PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`(51) International Patent Classification3 :
`(AVInternational Publication Number:
`WO 84/ 02000
`
` (43) International Publication Date:Al 24 May 1984 (24.05.84)
`
`GOIN 1/00, 35/08
`
`
`
`
`(21) International Application Number:
`PCT/GB82/00319
`
`
`(22) International Filing Date:
`9 November 1982 (09.11.82)
`
`
`(71)(72) Applicant and Inventor: SHAW STEWART,Patrick,
`Douglas [GB/GB]; Linplum House, Haddington, East
`Lothian (GB).
`
`
`
`(81) Designated States: AT (European patent), AU, BR, CH
`(European patent), DE (European patent), DK, FR
`(European patent), SE (European patent).
`(European patent), JP, LU (European patent), NL
`
`
`
`Published
`
`
`
`With international search report.
`
`(54) Title: CHEMICAL DROPLET REACTOR
`
`fe ee
`64
`65
`66
`
`.
`43
`
`57
`
`45
`4]
`42
`
`57) Abstract
`67
`
`A method and apparatus for combining chemi-
`cal reactants wherein the method comprises the steps
`of: 1) dispensing the reactants into a conduit system
`in the form of discrete volumes or droplets (5, 15, 21,
`22, 36) separated from each other by an inert immisci-
`ble liquid (1); and 2) changing the flow ofthe inert
`immiscible liquid within the conduit system in a pre-
`cise sequence in such a manner that predetermined
`discrete volumes coalesce with each other, thereby
`combining the reactants; and wherein the apparatus
`is formed by holding two plates (42, 44) together in
`face to face contact, where one or both plates pos-
`sesses a set of indentations (43) on the surface to be
`mated,
`thereby forming the conduits for reactant
`
`wo
`
`a
`
`OT
`
`A
`
`|
`
`56
`
`62
`
`60
`
`combinations. _
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages ofpamphlets publishing international ap-
`plications under the PCT.
`
`United States of America
`
`Austria
`Australia
`Belgium
`Brazil
`Central African Republic
`Congo
`Switzerland
`Cameroon
`Germany, Federal Republic of
`Denmark
`Finland
`France
`Gabon
`United Kingdom
`Hungary
`Japan
`Democratic Peopie’s Republic of Korea
`
`AT
`. AU
`BE
`BR
`CF
`CG
`CH
`CM
`DE
`DK
`FI
`FR
`GA
`GB
`HU
`JP
`KP
`
`Liechtenstein
`Sri Lanka
`Luxembourg
`Monaco
`Madagascar
`Mauritania
`Malawi
`Netherlands
`Norway
`Romania
`Sweden
`Senegal
`Soviet Union
`Chad
`Togo
`
`

`

`WO 84/02000
`
`PCT/GB82/00319
`
`7)
`
`CHEMICAL DROPLET REACTOR
`
`Tre invention is the subject of British Patent Application No. 8200642.
`
`This invention relates to a method for combining liquid chemical reactants and to
`
`apparatus for use therein.
`
`Description of prior art
`
`Automatic analysis apparatus for analysis of liquid samples as a flowing stream was
`disclosed by Skeggs in U.S. Patent No. 2,797,149 issued June 25 1957 and in U.S. Patent
`No. 2,879,141 issued March 24 1959. Such a flowing stream is eustomarily segmented
`by separating successive segments with air, but it may alternatively be segmented by |
`an inert immiscible liquid, as taught in U.S. 3,479,141 issued to John Smythe November
`18 1969. Such methods provide an extremely powerful means of analysing a number
`of liquid samples by
`subjecting them to a particular chemical test.
`
`SUMMARY OF THE INVENTION
`
`In contrast with continuous flow systems, the present invention does not operate with
`a continuous stream, where control is achieved by the selection of appropriate flow
`rates for each fluid by running a pump or cyclically operated piston at a predetermined
`rate, but rather the liquid components of the present invention are controlled by a
`sequence of distinct movements in closed conduits, with each movement or set of
`movements occurring after the previous movement
`is completed.
`For example, a
`known volume of a reactant is moved through an opening, this movement ceases, then
`the volume displaced is separated from the parent volume.
`It should be noted that the
`volumes of all
`the reactants to be combined are contained and defined by the
`immiscible liquid prior to combination, and that individual single reactant samples can
`easily be handled by virtue of the large amounts of the immiscible liquid present,
`ard of the method of control. Thus each sample is treated by a sequence of changes
`
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`

