Apparatus and method for combinatorial chemistry synthesis

• US 6,045,755 A
• Filed: 03/10/1997
• Issued: 04/04/2000
• Est. Priority Date: 03/10/1997
• Status: Expired due to Fees

• Current Assignee: Lion Bioscience AG (2invest AG)
• Original Assignee: Trega Biosciences, Inc. (2invest AG)
• Inventors: Pokorny, Vit, Lebl, Michael, Krchnak, Viktor
• Primary Examiner(s): Le, Long V.
• Application Number:
  US08/815,975
• Time in Patent Office: 1,121 Days
• Field of Search: 422/63, 422/65, 422/67, 422/68.1, 422/81, 422/100, 422/101, 422/102, 422/103, 422/104, 422/131, 422/134, 422/135, 436/43, 436/47, 436/48, 436/49, 436/174, 436/179, 436/180
• US Class Current: 506/33
• 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 2219/00283 Reactor vessels with top opening
• CPC Class Codes: B01J 2219/00308 interchangeably mounted in racks or blocks
• CPC Class Codes: B01J 2219/00313 the reactor vessels being formed by arrays of wells in blocks
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00322 the individual reactor vessels being arranged serially in stacks
• CPC Class Codes: B01J 2219/00335 Septa
• CPC Class Codes: B01J 2219/00337 Valves
• CPC Class Codes: B01J 2219/0034 in the shape of a ball or sphere
• CPC Class Codes: B01J 2219/00346 Screw-caps
• CPC Class Codes: B01J 2219/00349 Spheres
• CPC Class Codes: B01J 2219/00364 Pipettes
• CPC Class Codes: B01J 2219/00369 in multiple or parallel arrangements
• CPC Class Codes: B01J 2219/00376 in multiple or parallel arrangements
• CPC Class Codes: B01J 2219/00394 in multiple arrangements
• CPC Class Codes: B01J 2219/00414 using suction
• CPC Class Codes: B01J 2219/00423 using filtration, e.g. through porous frits
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00691 using robots
• CPC Class Codes: B01J 3/03 Pressure vessels, or vacuum vessels, having closure members or seals specially adapted therefor
• CPC Class Codes: B01J 3/04 : Pressure vessels, e.g. autoclaves
• CPC Class Codes: B01L 3/50853 : with covers or lids
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: G01N 2035/0405 : manipulating closing or opening means, e.g. stoppers, screw caps, lids or covers
• 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: Y10T 436/11 : Automated chemical analysis
• CPC Class Codes: Y10T 436/113332 : with conveyance of sample along a test line in a container or rack
• 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

Abstract

In a first embodiment, this invention includes an integrated robot apparatus for performing combinatorial chemistry synthesis protocols and having interchangeable work-stations, robot arm tools, and reaction vessels and reaction vessel arrays. The work-stations and tools are specialized to perform tasks necessary for the synthesis in a plurality of the reaction vessels grouped in a plurality of the reaction vessel arrays. Preferably, these elements function interchangeably because they have standardized sizes and conformation. The work-stations and tools include those for fluid dispensing or aspirating from individual reaction vessels or from all the reaction vessels in an array simultaneously. The reaction vessels can include, alternatively, stackable, ball-sealed reaction vessels, microtitre-like reaction vessel arrays, arrays of independent reaction vessels, valve-sealed reaction vessels, septum-sealed reaction vessels, and syringe reaction vessels. In alternative embodiments, this invention includes these work-stations, tools, reaction vessels and reaction vessel arrays in various combinations or sub-combinations either for use in partially integrated robots or for manual or standalone use.

