WO2004011938B1 - Method and device for screening molecules in cells - Google Patents

Method and device for screening molecules in cells

Info

Publication number
WO2004011938B1
WO2004011938B1 PCT/FR2003/002298 FR0302298W WO2004011938B1 WO 2004011938 B1 WO2004011938 B1 WO 2004011938B1 FR 0302298 W FR0302298 W FR 0302298W WO 2004011938 B1 WO2004011938 B1 WO 2004011938B1
Authority
WO
WIPO (PCT)
Prior art keywords
characterized
support
cell
method according
drops
Prior art date
Application number
PCT/FR2003/002298
Other languages
French (fr)
Other versions
WO2004011938A2 (en
WO2004011938A3 (en
Inventor
Francois Chatelain
Yves Fouillet
Brigitte Fouque
Alexandra Fuchs
Beatrice Schaack
Original Assignee
Francois Chatelain
Commissariat Energie Atomique
Yves Fouillet
Brigitte Fouque
Alexandra Fuchs
Beatrice Schaack
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
Priority to FR0209326 priority Critical
Priority to FR0209326A priority patent/FR2842747B1/en
Application filed by Francois Chatelain, Commissariat Energie Atomique, Yves Fouillet, Brigitte Fouque, Alexandra Fuchs, Beatrice Schaack filed Critical Francois Chatelain
Publication of WO2004011938A2 publication Critical patent/WO2004011938A2/en
Publication of WO2004011938A3 publication Critical patent/WO2004011938A3/en
Publication of WO2004011938B1 publication Critical patent/WO2004011938B1/en

Links

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5023Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on expression patterns
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5032Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on intercellular interactions
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5058Neurological cells
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00351Means for dispensing and evacuation of reagents
    • B01J2219/00364Pipettes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00351Means for dispensing and evacuation of reagents
    • B01J2219/00364Pipettes
    • B01J2219/00367Pipettes capillary
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00351Means for dispensing and evacuation of reagents
    • B01J2219/00378Piezo-electric or ink jet dispensers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00646Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports
    • B01J2219/0065Making arrays on substantially continuous surfaces the compounds being bound to beads immobilised on the solid supports by the use of liquid beads
    • CCHEMISTRY; METALLURGY
    • C40COMBINATORIAL TECHNOLOGY
    • C40BCOMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES, IN SILICO LIBRARIES
    • C40B60/00Apparatus specially adapted for use in combinatorial chemistry or with libraries
    • C40B60/14Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027General features of the devices
    • G01N2035/1034Transferring microquantities of liquid
    • G01N2035/1046Levitated, suspended drops

Abstract

The invention concerns a method for reacting a reagent R with a cell C, which consists in: setting the cell C on a support S comprising a substantially planar surface, in the form of an aqueous drop on said surface; covering the planar surface of the support S whereon the aqueous drop has been set containing the cell C with a separation film F, allowing through gases and preventing the aqueous drops set on the support S from evaporating, F being non-miscible with the reagent R; triggering the reaction between the reagent R and the cell C by introducing the reagent R in the aqueous drop containing the cell C. The invention also concerns a device for implementing said procedure and its applications.