`WO 84/02000
`
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`
`2°
`
`PCT/GBS82/00319
`
`of the movements of the liquid components causing it to combine with a reactant or
`reactants selected at will from a pleurality of reservoirs of different reactants. The
`reactants are thus metered within the conduit system. —
`
`It should also be noted that the conduits which are to contain the liquid components
`are preferably constructed by holding two plates together in face to face contact,
`where one or both plates possesses a set of indentations or channels on the surface to
`
`be mated.
`
`OBJECTS OF THE INVENTION
`
`Accordingly several objects of my invention are:
`
`1.
`
`2.
`
`3.
`
`4.
`
`to carry out chemical reactions using volumes of reactants that may range
`from more than a litre to less than 10 nanolitres, and
`
`to carry out repetitive chemical procedures automatically, and by less complex
`Means than in comparable systems, and
`
`to allow greater flexibility during operation, by continuously providing a choice
`of reactants, and
`
`to isolate workers from dangerous substances including radioisotopes and
`pathogens, and
`
`5.
`
`to reduce or eliminate contamination of the reactants, and
`
`6.
`
`to prevent accidental mixing spillage or losses of the reactants during transfer,
`and
`
`7.
`
`to provide a method and a means for metering samples and reactants within
`a conduit system.
`
`DRAWINGS
`
`Figure 1 is a plan view of two conduits being used in accordance with the method for
`producing droplets of reactants. The stippled areas represent carrier phase.
`
`Figure 2 is a plan view of conduits being used in accordance with an alternative method
`of producing droplets of reactants.
`
`
`
`

