Automated liquid handling apparatus and process with plate handler

Claim 3

An apparatus as claimed in claim 1 wherein said means for storing a test tube includes a carrousel for storing a plurality of test tubes and a motor for moving any one of said tubes to a predetermined position, the carrousel optionally including storage positions for pipette tips configured so as to be able to reach to the bottom of said tubes.

Claim 4

An apparatus as claimed in claim 1 or claim 2 wherein said means for moving liquid includes (a) means for moving a pipette between any of said test tubes and any of said wells and for drawing liquid from said test tube or said well and for ejecting liquid into said test tube or said well, and/or (b) means for injecting wash solution into any of said wells, letting it incubate and emptying said wells.

Claim 5

An apparatus as claimed in claim 3(a) further comprising means for sensing the pressure inside said pipette and detecting a rise in pressure and/or means for ejecting said pipette.

Claim 6

S. An apparatus as claimed in any one of the preceding claims further comprising means coupled to said controlling means for reading bar code labels on said test tubes and/or means for reading bar code labels on said trays.

Claim 8

An apparatus as claimed in claim 6 wherein said means for controlling includes means for interacting with the user to allow said user to customize the individual process parameters controlling the movements defined by selected ones of said files.

Claim 9

An apparatus as claimed in claim 7 further comprising means for storing each customized file upon command from said user.

Claim 10

An apparatus as claimed in claim 8 further comprising means in said means for controlling to allow said user to link any of said files into a chain of files which said apparatus will execute seriatem.

Claim 13

A method as claimed in claim 10 further comprising the steps of transferring another sample of said liquid into a third set of wells using said computer controlled liquid transfer apparatus and transferring a second set of reagents from a fourth set of wells into said third set of wells using said computer controlled liquid transfer apparatus, and optionally the steps of transferring a third sample of said liquid to be assayed to a fifth set of wells using said computer controlled liquid transfer apparatus and transferring a third set of reagents from a sixth set of wells into said fifth set of wells using said computer controlled liquid transfer apparatus.

Claim 14

A method as claimed in claim 10 or claim 11 wherein said liquid to be assayed is a centrifuged blood sample and said sample is blood plasma, said other sample preferably being red blood cells when the method is as claimed in claim 11. transferring a third set of reagents from a sixth set of wells into said fifth set of wells using said computer controlled liquid transfer apparatus.

Claim 15

A process for liquid handling to be carried out by a machine which includes a storage means for storing a test tube containing a liquid to be assayed, a tray containing wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus,comprising the steps of: dispensing diluent into a first set of wells using said transfer head; withdrawing an aliquot of liquid from said tube using said transfer head: depositing an aliquot of said liquid in each of a second set of wells using said transfer head; withdrawing an aliquot of said liquid from said tube using said transfer head; depositing an aliquot of said liquid in a third set of wells; withdrawing an aliquot of said liquid from a predetermined level in said tube; depositing an aliquot of said liquid in each of said first set of wells using said transfer head: mixing said liquid and said diluent: withdrawing an aliquot of the diluted liquid from each of said first set of wells: depositing each said aliquot of said diluted liquid into a fourth set of wells: withdrawing aliquots of a first reagent set from a fifth set of wells using said transfer head; depositing an aliquot of a reagent from said first reagent set in each of said fourth set of wells; withdrawing aliquots of a second reagent set from a sixth set of wells using said transfer head; depositing an aliquot of a reagent from said second reagent set in each of said third set of wells; withdrawing aliquots of a third reagent set from a seventh set of wells; and depositing an aliquot of reagent from said third reagent set in each of said second set of wells, the process optionally further comprising the step of adding bromelin to said diluent.

