507918A · 2009 [cited by applicant]
JP 2009521952A · 2009 [cited by applicant]
JP 2010504349A · 2010 [cited by applicant]
JP 2010504350A · 2010 [cited by applicant]
JP 2012532123A · 2012 [cited by applicant]
JP 50198430B2 · 2013 [cited by applicant]
JP 2013166766A · 2013 [cited by applicant]
JP 5535076B2 · 2014 [cited by applicant]
JP 2015504847A · 2015 [cited by applicant]
JP 2015518710A · 2015 [cited by applicant]
JP 2015518711A · 2015 [cited by applicant]
JP 2015518712A · 2015 [cited by applicant]
JP 2015518713A · 2015 [cited by applicant]
JP 2015518714A · 2015 [cited by applicant]
JP 2015519057A · 2015 [cited by applicant]
JP 2015523853A · 2015 [cited by applicant]
JP 2015523854A · 2015 [cited by applicant]
JP 2015523855A · 2015 [cited by applicant]
JP 50841024B2 · 2016 [cited by applicant]
JP 2016521556A · 2016 [cited by applicant]
JP 50971948B2 · 2016 [cited by applicant]
JP 6099868B2 · 2017 [cited by applicant]
JP 2017511694A · 2017 [cited by applicant]
JP 6704883B2 · 2020 [cited by applicant]
JP 6738841B2 · 2020 [cited by applicant]
JP 7130639B2 · 2022 [cited by applicant]
KR 20210139237A · 2012 [cited by applicant]
KR 101343616B1 · 2013 [cited by applicant]
KR 101596166B1 · 2016 [cited by applicant]
KR 20160113321A · 2016 [cited by applicant]
KR 101838308B1 · 2018 [cited by applicant]
KR 101853508B1 · 2018 [cited by applicant]
KR 101857090B1 · 2018 [cited by applicant]
WO 9641809A1 · 1996 [cited by applicant]
WO 03029459A2 · 2003 [cited by applicant]
WO 2006128245A1 · 2006 [cited by applicant]
WO 2006133022A2 · 2007 [cited by applicant]
WO 2007016548A2 · 2007 [cited by applicant]
WO 2007033023A2 · 2007 [cited by applicant]
WO 2007109236A2 · 2007 [cited by applicant]
WO 2008008430A2 · 2008 [cited by applicant]
WO 2008036718A2 · 2008 [cited by applicant]
WO 2008104974A2 · 2008 [cited by applicant]
WO 2008095096A2 · 2008 [cited by applicant]
WO 2009012468A2 · 2009 [cited by applicant]
WO 2009036236A1 · 2009 [cited by applicant]
WO 2009036332A1 · 2009 [cited by applicant]
WO 2009049129A1 · 2009 [cited by applicant]
WO 2009075787A1 · 2009 [cited by applicant]
WO 2009080437A1 · 2009 [cited by applicant]
WO 2009126726A1 · 2009 [cited by applicant]
WO 2009154835A2 · 2009 [cited by applicant]
WO 2010006111A2 · 2010 [cited by applicant]
WO 2010023658A2 · 2010 [cited by applicant]
WO 2010065156A1 · 2010 [cited by applicant]
WO 2010115050A2 · 2010 [cited by applicant]
WO 2010126370A2 · 2010 [cited by applicant]
WO 2010127195A2 · 2010 [cited by applicant]
WO 2011002200A2 · 2011 [cited by applicant]
WO 2011014980A1 · 2011 [cited by applicant]
WO 2011024157A1 · 2011 [cited by applicant]
WO WO2011057003A2 · 2011 [cited by examiner]
WO 2011108930A1 · 2011 [cited by applicant]
WO 2011111715A1 · 2011 [cited by applicant]
WO 2011128886A1 · 2011 [cited by applicant]
WO 2011146674A2 · 2011 [cited by applicant]
WO 2011157294A1 · 2011 [cited by applicant]
WO 2012009347A2 · 2012 [cited by applicant]
WO 2012009508A2 · 2012 [cited by applicant]
WO 2012082821A2 · 2012 [cited by applicant]
WO 2012092485A1 · 2012 [cited by applicant]
WO 2012096573A1 · 2012 [cited by applicant]
WO WO2012106586A1 · 2012 [cited by examiner]
WO 2013056216A1 · 2013 [cited by applicant]
WO WO2013158046A1 · 2013 [cited by examiner]
WO 2014100252A · 2014 [cited by applicant]
WO 2014186462A1 · 2014 [cited by applicant]
WO 2014201417A1 · 2014 [cited by applicant]
WO 2015127517A1 · 2015 [cited by applicant]
WO 2018085198A1 · 2018 [cited by applicant]
WO 2019245135A1 · 2019 [cited by applicant]
WO 2020061397A1 · 2020 [cited by applicant]
WO 23020102142A1 · 2020 [cited by applicant]
