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(12) United States Patent (10) Patent No.: US 6,645,716 B2 Wheeler Et Al

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(12) United States Patent (10) Patent No.: US 6,645,716 B2 Wheeler Et Al USOO6645716B2 (12) United States Patent (10) Patent No.: US 6,645,716 B2 Wheeler et al. (45) Date of Patent: Nov. 11, 2003 (54) METHODS FOR DETECTION OF CHLORAL (56) References Cited HYDRATE IN DICHLOROACETIC ACID U.S. PATENT DOCUMENTS (75) Inventors: Patrick Wheeler, Carlsbad, CA (US); 5.959,099 A 9/1999 Cheruvallath et al. ..... 536/26.1 Daniel C. Capaldi, Encinitas, CA (US) 6,005,094. A 12/1999 Simon et al. .............. 536/24.5 (73) Assignee: ISIS Pharmaceuticals, Inc., Carlsbad, OTHER PUBLICATIONS CA (US) Beaucage, S. L. et al., “Advances in the Synthesis of Notice: Subject to any disclaimer, the term of this Oligonucleotides by the Phosphormidite Approach, Tetra patent is extended or adjusted under 35 hedron, 1992, 48, 2223–2311. U.S.C. 154(b) by 20 days. Khorana, H. G. et al., “Studies on Polynucleotides: Total Synthesis of the Structural Gene for an Alanine Transfer Ribonucleic Acid from Yeast, J. Mol. Biol., 1972, 72, (21) Appl. No.: 10/059,776 209-217. (22) Filed: Jan. 29, 2002 Reese, C. B. et al., “The Chemical Synthesis of Oligo-and Poly-Nucleotides by the Phosphotriester Apporach, "Texra (65) Prior Publication Data hedron, 1978, 34, 3143–3179. US 2002/0119483 A1 Aug. 29, 2002 PCT International Search Report dated Jun. 5, 2002 (PCT/ US02/02503). Related U.S. Application Data (60) Provisional application No. 60/264,920, filed on Jan. 30, Primary Examiner Jezia Riley 2001. (74) Attorney, Agent, or Firm Woodcock Washburn LLP (51) Int. Cl." ............................ C12O 1/70; C12O 1/68; (57) ABSTRACT C07H 21/00; CO7H 21/02; CO7H 21/04 (52) U.S. Cl. .............................. 435/5; 435/6; 536/23.1; Methods for detecting chloral hydrate in dichloroacetic acid 536/25.3 are described. (58) Field of Search ........................ 435/5, 6; 536/23.1, 536/25.3 27 Claims, No Drawings US 6,645,716 B2 1 2 METHODS FOR DETECTION OF CHLORAL with antibodies and oligomeric compounds, DNA HYDRATE IN DICHLOROACETIC ACID Sequencing, in vitro amplification of DNA by the poly merase chain reaction, and in Site-directed mutagenesis of This application claims the benefit of Provisional Appli cloned DNA. See Book 2 of Molecular Cloning, A Labo cation No. 60/264,920, filed Jan. 30, 2001. ratory Manual, Supra. See also “DNA-protein interactions and The Polymerase Chain Reaction” in Vol. 2 of Current FIELD OF THE INVENTION Protocols. In Molecular Biology, Supra. Oligonucleotides and their analogs have also been developed and used in This invention relates generally to novel methods for molecular biology in a variety of procedures as probes, detecting chloral hydrate in dichoroacetic acid. primers, linkers, adapters, and gene fragments. BACKGROUND OF THE INVENTION The widespread use of Such oligonucleotides has increased the demand for rapid, inexpensive and efficient It is well known that most of the bodily states in multi procedures for their modification and Synthesis. Early Syn cellular organisms, including most disease States, are thetic approaches to oligonucleotide Synthesis included effected by proteins. Such proteins, either acting directly or phosphodiester and phosphotriester chemistries. Khorana et through their enzymatic or other functions, contribute in 15 al., J. Molec. Biol. 72 (1972), 209; Reese, Tetrahedron Lett. major proportion to many diseases and regulatory functions 34 (1978), 3143–3179. These approaches eventually gave in animals and man. For disease States, classical therapeutics way to more efficient modem methods, Such as the use of the has generally focused upon interactions with Such proteins popular phosphoramidite technique (see, e.g., Advances in in efforts to moderate their disease-causing or disease the Synthesis of Oligonucleotides by the Phosphoramidite potentiating functions. In newer therapeutic approaches, Approach, Beaucage, S. L.; Iyer, R. P., Tetrahedron, 48 modulation of the actual production of Such proteins is (1992) 2223-2311 and references cited therein), wherein a desired. By interfering with the production of proteins, the nucleoside or oligonucleotide having a free hydroxyl group maximum therapeutic effect may be obtained with minimal is reacted with a protected cyanoethyl phosphoramidite Side effects. It is therefore a general object of Such thera monomer in the presence of a weak acid to form a phosphite peutic approaches to interfere with or otherwise modulate 25 linked Structure. Oxidation of the phosphite linkage fol gene expression, which would lead to undesired protein lowed by hydrolysis of the cyanoethyl group yields the formation. desired phosphodiester or phosphorothioate linkage. One method for inhibiting Specific gene expression is with Solid phase techniques