`

`PCT/GB82/00319
`.
`3
`WO 84/02000
`Figure 3 is a plan view of conduits being used in accordance witn a metiiou ior
`coalescing droplets.
`
`Figure 4 is a plan view of an apparatus in accordance with the invention, which has
`been adapted to allow the separation of substances by electrophesis.
`
`Figure 5 is an exploded view of one embodiment of an apparatus in accordance with
`this invention.
`
`Figure 6 is a plan view of the apparatus of figure 5.
`
`DESCRIPTION OF THE INVENTION
`
`controlling
`The method and apparatus of the invention may be used for initiating and
`a chemical reaction, or preparing mixtures of reactants, wherein the method comprises
`steps of:
`
`into a conduit
`1. dispensing two or more reactants, optionally in a solvent phase,
`system in the form of discrete volumes, each volume being separated from
`each other by an inert and immiscible liquid, and
`
`2. moving the immiscible liquid and discrete volumes through the conduit system in
`such a sequence that predetermined discrete volumes individually coalesce with each
`other, thereby combining the reactants.
`
`The system is particularly suited to the manipvlation of microscopic quantities of
`reactant with volumes of less than 10 nanolitres, but larger quantities of more than a
`litre could also be used. The system is capable of treating single volumes of reactants
`
`individually.
`
`The discrete volumes may be separated from their parent volumes by passing a small
`volume of reactant from a reservoir, through a constriction and into a conduit meeting
`the reservoir at right angles. The diserete volume is now separated from the parent
`volume in the reservoir by passing carrier phase along the conduit.
`
`The discrete volumes of reactants are coalesced with each other by pressing volumes
`together by gravity, or by withdrawing the carrier phase from between a pleurality of
`discrete volumes,
`thereby causing them to move together until
`they collide, or by
`eausing one volume to remain in a position partially blocking the path of a second
`discrete volume,
`then moving this second discrete volume through the opening thus
`
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`WO 84/02000
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`formed, eausing the two discrete volumes to be pressed together and to coalesce.
`
`The reactants can be liquids, or gases capable of being condensed in the apparatus, or
`solids or gases dissolved in a suitable solvent. This reactant liquid, hereafter referred
`to as a reactant, will be supported, defined and moved by another, immiscible liquid,
`referred to hereafter as the carrier phase. Suitable carrier phases include mineral oils,
`light silicon oils, water, and fluorinated hydrocarbons. The carrier phase may be a
`mixture of several substances, and preferably has approximately the same density as
`the reactants. Surface acting agents may be included in the carrier and/or reactant
`phase to produce suitable surface properties, e.g. to allow efficient merging. Suitable
`surface acting agents include cholesterol, gelatine, sodium dioxyl, succinate Teepol, and
`
`Triton-x~-100.
`
`The cross-section of the conduits is generally of the same order of magnitude as the
`eross-section of the droplets which are to be used in them, but smaller conduits, or
`larger droplets or discrete volumes may be used, causing the droplets to become
`elongated.
`
`including the distortion of
`The carrier phase may be moved by any suitable means,
`flexible tubing or sheeting, blowing or sucking by mouth, pumps or pistons. Pistons can
`be moved by serew threads turned by electric motors,
`(which may optionally be
`controlled electronically using microprocessor technology).
`
`Figure 1 of the accompanying drawings illustra:es one method of separating droplets of
`a predetermined volume from a larger
`reservoir of reactant.
`The reactant
`is
`introduced into a conduit containing carrier phase 1 from a side arm 2, by being sucked
`or pushed through a small opening 3. When the correct volume has passed through into
`the conduit a flow of carrier phase separates it from the reactant in the reservoir, and
`-@arries it down the conduit. The volume of the droplet produced can be determined
`
`by at least three methods:
`
`through the opening is moved a
`1. The piston responsible for pushing the reactant
`known distance, corresponding to the volume of the reagent displaced. When this
`movement
`is complete the droplet
`is broken off by a relatively fast, shortlived
`eurrent of carrier phase.
`
`2. If large numbers of droplets are required, a continuous flow of carrier phase flows
`down the conduit. When reactant is simultaneously passed through the opening 3 a
`series of droplets will be formed, each broken off just before it spans the conduit.
`The exact size of the droplets thus produced will depend on the magnitudes of the
`
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`WO 84/02000
`
`two currents..
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`5
`
`PCT/GB82/00319
`
`3. The volume of the droplet before separation 5, is estimated visually, optionally using
`a telescope or microscope with a graduated eye piece. When the correct volume
`is achieved it is separated by a current of carrier phase.
`
`In this case the reactant 16
`Figure 2. illustrates another method of forming droplets.
`is passed into a conduit of considerably narrower width 11 than the droplets to be
`produced. The conduit is graduated relative to the opening 12 of a side arm 13. The
`reactant
`is passed into the narrow conduit
`to a certain graduation 14, whereupon
`earrier phase is introduced from the side arm, thus separating a droplet of the required
`size 15.
`
`Figure 3. illustrates a method of coalescing droplets, which ean be of different sizes.
`The coalescence is effected at a site where two conduits, 23 and 25 in figure 3, merge
`to form a single conduit 24, preferably in a Y-configuration as shown. A current from.
`conduit 23 to conduit 24 is produced which carries a droplet 21 to the site for
`eoalescence. When the surface of this droplet protrudes into the space where conduits
`23 and 25 converge, the valves feeding conduit 23 are closed. A current from conduit
`25 to conduit 24 now carries a second droplet past the first, and in doing so the two
`droplets are pressed together, and coalesce to form a single droplet.
`
`If either droplet is smaller than the other, then the eonduit through which it emerges
`should be correspondingly narrower. All conduits should have diameters approximately
`the same as the droplets to be used in them.
`
`The various movements of the fluids are produced by connecting the conduits to
`pistons, pumps or to reservoirs containing compressed gas or partial vacuum. Control
`is achieved by conventional valves.
`
`Conduits ean be heated by electric circuits or coils or by electromagnetic radiation,
`allowing coalesced droplets to be incubated at the desired temperature.
`Solid state
`heat pumps ean be used to cool conduits both for incubation at low temperatures and
`_ to allow the storage of unstable reactants. Heating can be achieved by reversing the
`heat pumps. Heating and cooling can also be achieved by circulating a fluid through
`separate ducts.
`
`After coalescence the reactants can be thoroughly mixed by moving the droplet up and
`down a conduit, or if required by passing it through a constriction several times.
`
`
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`

