Apparatus and method for synthesizing combinational libraries

• US 6,541,211 B1
• Filed: 11/24/1999
• Issued: 04/01/2003
• Est. Priority Date: 05/20/1998
• Status: Expired due to Term

• Current Assignee: Aventisub LLC (Sanofi )
• Original Assignee: Selectide Corp. (Sanofi )
• Inventors: Flynn, Gary A., Pavel, Safar, Wegrzyniak, Eric, Baum, Stephen A., Patek, Marcel, Smrcina, Martin, Strop, Peter
• Primary Examiner(s): Ponnaluri, Padmashri
• Assistant Examiner(s): FRIEND, TOMAS H F
• Application Number:
  US09/449,222
• Time in Patent Office: 1,224 Days
• Field of Search: 436/518, 436/155, 436/161, 436/173, 436/174, 436/178, 435/7.1, 435/DIG.46, 435/DIG.49, 435/DIG.43
• US Class Current: 506/30
• 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 2219/0031 the racks or blocks being mounted in stacked arrangements
• 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 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00319 the blocks being mounted in stacked arrangements
• CPC Class Codes: B01J 2219/00322 the individual reactor vessels being arranged serially in stacks
• CPC Class Codes: B01J 2219/00328 Movement by linear translation
• CPC Class Codes: B01J 2219/00459 Beads
• CPC Class Codes: B01J 2219/00461 Beads and reaction vessel together
• CPC Class Codes: B01J 2219/00468 by manipulation of individual beads
• CPC Class Codes: B01J 2219/00472 Replaceable crowns
• CPC Class Codes: B01J 2219/00475 Sheets
• CPC Class Codes: B01J 2219/00497 Features relating to the solid phase supports
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00502 Particles of irregular geometry
• CPC Class Codes: B01J 2219/00522 in a multiple parallel arrangement
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00565 Electromagnetic means
• CPC Class Codes: B01J 2219/00585 : Parallel processes
• CPC Class Codes: B01J 2219/0059 : Sequential processes
• 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 2219/00659 : Two-dimensional arrays
• CPC Class Codes: B01J 2219/00664 : Three-dimensional arrays
• CPC Class Codes: B01J 2219/00668 : Two-dimensional arrays within three-dimensional arrays
• CPC Class Codes: B01J 2219/00675 : In-situ synthesis on the substrate
• CPC Class Codes: B01J 2219/00689 : using computers
• 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: B01L 2300/0819 : Microarrays; Biochips
• CPC Class Codes: B01L 2300/0829 : Multi-well plates; Microtitration plates
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• 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 50/14 : Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: C40B 70/00 : Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
• CPC Class Codes: G01N 33/543 : with an insoluble carrier for immobilising immunochemicals
• CPC Class Codes: Y10T 436/24 : Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry
• CPC Class Codes: Y10T 436/25 : including sample preparation
• CPC Class Codes: Y10T 436/255 : including use of a solid sorbent, semipermeable membrane, or liquid extraction

Abstract

An apparatus and method for synthesizing a combinatorial library comprising a plurality of chemical compounds such that the chemical composition of each compound is easily tracked. The library compounds are synthesized on solid-phase supports, which are spatially arranged in frames during synthesis according to a predetermined protocol, such that each solid-phase support passes through a series of unique spatial 2D or 3D addresses by which the chemical composition of each compound may be determined at any point during synthesis. Solid-phase supports include hollow tubular-shaped lanterns and gears.

Claims

1. A method of synthesizing combinatorial libraries comprising:

providing Q numbers of 2-D frames, each an array of N rows by M columns of holes with supports inserted therein, wherein the supports in each hole of a column have attached the same building block diverse from the building blocks attached to the supports in the holes of the other columns;

immersing said 1 to Q 2-D frames into respective 1 to Q reactors, each having different reagents, thereby allowing each support building block to react with a respective reagent;

separating each 2-D frame into N subframes, each consisting of an individual 1 by M row of said 2-D frame;

regrouping one subframe from the same row of each original 2-D frame to form N numbers of 2-D frames, each an array of Q rows by M columns of holes with supports inserted therein; and

immersing the 1 to N 2-D frames into a respective set of 1 to N reactors, each containing a different reagent.

2. The method of claim 1 wherein said 2-D frames are breakable into individual rows, and said separating step comprises physically breaking said breakable 2-D frame into said N subframes consisting of individual 1 by M rows.

3. The method of claim 1, further comprising:

transferring the solid supports from a 1 to N 2-D frame to a plate comprising a corresponding 2-D Q by M array of wells in rows and columns, so that the spatial addresses of the supports are retained.

4. The method as in claim 1, wherein the solid supports are lanterns.

5. The method as in claim 4, wherein the lanterns are made of polypropylene with a surface of polystyrene and having a tubular structure with an outer diameter of from about 4.0 mm to about 6.0 mm and an inner bore diameter of from about 2.0 mm to about 3.0 mm.

6. The method of claim 5, wherein the outer diameter of each lantern is about 5.0 mm, and the inner bore diameter is about 2.5 mm.

7. The method as in claim 1, wherein the solid supports are gears, having a tubular structure with a plurality of outwardly projecting fins.

8. The method of claim 7, wherein the gear is made of polypropylene with a surface of polystyrene and having an outer diameter of from about 4.0 mm to about 6.0 mm.

9. The method of claim 8, wherein the outer diameter of each gear is about 5.0 mm.

10. The method as in claim 1, wherein the solid supports are rings, having an inner borehole and an outer diameter.

11. The method of claim 10, wherein the rings are made of polypropylene with a surface of polystyrene, with an outer diameter of from about 7.8 mm, an inner bore diameter of about 6.9 mm, and a height of about 3.1 mm.

12. The method of claim 1, further comprising a radio frequency identification (RFID) chip attached to a frame or subframe.