Systems and methods for rapidly identifying useful chemicals in liquid samples

• US 5,985,214 A
• Filed: 05/16/1997
• Issued: 11/16/1999
• Est. Priority Date: 05/16/1997
• Status: Expired due to Term

• Current Assignee: Aurora Biotechnologies, Inc. (Azenta, Inc.)
• Original Assignee: Aurora Biosciences Corporation (Vertex Pharmaceuticals Incorporated)
• Inventors: Beckey, Samuel S., Coassin, Peter J., Stylli, Chari, Shumate, Christopher Bentley
• Primary Examiner(s): Achutamurthy, Ponnathapura
• Assistant Examiner(s): Ricigliano, Joseph W.
• Application Number:
  US08/858,016
• Time in Patent Office: 914 Days
• Field of Search: 435/7.1, 435/287.1, 435/288.3, 435/288.7, 422/50, 422/63, 422/68.1, 422/82.05, 422/65, 422/66, 422/67, 422/100, 364/478.02, 364/468.19
• US Class Current: 422/65
• CPC Class Codes: B01J 19/00 Chemical, physical or physico-chemical processes in general; Their relevant apparatus
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00011 Laboratory-scale plants
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00328 Movement by linear translation
• CPC Class Codes: B01J 2219/00691 using robots
• CPC Class Codes: B01J 2219/00695 Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/007 Simulation or vitual synthesis
• CPC Class Codes: B01J 2219/00702 Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/00707 separated from the reactor apparatus
• CPC Class Codes: B01L 2300/0829 Multi-well plates; Microtitration plates
• CPC Class Codes: B01L 2300/0893 having a very large number of wells, microfabricated wells
• CPC Class Codes: B01L 9/52 Supports specially adapted for flat sample carriers, e.g. for plates, slides, chips
• CPC Class Codes: B01L 9/523 for multisample carriers, e.g. used for microtitration plates
• CPC Class Codes: C40B 60/14 for creating libraries
• CPC Class Codes: G01N 2035/00326 Analysers with modular structure
• CPC Class Codes: G01N 2035/042 moved independently, e.g. by fork manipulator
• CPC Class Codes: G01N 2035/0422 carried on a linear conveyor
• CPC Class Codes: G01N 2035/0425 Stacks, magazines or elevators for plates
• CPC Class Codes: G01N 35/0099 comprising robots or similar manipulators robots per se B25J
• CPC Class Codes: G01N 35/028 : having reaction cells in the form of microtitration plates
• CPC Class Codes: G01N 35/1002 : Reagent dispensers
• CPC Class Codes: G01N 35/1074 : arranged in a two-dimensional array
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis
• CPC Class Codes: Y10T 436/110833 : Utilizing a moving indicator strip or tape
• CPC Class Codes: Y10T 436/113332 : with conveyance of sample along a test line in a container or rack
• CPC Class Codes: Y10T 436/114165 : with step of insertion or removal from test line
• CPC Class Codes: Y10T 436/114998 : with treatment or replacement of aspirator element [e.g., cleaning, etc.]
• CPC Class Codes: Y10T 436/25 : including sample preparation
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

The present invention provides for systems and methods that utilize automated and integratable workstations for identifying chemicals having useful activity. The present invention is also directed to chemical entities and information (e.g., chemical or biological activities of chemicals) generated or discovered by operation of workstations of the present invention. The present invention includes automated workstations that are programmably controlled to minimize processing times at each workstation and that can be integrated to minimize the processing time of the liquid samples from the start to finish of the process.

Claims

1. A device for identifying useful chemicals, comprising:

a) a storage and retrieval module comprising storage locations for storing a plurality of chemicals in solution in addressable chemical wells, a chemical well retriever, and having programmable selection and retrieval of said addressable chemical wells,

b) a sample distribution module comprising a liquid handler to aspirate or dispense solutions from selected said addressable chemical wells, said sample distribution module having programmable selection of, and aspiration from, said selected addressable chemical wells and programmable dispensation into selected addressable sample wells,

c) at least one multi-lane sample transporter to transport said selected addressable chemical wells to said sample distribution module and optionally having programmable control of transport of said selected addressable chemical wells, wherein at least one lane of said multi-lane sample transporter functions to provide bidirectional transport of said selected addressable chemical wells to or from said storaRe and retrieval module,

d) a reaction module comprising either a reagent dispenser to dispense reagents into said selected addressable sample wells or a fluorescent detector to detect chemical reactions in said selected addressable sample wells, and

e) a data processing and integration module;

wherein said storage and retrieval module, said sample distribution module, and said reaction module are integrated and programmably controlled by said data processing and integration module; and

said storage and retrieval module, said sample distribution module, said multi-lane sample transporter, said reaction module and said data processing and integration module are operably linked to facilitate rapid processing of said addressable sample wells.

