WO2000039581A2 - Systeme de test pour reconnaitre differents marqueurs, sa production et son utilisation - Google Patents

Systeme de test pour reconnaitre differents marqueurs, sa production et son utilisation Download PDF

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Publication number
WO2000039581A2
WO2000039581A2 PCT/EP1999/010333 EP9910333W WO0039581A2 WO 2000039581 A2 WO2000039581 A2 WO 2000039581A2 EP 9910333 W EP9910333 W EP 9910333W WO 0039581 A2 WO0039581 A2 WO 0039581A2
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WO
WIPO (PCT)
Prior art keywords
natural
nucleic acid
stranded
derivative
antibody
Prior art date
Application number
PCT/EP1999/010333
Other languages
German (de)
English (en)
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WO2000039581A3 (fr
Inventor
Thomas Wagner
Norbert Windhab
Original Assignee
Aventis Research & Technologies Gmbh & Co. Kg
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Aventis Research & Technologies Gmbh & Co. Kg filed Critical Aventis Research & Technologies Gmbh & Co. Kg
Priority to EP99968373A priority Critical patent/EP1141725A2/fr
Priority to JP2000591429A priority patent/JP2002533724A/ja
Priority to CA002353920A priority patent/CA2353920A1/fr
Priority to AU25390/00A priority patent/AU773046B2/en
Publication of WO2000039581A2 publication Critical patent/WO2000039581A2/fr
Publication of WO2000039581A3 publication Critical patent/WO2000039581A3/fr

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    • 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
    • C12Q1/6816—Hybridisation assays characterised by the detection means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/536—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase
    • G01N33/542—Immunoassay; Biospecific binding assay; Materials therefor with immune complex formed in liquid phase with steric inhibition or signal modification, e.g. fluorescent quenching
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54306—Solid-phase reaction mechanisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances

