Chemical synthesis apparatus employing a droplet generator

• US 20010028866A1
• Filed: 05/23/2001
• Published: 10/11/2001
• Est. Priority Date: 09/21/1994
• Status: Abandoned Application

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Wyatt, Jacqueline R., Acevedo, Oscar, Ecker, David J., Hebert, Normand, Kiely, John S., Davis, Peter W.
• Application Number:
  US09/863,158
• Publication Number:
  US 20010028866A1
• Time in Patent Office: Days
• US Class Current: 422/131
• 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 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00333 Closures attached to the reactor vessels
• CPC Class Codes: B01J 2219/00351 Means for dispensing and evacuation of reagents
• CPC Class Codes: B01J 2219/00378 Piezoelectric or ink jet dispensers
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00617 by chemical means
• CPC Class Codes: B01J 2219/00621 by physical means, e.g. trenches, raised areas
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/0063 Other, e.g. van der Waals forces, hydrogen bonding
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00641 the porous medium being continuous, e.g. porous oxide substrates
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/0072 Organic compounds
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01J 2219/00729 : Peptide nucleic acids [PNA]
• CPC Class Codes: B01L 3/0268 : using pulse dispensing or spraying, eg. inkjet type, piezo actuated ejection of droplets from capillaries
• CPC Class Codes: C07B 2200/11 : Compounds covalently bound to a solid support
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07K 1/047 : Simultaneous synthesis of different peptide species; Peptide libraries
• CPC Class Codes: C12P 19/34 : Polynucleotides, e.g. nucleic acids, oligoribonucleotides
• CPC Class Codes: C40B 40/06 : Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 40/10 : Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries

Abstract

Chemical reaction apparatus, materials and methods are provided for the automatable, efficient synthesis of chemical species and libraries. In accordance with preferred embodiments, chemical droplet generation and direction techniques are employed to prepare oligomers and libraries of chemical species. Reaction assemblies adapted for efficient synthetic employment and for improved collection are also disclosed.

Claims

1. A chemical reaction apparatus comprising

a. a reaction support having a plurality of reaction sites upon a first surface thereof;

b. a first droplet generator for jetting first reactant droplets upon the first surface;

c. a second droplet generator for jetting second reactant droplets upon the first surface; and

d. control means for causing the droplets from each of the droplet generators, to impact upon preselected sets of said reaction sites.

2. The apparatus of

claim 1

wherein said reaction support is porous.

3. The apparatus of

claim 2

wherein the porous support comprises controlled pore glass.

4. The apparatus of

claim 2

wherein the porous support comprises a porated solid.

5. The apparatus of

claim 2

wherein the porous support comprises fibers having a substantially common axis normal to the first surface.

6. The apparatus of

claim 2

wherein the porous support is an anisotropic membrane.

7. The apparatus of

claim 1

wherein the support comprises a second surface substantially parallel with the first surface, the support being capable of transporting fluid contacting the first surface to the second surface of the support in a direction substantially normal to the first surface.

8. The apparatus of

claim 7

further comprising a collection plate adjacent to the second surface.

9. The apparatus of

claim 8

, wherein said collection plate has a plurality of wells for receiving fluid transported through said support.

10. The apparatus of

claim 1

further comprising additional droplet generators for jetting chemical reactant upon said first surface.

11. The apparatus of

claim 1

wherein said control means is a digital computer.

12. The apparatus of

claim 1

wherein at least one droplet generator is adapted for traversing over the first surface of the reaction support.

15. The apparatus of

claim 1

wherein said reaction support is porous.

16. The apparatus of

claim 15

wherein the porous support comprises controlled pore glass.

17. The apparatus of

claim 15

wherein the porous support comprises a porated solid.

18. The apparatus of

claim 15

wherein the porous support comprises fibers having a substantially common axis normal to the first surface.

19. The apparatus of

claim 15

wherein the porous support is an anisotropic membrane.

25. The apparatus of

claim 1

wherein the droplet generator is adapted for traversing over the first surface of the reaction support.

13. A chemical reaction apparatus comprising

a. a reaction support having a plurality of preselected reaction sites upon a first surface thereof;

b. a droplet generator for jetting droplets of chemical reactant upon the first surface;

c. a plurality of reactant reservoirs in fluid communication with said droplet generator;

d. control means for causing chemical reactants from selected ones of said plurality of reactant reservoirs to be jetted by said droplet generator upon preselected sets of said reaction sites.

14. The apparatus of

claim 13

further comprising valve means for directing chemical reactants from said reactant reservoirs to the droplet generator in response to control signals from said control means.

20. The apparatus of

claim 13

wherein the support comprises a second surface substantially parallel with the first surface, the support being capable of transporting fluid contacting the first surface to the second surface of the support in a direction substantially normal to the first surface.