2. The device of claim 1, wherein said storage and retrieval module has storage locations for at least 200,000 said addressable chemical wells in a plurality of addressable chemical plates, said addressable chemical plates are operably linked to at least one plate buffer that loads and unloads said addressable chemical plates in a predetermnined order that is either dependent or independent of the order of selection of said addressable chemical plates, said chemical well retriever is adapted to retrieve and replace selected said addressable chemical plates and is controlled by a program to reduce retrieval and replacement time of said chemical well retriever during retrieval and replacement.

3. The device of claim 1, wherein an addressable chemical plate of said plurality of addressable chemical plates has a standard footprint and said liquid handler can dispense into arrays of addressable wells with different densities of addressable wells per centimeter squared.

4. The device of claim 3, wherein said addressable chemical plates have a well-to-well distance of about 4 mm or less.

5. The device of claim 1, wherein said storage and retrieval module further comprises storage locations for at least 20,000 addressable sample wells in a plurality of sample plates each having said standard footprint and said chemical well retriever is adapted to store and retrieve selected said addressable sample plates, and said chemical well retriever is adapted to retrieve addressable sample plates of a different height than said addressable chemical plates.

6. The device of claim 2, wherein said storage and retrieval module further comprises an environmental control unit to modulate temperature and humidity of said storage and retrieval module.

7. The device of claim 1, wherein said multi-lane sample transporter is a reduced friction, ortho-multilane conduit that operably connects a plate buffer to said sample distribution module to facilitate transport of said addressable chemical plates or said addressable sample plates.

8. The device of claim 5, wherein said chemical well retriever is adapted to store and retrieve selected of said addressable chemical plates having lids.

9. The device of claim 8, wherein said chemical well retriever has a universal plate handler.

10. The device of claim 1, wherein said liquid handler comprises a plurality of dispensers that can individually dispense a predetermined minimum volume of less than approximately 2,000 nanoliters of liquid aspirated from a predetermined selection of said addressable chemical wells into a predetermined selection of said addressable sample wells.

11. The device of claim 10, wherein said dispensers comprise solenoid valves fluidly connected to a reservoir for liquid aspirated from an addressable chemical well and said solenoid valves control release of hydraulic pressure in said reservoir.

12. The device of claim 10, wherein said dispenser comprises a fluid channel to aspirate liquid from a predetermined selection of said addressable chemical wells.

13. The device of claim 10, wherein said dispenser comprises an electrically sensitive volume displacement unit in fluid communication with a dispensing nozzle.

14. The device of claim 1, wherein said reaction module comprises a detector to detect signals in said addressable sample wells, wherein said detector is optically connected to illuminate selected said addressable sample wells.

15. The device of claim 14, wherein said detector illuminates a predetermined selection of said addressable sample wells and detects fluorescence from said addressable sample wells.

16. The device of claim 14, further comprising a positioner that positions said addressable sample wells to permit interrogation of a predeternined selection of addressable sample wells and said detector is disposed to illuminate without substantial interference from said positioner.

17. The device of claim 16, wherein said positioner can position said addressable sample wells with a minimal ccnter-to-center distance between approximately 0.5 mm to 1.0 mm.

18. The device of claim 1, wherein said data processing and integration module controls the retrieval of selected said addressable chemical wells, aspiration of selected reagents from said addressable chemical wells, transport of said sample wells to said sample distribution module, dispensing into selected sample wells, routing said sample wells to said detector and collecting and storing data output from said detector.

19. The device of claim 1, wherein said data processing and integration module comprises an adaptive processing program to route said addressable sample wells to workstations.

20. The device of claim 1, wherein said storage and retrieval module, said sample distribution module, said multi-lane sample transporter, said reaction module and said data processing and integration module process said addressable samples at a rate of about 100,000 per day and said sample distribution module, said multi-lane sample transporter, and said reaction module are adapted to process miniaturized addressable sample wells having sample volumes of less than about 5 microliters.