Definitions

  • the present invention relates to a test system containing at least two detection species. recognize the at least two different markers to form a complex. its manufacture and use in a suitable detection method.
  • test systems such as. B. Diagnostics are in biology, biochemistry. Medicine and pharmacology widely used. Especially in medicine, a reliable and clear diagnosis of diseases, such as B. viral infections or cancer. of extraordinary importance for increasing the quality of life, because timely and effective treatment can only be achieved by early detection of an illness.
  • disease-specific markers or ligands such as B. nucleic acid sequences, proteins or antigens
  • the pathogen or the disease is detected in the biological sample. Diagnostic tests are widespread, in which a marker or a class of markers is detected, such as. B. in ELISA or amplification methods such as PCR, b-DNA, Southern, Western or Northern blotting.
  • the types of detection used range from simple staining methods and calorimetric methods to fluorescence energy transfer (FRET) and fluorescence quenching to scintillation proximity assay (SPA).
  • FRET fluorescence energy transfer
  • SPA scintillation proximity assay
  • a major disadvantage when using only one marker or one marker class is that positive test results are easily erroneously produced, which also lead to incorrect conclusions regarding a specific disease. Often, therefore, a second Test or other tests on the same or complementary analytes are carried out in order to be able to make a reliable statement regarding ill / healthy. This leads to several tests, the results of which can be compared with one another, which is at the same time complex and cost-intensive.
  • the object of the present invention is therefore to develop qualitatively better, less complex and less expensive analytical tests than those already known.
  • the invention therefore relates to a detection method comprising the following steps: (a) Treatment of a sample containing a first and a second marker with a first recognition species. that recognizes the first marker,
  • the present invention furthermore relates to a detection method comprising the following steps:
  • the detection method is carried out in a homogeneous, partially homogeneous (modular) or immobilized form.
  • the binding events are generated step by step and the complex that may be formed is detected in a so-called proximity assay.
  • the first and last components are preferably marked so that they can only generate a signal when they are close together.
  • Preferred detection methods are e.g. B. LOCI (Ullmann, E. et al. (1994) Proc. Natl. Acad. Sci. USA 91, 5426), Fluorescence Energy Transfer (FRET) Cordullo. RA (1992) in Nonradioactive Labeling and Detection of Biomolecules' * , 414-423.
  • the binding events are generated step by step and in solution and, once the complex has formed, are bound to a solid support via one of the components.
  • the complex which is formed is detected by a label, in particular a non-radioactive label or radioactive label, preferably by means of fluorescent labeling, enzymatic labeling, redox labeling or spin labeling (Kessler, C. (Ed.) Nonradioactive Labeling and Detection of Biomolecules (1992 ), Springer Verlag, 414-423).
  • a recognition species preferably the first recognition species, is bound to a solid support and the complex is subsequently built up by gradually adding the further components.
  • the marking is preferably carried out according to the same or similar methods as in the partially homogeneous embodiment.
  • Solid or gel-like material in particular chip material and / or thin layers of the material, preferably ceramic, metal, in particular noble metal, glasses, plastics, crystalline materials or (bio) molecular filaments, in particular cellulose or framework proteins, are particularly suitable as supports for the immobilization.
  • the recognition species and / or markers used in the detection method according to the invention are in particular a synthetic substance, a natural product and / or a natural product derivative, preferably a peptide, peptoid, protein, saccharide or a nucleic acid.
  • a receptor or a functional part thereof in particular a functional part originating from the extracellular domain of a membrane-standing receptor, an antibody or a functional part thereof, in particular an Fv fragment (Skerra & Plückthun (1988 ), Science 240, 1038), a single chain Fv fragment (scFv; Bird et al. (1988), Science 242, 423; Huston et al. (1988), Proc. Natl. Acad. Sci.
  • an aptamer for example a DNA or RNA aptamer or derivatives thereof, for example aptamers provided with protective groups customary in nucleic acid chemistry, a cell component, in particular a Lipid, glycoprotein, filament component, lectin, liposome, mitogen, antigen.
  • a cell in particular a lymphoid cell, or a virus, in particular a virus component, in particular a capsid, or a viroid or a derivative, in particular an acetate, or its active parts, or a single-stranded or double-stranded nucleic acid , in particular DNA, RNA, p-RNA (Pitsch, S. et al., Helv. Chim. Acta. (1993), 76, 2161; Pitsch, S. et al., Helv. Chim. Acta. (1995), 78, 1621), p-DNA (DE 198 37 387.2), PNA (peptide nucleic acid (Nielsen, PE et al.
  • aptamers count due to their binding properties to specific molecules other than nucleic acids, such as. B. proteins, not to the nucleic acids, but to antibody derivatives. DNA aptamers or RNA aptamers are preferred.
  • nucleic acids according to the invention can also be modified.
