CA1211058A - Binding nucleic acid to a support - Google Patents
Binding nucleic acid to a supportInfo
- Publication number
- CA1211058A CA1211058A CA000443141A CA443141A CA1211058A CA 1211058 A CA1211058 A CA 1211058A CA 000443141 A CA000443141 A CA 000443141A CA 443141 A CA443141 A CA 443141A CA 1211058 A CA1211058 A CA 1211058A
- Authority
- CA
- Canada
- Prior art keywords
- nucleic acid
- binding
- support
- organic solvent
- alcohol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
Abstract
Abstract of the Disclosure Method of binding nucleic acid to a nucleic acid-binding support comprising depositing the nucleic acid onto the support and then contacting the nucleic acid and the support with a liquid binding solution which is compatible with the support and which contains an organic solvent which is capable of binding the DNA to the support, for a period of time sufficient to effect the binding.
Description
~12-1410 Background of the Invention This invention relates to binding nucleic acids RAN and DNA) to supports, ego to carry out DNA hybridization assays.
Such assays have been used to detect specific DNA
sequences in samples for several years, and are described in the patent and technical literature, e.g. Fallow et at. US. Pat. No 4,35~,535. Such assays typically involve spotting a sample, e.g.
urine, suspected of containing a particular DOW sequence (in viruses or prokaryotic or eukaryotic cells in the sample) onto a DNA-binding support, e.g. a nitrocellulose membrane, lying the cells, if necessary, denaturing and neutralizing the DNA, and then affixing the DNA to the support prior to carrying out the hybrid ization assay. Affixation is typically carried out by air drying followed by drying in a vacuum oven for two hours, as described, e.g., in Gillespie et at. (1965) J. Mol. Blot. 12, 829.
Summary of the Invention In general, the invention features a method of binding nucleic acid EDNA ox RNA) to a nucleic acid-binding support including depositing the nucleic acid on the support and then contacting the nucleic acid and the support with a liquid binding solution which is compatible with the support and which contains an organic solvent capable of binding the nucleic acid to the support, for a period of time sufficient to effect binding.
`~$
.
In preferred embodiments, the nucleic acid is included in a sample to be assayed by hybridization and the binding solution does not alter the DNA in a manner which interferes with hybridization; and the organic solvent contains fewer than 20 carbon atoms, makes up substantially all of the solvent, and is an alcohol, ether, aromatic compound, or kitten, most preferably ethanol, methanol, sec-bu~yl alcohol, iso-amyl alcohol, isopropyl alcohol, isobutyl alcohol r ethyl ether, or Tulane. In other preferred embodiments 9 the binding solution contains a mixture of more than one such organic solvent and the period of time during which the nucleic acid and the support are contacted with the binding solution is 1 second to 10 minutes, most preferably about 5 minutes.
The method of the invention permits nucleic immobilization in very short times; ire., in most instances on the order of five minutes or less. Thus the total time required Jo complete Dot blots, Southern blots, colony lifts, and any other technique requiring denatured nucleic acid immobilization on a support is greatly reduced.
Furthermore, the method obviates he use of expensive equipment such as vacuum pumps and vacuum ovens.
Other features and advantages of the invention will be apparent from the following description of tune preferred embodiments, and from the claims.
., ...~
so Description of the Preferred Embodiments A very wide range of organic solvents, in many different classes of organic compounds, can be used to bind nucleic acid to nuclei acid-binding membranes. The most preferred class of compounds are alcohols, which are generally less toxic and ! therefore easier to work with than other classes of compounds. Other classes of compounds which Jill bind nucleic acid, but which are less desirable than alcohols, are ethers, e.g. ethyl ether;
aromatic compounds, e.g. Tulane; and kittens, e.g.
acetone. Still other classes of organic solvents are alikeness, alikeness, alikeness, esters, and hetero-organic compounds such as halogenated alikeness, e.g. chloroform and carbon tetrachloride~
For all classes of organic solvents, considerations such as expense dictate a preferred size of fewer than 20 carbon atoms, and most preferably fewer than 10 carbon atoms.
The choice of solvent in a particular - instance will be dictated by several factors.