21. The device of claim 1, wherein said device can process at least 100,000 addressable sample wells in 24 hours.

22. The device of claim 1, wherein storage and retrieval module can store at least about 1,000,000 addressable chemical wells and said device can process at least 250,000 addressable sample wells in 24 hours.

23. A device for rapidly identifying or processing liquid chemical samples, comprising:

a storage and retrieval module comprising storage locations for storing a plurality of reagents in solution in addressable chemical wells, and having programmable selection and retrieval of said addressable chemical wells and having a storage capacity for said addressable chemical wells,

a sample distribution module comprising a liquid handler to aspirate or dispense solutions from selected said addressable chemical wells, said sample distribution module havin, programmable selection said selected addressable chemical wells,

at least one multi-lane sample transporter to transport of said selected addressable chemical wells to said sample distribution module and optionally having programmable control of transport of said selected addressable chemical wells, wherein said multi-lane sample transporter comprises at least four tracks and at least two tracks of said four tracks transport in one direction,

a reaction module comprising either a reagent dispenser to dispense reagents into said selected addressable sample wells for reaction or a detector to detect chemical reactions in said selected addressable sample wells, and

a data processing and integration module;

wherein said storage and retrieval module, said sample distribution module, and said reaction module are integrated and programmably controlled by said data processing and integration module; and

said storage and retrieval module, said sample distribution module, said multi-lane sample transporter, said reaction module and said data processing and integration module are operably linked to facilitate rapid processing of said addressable sample wells;

further wherein said device can process at least 25,000 addressable sample wells in 24 hours.

24. The device of claim 23, wherein said device can process at least 100,000 addressable sample wells in 24 hours.

25. The device of claim 23, wherein storage and retrieval module can store at least about 1,000,000 addressable chemical wells and said device can process at least 250,000 addressable sample wells in 24 hours.

26. The device of claim 23, wherein further said multi-lane sample transporter comprises a conveyor means.

27. The device of claim 24, wherein said storage and retrieval module has storage locations for at least 200,000 said addressable chemical wells in a plurality of addressable chemical plates, said addressable chemical plates are operably linked to at least one plate buffer that loads and unloads said addressable chemical plates in a predetermined order that is either dependent or independent of the order of selection of said addressable chemical plates.

28. A device for rapidly screening samples containing a molecular target, comprising:

a) a storage and retrieval module comprising a plurality of putative modulator solutions, said plurality disposed of putative modulator solutions in addressable storage modulator plates, and having programmable selection and retrieval of said addressable modulator plates, wherein said storage and retrieval module has storage locations for said addressable modulator plates,

b) a sample distribution module comprising a liquid handler to aspirate or dispense solutions from selected said addressable modulator plates, said sample distribution module having programmable selection of said selected addressable modulator plates,

c) at least one multi-lane transporter for transporting modulators and to parallel transport and facilitate parallel processing of modulator plates said selected addressable modulator plates to said sample distribution module and optionally having programmable control of transport of said selected addressable modulator plates, wherein at least one lane of said multi-lane sample transporter functions to provide bidirectional transport said selected addressable chemical wells to or from said storage and retrieval module,

d) a reagent dispenser to dispense reagents into said addressable sample wells for reaction,

e) a detector to detect activity of a modulator with respect to molecular targets in said addressable sample wells, and

a data processing and integration module;

wherein said storage and retrieval module, said sample distribution module, and said reagent dispenser are integrated and programmably controlled by said data processing and integration module; and

said storage and retrieval module, said sample distrbution module, and said multi-lane transporter are optionally not mechanically linked to said reagent dispenser and said detector by said multi-lane transporter; and

said reagent dispenser, said detector and said data processing and integration module are operably linked to facilitate screening of molecular targets in said addressable sample wells, wherein said detector and said data processing and integration module can process said addressable sample wells at rate of at least 50,000 per day.

29. The device of claim 28, wherein said data processing and integration module comprises an adaptive processing program to route said addressable modulator plates to workstations.

30. The device of claim 29, wherein said multi-lane sample transporter is a reduced friction, ortho-multilane conduit that operably connects a plate buffer to said sample distribution module to facilitate transport of said addressable chemical plates or said addressable sample plates.