`WO 84/02000 —
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`6
`
`PCT/GB82/00319
`
`Ports can be provided to allow droplets to be removed or introduced with a syringe
`needle.
`
`The droplet can be passed into a tube and transferred to any standard instrument of
`chemical or biochemical analysis. Alternatively parts of the device itself can be
`adapted to form the sample chambers of such instruments. For example conduits can
`be formed with two plain transparent walls
`to form the sample chambers of
`photometers.
`A single transparent wail opposite a reflecting surface could also be
`
`used.
`
`Conduits can also be packed with the materials used for electrophoresis and
`
`chro=-
`
`matography.
`
`Figure 4. shows a conduit which is adapted for electrophoresis. The electrophoretic
`
`is packed with electrophoretic material. The sample to be separated by
`eonduit 31,
`electrophoresis is introduced as a droplet from conduit 32, and this droplet is merged
`en one side with the surface of the electrophoretic material (e.g. agarose, poly-
`acrylamide or cellulose) and on the other side with a semipermeable membrane. This
`semipermeable membrane 33 encloses a chamber
`filled with buffer, containing an
`electrode 34 and provided with a gas vent 35 if required. Another droplet 36 is merged
`on to the other end of the electrophoretic material and to another semipermeable
`membrane and electrode assembly 37. A current
`is passed between the electrodes
`which eauses the constituents to migrate at various speeds.
`The fastest fractions
`migrate into the receiving droplet first. This droplet is now exchanged for another 38
`after a period, allowing the collection of a series of droplets containing different
`fractions.
`
`The ability to handle very small samples makes the system suited to use with High
`Performance Liquid Chromatography.
`
`The system can be connected to a conventional H.P.L.C. system by fine bore tubing or
`
`to a mass spectroscopy system.
`
`The progress of droplets can be automatically monitored by detecting fluctuations in
`the light propagated through the conduit as the droplets pass.
`Similarly, when two
`droplets merge the light scattered from a beam passing through both droplets suddenly
`decreases. Windows in an opaque coating of the conduits can be used, and in cases
`where the monitoring of many sites is required, optie fibres could carry light to or from
`a central emitter or detector. The position of droplets could also be detected when
`they pass between an infra-red emmiter and detector, or when they pass between the
`
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`WO 84/02000
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`plates of a conductance cell, or by the resultant change in the refractive index of the
`eontents of the conduits.
`In any automatic embodiment of the device, all pressure
`generating and monitoring means can be controlled by microprocessors or computers.
`
`The preferred method of construction of the apparatus is by producing indentations or
`channels of the appropriate configuration in the surface of a plate, and to clamp or
`hold this plate against another, producing closed ducts or eonduits. The second plate
`may have a planar surface, or it may have indentations, either in the mirror image of
`the first plate's or in a different configuration. Also it is possible to produce three
`dimensional configurations, where conduits cross over each other, by using three or
`more plates. Preferably at least one of the plates is transparent, e.g. glass or perspex,
`allowing visual inspection of the procedures. The other plate may be Kel-F or Teflon
`(materials suited for use with aqueous reactants) or glass, perspex, metal, polyvinyl-
`chloride, polypropylene etc.
`
`Indentations in glass can be etched. Plasties and metals can be etched, moulded or
`machined. Electrical contacts can be produced by depositing a metallic layer of the
`desired configuration on either plate.
`
`Miero-organisms can be cultured in droplets containing the appropriate nutrients and
`incubated at the correct temperature.
`
`In place of droplets, larger segments occupying a considerable length of conduit ean be
`separated from reservoirs of reactants and coalesced with other segments in the same
`way as droplets.
`
`Contamination of the walls can be reduced by:
`
`1. constructing conduits with highly polished walls,
`
`2. constructing conduits with walls coated with or constructed from a material
`which repels the reactant phase but attracts the carrier phase,
`
`3. washing the conduits with segments of a cleaning liquid prior to the passage of each
`volume of reactant.
`
`4. preventing the droplets or segments from remaining stationary by oscillating the
`flow of carrier phase thus maintaining a film of carrier phase around the reactant.
`
`
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`