Claims

1. An integrated apparatus for performing combinatorial-chemistry synthetic reactions comprising:

a. means for containing one or more of a plurality of combinatorial-chemistry synthetic reactions, each said means for containing having an aperture for aspirating a fluid from and for dispensing a fluid into the interior of said containing means;

b. means for sealing said apertures of said containing means;

c. means for dispensing a selected one or more of a plurality fluids into said containing means;

d. means for aspirating fluids from said containing means; and

e. robot arm means for gripping one or more of said containing means and transporting said means for containing between said means for sealing, said means for dispensing, and said means for aspirating,

wherein said means for sealing comprises a plurality of means for sealing, and wherein said robot arm means is further capable of gripping and transporting one of said means for sealing and engaging it with one or a plurality of containing means in order to seal said plurality of containing means,

whereby said integrated apparatus can perform a protocol for said combinatorial-chemistry synthetic reactions.

2. The integrated apparatus of claim 1 further comprising storage means for storing a plurality of storage containers, each said storage container holding one of said plurality of fluids, wherein said robot arms means is further capable of gripping said storage containers, and wherein said storage means stores said containers so that they are accessible for gripping by said robot arm means.

3. The integrated apparatus of claim 1 wherein said means for dispensing comprises means for dispensing selected individual fluids into selected ones of said containing means, and wherein said robot arm means is further capable of gripping and transporting said means for dispensing individual fluids in order to dispense individual fluids into selected single ones of said containing means.

4. The integrated apparatus of claim 1 wherein said robot arm means comprises one or more robot arms each capable of attaching and actuating tools for gripping one or more of said containing means and for gripping said means for dispensing fluids.

5. The integrated apparatus of claim 1 wherein said containing means and said means for sealing further comprise:

a. a plurality of individual fluid containers, each said individual container having a septum with said aperture, said aperture being substantially circular and capable of being sealed by a ball;

b. a plurality of balls for sealing said individual containers;

c. a plurality of holding blocks, each said holding block, capable of holding a plurality of said individual containers in a substantially spatially-regular configuration during the dispensing fluids to or during the aspirating of fluids from the interior of said individual containers; and

d. a plurality of cylinders for retaining a plurality of said individual containers sealed by said balls during a temperature controlled incubation.

6. The integrated apparatus of claim 5 further comprising incubation means for temperature controlled incubation of said cylinders.

7. The integrated apparatus of claim 5 further comprising a plurality of retaining clips, each said retaining clip for engaging a base of each said cylinder for retaining said plurality of individual containers during said incubation.

8. The integrated apparatus of claim 5 further comprising an assembly/disassembly workstation means for moving a plurality of said individual containers and said sealing balls into one or more of said plurality of cylinders from one or more of said holding blocks, and for removing a plurality of said individual containers from one or more of said cylinders into one or more of said holding blocks.

9. The integrated apparatus of claim 8 wherein each of said cylinders further comprises one or more rotatably-mounted clips for retaining said individual containers and said sealing balls during processing by said assembly/disassembly workstation means.

10. The integrated apparatus of claim 1 wherein said containing means further comprises a plurality of reaction vessel arrays, each said reaction vessel array comprising a substantially spatially-regular array of individual containers for individual combinatorial chemistry synthetic reactions.

11. The integrated apparatus of claim 10 wherein said means for sealing said apertures further comprises a plurality of individual means for sealing, each individual means for sealing adapted to seal the apertures of said individual containers of said reaction vessel arrays, each said individual means for sealing comprising:

a. a plate sized to cover said apertures of said individual containers of one of said reaction vessel arrays;

b. one or more clips attached to said plate and engaging with said reaction vessel array to fix said plate to said reaction vessel array; and

c. sealing surface means attached to one surface of said plate for engaging with and for sealing said apertures of said individual containers of said reaction vessel array.

12. The integrated apparatus of claim 11 wherein said sealing surface means further comprises a compressible rubber layer.

13. The integrated apparatus of claim 11 wherein said sealing surface means further comprises an inflatable bag, said inflatable bag being inflatable to engage and seal said apertures.

14. The integrated apparatus of claim 11 wherein said apertures are substantially circular and said sealing surface means further comprises a plurality of balls, each ball being attached to said plate and capable of sealing said substantially circular aperture.