Claim 16

A process for liquid handling to be carried out by a machine which includes a storage means for storing a test tube containing a liquid to be assayed, a tray containing wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus,comprising the steps of: dispensing diluent into a first set of wells using said transfer head; withdrawing an aliquot of liquid from said tube using said transfer head: depositing an aliquot of said liquid in each of a second set of wells using said transfer head; withdrawing an aliquot of said liquid from said tube using said transfer head; depositing an aliquot of said liquid in a third set of wells; withdrawing an aliquot of said liquid from a predetermined level in said tube; depositing an aliquot of said liquid in each of said first set of wells using said transfer head: mixing said liquid and said diluent: withdrawing an aliquot of the diluted liquid from each of said first set of wells: depositing each said aliquot of said diluted liquid into a fourth set of wells: withdrawing aliquots of a first reagent set from a fifth set of wells using said transfer head; depositing an aliquot of a reagent from said first reagent set in each of said fourth set of wells; withdrawing aliquots of a second reagent set from a sixth set of wells using said transfer head; depositing an aliquot of a reagent from said second reagent set in each of said third set of wells; withdrawing aliquots of a third reagent set from a seventh set of wells; and depositing an aliquot of reagent from said third reagent set in each of said second set of wells, the process optionally further comprising the step of adding bromelin to said diluent.

Claim 17

A process for liquid handling to be carried out by a machine which includes a storage means for storing a test tube containing a liquid to be assayed, a tray containing wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus, comprising the steps of: (1) moving liquid from said test tube to a first well using said transfer head; (2) moving liquid from a second well to said first well using said transfer head.

Claim 18

A process for liquid handling to be carried out by a machine which includes a storage means for storing a test tube containing a liquid to be assayed, a tray containing wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus, comprising the steps of: (1) moving liquid from said test tube to a first well using said transfer head; (2) moving liquid from a second well to said first well using said transfer head.

Claim 19

A process as claimed in claim 14, further comprising the steps of having the controller consult the user through a user interface regarding the process parameters desired by the user, reading the responses, and performing the process steps using the user defined process parameters as a guide and preferably for storing the user defined parameters in a memory for future reference, and, when the user defined parameters are stored, further preferably comprising the step of having the controller consult the user regarding which if any other files of user defined parameters stored in said memory for specific processes the steps of which are also stored in memory to execute upon completion of the current file.

Claim 20

A process for liquid handling to be carried out by a machine which includes a storage means for storing a test tube containing a liquid to be assayed, a tray containing a plurality of wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus, comprising the steps of: (1) dispensing diluent into a first plurality of said wells using said transfer head; (2) sensing the liquid level in said test tube; (3) withdrawing an aliquot of liquid out of said tube using said transfer head; (4) depositing an aliquot of said liquid in a second well; (5) withdrawing an aliquot of said liquid from said tube using said transfer head; (6) depositing an aliquot of said liquid into a first well in said first plurality of wells using said transfer head; (7) withdrawing an aliquot of the diluted liquid using said transfer head; and (8) depositing an aliquot of the diluted liquid into a third well using said transfer head. 17. An apparatus for washing wells in a plate of wells comprising: means for dispensing liquid into a well; and means for aspirating liquid out of a well after a delay period of from zero to a predetermined amount of time.

Claim 21

A process for liquid handling to be carried out by a machine which includes a storage means for storing a test tube containing a liquid to be assayed, a tray containing a plurality of wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus, comprising the steps of: (1) dispensing diluent into a first plurality of said wells using said transfer head; (2) sensing the liquid level in said test tube; (3) withdrawing an aliquot of liquid out of said tube using said transfer head; (4) depositing an aliquot of said liquid in a second well; (5) withdrawing an aliquot of said liquid from said tube using said transfer head; (6) depositing an aliquot of said liquid into a first well in said first plurality of wells using said transfer head; (7) withdrawing an aliquot of the diluted liquid using said transfer head; and (8) depositing an aliquot of the diluted liquid into a third well using said transfer head. 17. An apparatus for washing wells in a plate of wells comprising: means for dispensing liquid into a well; and means for aspirating liquid out of a well after a delay period of from zero to a predetermined amount of time.

Claim 22

An apparatus as claimed in claim 17 which further comprises means for interacting with a user to determine which wells to wash and how long to delay between filling and emptying and/or in which said means for dispensing includes a cannula which ejects a stream of wash liquid at an angle to the axis of the well such the wash liquid swirls in said well when dispensed.