WO 23020154207A1 · 2020 [cited by applicant]
WO 2020186124A1 · 2020 [cited by applicant]
WO 2021097437A1 · 2021 [cited by applicant]
Elliott et al. (Journal of Molecular and Cellular Cardiology, 62, 2013, 1-7). [cited by applicant]
Yu et al. (Gene, 532, 2013, 87-93). [cited by applicant]
Zhang et al. (Journal of Hematology & Oncology, 2010, 3:46, pp. 1-9). [cited by applicant]
Peacock, H., et al., “Chemical Modification of siRNA Bases to Probe and Enhance RNA Interference”, J Org Chem., Sep. 16, 2011, pp. 7295-7300, 76(18). [cited by applicant]
Chinese Office Action dated Jun. 16, 2023 received in Chinese Patent Application No. 201780081456.7, 18 pages. [cited by applicant]
Accession No. MIMAT0000062 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0004481 (2 pages) (2018). [cited by applicant]
NCBI Reference Sequence No. NG_029591.1 (25 pages) (Oct. 21, 2017). [cited by applicant]
U.S. Office Action dated Aug. 9, 2021 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
U.S. Office Action dated Oct. 23, 2020 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
U.S. Office Action dated Jan. 13, 2020 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
U.S. Office Action dated Jan. 25, 2022 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
U.S. Office Action dated Feb. 23, 2021 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
U.S. Office Action dated May 21, 2020 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
U.S. Office Action dated Jun. 3, 2019 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
Advisory Action dated Oct. 18, 2021 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
Advisory Action dated Jan. 11, 2021 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
Advisory Action dated Mar. 20, 2020 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
Notice of Allowance dated Aug. 31, 2022 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
Notice of Allowance dated Oct. 14, 2022 issued in U.S. Appl. No. 16/176,137. [cited by applicant]
Partial Supplementary European Search Report dated Jul. 11, 2023 received in European Patent Application No. 19878184.1, 11 pages. [cited by applicant]
Notice of Reasons for Rejection dated Aug. 4, 2023 received in Japanese Patent Application No. 2022-133279, 11 pages. [cited by applicant]
Mexican Office Action dated Mar. 29, 2022 received in Mexican Application No. MX/a/2019/005101, together with an English-language translation. [cited by applicant]
Chinese Office Action dated Jun. 1, 2022 received in Chinese Patent Application No. 201780081456.7, together with an English-language translation. [cited by applicant]
Japanese Notice of Reasons for Rejection dated Feb. 7, 2022 received in Japanese Application No. 2019-523008, together with an English-language translation. [cited by applicant]
Korean Office Action dated May 10, 2022 received in Korean Patent Application No. 10-2019-7015788, together with an English-language translation. [cited by applicant]
Peng F. et al., Direct Targeting of SUZ12/ROCK2 by miR-200b/c Inhibits Cholangiocarcinoma Tumourigenesis and Metasis, British Journal of Cancer 109:3092-3104 (2013). [cited by applicant]
Invitation to Pay Additional Fees dated Oct. 6, 2021 received in International Application No. PCT/US21/38796. [cited by applicant]
Chen Z. et al., “miR-124 and miR-506 Inhibit Colorectal Cancer Progression by Targeting DNMT3B and DNMT1”, oncotarget 6(35):38139-38150 (2015). [cited by applicant]
Yu X. et al., “Growth Inhibitory Effects of Three miR-129 Family Members on Gastric Cancer” Gene 535:87-93 (2013). [cited by applicant]