15. The integrated apparatus of claim 14 wherein said balls are attached to said plate in a compliant manner permitting said balls to move laterally in order to engage said substantially circular apertures.

16. The integrated apparatus of claim 10 wherein said reaction vessel arrays comprise individual containers integrally formed in said reaction vessel array.

17. The integrated apparatus of claim 16 wherein said reaction vessel arrays are microtiter plates or ELISA plates.

18. The integrated apparatus of claim 10 wherein said individual containers are separate and independent containers, and wherein said reaction vessel arrays are capable of holding said separate and independent containers in a substantially spatially-regular configuration.

19. The integrated apparatus of claim 18 wherein said sealing means further comprise:

a. a plurality of caps, one of said caps being attached to each independent container and having a valve orifice permitting fluid communication between the interior and the exterior of said independent container;

b. a plurality of valve rods containing a plurality of valve rod orifices, each said rod movably mounted in a certain plurality of said caps and capable of motion between (i) a first position in which said rod occludes said valve orifices of said certain plurality of caps thereby sealing the attached containers, and (ii) a second position in which said valve rod orifices are aligned with said valve orifices of said certain plurality of caps thereby opening the interiors of the attached containers to fluid communication with the exterior; and

c. a linkage segment for fixing a plurality of valve rods for simultaneous motion so that a plurality of independent containers in one of said reaction vessel arrays can be simultaneously sealed or simultaneously opened by causing motion of said linkage segment.

20. The integrated apparatus of claim 18 wherein said sealing means comprise a plurality of septums, one of said septums sealing said aperture of each independent container and made of a material capable of being punctured by a fluid-manipulating needle and of resealing upon withdrawal of said needle.

21. The integrated apparatus of claim 20 wherein said sealing means further comprises:

a. a plurality of compressible collars, each compressible collar having a collapsible central orifice and being disposed adjacent to said septum sealing each independent container; and

b. a plurality of screw caps for exerting pressure on said compressible collars in order to collapse said central orifice and to further seal each said independent container.

22. The integrated apparatus of claim 10 wherein said individual containers comprise syringe bodies, wherein said means for sealing further comprise plungers adapted to fit in and seal said syringe bodies, and wherein said integrated apparatus further comprises a plurality of plunger holders, said plungers sealing said syringes of each said reaction vessel array being fixed to one of said plunger holders.

23. The integrated apparatus of claim 22 wherein said means for aspirating and means for dispensing fluids further comprises a plurality of fluid distribution block means, one such distribution block means being linked to each of said reaction vessel arrays and comprising a plurality of internal fluid passageways establishing fluid communication between the interior of each of said syringe bodies and the exterior of said distribution block.

24. The integrated apparatus of claim 23 wherein said plurality of fluid distribution blocks further comprise a plurality of needles, an exterior opening of each said internal fluid distribution passageway is attached to one of said needles.

25. The integrated apparatus of claim 23 wherein said plurality of fluid distribution blocks further comprise a plurality of septums made of a material capable of being punctured by a fluid-manipulating needle and of resealing upon withdrawal of said needle, and wherein an exterior opening of each said internal fluid distribution passageway is sealed by one of said septums.

26. The integrated apparatus of claim 23 wherein said plurality of fluid distribution blocks further comprise a common internal fluid passageway in fluid communication with all said internal fluid distribution passageways and with a common exterior port.

27. The integrated apparatus of claim 1 wherein said means for containing further comprises a plurality of reaction vessel arrays, each said reaction vessel array comprising a substantially spatially-regular array of individual containers for individual combinatorial-chemistry synthetic reactions, and wherein said fluid dispensing means and said fluid aspirating means further comprise a fluid handling workstation means capable of dispensing or aspirating fluids from all the individual containers in one of said reaction vessel arrays simultaneously.

28. The integrated apparatus of claim 27 wherein said fluid handling workstation means further comprises an array of fluid-manipulating needles so spaced and arranged in order that all the needles of said array of needles can simultaneously access all the individual containers of a reaction vessel array for fluid aspirating or dispensing.