  • the methods known to the person skilled in the art from nucleic acid chemistry can be used for this purpose. Modifications which lead to stabilization of the nucleic acids are preferred (see, for example, Uhlmann, E. & Peyman, A. (1990) Chemical Reviews, 90, 543, No. 4).
  • a marker is usually recognized by a recognition species via non-covalent interactions, in particular via hydrogen bridges, salt bridges. Stacking, metal lining, charge transfer complexes, Van der Waals forces or hydrophobic interactions.
  • a nucleic acid is recognized as a marker by a completely or partially complementary nucleic acid or a synthetic substance, such as. B. a chemical, a natural product and / or a natural product derivative as antigenic substances are recognized by a corresponding antibody or antibody derivative.
  • the markers can belong to any substance class, but preferably from at least two different ones.
  • the marking can, depending on whether it is a homogeneous, partially homogeneous (modular) or immobilized embodiment, be non-radioactive or radioactive, preferably LOCI, FRET. Fluorescence quenching, SPA, a fluorescent label, enzymatic label, redox label or spin label.
  • the marker and / or the signal can be amplified, which leads to an increase in the sensitivity of the detection method.
  • Amplification of the marker relates in particular to the amplification of nucleic acids, for example by PCR, NASBA, LCR, SDA, Qß replication or RT-PCR (Kessler, C. (1992) supra).
  • the signal amplification is achieved, for example, by so-called cross-linking of binding partners, antibody or nucleic acid trees (e.g. b-DNA), catalytic substrate conversion (e.g. alkaline phosphatase, peroxidase, ß-galactosidase) or signal cascades.
  • in vivo amplification e.g. B. Detection of r-RNA, indirect detection of antigens possible.
  • the markers can be divided into two classes. In the case of so-called positive markers, the absence of these markers is detected, e.g. B. about the lack of a signal. Positive markers generally refer to markers present in a healthy organism, e.g. m-RNA. Negative markers are generally the substances of a pathogen or a diseased organism which can be determined using the detection method according to the invention.
  • either two or more negative, two or more positive or two or more positive and negative markers can be detected.
  • Evidence is thus provided either about the occurrence or the absence of a signal.
  • a displacement of a signal e.g. by displacing a molecule from a complex or from its binding conformation (e.g. Molecular Beacons, S. Tyaki, Kramer FR, Nature Biotechnology 14, 303-308, 1996; RP Ekins. Clinical Chemistry, 44/9, 2015-2030 , 1998) in a competitive assay.
  • a substance is added to the test system which displaces one of the markers to be detected, whereby the molecular complex built up from markers and recognition species and thus also the signal associated therewith disappears.
  • the concentration of the displaced marker can thus be determined in a simple manner via a titration.
  • At least one marker is a natural or non-natural, single-stranded or double-stranded nucleic acid and each further marker is a synthetic substance, natural product or derivative of a natural substance, preferably an antigen, which is different from a nucleic acid.
  • the first marker and each additional marker is a natural or non-natural, single-stranded or double-stranded nucleic acid or alternatively a synthetic substance other than a nucleic acid, a natural product or a natural product derivative, preferably an antigen.
  • a natural or non-natural, single-stranded or double-stranded nucleic acid as a marker is recognized by a natural or non-natural, single-stranded or double-stranded nucleic acid as a recognition species.
  • a synthetic substance, a natural product or a natural product derivative is recognized as a recognition species by a synthetic substance, a natural product or a natural product derivative, preferably by an antibody or an antibody derivative.
  • At least one recognition species is a natural or non-natural, single-stranded or double-stranded nucleic acid and each further recognition species is a synthetic substance, different natural product or different natural product derivative different from a nucleic acid, preferably an antibody or an antibody derivative.
  • the first recognition species and each further recognition species is a natural or non-natural, single-stranded or double-stranded nucleic acid or alternatively a synthetic substance, different natural product or different natural product derivative different from a nucleic acid, preferably an antibody or an antibody derivative.
  • At least one recognition species is a hybrid of a natural or unnatural, single-stranded or double-stranded nucleic acid and another natural or unnatural, single-stranded or double-stranded nucleic acid.
  • At least one recognition species is a hybrid of a synthetic substance, a natural substance or a natural substance derivative and another synthetic substance, another natural substance or another natural substance derivative.
  • At least one recognition species is a hybrid of a natural or unnatural, single-stranded or double-stranded nucleic acid and a synthetic substance different from a nucleic acid, a different natural product or a different natural product derivative, preferably an antibody or antibody derivative.
  • a first recognition species is a natural or non-natural, single-stranded or double-stranded nucleic acid
  • a second recognition species is a hybrid of a natural or non-natural, single-stranded or double-stranded nucleic acid and a synthetic substance, a natural product or a natural product derivative, preferably an antibody or antibody derivative.