continue to play a large role in the use of oligonucleotides, especially oligonucleotides oligonucleotide Synthetic approaches. Typically, the 3'-most which are complementary to a specific target messenger nucleoside is anchored to a Solid Support which is function RNA (mRNA) sequence. Several oligonucleotides are alized with hydroxyl or amino residues. The additional undergoing clinic trials for Such uses. Oligonucleotides can nucleosides are Subsequently added in a Step-wise fashion to also serve as competitive inhibitors of transcription factors, form the desired linkages between the 3'-functional group of which interact with double-stranded DNA during regulation the incoming nucleoside and the 5'-hydroxyl group of the of transcription, to modulate their action. Several recent Support bound nucleoside. Implicit to this Step-wise assem reports describe Such interactions (see, for example, 35 bly is use of a protecting group to render unreactive the Bielinska, A., et. al., Science, 250 (1990), 997-1000; and 5'-hydroxy group of the incoming nucleoside. Following Wu, H., et. al., Gene, 89, (1990), 203-209). coupling, the 5'-hydroxy group is removed through the In addition to Such use as both indirect and direct regu judicious choice of a deprotecting reagent. lators of proteins, oligonucleotides and their analogs also Dichloroacetic acid (DCA) is a commonly used reagent have found use in diagnostic tests. Such diagnostic tests can 40 for deblocking nucleotides during oligonucleotide Synthesis. be performed using biological fluids, tissues, intact cells or Because the addition of new nucleosides involves the isolated cellular components. AS with gene expression repeated use of dichloroacetic acid for deprotecting the inhibition, diagnostic applications utilize the ability of oli 5'-hydroxy group, it is important that this reagent be as free gonucleotides and their analogs to hybridize with a comple as possible of contaminants which may propagate impurities mentary Strand of nucleic acid. 45 and produce improper Sequences of the target oligonucle Oligonucleotides and their analogs are also widely used as otide. Accordingly, methods are needed for detecting Such research reagents. They are useful for understanding the impurities in dichloroacetic acid. The present invention is function of many other biological molecules as well as in the preparation of other biological molecules. For example, the directed to these, as well as other, important ends. use of oligonucleotides and their analogs as primers in PCR 50 SUMMARY OF THE INVENTION reactions has given rise to an expanding commercial indus try. PCR has become a mainstay of commercial and research It has been discovered that chloral hydrate is a common laboratories, and applications of PCR have multiplied. For contaminant in commercially prepared dichloroacetic acid. example, PCR technology now finds use in the fields of It has been further discovered that chloral hydrate reacts forensics, paleontology, evolutionary Studies and genetic with the 5'-hydroxy group of nucleosides during the course counseling. Commercialization has led to the development 55 of oligonucleotide Synthesis to form undesired Side-products of kits which assist non-molecular biology-trained perSonnel that are removed, if at all, only with great difficulty. It has in applying PCR. Oligonucleotides and their analogs, both been further discovered that chloral hydrate in dichloroace natural and Synthetic, are employed as primers in Such PCR tic acid can be detected and its concentration accurately technology. measured, by comparing the integral of a nuclear magnetic Oligonucleotides and their analogs are also used in other 60 resonance peak of the CH proton of chloral hydrate with a laboratory procedures. Several of these uses are described in known amount of internal Standard. common laboratory manuals Such as Molecular Cloning, A Accordingly, it is an object of the present invention to Laboratory Manual, Second Ed., J. Sambrook, et al., Eds., provide methods for detecting chloral hydrate in dichloro Cold Spring Harbor Laboratory Press, 1989; and Current acetic acid. Protocols. In Molecular Biology, F. M. Ausubel, et al., Eds., 65 It is a further object of the present invention to provide Current Publications, 1993. Such uses include as synthetic methods for measuring the concentration of chloral hydrate oligonucleotide probes, in Screening expression libraries in dichloroacetic acid, particularly, for detecting chloral US 6,645,716 B2 3 4 hydrate and measuring its concentration in dichloroacetic roacetic acid based upon Said comparison of integrals acid which is to be used as a deprotecting reagent in of nuclear magnetic resonance peaks. In certain pre oligonucleotide Synthesis. ferred embodiments, the calculated concentration of It is a further object of the present invention to provide chloral
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