First, the binding solution containing the solvent should not alter the nucleic acid in a way which interferes with the intended purpose of the binding procedure e.g., if the nucleic acid it being immobilized for a hybridization assay, it must be capable of hybridizing after treatment with the solvent -Secondly, binding solution containing the solvent must be compatible with the support being used; i.e. the solvent should nut dissolve the support to an extent which interferes with the - ., .
.
I
purpose of the binding procedure. Some nucleic acid-binding supports are more susceptible to being dissolved by organic solvents than others. Thus, practically any organic solvent can safely be used with the highly solvent-resistant nylon-based supports, while the choice is more limited for more easily dissolved supports such as nitrocellulose.
Thus, for example, absolute methanol and acetone are incompatible with nitrocellulose, since they cause a degree of softening of the membrane which is unacceptable in hybridization assays, but are compatible with nylon-based supports. Where the organic solvent and the support are incompatible, the nucleic acid binding solution can often be modified, ego by dilution with water or by combination with a milder organic solvent. Thus, for example, 90% methanol is an effective binding solution and is compatible with nitrocellulose, while absolute methanol is not.
20~ Finally, the binding solution should be a liquid at the temperature of use. In many case this will be room temperature buy in some instances may be higher or lower.
An example of the method, in which Hepatitis B viral DNA is detected in blood serum, is as follows. A 7 I sample of blood serum is spotted onto a 0.45 EM nitrocellulose membrane and allowed to air-dry. The DNA in the sample is denatured by immersing the membrane in 9.5M Noah, 1.5M Nail for 1 min., and then neutralized by immersing the membrane in loom Trip 1PH 7.5), EM
Nail for 1 min. The membrane is then allowed to air-dry and the DNA
I, :, .
I
bound to -the membrane by immersing the membrane in an hydrous sea-bottle alcohol for 5 min. The membrane is then removed and air-dried.
The membrane, to which DNA is bound, is placed in a plastic bag, to which is then added hybridization solution of the composition 6X SKIP (0.9OM Nail, O.O90M Nay Citrate, 0.12M Pros-plate buffer pi 7.0), 2X Denhardt's solution (0.04% bovine serum albumin, 0.04% polyvinylpyrollidine, 0.04~ focal 500), 40%
formamide, 10% Dextran sulfite, 500 gel salmon sperm DNA, 1.6 mg/ml additional bovine serum albumin. Radioactively labeled Hepatitis B DNA probe (specific activity = 2-3X 108 cpm/~g) is then added, in an amount corresponding to 1~107 counts per ml hybridization solution.
The plastic bag is sealed and hybridization allowed to proceed for 2-3 hours at 37C. I've membrane is then removed and washed with 3mM tris-base for 20 min. to remove non-specifically bound probe. The washed membrane is placed under X-ray film and autoradiographed for 4-24 hours, to quantitatively determine Hope-tilts B DNA in the blood serum sample.
Other Embodiments . _ Other embodiments are within the following claims. For example, the nucleic acid binding technique can be used in conjunction with any suitable nucleic acid binding support, e.g., Pall Bedouin nylon membranes, and the sample and nucleic acid can be from any desired source (e.g. bacterial or eukaryotic DUN in urine of sputum samples, viral RAM in blood samples); and the nucleic acid can be purified prior to spotting.
Such assays have been used to detect specific DNA
sequences in samples for several years, and are described in the patent and technical literature, e.g. Fallow et at. US. Pat. No 4,35~,535. Such assays typically involve spotting a sample, e.g.
urine, suspected of containing a particular DOW sequence (in viruses or prokaryotic or eukaryotic cells in the sample) onto a DNA-binding support, e.g. a nitrocellulose membrane, lying the cells, if necessary, denaturing and neutralizing the DNA, and then affixing the DNA to the support prior to carrying out the hybrid ization assay. Affixation is typically carried out by air drying followed by drying in a vacuum oven for two hours, as described, e.g., in Gillespie et at. (1965) J. Mol. Blot. 12, 829.
Summary of the Invention In general, the invention features a method of binding nucleic acid EDNA ox RNA) to a nucleic acid-binding support including depositing the nucleic acid on the support and then contacting the nucleic acid and the support with a liquid binding solution which is compatible with the support and which contains an organic solvent capable of binding the nucleic acid to the support, for a period of time sufficient to effect binding.