`

`WO 84/02000
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`An apparatus can be constructed in accordance with the method of the invention by
`joining tubes and pipes in the desired configuration.
`
`This invention has applications in many branches of medicine, chemistry, biochemistry,
`geology, etce., notably in procedures which utilize very small volumes, such as forensic
`and molecular biology work.
`The invention could be used to perform biological or
`chemical assays of sub-samples during purification procedures, and to produce chemical
`derivatives of samples prior to analysis by chromatography or mass
`spectroscopy.
`1:
`could also be used for chemical analysis or synthesis in outer space,
`in conditions of
`very low gravity and pressure.
`
`OQPERATION OF INVENTION
`
`Figure 5 is an exploded view of one embodiment of an apparatus in accordance with
`the method of the invention. This embodiment
`is capable of mixing predetermined
`
`volumes of two aqueous reactants under sterile conditions.
`
`The device comprises a steel base 41 supporting a Teflon block 42 in which U-
`
`sectioned indentations 43, of the configuration shown, have been machined. A sheet
`
`tightened
`of siliconized glass 44 is pressed against this block by a clamp 45 which is
`by nuts 46 and bolts 47. The five branches of the U-sectioned conduits thus formed
`
`lead to five stop-cock valves 48. The middie and outer pair of these conduits are
`
`connected by Teflon tubing 49 to reservoirs of the carrier phase, which is mineral
`spirit. The remaining two branches are connected to glass syringes, each containing
`one of the two reactants to be mixed.
`
`Figure 6 is a plan view of the device of figure 5 and uses the same reference numerals.
`Reservoirs 55 and 38 are half-filled with mineral spirit with the ends of the tubing 56
`opening below the surface of the mineral spirit, while the end of an air vent 57 opens
`above the surface in each. A syringe containing air 60 is connected to reservoir 59
`above the surface of the mineral spirit.
`
`The ports serving the valves 51 and 53 lead to two syringes 61 and 62 containing the
`two reactants. The conduits are initially filled with white spirit.
`
`An operating sequence for one eycle is as follows:
`
`1. Valves 48, 51, and 52 are opened. Valves 53 and 54 are closed.
`
`2. Syringe 61 is moved in until reactant reaches constriction 3.
`
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`
`