21. The apparatus of

claim 20

further comprising a collection plate adjacent to the second surface.

22. The apparatus of

claim 21

wherein said collection plate has a plurality of wells for receiving fluid transported through said support.

23. The apparatus of

claim 13

further comprising additional droplet generators for jetting chemical reactant upon said first surface.

24. The apparatus of

claim 13

wherein said control means is a digital computer.

26. A method for synthesizing a chemical species comprising

a. identifying a plurality of reaction sites upon a first surface of a reaction support;

b. jetting upon a first set of said reaction sites, drops of fluid comprising a first chemical reactant species; and

c. jetting upon a second set of said reaction sites, drops of fluid comprising a second chemical reactant species.

27. The method of

claim 26

wherein said reaction support is porous.

28. The method of

claim 27

wherein the porous support comprises controlled pore glass.

29. The method of

claim 27

wherein the porous support comprises a porated solid.

30. The method of

claim 27

wherein the porous support comprises fibers having a substantially common axis normal to the first surface.

31. The method of

claim 27

wherein the porous support is an anisotropic membrane.

32. The method of

claim 26

wherein the support comprises a second surface substantially parallel with the first surface, the support being capable of transporting fluid contacting the first surface to the second surface of the support in a direction substantially normal to the first surface.

33. The method of

claim 26

further comprising collecting fluid from the first surface on a collection plate adjacent to the second surface.

34. The method of

claim 33

, wherein said collection plate has a plurality of wells for receiving said fluid.

35. The method of

claim 26

under control of a digital control means.

36. The method of

claim 26

wherein said first and second sets are substantial identical.

37. The method of

claim 26

wherein said synthesis is of an oligonucleotide.

38. A method for synthesizing a chemical species comprising

a. bonding an initial reaction fragment to a first surface of a reaction support, said first surface having a plurality of preselected reaction sites;

b. jetting upon a first set of said reaction sites a first chemical reactant species to effect a chemical reaction with the initial reaction fragment at the first set of reaction sites; and

c. jetting upon a second set of said reaction sites a second chemical reactant species to effect a chemical reaction with either

i. the initial reaction fragment at sites not in common with said first set of reaction sites, or

ii. the reaction product of the initial reaction fragment and the first chemical reactant at those sites which are in common with said first set of reaction sites.

39. The method of

claim 38

further comprising

d. jetting upon a further set of said reaction sites a further chemical reactant species, which may be the same as or different from any prior chemical reactant species, to effect a chemical reaction with either

i. the initial reaction fragment at sites not in common with any prior set of reaction sites, or

ii. the reaction product of the initial reaction fragment and the additional chemical reactants delivered to sites of said further set.

40. The method of

claim 39

performed iteratively.

41. The method of

claim 38

further comprising recovering the chemical synthesized.

42. The method of

claim 38

wherein said synthesis is of oligonucleotide.

43. A chemical reaction assembly comprising a reaction support having first and second surfaces and being capable of transporting fluid contacting the first surface to the second surface of the support in a direction substantially normal to the first surface, and a collection plate adjacent to the second surface having a plurality of wells for receiving fluid transported through said support.

44. A chemical reaction apparatus comprising

a. a shaped body having first and second surfaces;

b. said body having an array of reaction wells therein in fluid communication with each of said first and second surfaces; and

c. porous reaction support in said reaction wells.

45. The apparatus of

claim 44

further comprising

d. a collection plate adjacent the second surface of the shaped body, said collection plate having a plurality of collection wells in an cooperative array with the array of said reaction wells.

46. The apparatus of

claim 44

wherein said reaction support has a plurality of reaction sites defined thereupon.

47. The apparatus of

claim 44

wherein the reaction support is porous.

48. The apparatus of

claim 44

wherein the porous support comprises controlled pore glass.

49. The apparatus of

claim 44

wherein the porous support comprises a porated solid.

50. The apparatus of

claim 44

wherein the porous support comprises fibers having a substantially common axis normal to the first surface.

51. The apparatus of

claim 44

wherein the porous support is an anisotropic membrane.

52. A method for chemical synthesis comprising

a. providing a reaction support having first and second surfaces;

b. transporting to selected sites on the first surface of said reaction support a plurality of chemical reagents, the chemical nature, amount and sequence of which is predetermined and under the control of a control means to effect synthesis of a chemical species;

c. transporting said chemical species through the reaction support to the second surface thereof;

d. providing a collection plate having a plurality of collection wells adjacent to said second surface such that the chemical species is recovered in a well or wells.

53. The method of

claim 52

further comprising challenging said chemical species in an assay.