Claim 23

A process of washing wells in an automated liquid handling apparatus comprising a tray containing a well, a wash head having an empty cannula supplied by a vacuum through a solenoid operated valve, a wash cannula, a pump for forcing wash liquid through said wash cannula and a controller for controlling said pump and said solenoid operated valve, comprising the steps of: (1) blocking vacuum to said empty cannula using said controller and said solenoid operated valve; (2) pumping wash liquid into said well by activating said pump using said controller; (3) delaying for a time established by said controller to allow said wash liquid to incubate with any matter in said well; (4) opening said solenoid operated valve using said controller to allow vacuum to said empty cannula to empty said well.

Claim 24

A process of washing wells in an automated liquid handling apparatus comprising a tray containing a well, a wash head having an empty cannula supplied by a vacuum through a solenoid operated valve, a wash cannula, a pump for forcing wash liquid through said wash cannula and a controller for controlling said pump and said solenoid operated valve, comprising the steps of: (1) blocking vacuum to said empty cannula using said controller and said solenoid operated valve; (2) pumping wash liquid into said well by activating said pump using said controller; (3) delaying for a time established by said controller to allow said wash liquid to incubate with any matter in said well; (4) opening said solenoid operated valve using said controller to allow vacuum to said empty cannula to empty said well.

Claim 25

A process as claimed in claim 19 which further comprises the steps of: (1) closing the solenoid operated valve using said controller to block vacuum to said empty cannula; (2) pumping an amount of rinse liquid into said well by activating said pump using said controller; and (3) opening said solenoid operated valve using said controller to allow vacuum to said empty cannula to empty said well, and/or in which said apparatus includes an overflow cannula and further comprising the step of supplying vacuum to said overflow cannula.

Claim 28

A process for sensing the total liquid level in a liquid container in an apparatus having a movable transfer head with a pipette and a means for moving said pipette into and out of said liquid container under the control of a controller, said transfer head having a movable plunger and means controlled by said controller coupled to said plunger for moving it so as to change the volume of said pipette and having a pressure transducer means coupled to said pipette and to said controller, comprising the steps of: (1) actuating said means for moving said pipette so as to move said pipette into said liquid container; (2) actuating said means for moving said plunger so as to expel air from said pipette before and simultaneously with the pipette's entry into said liquid; (3) monitoring said pressure transducer to sense a rise of pressure inside said pipette; and preferably (4) signaling said controller when a rise in pressure is detected.

Claim 29

A process for sensing the total liquid level in a liquid container in an apparatus having a movable transfer head with a pipette and a means for moving said pipette into and out of said liquid container under the control of a controller, said transfer head having a movable plunger and means controlled by said controller coupled to said plunger for moving it so as to change the volume of said pipette and having a pressure transducer means coupled to said pipette and to said controller, comprising the steps of: (1) actuating said means for moving said pipette so as to move said pipette into said liquid container; (2) actuating said means for moving said plunger so as to expel air from said pipette before and simultaneously with the pipette's entry into said liquid; (3) monitoring said pressure transducer to sense a rise of pressure inside said pipette; and preferably (4) signaling said controller when a rise in pressure is detected.

Claim 32

A process for mixing liquids in a liquid handling system having a well, a liquid transfer head having a pipette, a means for changing the volume in said pipette and a means for moving said pipette within said well and having a controller for controlling movements by both said means, comprising the steps of: controlling said means for changing volume to increase the volume so as to aspirate liquid from said well; controlling said means for changing volume to decrease the volume in said pipette so as to dispense said aspirated liquid back into said well while controlling the means for moving said pipette to move said pipette from the bottom of said well toward the top of the liquid in said well.

Claim 33

A process for mixing liquids in a liquid handling system having a well, a liquid transfer head having a pipette, a means for changing the volume in said pipette and a means for moving said pipette within said well and having a controller for controlling movements by both said means, comprising the steps of: controlling said means for changing volume to increase the volume so as to aspirate liquid from said well; controlling said means for changing volume to decrease the volume in said pipette so as to dispense said aspirated liquid back into said well while controlling the means for moving said pipette to move said pipette from the bottom of said well toward the top of the liquid in said well.