`

`PCT/GB82/00319
`wo 84/02000
`9
`Syringe 61 is moved further by the required amount, pushing a known volume Or
`reactant through the constriction 3.
`
`3-
`
`4.
`
`Valve 51 is closed.
`
`5.
`
`Ga
`
`7.
`
`8.
`
`9.
`
`Syringe 60 is moved out until the volume of reactant protruding through constriction
`3 is broken off, and the resultant droplet moves towards the Y-junction 64. Valve
`48 is closed.
`
`Valves 53 and 54 are opened and a similar sequence of events produces a droplet of
`the reactant from syringe 62.
`
`Syringe 60 moves out until the droplet originating from syringe 52 protrudes into the
`Y-junction.
`Valves 53 and 54 are closed.
`The positions of
`the droplets are
`illustrated at this stage in Figure 6.
`
`Valve 48 is opened and syringe 60 moves out until the droplet of the reactant from
`syringe 61 moves into the Y-junction 64, where it
`is pressed against
`the other
`droplet eausing the droplets to coalesce.
`
`If a colour change reaction is involved, such a eolour change can be recorded
`immediately, or after incubation using a thermostatically controlled coil 57. The
`droplet can be discarded by passing it into a reservoir 59 of mineral spirit.
`
`If the droplet is to be analysed using external instrumentation, it can be moved to
`a site opposite port 65, all valves closed, plug 66 removed and the droplet impaled
`and removed by a needle and syringe and transferred to the instrument. The plug
`is then replaced.
`
`10.Syringe 60 is disconnected, emptied of air, and reconnected,
`primed for another cycle of operation.
`
`leaving the device
`
`is emphasised that Figure 5 shows a very simple embodiment of the invention.
`It
`Embediments are envisaged having reservoirs for the introduction of more than twenty
`different reactants.
`It is also proposed to operate the valves automatically, and heat
`and cool regions of the conduits to allow incubation of reacting mixtures, and the
`storage of reactants for long periods.
`
`While the above description contains many specificities, these should not be construed
`as limitations on the scope of the invention, but rather as an exemplification of a few
`
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`
`preferred embodiments thereof. Many other variations are possime, ist caaspas co co
`possible to press together and coalesce droplets by gravity, and to use water as the
`carrier phase for oil soluable reactants. Accordingly, the scope of the invention should
`not be determined by the embodimentsillustrated but by the following claims and their
`legal equivalents.
`
`
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`Wo 84/02000
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`
`CLAIMS
`
`1.
`
`A method of combining chemical reactants comprising the steps of:
`
`dispensing two or more liquid reactants into a conduit system in the form of
`discrete volumes of liquid, each volume being separated from each other and from
`all undispensed reactants by an inert
`immiscible liquid,
`thereby metering the
`reactants within the conduit system; and
`
`changing the flow of said immiscible liquid and said discrete volumes through said
`conduit system in a precise sequence, in such a mannerthat predetermined discrete
`volumes are individually coalesced with each other,
`thereby eombining the
`
`reactants.
`
`A method as claimed in claim 1 in which said discrete volumes of chemical
`reactants are sufficiently small
`in relation to said conduits to form substantially
`spherical droplets with diameters less than the conduits.
`
`in which said discrete volumes of chemical
`A method as claimed in claim 1
`reactants are sufficiently large in relation to said conduits to be elongated by the
`
`conduits.
`
`4.
`
`A method as claimed in claim 1 in which each of said diserete volumes of reactants
`is formed by passing each chemical reactant from a reservoir, through an opening,
`into a conduit initially containing said carrier phase, then moving said carrier phase
`eausing a volume of said reactant to become separated from the reactant in the
`reservoir, said opening being optionally constricted, thereby metering the reactant
`within the conduit system.
`
`A method as claimed in claim 4 in which the volume of reactant passed out of the
`reservoir is estimated by assuming it to be spherical, and by measuring the diameter
`
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`of such a sphere optically, after which said volume is adjusted and separated.
`
`6.
`
`Te
`
`A method as claimed in claim 4 in which the volume of reactant passed out of the
`reservoir is estimated before separation by measuring the length of conduit which
`it occupies, after whieh said volume is adjusted and separated.
`
`A method as claimed in claim 4 in which the volume of reactant passed out of the
`reservoir is determined by displacing said volume by moving & piston a know:.
`distance, or by means of a well calibrated pump, prior to the separation of said
`
`volume.
`
`A method as claimed in claim 1 in which the immiscible liquid is moved until «¢
`discrete volume of reactant partially blocks the opening of a conduit, whereupon
`another discrete volume of reactant is: moved out of or into said opening causing
`these two discrete volumes to be pressed together, causing them to coalesce.
`
`9.
`
`A method as claimed in claim 1 in which said discrete volumes of reactants contain
`
`suspended micro-organisms.
`
`in which surface acting chemical agents are
`10.4 method as elaimed in claim 1
`dissolved in said chemical reagents or in said immiscible liquid, or in both.
`
`11.An apparatus for combining chemical reactants comprising two or more plates held
`in face to face contact, in which one or more plates possesses a set of indentations
`or channels, and bores, on the surface to be mated, such that closed conduits are
`formed,
`these conduits being in communication with reservoirs to contain two or
`more reactants and an inert immiscible liquid and with means for producing and
`controlling movements of the liquid components, said plates having surfaces with
`low affinity for the reactant to be used, which apparatus includes at least one zone
`where at
`least
`three conduits meet, which zones allow the formation and
`
`coalescence of chemical reactants.
`
`12.An apparatus as claimed in elaim 8 but in which said conduits are constructed by
`joining a set of tubular elements in the appropriate conformation.
`
`13.An apparatus as claimed in claim 11 or 12, comprising three conduits which join in
`a T or Y configuration, these three conduits leading to reservoirs for an immiscible
`liquid, each reservoir possessing means for moving said immiscible liquid, in which
`one or more of said conduits communicates with reservoirs for a pleurality of
`
`reactants.
`
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`WO 84/02000
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`
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`Figure 1.
`
`
`
`12
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`15
`
`16
`
`8613
`
`Figure 2.
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`214
`
`
`
`Figure3.
`
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`