Claims

 40
MODIFIED CLAIMS
[received by the International Bureau on 06 August 2004 (06.08.04); original claims 1-59 replaced by new claims 1-56 (7 pages)]
1) Method for reacting a reagent R with at least one cell C, said method being characterized in that: the cell C is deposited on a support S comprising a substantially flat surface in the form of a drop aqueous on said surface,
- The substantially flat surface of the support S on which was deposited the aqueous drop containing the cell C is covered by a separating film F, allowing the passage of gases and preventing the evaporation of aqueous drops deposited on the support S, F being immiscible with reagent R,
the reaction between the reagent R and the cell C is triggered by the introduction of the reagent R into the aqueous droplet containing the cell C,
- The support S has on its flat surface a hydrophobic character and at least one means for receiving aqueous drops consisting of one or more hydrophilic zones.
2) Method according to claim 1, characterized in that the attachment of the drops on the support S is by capillarity.
3) Method according to claim 1 or claim 2, characterized in that the support S is constituted by a plate of a material selected from silicon, glass or a polymer.
4) Method according to any one of claims 1 to 3, characterized in that an aqueous drop containing the cell C is deposited on the support S, a second aqueous drop containing the reagent R is injected with the aid of all or appropriate injection means, directly in the drop containing the cell C. 5 °) Method according to any one of claims 1 to 3, characterized in that a first aqueous drop is deposited on the support S and then a second The aqueous drop is deposited on the same support near the first, one of these drops contains the cell C, the other the reagent R, the reaction of the reagent R with the cell C is triggered by the melting of the two drops. Process according to any one of Claims 1 to 3, characterized in that the reagent R is attached to the support S or to the film F, the cell C is 41
deposited in the form of an aqueous drop on the support S and the reagent R is then unhooked from the support S or the film F to allow its reaction with the cell.
7 °) Method according to any one of claims 1 to 6, characterized in that the separating film F is a liquid selected from oils and organic solvents.
8 °) Method according to claim 7, characterized in that the separating film F is selected from mineral oils and silicone oils.
9 °) Method according to any one of claims 1 to 6, characterized in that the separating film F is air saturated with moisture. 10 °) Method according to one of claims 1 to 6, characterized in that the separating film F is a flexible film, solid.
11 °) A method according to claim 10, characterized in that the separating film F is polydimethylsiloxane or nitrocellulose.
12 °) Method according to any one of claims 1 to 6, characterized in that the separating film F is a rigid honeycomb bonnet of porous material.
13 °) Method according to any one of claims 1 to 12 characterized in that the deposition of aqueous drops containing one or more cells or a reagent on the support S is by means of fine capillaries. 14 °) Method according to any one of claims 1 to 12 characterized in that the deposition of aqueous drops containing one or more cells or a reagent on the support S is by means of a nozzle.
15 °) Method according to any one of claims 1 to 14, characterized in that it comprises a step of moving the support S after the deposition on the support S of the first series of drops.
16 °) Method according to any one of claims 1 to 15, characterized in that the cultures of cells in the form of aqueous drops are stored for at least 24 hours.
17 °) Method according to any one of claims 1 to 16, characterized in that several aqueous drops each comprising at least one cell are deposited on the support S, under the separating film F, said drops being isolated from each other . 42
18 °) Method according to any one of claims 1 to 17, characterized in that a drop contains from 1 to 100 cells
19 °) Method according to any one of claims 17 and 18, characterized in that one places different cells in the different drops. 20 °) Method according to any one of claims 17 and 18, characterized in that one places identical cells in the different drops.
21 °) Method according to claim 20, characterized in that the support is a hydrophobic plate having hydrophilic zones and that the step of injecting the aqueous drops containing cells is replaced by immersing the plate in an aqueous solution containing the cells.
22 °) A method according to any one of claims 1 to 21, characterized in that the reagent molecules are prepared directly after deposition on the support, by a method selected from in situ synthesis, in vitro transcription in the drop, the peptide and nucleic chain polymerization reaction. 23 °) Method according to any one of claims 1 to 22, characterized in that the reagent is a DNA molecule.
24 °) Method according to claim 23, characterized in that the DNA is in precipitated form, especially in the form of calcium phosphate.
25 °) Method according to any one of claims 1 to 22, characterized in that the reagent is transcription factor.
26 °) Method according to any one of claims 1 to 25, characterized in that one deposits successively several reagents for reacting with the same cell.
27 °) A method according to any one of claims 1 to 26, characterized in that is deposited several aqueous drops containing cells and is fused these drops.
28 °) Method according to claim 27, characterized in that glial cells and neurons are deposited to make them communicate within a single drop. 29 °) A method according to any one of claims 1 to 28, characterized in that reagents are reacted in a first type of cells so as to trigger a cellular reaction, such as the production of a protein recombinant then this first cell is reacted with a cell of another type by melting with another drop.
30 °) Method according to any one of claims 1 to 29 wherein the support comprises separation means, characterized in that is deposited an aqueous drop comprising at least one cell of a first type on one side of the separating means and an aqueous drop comprising at least one cell of a second type on the other side of the separating means and then the melting of the cell drops is performed.
31 °) Method according to any one of claims 1 to 30, characterized in that the reagent is selected from the labeled molecules, including fluorescent and radioactive markers.
32 °) Method according to any one of claims 1 to 31, characterized in that the cell is selected from: primary cells, hybridomas, cell lines, stem cells, a piece of cellular tissue, and mixtures thereof .
33 °) Device for reacting a reagent R with a cell C, this device being characterized in that it comprises:
a support S comprising a substantially flat surface of hydrophobic character and at least one means for receiving aqueous drops, consisting of one or more hydrophilic zones, the surface S being covered with a separation film F allowing the passage of gas and preventing the evaporation of the aqueous drops deposited on the support, F being immiscible with the reagent R,
- Means for depositing on said surface and under the film F, aqueous drops containing the cell C - a controlled atmosphere chamber in which the support S is placed so as to allow the survival of the cell C.
34 °) Device according to claim 33, characterized in that the support S is constituted by a plate of a material selected from silicon, glass or a polymer. 35 °) Device according to claim 33 or claim 34, characterized in that the means for receiving aqueous drops consists of areas of the flat surface of the support S with a size ranging from 5 microns 2 to 5 mm 2 . 44
36 °) Device according to any one of claims 33 to 35, characterized in that the support S has at least one of the characteristics a) to c) below: a) the support S has on its flat surface cavities, of a depth ranging from 1 micron to 1 millimeter constituting the receiving means; b) the support S is a plate provided with excrescences of thickness ranging from 1 micron to 1 millimeter, arranged on its surface and intended to promote the attachment of the drops; c) the support S is a plate provided with at least one wire, on which hang the drops.
37 °) Device according to any one of claims 33 to 36, characterized in that the means for depositing aqueous drops on the support S consist of fine capillaries.
38 °) Device according to any one of claims 33 to 37, characterized in that the means for depositing the aqueous drops on the support S consist of a piezoelectric system provided with a nozzle.
39 °) Device according to any one of claims 33 to 38, characterized in that the support S of the device is movable.
40 °) Device according to any one of claims 33 to 39, characterized in that the support S consists of a solid film attached to rollers at both ends, the rollers being provided with winding means so as to allow the displacement of the film and thus the displacement of the drops which have been deposited on it.
41 °) Device according to any one of claims 33 to 40, characterized in that it further comprises at least one means selected from:
means for supplying energy to one or more drops deposited on the support;
means for optically treating one or more drops deposited on the support; means for applying a magnetic field or an electric field to one or more drops deposited on the support; 45
detection means focused on one or more drops deposited on the support;
means for promoting transfection.
42 °) Device according to any one of claims 33 to 41, characterized in that the means used in the device are connected to a control device for its automation.
43 °) Device according to any one of claims 33 to 42, characterized in that the support comprises receiving means regularly arranged in the form of dies. 44 °) Device according to any one of claims 33 to 43, characterized in that the support is provided with separation means for separating two distinct types of cells but allowing the passage of small molecules between these cells.
45 °) Device according to claim 44, characterized in that the separating means are arranged at the receiving means, on the support.
46 °) Device according to any one of claims 33 to 45, characterized in that the aqueous drops containing one or more cells comprise a culture medium.
47 °) Device according to any one of claims 33 to 46, characterized in that the support is provided with a surface whose hydrophilic / hydrophobic properties may vary under the influence of a parameter such as temperature, an electric field, a magnetic field, an irradiation.
48 °) Use of a device according to any one of claims 33 to 47 to realize simultaneously and automatically a large number of reactions of a reagent on a cell by varying the nature of the reagent and the cell.
49 °) Use according to claim 48 for performing the screening of a set of chemical compounds on living cells.
50 °) Use of a device according to any one of claims 33 to 47 to study cellular systems selected paraii: neural networks, the epidermis. 46
51 °) Use of a device according to any one of claims 33 to 47 to study the action on a cell of a reagent chosen from: nucleic acid molecules, proteins, peptides, molecules of peptide nucleic acid. 52 °) Use of a device according to any one of claims 33 to 47 for the expression of recombinant proteins.
53 °) Use of a device according to any one of claims 33 to 47 for performing the screening of nucleic molecules intended to modify the expression of genes in the cells. 54 °) Use of a device according to any one of claims 33 to 47 to search promoter genomic sequences.
55 °) Use of a device according to any one of claims 33 to 47 to study the interactions between cells of different types. 56 °) Use of a device according to any one of claims 33 to 47 for the preparation and screening of siRNA.
PCT/FR2003/002298 2002-07-23 2003-07-21 Method and device for screening molecules in cells WO2004011938A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
FR0209326 2002-07-23
FR0209326A FR2842747B1 (en) 2002-07-23 2002-07-23 Method and device for the screening of molecules into cells