Claim 36

A process for delivering multiple reagents to a single well without cross contamination in a machine which includes a tray containing wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus,comprising the steps of: (1) drawing an aliquot of a first reagent from a first well using said transfer head pipette; (2) moving said pipette to a second well and lowering the tip of said pipette using said transfer head until said tip is in the well but not in contact with any liquid in said well: (3) shifting said pipette tip relative to the side of said well under control of said controller until said tip is in contact with the side of said well and dispensing an aliquot of said reagent; (4) repeating steps 1 and 2 and 3 above for a second reagent from a third well except including the step of picking up a new pipette tip before aspirating said second reagent and shifting said pipette tip relative to said well under control of said controller such that said tip is in contact with a different portion of the side wall of said well not previously touched.

Claim 37

A process for delivering multiple reagents to a single well without cross contamination in a machine which includes a tray containing wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus,comprising the steps of: (1) drawing an aliquot of a first reagent from a first well using said transfer head pipette; (2) moving said pipette to a second well and lowering the tip of said pipette using said transfer head until said tip is in the well but not in contact with any liquid in said well: (3) shifting said pipette tip relative to the side of said well under control of said controller until said tip is in contact with the side of said well and dispensing an aliquot of said reagent; (4) repeating steps 1 and 2 and 3 above for a second reagent from a third well except including the step of picking up a new pipette tip before aspirating said second reagent and shifting said pipette tip relative to said well under control of said controller such that said tip is in contact with a different portion of the side wall of said well not previously touched.

Claim 40

A process for handling liquids in a machine which includes a storage means for storing a test tube containing a liquid, a tray containing wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus, comprising the steps of: (1) performing a sequence of liquid handling steps defined by data stored in a sequence of memory locations: (2) looking for a linking address to another sequence of liquid handling steps defined by data stored in a sequence of memory locations; (3) vectoring processing by said controller to said starting address; (4) performing the sequence of liquid handling steps defined by the data stored in the sequence of memory locations beginning with said starting address; (5) repeating steps (2)-(4) until no more linking addresses are found; and preferably (6) requesting the user to define process parameters to control some or all of the process steps in each sequence of liquid handling steps defined by data stored in a sequence of memory locations.

Claim 41

A process for handling liquids in a machine which includes a storage means for storing a test tube containing a liquid, a tray containing wells and a liquid transfer head having removable pipette tips for moving liquid between said tubes and said wells and for dispensing liquid into selected wells and a controller for controlling the movements of the elements of said apparatus, comprising the steps of: (1) performing a sequence of liquid handling steps defined by data stored in a sequence of memory locations: (2) looking for a linking address to another sequence of liquid handling steps defined by data stored in a sequence of memory locations; (3) vectoring processing by said controller to said starting address; (4) performing the sequence of liquid handling steps defined by the data stored in the sequence of memory locations beginning with said starting address; (5) repeating steps (2)-(4) until no more linking addresses are found; and preferably (6) requesting the user to define process parameters to control some or all of the process steps in each sequence of liquid handling steps defined by data stored in a sequence of memory locations.

Claim 44

An apparatus as defined in claim 29 wherein said means for placing a plate on the work surface and said means for removing a plate from said work surface include: a conveyor belt for moving plates; slots in a loading and unloading surface of said apparatus which is parallel with and at the same height as said work surface; means for moving predetermined portions of said conveyor belt through said slots so as to project above said surface at predetermined times; and means for controlling the direction of movement of said conveyor belt and the times when said means for moving is activated; and preferably a plurality of partitions above said loading and unloading surface forming at least two storage bins; and latches for supporting said plates in stacks in said storage bins between said partitions.