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`WO 84/02000
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`PCT/GB82/00319
`
`
`
`

`

`WO 84/02000
`
`PCT/GB82/00319
`
`|
`
`|
`
`4.7.
`
`46
`
`|
`
`ERnNaTION
`
`A414
`65 66
`
`64
`
`57
`
`——L5
`41
`
`42
`
`BUREA
`OMPI
`Vn. WIPO Mv
`
`

`

`INTERNATIONAL SEARCH REPORT
`International Application No PCT/GB 82/00319
`.
`l. CLASSIFICATION OF SUBJECT MATTER(if several classification symbols apply, Indicate ail) *
`According to International Patent Classification (1PC) or to both National Classification and IPC
`pce: G01 N 1/00; G 01 N 35/08
`
`ll, FIELDS SEARCHED
`Mintmum Documentation Searched 4
`Classification Systam |
`Classification Symbois
`
`tpcd
`
`G 01 N 1/00;
`
`;
`
`G 01 N 35/
`/00
`
`Documentation Searched other than Minimum Documentation
`to the Extent that such Documents are Included in the Fields Searched 5eeAC—O
`
`emeePPPCPAATE
`il. DOCUMENTS CONSIDERED TO BE RELEVANT14
`Category * |
`Citation of Document, 16 with indication, where appropriate, of the relevant passages 17
`
`Relevant to Claim No. 18
`
`x
`
`x
`
`A
`
`A
`
`EP, A, 0047130 (VICKERS LTD.)
`1982
`line 25 - page 3, line 35;
`see page 2,
`page 6, line 31 - page 7,
`line 19;
`page 8, line 1
`—- page 9, line 1;
`figures
`
`10 March
`
`US, A, 4315754 (J. RUZICKA et al.) 16
`February 1982
`see column 6,
`
`lines 4-34; figures 2,4,6|
`
`US, A, 4253846 (W.J. SMYTHE et al.)
`3 March 1981
`see column 5, line 13 - column 6,
`Line 18; column 7,
`lines 6-49; figures
`2,4-6
`
`—
`
`|
`aa
`
`1,4,7,12,13
`
`1,4
`
`1,7
`
`US, A, 4022575 (E.H. HANSEN et al.) 10 May
`1977
`see column 5, lines 6-30; figure 2
`
`7
`
`19 Decem-
`uS, A, 4130394 (K.M. NEGERSMITH)
`A
`ber 1978 o/s
`
`“T" later document published after the international filing date
`* Special categories of cited documents: 15
`:
`or priority date and not in conflict with the appiication but
`;
`sas
`“A" document defining the general state of the art which is not
`considered to be of particular relevance
`citedtounderstand the principle or theory underlying the
`earlierdocument but published on or after the international
`“X%" document of particular relevanca;
`the claimed invention
`E'
`iting
`date
`cannot be considered novel or cannot be considered to
`“Ln document which may throw Goubtson priority claim(s)or
`involve an inventive siep
`the claimed invention
`
`
`which.
`is cited
`
`to establish>
`
`the publication date of another:
`“Y* document of
`.particular relevance;
`citation or other special reason (as specified)
`cannot be considered to involve an inventive step when the
`"©" document referring to an oral disclosure, use, exhibition or
`document is combined with one or mora other such docu-
`other means
`ments, such combination being obvious to a person skilled
`“Pp document pubiished prior to the internationalfiling date but
`in the art.
`family
`later than the priority date claimed
`-
`“&" document memberof the same patent
`Z_*
`IV. CERTIFICATION
`{fl
`Report 2
`
`Date of Mailing of this International Search
`
`rh
`18 JUL 1983
`iA af
`Signature ofAuthorized Officer 29
`H
`G.L.M% {Mo
`denberg
`.
`»
`.
`ine “4
`eo
`y
`
`Date of the Actual Completion of the International Search *
`
`17th June 1983
`International Searching Authority }
`EUROPEAN PATENT OFFICE
`Form PCT/ISA/210 (second sheet) (October 1981)
`
`