Japanese Notice of Reasons for Rejection dated Jul. 26, 2021 received in Japanese Application No. 2019-523008, together with an English-language translation. [cited by applicant]
Brazilian Search Report dated Sep. 15, 2021 received in Brazilian Application No. BR112019008810-5, together with an English-language translation. [cited by applicant]
Chiu Y-L et al., “siRNA Function in RNAi: A Chemical Modification Analysis”, RNA 9(9):1034-1048 (Jan. 1, 2003). [cited by applicant]
Lam J KW et al., “siRNA Versus miRNA as Therapeutics for Gene Silencing”, Molecular Therapy-Nucleic Acids 4: e252 (Jan. 1, 2015). [cited by applicant]
Watts J.K. et al., “Chemically Modified siRNA: Tools and Applications”, Drug Discovery Today 13(19/20):842-855 (Oct. 1, 2008). [cited by applicant]
Wu S-Y et al., “Development of Modified siRNA Molecules Incorporating 5-Fluoro-2-Deoxyuridine Residues to Enhance Cytotoxicity”. Nucleic Acids Research 41 (8): 4650-4659 (Apr. 1, 2013). [cited by applicant]
Supplementary Partial European Search Report dated May 29, 2020 received in European Application No. 17 86 17742.3. [cited by applicant]
Extended Supplementary European Search Report dated Sep. 3, 2020 received in European Application No. 17 66 7742.3. [cited by applicant]
Fesler A. et al., “Development of 5-FU Modified Tumor Suppressor miRNAs as a Platform for miRNA Based Cancer Therapeutics”, Abstract 4403, In Proceedings of the American Association for Cancer Research Annual Meeting, M… [cited by applicant]
International Search Report and Written Opinion dated Mar. 5, 2020 received in International Application No. PCT/US19/58706. [cited by applicant]
Wu N. et al., “Development of Novel miR-129 Mimics With Enhanced Efficacy to Eliminate Chemoresistant Colon Cancer Stem Cells”, Oncotarget 9(10):8887-8897 (2018). [cited by applicant]
Invitation to Pay Additional Fees dated Dec. 31, 2019 received in International Application No. PCT/US19/58706. [cited by applicant]
NCBI Reference Sequence No. NP_001230005.1 (3 pages) (Oct. 21, 2018). [cited by applicant]
NCBI Reference Sequence No. NG_009361.1 (48 pages) (Apr. 13, 2018). [cited by applicant]
NCBI Reference Sequence No. NM_000633.2 (7 pages) (Oct. 21, 2018). [cited by applicant]
NCBI Reference Sequence No. NP_000624.2 (4 pages) (Oct. 21, 2018). [cited by applicant]
NCBI Reference Sequence No. NM_000657.2 (4 pages) (Oct. 21, 2018). [cited by applicant]
NCBI Reference Sequence No. NP_000648.2 (3 pages) (Oct. 21, 2018). [cited by applicant]
NCBI Reference Sequence No. NG_028255.1 (14 pages) (Oct. 23, 2018). [cited by applicant]
NCBI Reference Sequence No. NM _001071.2 (4 pages) (Aug. 21, 2017). [cited by applicant]
NCBI Reference Sequence No. NP _001062 1 (3 pages) (Oct. 22, 2018). [cited by applicant]
NCBI Reference Sequence No. NM_001243076.2 (5 pages) (Oct. 21, 2018). [cited by applicant]
Accession No. MIMAT0004557 (1 page) (2018). [cited by applicant]
Accession No. MI0000737 {2 pages) (2018). [cited by applicant]
Accession No. MIMAT0001620 {1 page) (2018). [cited by applicant]
Accession No. MIMA T000682 (2 pages) (2018). [cited by applicant]
Accession No. MI0000342 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT00004571 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0000318 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0004657 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT000617 (2 pages) (2018). [cited by applicant]
Accession No. MIMA T0000437 (2 pages) (2018). [cited by applicant]
Waizumi M. et al., “DNA Mismatch Repair Proficiency Executing 5-Fluorouracil Cytotoxicity in Colorectal Cancer Cells”, Cancer Biology & Therapy 12(8):756-764 (Oct. 15, 2011). [cited by applicant]