  • a first recognition species is a natural or non-natural, single-stranded or double-stranded nucleic acid
  • a second recognition species is a hybrid of a natural or non-natural, single-stranded or double-stranded nucleic acid and another natural or non-natural single-stranded or double-stranded Nucleic acid
  • the third recognition species is another natural or non-natural, single-stranded or double-stranded nucleic acid.
  • a first recognition species is a synthetic substance, a natural product or a natural product derivative, preferably an antibody or antibody derivative, a second
  • the recognition species is a hybrid of a synthetic substance, a natural substance or a natural product derivative, preferably an antibody or antibody derivative, and another synthetic substance another natural product or another natural product derivative, preferably another antibody or antibody derivative, and a third recognition species is another synthetic substance, another natural product or another different natural product derivative, preferably another antibody or another antibody derivative.
  • Another object of the present invention is a test system containing at least two recognition species that recognize at least two different markers to form a complex, preferably the recognition species or markers already described above.
  • at least one recognition species is immobilized on a support, as preferably described above.
  • At least one recognition species is a natural or non-natural, single-stranded or double-stranded nucleic acid and at least one other recognition species is another natural or non-natural, single-stranded or double-stranded nucleic acid.
  • At least one recognition species is a synthetic substance, a different natural product or a different natural product derivative different from a nucleic acid, preferably an antibody or antibody derivative, and at least one other recognition species is another synthetic substance, different natural product or different from a nucleic acid various natural product derivative, preferably an antibody or antibody derivative.
  • At least one recognition species is a hybrid of a natural or unnatural, single-stranded or double-stranded nucleic acid and one of one Nucleic acid different synthetic substance, different natural product or different natural product derivative, preferably an antibody or antibody derivative.
  • At least one recognition species is a hybrid of a natural or unnatural, single-stranded or double-stranded nucleic acid and another natural or unnatural single-stranded or double-stranded nucleic acid.
  • At least one recognition species is a hybrid of a synthetic substance different from a nucleic acid, different natural product or different
  • Natural product derivative preferably an antibody or antibody derivative and another synthetic substance different from a nucleic acid, different natural product or different natural product derivative, preferably an antibody or antibody derivative.
  • test system according to the invention can be produced, for example, by assembling the recognition species necessary for the individual embodiments. or that at least one recognition species is immobilized on a support, as already preferably described above, according to methods generally known to the person skilled in the art.
  • the test system according to the invention can be used in the detection method according to the invention. as described in more detail above.
  • it serves to detect the presence and / or absence of at least two different markers in a sample.
  • It is preferably in the form of a diagnostic agent or an analyte. It is therefore used in particular for the detection of diseases or for environmental analysis, in particular for the detection of toxins and / or allergens.
  • FIG. 1 schematically shows the detection of two analytes (A and B) in an assay in the immobilized embodiment.
  • FIG 2 schematically shows the detection of two analytes (antigens A and B) in an assay in the immobilized embodiment.
  • FIG 3 schematically shows the detection of two analytes (nucleic acid A and B) in an assay in the immobilized embodiment.
  • Example 4 schematically shows the complex of markers and recognition species according to Example 1.
  • the reagents required for the example such as Texas-Red® labeled oligonucleotide conjugate (24-mer DNA; from Interactiva; DNA 1), a biotinylated oligonucleotide conjugate (24-mer DNA; from Interactiva; DNA 3); a synthetic oligonucleotide (57-mer DNA; Interepteptavidin-conjugated anti-human IgG F (ab ') 2 (goat; Rockland) and a fluorescein labeled human IgG F (ab ') 2 fragment (Rockland) as antigen, are all commercially available
  • DNA 2 5'-ATT-GTC-ATA-ATC-ATC-TTG-AGA-CGC-TTT-TTT-TTT- TTT-ACA-TCA-CGA-CGA-CAT-GCA-TTT-3 '
  • the supernatant solution was pipetted off and the carrier was washed 5 times with 500 ⁇ l 0.9% NaCl solution.
  • 200 ⁇ l of a solution of 200 ⁇ l streptavidin-anti-human-IgG F (ab ') 2 (goat) solution (1.6 mg / ml) and 40 ⁇ l of the fluorescein-labeled solution, preincubated at RT for 2 h, were then added IgG F (ab ') 2 - fragment solution (5.0 mg / ml) and allowed to incubate for 1-2 h at RT.
  • the supernatant solution was again pipetted off and the carrier was washed 5 times with 500 ⁇ l 0.9% NaCl solution.
  • the formation of the complex was verified by measuring the fluorescence of the fluorescein ( ⁇ ma v 494 nm, ⁇ max E : 525 nm).
  • DNA 2 5'-ATT-GTC-ATA-ATC-ATC-TTG-AGA-CGC-TTT-TTT-TTT- TTT-ACA-TCA-CGA-CGA-CAT-GCA-TTT-3 ' (marker 1)
  • Antibody streptavidin-conjugated anti-human IgG F (ab ') (goat)