`

`Hl. DOCUMENTS CONSIDERED TO BE REL. :VANT
`(CONTINUED FROM THE SECOND SHEET)
`
` ‘Categor:* i Citat on of Document, 16 with ind.cation, whera appropriate, of the relevant passages ‘7
`| Ralev. nt to Claim No 18
`
`international Application No. PCT/GB 82/ 00319 -2=
`
`see column 2, lines 18-33; column 4,
`line 62 ~— column 5, line 20; figure 1A
`
`A
`
`US, A, 4210809 (M.H. PELAVIN)
`see column 2,
`lines 47-67
`
`1 July 1986
`
`6
`
`6
`
`\ i‘F
`
`Form PCT ISA 210 (extra sheet) (October 1981)
`
`ee Te
`
`

`

`ANNEX TO THE INTERNATIONAL SEARCH REPORT ON
`oe cee ee re ene: me) eee ee ae ee ey ee ey ce Cm SE ee eeee ee ce toe me ee ms ee oe oe
`
`INTERNATIONAL APPLICATION NO.
`
`PCT/GB 82/00319 (SA
`
`4439)
`
`This Annex lists the patent family members relating to the
`patent documents cited in the above-mentioned international
`search report. The members are as contained in the European
`Patent Office EDP file on 11/07/83
`
`The European Patent Office is in no way liable for these
`particulars which are merely given for the purpose of
`information.
`
`
`Patent document
`cited in search
`report
`
`Publication
`date
`
`Patent family
`member(s)
`
`Publication
`date
`
`EP-A= 0047130
`
`10/03 /82
`
`US-A- 4315754
`
`16/02/82
`
`US-A- 4253846
`
`03/03/81
`
`US-A- 4022575
`
`10/05/77
`
`US-A- 4130394
`
`19/12/78
`
`US-A= 4210809
`
`01/07/80
`
`None
`
`GB-A-
`JP-A=-
`FR-A-
`DE-A-
`
`BE-A-
`GB~A-
`FR-A-
`NL-A-
`DE-A-
`JP-]A-
`AU-A-
`CA-A-
`
`None
`
`BE-A-
`GB-A-
`L-A-=
`FR-A=
`DE-A-
`JP-A-
`AU-A-
`CA-A-
`
`FR=~A-
`DE-A-=
`GB-A-
`JP-A=
`CA~A-=-
`
`2062225
`56036053
`2469714
`3031417
`
`886132
`2064114
`2470385
`8005809
`3042915
`56124052
`6415380
`1139125.
`
`870629
`2005224
`7806226
`2404834
`2842241
`54055495
`4032078
`1093344
`
`2451579
`3009835
`2047880
`55125472
`1136885
`
`20/05/81
`09/04/81
`22/05/81
`11/06/81
`
`13/05/81
`10/06/81
`29/05/31
`16/06/81
`03/03/81
`29/09/81
`28/05/81
`11/01/83
`
`20/03/79
`19/04/79
`05/04/79
`27/04/79
`12/04/79
`02/05/79
`03 /04/80
`13/01/81
`
`10/10/80
`25/09/80
`03/12/80
`27/09/80
`07/12/82
`
`For more details about this annex
`see Official Journal of the European Patent Office, No. 12/82
`
`