`~$
.
In preferred embodiments, the nucleic acid is included in a sample to be assayed by hybridization and the binding solution does not alter the DNA in a manner which interferes with hybridization; and the organic solvent contains fewer than 20 carbon atoms, makes up substantially all of the solvent, and is an alcohol, ether, aromatic compound, or kitten, most preferably ethanol, methanol, sec-bu~yl alcohol, iso-amyl alcohol, isopropyl alcohol, isobutyl alcohol r ethyl ether, or Tulane. In other preferred embodiments 9 the binding solution contains a mixture of more than one such organic solvent and the period of time during which the nucleic acid and the support are contacted with the binding solution is 1 second to 10 minutes, most preferably about 5 minutes.
The method of the invention permits nucleic immobilization in very short times; ire., in most instances on the order of five minutes or less. Thus the total time required Jo complete Dot blots, Southern blots, colony lifts, and any other technique requiring denatured nucleic acid immobilization on a support is greatly reduced.
Furthermore, the method obviates he use of expensive equipment such as vacuum pumps and vacuum ovens.
Other features and advantages of the invention will be apparent from the following description of tune preferred embodiments, and from the claims.
., ...~
so Description of the Preferred Embodiments A very wide range of organic solvents, in many different classes of organic compounds, can be used to bind nucleic acid to nuclei acid-binding membranes. The most preferred class of compounds are alcohols, which are generally less toxic and ! therefore easier to work with than other classes of compounds. Other classes of compounds which Jill bind nucleic acid, but which are less desirable than alcohols, are ethers, e.g. ethyl ether;
aromatic compounds, e.g. Tulane; and kittens, e.g.
acetone. Still other classes of organic solvents are alikeness, alikeness, alikeness, esters, and hetero-organic compounds such as halogenated alikeness, e.g. chloroform and carbon tetrachloride~
For all classes of organic solvents, considerations such as expense dictate a preferred size of fewer than 20 carbon atoms, and most preferably fewer than 10 carbon atoms.
The choice of solvent in a particular - instance will be dictated by several factors.
First, the binding solution containing the solvent should not alter the nucleic acid in a way which interferes with the intended purpose of the binding procedure e.g., if the nucleic acid it being immobilized for a hybridization assay, it must be capable of hybridizing after treatment with the solvent -Secondly, binding solution containing the solvent must be compatible with the support being used; i.e. the solvent should nut dissolve the support to an extent which interferes with the - ., .
.
I
purpose of the binding procedure. Some nucleic acid-binding supports are more susceptible to being dissolved by organic solvents than others. Thus, practically any organic solvent can safely be used with the highly solvent-resistant nylon-based supports, while the choice is more limited for more easily dissolved supports such as nitrocellulose.
Thus, for example, absolute methanol and acetone are incompatible with nitrocellulose, since they cause a degree of softening of the membrane which is unacceptable in hybridization assays, but are compatible with nylon-based supports. Where the organic solvent and the support are incompatible, the nucleic acid binding solution can often be modified, ego by dilution with water or by combination with a milder organic solvent. Thus, for example, 90% methanol is an effective binding solution and is compatible with nitrocellulose, while absolute methanol is not.
20~ Finally, the binding solution should be a liquid at the temperature of use. In many case this will be room temperature buy in some instances may be higher or lower.
An example of the method, in which Hepatitis B viral DNA is detected in blood serum, is as follows. A 7 I sample of blood serum is spotted onto a 0.45 EM nitrocellulose membrane and allowed to air-dry. The DNA in the sample is denatured by immersing the membrane in 9.5M Noah, 1.5M Nail for 1 min., and then neutralized by immersing the membrane in loom Trip 1PH 7.5), EM
Nail for 1 min. The membrane is then allowed to air-dry and the DNA
I, :, .
I
bound to -the membrane by immersing the membrane in an hydrous sea-bottle alcohol for 5 min. The membrane is then removed and air-dried.