Karaayvaz M. et al., “miR-129 Promotes Apoptosis and Enhances Chemosensitivity to 5-Fluorouracil in Colorectal Cancer”, Cell Death and Disease 4:e659 (2013). [cited by applicant]
Pettersen H.S. et al., “UNG-Initiated Base Excision Repair is the Major Repair Route for 5-Fluorouracil in DAN, But 5-Fluorouracil Cytotoxicity Depends Mainly on RNA Incorporation”, Nucleic Acids Research 39(19):8430-84… [cited by applicant]
International Search Report and Written Opinion dated Feb. 6, 2018 received in International Patent Application No. PCT/US2017/059011. [cited by applicant]
Acunzo M. et al., “Downregulation of miR-15a and miR-16-1 at 13q14 in Chronic Lymphocytic Leukemia”, Clinical Chemistry 62(4):655-656 (2016). [cited by applicant]
Altuvia Y. et al., “Clustering and Conservation Patterns of Human microRNAs”, Nucleic Acids Research 33(8):2697-2706 (2005). [cited by applicant]
Ambros V., “The Functions of Animal microRNAs”, Nature 431:350-355 (Sep. 16, 2004). [cited by applicant]
Aqeilan RI et al., “miR-15a and miR-16-1 in Cancer; Discovery, Function and Future Perspectives”, Cell Death and Differentiation 17:215-220 (2010). [cited by applicant]
Bartel D.P., “MicroRNAs: Target Recognition and Regulatory Functions”, Cell 136(2):215-233 (Jan. 23, 2009). [cited by applicant]
Bartel DP, “MicroRNAs: Genomics, Biogenesis, Mechanism, and Function”, Cell 116:281-297 (Jan. 23, 2004). [cited by applicant]
Beaucage SL et al., “Deoxynucleoside Phosphoramidites—A New Class of Key Intermediates for beoxypolynucleotides Synthesis”, Tetrahedron Letters 22(20):1856-1862 (1981). [cited by applicant]
Carreras C.W. et al., “The Catalytic Mechanism and Structure of Thymidylate Synthase”, Annu. Rev. Biochem. 64:721-762 (1995). [cited by applicant]
Crose C.M., “Causes and Consequences of microRNA Dysregulation in Cancer”, Nature Reviews Genetics 10:704-714 (Oct. 2009). [cited by applicant]
Dunham CM et al., “Recombinant RNA Expression”, Nature Methods 4(7):547-548 (Jul. 2007). [cited by applicant]
Gottesman M.M. et al., “Multidrug Resistance in Cancer: Role of ATP-Dependent Transporters”, Nature Reviews—Cancer 2:48-58 (Jan. 2002). [cited by applicant]
Kasashima K. et al., “Altered Expression Profiles of MicroRNAs During TPA-Induced Differentiation of HL-60 Cells”, Biochemical and Biophysical Research Communications 322:403-410 (2004). [cited by applicant]
Lagos-Quintana M. et al., “New microRNAs from Mouse and Human”, RNA 9(2):175-179 (2003). [cited by applicant]
Landgraf P. et al., “A Mammalian microRNA Expression Atlas Based on Small RNA Library Sequencing”, Cell 129:1401-1414 (Jun. 29, 2007). [cited by applicant]
Li J. et al., “The Emerging role of miR 506 in Cancer”, Oncotarget 7 (38) 62778-62788 (2016). [cited by applicant]
Li J. et al., “Downregulated miR-506 Expression Facilitates Pancreatic Cancer Progression and Chemoresistance Via SPHK1/Akt/NF-KB Signaling”, Oncogene 35:5501-5514 (2016). [cited by applicant]
Lui W-O et al., “Patterns of Known and Novel Small RNAs in Human Cervical Cancer”, Cancer Research 67(13):6031-6043 (Jul. 1, 2007). [cited by applicant]
Maitra A. et al., “Pancreatic Cancer”, Annual Review of Pathology: Mechanisms of Disease 3:157-188 (2008). [cited by applicant]
Matteucci M.D. et al., “Synthesis of Deoxyoligonucleotides on a Polymer Support”, J. Am. Chem. Soc. 103:3185-3191 (1981). [cited by applicant]
Oettle H. et al., “Adjuvant Chemotherapy With Gemcitabine and Long-Term Outcomes Among Patients With Resected Pancreatic Cancer”, JAMA 310(14):1473-1481 (Oct. 9, 2013). [cited by applicant]