Abstract

L'invention concerne un système de test contenant au moins deux espèces de reconnaissance qui reconnaissent au moins deux marqueurs différents, en formant un complexe. L'invention concerne également la production de ce système de test et son utilisation dans un procédé de dépistage approprié.
PCT/EP1999/010333 1998-12-23 1999-12-22 Systeme de test pour reconnaitre differents marqueurs, sa production et son utilisation WO2000039581A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP99968373A EP1141725A2 (fr) 1998-12-23 1999-12-22 Systeme de test pour reconnaitre differents analytes
JP2000591429A JP2002533724A (ja) 1998-12-23 1999-12-22 異なるマーカーの認識のための試験系、その調製および使用
CA002353920A CA2353920A1 (fr) 1998-12-23 1999-12-22 Systeme de test pour reconnaitre differents marqueurs, sa production et son utilisation
AU25390/00A AU773046B2 (en) 1998-12-23 1999-12-22 Test system for detecting different markers, and production and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19859912.9 1998-12-23
DE19859912A DE19859912C2 (de) 1998-12-23 1998-12-23 Testsystem zur Erkennung verschiedener Marker, seine Herstellung sowie Verwendung

Publications (2)

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WO2000039581A2 true WO2000039581A2 (fr) 2000-07-06
WO2000039581A3 WO2000039581A3 (fr) 2000-11-23

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EP (1) EP1141725A2 (fr)
JP (1) JP2002533724A (fr)
AU (1) AU773046B2 (fr)
CA (1) CA2353920A1 (fr)
DE (1) DE19859912C2 (fr)
WO (1) WO2000039581A2 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6893822B2 (en) 2001-07-19 2005-05-17 Nanogen Recognomics Gmbh Enzymatic modification of a nucleic acid-synthetic binding unit conjugate
EP1386164B1 (fr) * 2000-08-24 2007-08-08 Spectral Diagnostics Inc. Dosage immunologique differentiel pour la myoglobine
EP1947459A3 (fr) * 2000-08-24 2008-09-24 Nanogen, Inc. Dosage immunologique différentiel
US9816984B2 (en) 2009-07-31 2017-11-14 Invisible Sentinel, Inc. Device for detection of target molecules and uses thereof
US9823240B2 (en) 2012-03-09 2017-11-21 Invisible Sentinel, Inc. Methods and compositions for detecting multiple analytes with a single signal
US10495638B2 (en) 2009-10-09 2019-12-03 Invisible Sentinel, Inc. Device for detection of analytes and uses thereof
US10705084B2 (en) 2009-07-31 2020-07-07 Invisible Sentinel, Inc. Analyte detection devices, multiplex and tabletop devices for detection of analytes, and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11604186B2 (en) * 2018-10-17 2023-03-14 Molecular Devices (Austria) GmbH Real time western blot assays utilizing fluorescence resonance energy transfer (FRET)

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WO1992018866A1 (fr) * 1991-04-10 1992-10-29 Biosite Diagnostics Incorporated Nouveaux conjugues et dosages destines a la detection simultanee de ligands multiples
WO1998023956A1 (fr) * 1996-11-28 1998-06-04 University College London Test d'immunocapture

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JPH081438B2 (ja) * 1986-05-13 1996-01-10 三洋化成工業株式会社 酵素免疫測定法
US5296347A (en) * 1991-02-08 1994-03-22 Ciba Corning Diagnostics Corp. Bridge immunoassay

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WO1992018866A1 (fr) * 1991-04-10 1992-10-29 Biosite Diagnostics Incorporated Nouveaux conjugues et dosages destines a la detection simultanee de ligands multiples
WO1998023956A1 (fr) * 1996-11-28 1998-06-04 University College London Test d'immunocapture

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1386164B1 (fr) * 2000-08-24 2007-08-08 Spectral Diagnostics Inc. Dosage immunologique differentiel pour la myoglobine
EP1947459A3 (fr) * 2000-08-24 2008-09-24 Nanogen, Inc. Dosage immunologique différentiel
US6893822B2 (en) 2001-07-19 2005-05-17 Nanogen Recognomics Gmbh Enzymatic modification of a nucleic acid-synthetic binding unit conjugate
US9816984B2 (en) 2009-07-31 2017-11-14 Invisible Sentinel, Inc. Device for detection of target molecules and uses thereof
US10705084B2 (en) 2009-07-31 2020-07-07 Invisible Sentinel, Inc. Analyte detection devices, multiplex and tabletop devices for detection of analytes, and uses thereof
US10495638B2 (en) 2009-10-09 2019-12-03 Invisible Sentinel, Inc. Device for detection of analytes and uses thereof
US9823240B2 (en) 2012-03-09 2017-11-21 Invisible Sentinel, Inc. Methods and compositions for detecting multiple analytes with a single signal
US10018626B2 (en) 2012-03-09 2018-07-10 Invisible Sentinel, Inc. Methods and compositions for detecting multiple analytes with a single signal
US10732177B2 (en) 2012-03-09 2020-08-04 Invisible Sentinel, Inc. Methods and compositions for detecting multiple analytes with a single signal

Also Published As

Publication number Publication date
EP1141725A2 (fr) 2001-10-10
AU2539000A (en) 2000-07-31
AU773046B2 (en) 2004-05-13
JP2002533724A (ja) 2002-10-08
DE19859912C2 (de) 2001-06-21
CA2353920A1 (fr) 2000-07-06
WO2000039581A3 (fr) 2000-11-23
DE19859912A1 (de) 2000-07-06

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