The membrane, to which DNA is bound, is placed in a plastic bag, to which is then added hybridization solution of the composition 6X SKIP (0.9OM Nail, O.O90M Nay Citrate, 0.12M Pros-plate buffer pi 7.0), 2X Denhardt's solution (0.04% bovine serum albumin, 0.04% polyvinylpyrollidine, 0.04~ focal 500), 40%
formamide, 10% Dextran sulfite, 500 gel salmon sperm DNA, 1.6 mg/ml additional bovine serum albumin. Radioactively labeled Hepatitis B DNA probe (specific activity = 2-3X 108 cpm/~g) is then added, in an amount corresponding to 1~107 counts per ml hybridization solution.
The plastic bag is sealed and hybridization allowed to proceed for 2-3 hours at 37C. I've membrane is then removed and washed with 3mM tris-base for 20 min. to remove non-specifically bound probe. The washed membrane is placed under X-ray film and autoradiographed for 4-24 hours, to quantitatively determine Hope-tilts B DNA in the blood serum sample.
Other Embodiments . _ Other embodiments are within the following claims. For example, the nucleic acid binding technique can be used in conjunction with any suitable nucleic acid binding support, e.g., Pall Bedouin nylon membranes, and the sample and nucleic acid can be from any desired source (e.g. bacterial or eukaryotic DUN in urine of sputum samples, viral RAM in blood samples); and the nucleic acid can be purified prior to spotting.
Claims (18)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of binding nucleic acid to a nucleic acid-binding support comprising depositing said nucleic acid onto said support and then contacting said nucleic acid and said support with a liquid binding solution which is compatible with said support and which contains an organic solvent which is capable of binding said nucleic acid to said support, for a period of time sufficient to effect said binding.
2. The method of claim 1 wherein said nucleic acid is included in a sample to be assayed by hybridization for a prede-termined type of nucleic acid, said sample being deposited on said nucleic acid-binding support.
3. The method of claim 2 wherein said nucleic acid is DNA
and, prior to said binding, said DNA is denatured and then neutralized for use in said hybridization assay.
and, prior to said binding, said DNA is denatured and then neutralized for use in said hybridization assay.
4. The method of claim 1 wherein said nucleic acid and said support, after said depositing, are permitted to air-dry prior to being contacted with said nucleic acid-binding solution.
S. The method of claim 2 wherein said contacting with said nucleic acid-binding solution does not alter said nucleic acid in a manner which interferes with said hybridization.
6. The method of claim 1 wherein said organic solvent contains fewer than 20 carbon atoms.
7. The method of claim 1 wherein said nucleic acid binding solution is made up substantially entirely of said organic solvent.
8. The method of claim 6 wherein said organic solvent is an alcohol, an ether, an aromatic compound, or a ketone.
9. The method of claim 1 wherein said nucleic acid binding solution contains a mixture of more than one organic solvent, said mixture being capable of binding said nucleic acid to said nucleic acid-binding support.
10. The method of claim 9 wherein each said organic solvent contains fewer than 20 carbon atoms.
11. The method of claim 9 wherein each said organic solvent, independently, is an alcohol, an ether, an aromatic compound, or a ketone.
12. The method of claim 8 wherein said organic solvent is ethanol, methanol, sec-butyl alcohol, iso-amyl alcohol, isopropyl alcohol, isobutyl alcohol, ethyl ether, or toluene.
13. The method of claim 11 wherein each said organic solvent, independently, is ethanol, methanol, sec-butyl alcohol, iso-amyl alcohol, isopropyl alcohol, isobutyl alcohol ethyl ether, or toluene.