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
AU2003269041A AU2003269041A1 (en) 2002-07-23 2003-07-21 Method and device for screening molecules in cells
CA 2492933 CA2492933A1 (en) 2002-07-23 2003-07-21 Method and device for screening molecules in cells
EP03750828A EP1525472A2 (en) 2002-07-23 2003-07-21 Method and device for screening molecules in cells
JP2004523860A JP2005533509A (en) 2002-07-23 2003-07-21 Method and apparatus for screening a molecule in a cell

Publications (3)

Publication Number Publication Date
WO2004011938A2 WO2004011938A2 (en) 2004-02-05
WO2004011938A3 WO2004011938A3 (en) 2004-08-05
WO2004011938B1 true WO2004011938B1 (en) 2004-09-16

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PCT/FR2003/002298 WO2004011938A2 (en) 2002-07-23 2003-07-21 Method and device for screening molecules in cells

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EP (1) EP1525472A2 (en)
JP (1) JP2005533509A (en)
AU (1) AU2003269041A1 (en)
CA (1) CA2492933A1 (en)
FR (1) FR2842747B1 (en)
WO (1) WO2004011938A2 (en)

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Also Published As

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WO2004011938A2 (en) 2004-02-05
CA2492933A1 (en) 2004-02-05
FR2842747A1 (en) 2004-01-30
WO2004011938A3 (en) 2004-08-05
JP2005533509A (en) 2005-11-10
FR2842747B1 (en) 2004-10-15
AU2003269041A1 (en) 2004-02-16
EP1525472A2 (en) 2005-04-27
AU2003269041A8 (en) 2004-02-16

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