Process and apparatus for combinatorial synthesis

• US 20070117099A1
• Filed: 11/18/2005
• Published: 05/24/2007
• Est. Priority Date: 11/18/2005
• Status: Active Grant

• Current Assignee: MEI Technologies, Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: MEI Technologies, Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Luxon, Bruce, Engelhardt, Johnnie, Gorenstein, David
• Granted Patent: US 7,576,037 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• 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 2219/00286 Reactor vessels with top and bottom openings
• CPC Class Codes: B01J 2219/00466 in a slurry
• CPC Class Codes: B01J 2219/00497 Features relating to the solid phase supports
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00576 fluorophore
• CPC Class Codes: B01J 2219/00592 Split-and-pool, mix-and-divide processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00722 Nucleotides
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: C40B 60/14 for creating libraries

Abstract

Apparatus and methods are described for split synthesis combinatorial chemistry that provides candidate libraries where an even distribution of theoretical products is obtainable through even mixing during the pooling step, followed by controlled redistribution of the mixed pooled products from the prior addition step into separate synthesis columns, one for each different specie of subunit to be added.

Claims

1. A reaction assembly for synthesis of oligomers of random sequence subunits on fluidized solid supports comprising:

a plurality of synthesizer columns for containing the fluidized solid supports during addition of a monomer subunit to the oligomer;

a static mixer in fluid communication with each of the synthesizer columns via a plurality of conduits; and

a mixing chamber in fluid communication with the static mixer.

2. The reaction assembly of claim 1, wherein the mixing chamber is configured to resist trapping of the solid supports.

3. The reaction assembly of claim 2, wherein the mixing chamber is devoid of recesses and interior angles of less than approximately 90°

.

4. The reaction assembly of claim 1, wherein the static mixer comprises a chamber intersected by fixed elements that create turbulence in a fluid conveying the solid supports through the chamber.

5. The reaction assembly of claim 4, wherein the fixed elements comprise one or more bars intersecting the chamber.

6. The reaction assembly of claim 4, wherein the fixed elements comprise one or more helical elements arranged longitudinally in the chamber.

7. The reaction assembly of claim 1, wherein the plurality of conduits is of approximately equal dimension that provides for an equal fluid path between each synthesizer chamber and the static mixer.

8. A synthesizer for combinatorial chemistry comprising:

a plurality of synthesizer columns adapted to retain solid reaction supports within the columns during a series of reaction steps, each column comprising a reagent fluid path controlled by inlet and outlet reagent valves disposed on essentially opposing ends of each column, and a mixing fluid path controlled by first and second mixing valves disposed on essentially opposite ends of each column, wherein the mixing fluid path is able to transport a stream of fluidized solid supports into the synthesizer columns for the series of reaction steps as well as out of the synthesizer columns and into a common mixing chamber between reaction steps.

9. The synthesizer of claim 8, further comprising a programmable interface for controlling a sequence of valve and fluid path movement.

10. The synthesizer of claim 8, further comprising a static mixer disposed in fluid communication and in-line between the first mixing valve and the common mixing chamber.

11. The synthesizer of claim 8, wherein a motive force for the mixing fluid path is provided by pressure controllable fluid reservoirs disposed at essentially opposite ends of the mixing fluid path.

12. The synthesizer of claim 11, wherein the mixing fluid path is configured to provide an essentially equal fluid volume and pressure to and from each column and the common mixing chamber.

13. The synthesizer of claim 8, wherein the solid reaction supports are fluidized and are retained in each column during reaction steps by at least one fritted aperture.

14. The synthesizer of claim 8, wherein reagent valves and the mixing valves are solenoid valves.

15. The synthesizer of claim 8, further comprising at least one splitter box disposed in the mixing fluid path between the columns and at least one of the pressure controllable fluid reservoirs.

16. The synthesizer of claim 15, wherein splitter boxes are disposed in the mixing fluid path between the columns and both of the pressure controllable fluid reservoirs.

17. The synthesizer of claim 8, wherein the mixing chamber is configured to resist trapping of the fluidized solid supports.

18. The synthesizer of claim 17, wherein the mixing chamber is devoid of recesses and interior angles of less than approximately 90°

.

19. The synthesizer of claim 8, wherein the static mixer comprises a conduit intersected by fixed elements that create turbulence in a fluid conveying the solid supports through the conduit.

20-36. -36. (canceled)