14. The method of claim 8 wherein said organic solvent is sec-butyl alcohol.
15. The method of claim 13 wherein one of said organic solvents is sec-butyl alcohol.
16. The method of claim 1 wherein said period of time is between 1 second and 10 minutes.
17. The method of claim 16 wherein said period of time is about 5 minutes.
18. The method of claim 1 wherein, following said contacting, said support and said nucleic acid are permitted to air-dry.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/448,979 US4588682A (en) | 1982-12-13 | 1982-12-13 | Binding nucleic acid to a support |
| US448,979 | 1982-12-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1211058A true CA1211058A (en) | 1986-09-09 |
Family
ID=23782403
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000443141A Expired CA1211058A (en) | 1982-12-13 | 1983-12-13 | Binding nucleic acid to a support |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4588682A (en) |
| EP (1) | EP0111340B1 (en) |
| JP (1) | JPS59122499A (en) |
| AT (1) | ATE82330T1 (en) |
| CA (1) | CA1211058A (en) |
| DE (1) | DE3382639T2 (en) |
Families Citing this family (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4849077A (en) * | 1984-08-06 | 1989-07-18 | Akademie Der Wissenschaften Der Ddr | Process for solid phase-sequencing of nucleic acid fragments |
| JPS61162752A (en) * | 1985-01-11 | 1986-07-23 | Sekisui Chem Co Ltd | Detection of dna and/or rna |
| US4806546A (en) * | 1985-09-30 | 1989-02-21 | Miles Inc. | Immobilization of nucleic acids on derivatized nylon supports |
| US4806631A (en) * | 1985-09-30 | 1989-02-21 | Miles Inc. | Immobilization of nucleic acids on solvolyzed nylon supports |
| US5604099A (en) * | 1986-03-13 | 1997-02-18 | Hoffmann-La Roche Inc. | Process for detecting specific nucleotide variations and genetic polymorphisms present in nucleic acids |
| CA1284931C (en) * | 1986-03-13 | 1991-06-18 | Henry A. Erlich | Process for detecting specific nucleotide variations and genetic polymorphisms present in nucleic acids |
| GB8608269D0 (en) * | 1986-04-04 | 1986-05-08 | Brown J J | Ice-maker |
| GB8608629D0 (en) * | 1986-04-09 | 1986-05-14 | Biotechnica Ltd | Labelling |
| EP0261955A3 (en) * | 1986-09-26 | 1989-06-07 | E.I. Du Pont De Nemours And Company | Process for immobilization of dna |
| DE3717212A1 (en) * | 1987-05-22 | 1988-12-08 | Viktor Dr Dr Med Balazs | METHOD FOR THE EXAMINATION OF A CELLULAR BIOLOGICAL LIQUID FOR CELLULAR ONCOGEN TRANScripts or THEIR FRAGMENTS |
| DE3721400A1 (en) * | 1987-06-29 | 1989-01-12 | Viktor Dr Dr Med Balazs | METHOD FOR THE EXAMINATION OF A CELLULAR BIOLOGICAL LIQUID ON CELLULAR ONCOGEN DNA OR THEIR FRAGMENTS |
| US4942124A (en) * | 1987-08-11 | 1990-07-17 | President And Fellows Of Harvard College | Multiplex sequencing |
| US5925525A (en) * | 1989-06-07 | 1999-07-20 | Affymetrix, Inc. | Method of identifying nucleotide differences |
| US5800992A (en) | 1989-06-07 | 1998-09-01 | Fodor; Stephen P.A. | Method of detecting nucleic acids |
| US5744101A (en) | 1989-06-07 | 1998-04-28 | Affymax Technologies N.V. | Photolabile nucleoside protecting groups |
| US6955915B2 (en) * | 1989-06-07 | 2005-10-18 | Affymetrix, Inc. | Apparatus comprising polymers |
| US6919211B1 (en) * | 1989-06-07 | 2005-07-19 | Affymetrix, Inc. | Polypeptide arrays |
| US6416952B1 (en) | 1989-06-07 | 2002-07-09 | Affymetrix, Inc. | Photolithographic and other means for manufacturing arrays |
| US6551784B2 (en) | 1989-06-07 | 2003-04-22 | Affymetrix Inc | Method of comparing nucleic acid sequences |
| US5143854A (en) | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
| EP0405913B1 (en) * | 1989-06-30 | 1998-12-23 | Chiron Corporation | Hydrophobic nucleic acid probe |
| DK0834576T3 (en) * | 1990-12-06 | 2002-04-22 | Affymetrix Inc A Delaware Corp | Detection of nucleic acid sequences |