Claim 45

An assay well plate handling mechanism for a liquid handling apparatus, comprising: a loading and unloading surface; partition means for forming a first and second storage bin for a plurality of said assay well plates; means for loading a plate from said first storage stack upon receipt of a predetermined signal; means for unloading a plate from the work surface of said liquid handling apparatus upon receipt of a predetermined signal and for pushing it onto a storage stack in said second storage bin; means for controlling said means for unloading and loading in accordance with signals from said liquid handling apparatus, said means for loading and unloading preferably including conveyor belt means for moving plates in selected directions and/or elevator means for releasing plates from one of said storage bins and for pushing plates into the other of said storage bins.

Claim 46

An assay well plate handling mechanism for a liquid handling apparatus, comprising: a loading and unloading surface; partition means for forming a first and second storage bin for a plurality of said assay well plates; means for loading a plate from said first storage stack upon receipt of a predetermined signal; means for unloading a plate from the work surface of said liquid handling apparatus upon receipt of a predetermined signal and for pushing it onto a storage stack in said second storage bin; means for controlling said means for unloading and loading in accordance with signals from said liquid handling apparatus, said means for loading and unloading preferably including conveyor belt means for moving plates in selected directions and/or elevator means for releasing plates from one of said storage bins and for pushing plates into the other of said storage bins.

Claim 49

A machine for transferring liquid samples and reagents to the wells of an assay tray,coaprising in combination (a) a fusion head assembly translatable between upper and lower positions along a vertical axis and including a sample transfer pipette assembly mounted on said head for movement therewith and for horizontal translation relative thereto to a plurality of liquid handling positions, said positions including a sample transfer position and a plurality of positions for depositing the sample in assay tray wells, said pipette assembly including a pipette nozzle having a depending end for receiving pipette tips. a plunger disposed within said pipette nozzle and means for moving said plunger within said pipette nozzle to vary the internal volume of said nozzle and a tip supported thereby: (b) a horizontal liquid reagent dispensing manifold mounted on said fusion head and connected to a pump for dispensing liquid through the manifold: (c) means for moving the fusion head assembly to upper and lower positions along its vertical axis and for moving the sample transfer pipette along its horizontal axis: ( d ) a table mounted beneath the fusion head assembly and adapted to carry the assay tray, the table and/or head being shiftable horizontally relative to one another: (e) means for moving the table and/or fusion head horizontally to position the rows of wells in registry first with the pipette tip and thereafter in registry with the liquid dispensing manifold: and ( f ) means for controlling each of the moving means for the fusion head assembly, the table, the plunger means and the dispensing pump means whereby predetermined volumes of liquid materials are added to one or more wells via the pipette tip and liquid reagent is deposited in the wells in a predetermined sequence.

Claim 50

A machine for transferring liquid samples and reagents to the wells of an assay tray,coaprising in combination (a) a fusion head assembly translatable between upper and lower positions along a vertical axis and including a sample transfer pipette assembly mounted on said head for movement therewith and for horizontal translation relative thereto to a plurality of liquid handling positions, said positions including a sample transfer position and a plurality of positions for depositing the sample in assay tray wells, said pipette assembly including a pipette nozzle having a depending end for receiving pipette tips. a plunger disposed within said pipette nozzle and means for moving said plunger within said pipette nozzle to vary the internal volume of said nozzle and a tip supported thereby: (b) a horizontal liquid reagent dispensing manifold mounted on said fusion head and connected to a pump for dispensing liquid through the manifold: (c) means for moving the fusion head assembly to upper and lower positions along its vertical axis and for moving the sample transfer pipette along its horizontal axis: ( d ) a table mounted beneath the fusion head assembly and adapted to carry the assay tray, the table and/or head being shiftable horizontally relative to one another: (e) means for moving the table and/or fusion head horizontally to position the rows of wells in registry first with the pipette tip and thereafter in registry with the liquid dispensing manifold: and ( f ) means for controlling each of the moving means for the fusion head assembly, the table, the plunger means and the dispensing pump means whereby predetermined volumes of liquid materials are added to one or more wells via the pipette tip and liquid reagent is deposited in the wells in a predetermined sequence.