Scaringe S.A. et al., “Novel RNA Synthesis Method Using 5′-O-Silyl-2′-O-Orthoester Protecting Groups”, J. Am. Chem Soc. 120(45):11820-11821 (1998). [cited by applicant]
Siegel R.L. et al., “Cancer Statistics”, Cancer J. Clin. 65(1):5-29 (Jan./Feb. 2015). [cited by applicant]
Song B. et al., “Molecular Mechanism of Chemoresistance by miR-215 in Osteosarcoma and Colon Cancer Cells”, Molecular Cancer 9(96):1476-1498 (2010). [cited by applicant]
Song B. et al., “miR-192 Regulates Dihydrofolate Reductase and Cellular Proliferation Through the p53-microRNA Circuit”, Clin. Cancer Res. 14(24):8080-8086 (Dec. 15, 2008). [cited by applicant]
Wu J. et al., “miR-129 Regulates Cell Proliferation by Downregulating Cdk6 Expression”, Cell Cycle 9(9):1809-1818, (May 1, 2010). [cited by applicant]
Zhai H. et al., “Inhibition of Colorectal Cancer Stem Cell Survival and Invasive Potential by Has-miR-140-5p Mediated Suppression of Smad2 and Autophagy”, Oncotarget 6(23):19735-19746 (2015). [cited by applicant]
Zhai H. et al., “Inhibition of Autophagy and Tumor Growth in Colon Cancer by miR-502”, Oncogene 32(12):1570-1579 (2013). [cited by applicant]
Accession No. MI0000252 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0000242 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0004548 (1 page) (2018). [cited by applicant]
Accession No. MI0000069 (3 pages) (2018). [cited by applicant]
Accession No. MI0000068 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0004488 (2 pages) (2018). [cited by applicant]
Accession No. MI0000456 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0000431 (2 pages) (2018). [cited by applicant]
NCBI Reference Sequence No. NT_010498.16 (6 pages) (Mar. 26, 2018). [cited by applicant]
Accession No. MIMAT0004597 (2 pages) (2018). [cited by applicant]
Accession No. MI0000234 (2 pages) (2018). [cited by applicant]
Accession No. MI0000291 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0000222 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0000272 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0004543 (1 page) (2018). [cited by applicant]
Accession No. MIMAT0026476 (1 page) (2018). [cited by applicant]
Accession No. MI0003186 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0002873 (1 page) (2018). [cited by applicant]
Accession No. MIMAT0004775 (1 page) (2018). [cited by applicant]
Accession No. MI0003193 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0002878 (1 page) (2018). [cited by applicant]
Accession No. MI0000268 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0000255 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0004601 (1 page) (2018 ). [cited by applicant]
Accession No. MI0000488 (2 pages) (2018). [cited by applicant]
Accession No. MI0000732 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0000460 (2 pages) (2018). [cited by applicant]
Accession No. MIMAT0004671 (2 pages) (2018). [cited by applicant]
Accession No. MI0000060 (3 pages) (2018). [cited by applicant]
Chinese Office Action dated Jan. 7, 2024 received in Chinese Patent Application No. 201980087509.5, 22 pages. [cited by applicant]
Office Action dated Aug. 30, 2024 received in U.S. Appl. No. 17/534,520, 16 pages. [cited by applicant]
Second Office Action received in CN 201980087509.5 dated Oct. 1, 2024, 27 pages. [cited by applicant]
Third Office Action received in CN Patent Application No. 201980087509.5 dated Feb. 15, 2025, 137 pages. [cited by applicant]
Decision of Rejection received in KR Patent Application No. 10-2021-7016590 dated Feb. 19, 2025, 10 pages. [cited by applicant]