| US6943034B1 (en) | 1991-11-22 | 2005-09-13 | Affymetrix, Inc. | Combinatorial strategies for polymer synthesis |
| US6864101B1 (en) | 1991-11-22 | 2005-03-08 | Affymetrix, Inc. | Combinatorial strategies for polymer synthesis |
| GB9201073D0 (en) * | 1992-01-18 | 1992-03-11 | Cytocell Ltd | Chromosome hybridisation methods |
| US7323298B1 (en) | 1994-06-17 | 2008-01-29 | The Board Of Trustees Of The Leland Stanford Junior University | Microarray for determining the relative abundances of polynuceotide sequences |
| US7625697B2 (en) | 1994-06-17 | 2009-12-01 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for constructing subarrays and subarrays made thereby |
| ES2110916B1 (en) * | 1996-05-24 | 1998-10-01 | Ivia | TARGET PREPARATION PROCEDURE FOR POLYMERASE CHAIN REACTION (PCR). |
| CN1148227A (en) * | 1996-08-02 | 1997-04-23 | 韩苏 | Application of analysis tech. of nucleic acid code used as counterfeit-proof method |
| US6703228B1 (en) | 1998-09-25 | 2004-03-09 | Massachusetts Institute Of Technology | Methods and products related to genotyping and DNA analysis |
| EP1001037A3 (en) * | 1998-09-28 | 2003-10-01 | Whitehead Institute For Biomedical Research | Pre-selection and isolation of single nucleotide polymorphisms |
| US6861214B1 (en) * | 2000-10-23 | 2005-03-01 | Beckman Coulter, Inc. | Immobilization of biopolymers to aminated substrates by direct adsorption |
| US7189509B2 (en) * | 2001-08-16 | 2007-03-13 | Zhifeng Shao | Analysis of gene expression profiles using sequential hybridization |
| EP1623996A1 (en) * | 2004-08-06 | 2006-02-08 | Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts | Improved method of selecting a desired protein from a library |
| US8524507B2 (en) * | 2009-08-19 | 2013-09-03 | The Cleveland Clinic Foundation | Method for detecting a target molecule in a biological sample |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2125699B2 (en) * | 1971-05-25 | 1973-05-17 | Phywe AG, 3400 Gottingen | PREPARATION OF CELLS FOR THE MEASUREMENT OF DNA |
| US3899297A (en) * | 1973-12-19 | 1975-08-12 | Block Engineering | Biological staining technique and mixture thereof |
| US4139346A (en) * | 1977-11-28 | 1979-02-13 | Enzo Bio Chem Incorporated | Nucleic acid and protein binding paper |
| US4257774A (en) * | 1979-07-16 | 1981-03-24 | Meloy Laboratories, Inc. | Intercalation inhibition assay for compounds that interact with DNA or RNA |
| US4286964A (en) * | 1979-10-12 | 1981-09-01 | Seed Brian S | Polyfunctional epoxides and halohydrins used as bridging groups to bind aromatic amine group-containing alcohols and thiols to hydroxyl bearing substrates |
| DD154622A1 (en) * | 1980-11-20 | 1982-04-07 | Hunger Hans Dieter | PROCESS FOR STABILIZING PAPER ACTIVATED WITH CYANOIC ACID CHLORIDE |
| US4358535A (en) * | 1980-12-08 | 1982-11-09 | Board Of Regents Of The University Of Washington | Specific DNA probes in diagnostic microbiology |
| WO1983000877A1 (en) * | 1981-08-31 | 1983-03-17 | Icl Scient | Glucose oxidase immunohistochemical detection of antinuclear antibodies |
-
1982
- 1982-12-13 US US06/448,979 patent/US4588682A/en not_active Expired - Fee Related
-
1983
- 1983-12-12 DE DE8383112471T patent/DE3382639T2/en not_active Expired - Fee Related
- 1983-12-12 EP EP83112471A patent/EP0111340B1/en not_active Expired - Lifetime
- 1983-12-12 AT AT83112471T patent/ATE82330T1/en not_active IP Right Cessation
- 1983-12-13 JP JP58234928A patent/JPS59122499A/en active Granted
- 1983-12-13 CA CA000443141A patent/CA1211058A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| EP0111340A3 (en) | 1987-03-25 |
| US4588682A (en) | 1986-05-13 |
| EP0111340A2 (en) | 1984-06-20 |
| EP0111340B1 (en) | 1992-11-11 |
| JPH0515438B2 (en) | 1993-03-01 |
| JPS59122499A (en) | 1984-07-14 |
| DE3382639D1 (en) | 1992-12-17 |
| ATE82330T1 (en) | 1992-11-15 |
| DE3382639T2 (en) | 1993-07-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |