Substrate preparation process

Abstract

The present invention provides novel processes for the large scale preparation of arrays of polymer sequences wherein each array includes a plurality of different, positionally distinct polymer sequences having known monomer sequences. The methods of the invention combine high throughput process steps with high resolution photolithographic techniques in the manufacture of polymer arrays.

1 . A method of forming an array of polymers on a surface of a substrate, comprising: 
 providing a substrate having a first surface coated with functional groups protected with a photolabile protecting group, and a second surface having a layer disposed thereon, said layer including one or more of an index matching compound, a light absorbing compound and an antireflective compound; and    sequentially activating and coupling monomers in different selected regions of said substrate to form a plurality of different polymer sequences in different known locations on said surface of said substrate, wherein said activating step comprises directing an activation radiation at said first surface of said substrate.    
     
     
         2 - 49 . (canceled)  
     
     
         50 . A method for synthesizing an array of chemical compounds on the surface of a support wherein said synthesis comprises a plurality of steps, said method comprising performing at least two of said steps by: (a) placing a support having a functionalized surface into a chamber of a flow cell and subjecting said surface to one step of said synthesis and (b) placing said support into a chamber of another flow cell and subjecting said surface to another step of said synthesis.  
     
     
         51 . A method according to  claim 50  further comprising placing said support after step (b) of said synthesis into a chamber of another flow cell and subjecting said surface to another step of said synthesis.  
     
     
         52 . A method according to  claim 50  wherein said synthesis comprises “n” number of steps and said method comprises independently placing a support into a chamber of one of “n” number of flow cells and subjecting said surface to a different step of said synthesis in each of said flow cells.  
     
     
         53 . A method according to  claim 50  wherein reagents for step (a) of said synthesis are in separate fluid communication with said flow cell of step (a) and reagents for step (b) of said synthesis are in separate fluid communication with said flow cell of step (b).  
     
     
         54 . A method according to  claim 50  wherein at least one of said steps of said synthesis comprises contacting said surface with a fluid reagent and washing said surface.  
     
     
         55 . A method according to  claim 50  wherein said chemical compounds are polymers.  
     
     
         56 . A method according to  claim 55  wherein said polymers are biopolymers.  
     
     
         57 . A method according to  claim 50  wherein said flow cells comprise a holder for said support.  
     
     
         58 . A method according to  claim 50  wherein said flow cells comprise at least one inlet and an outlet.  
     
     
         59 . A method according to  claim 58  wherein a condition of fluid exiting said outlet is determined and based on said determination at least a portion of said fluid is directed to said inlet or to a waste container for said fluid.  
     
     
         60 . A method according to  claim 58  wherein fluid exiting said outlet is subjected to purification and a condition of said fluid is determined and based on said determination at least a portion of said fluid is directed to said inlet or to a waste container for said fluid.  
     
     
         61 . A method according to  claim 58  wherein a wash solution and a reagent for said synthesis are independently directed to said inlet.  
     
     
         62 . A method for synthesizing an array of biopolymers on the surface of a support wherein said synthesis comprises a plurality of monomer additions, said method comprising after each of said monomer additions (a) placing said support into a chamber of a flow cell and subjecting said surface to a step of said synthesis that is subsequent to a monomer addition and (b) placing said support into a chamber of another flow cell and subjecting said surface to another step of said synthesis that is subsequent to step (a).  
     
     
         63 . A method according to  claim 62  wherein each of said steps comprises a wash.  
     
     
         64 . A method according to  claim 62  wherein said biopolymers are polynucleotides.  
     
     
         65 . A method according to  claim 62  wherein step (a) comprises subjecting said surface to an oxidizing agent.  
     
     
         66 . A method according to  claim 62  wherein step (b) comprises subjecting said surface to an agent for removing a protecting group.  
     
     
         67 . A method according to  claim 62  wherein said flow cells comprise at least one inlet and an outlet and a holder for said support.  
     
     
         68 . A method according to  claim 62  wherein a condition of fluid exiting said flow cell is determined and based on said determination at least a portion of said fluid is directed to said flow cell or to a waste container for said fluid.  
     
     
         69 . A method according to  claim 67  wherein fluid exiting said flow cell is subjected to purification and a condition of said fluid is determined and based on said determination at least a portion of said fluid is directed to said flow cell or to a waste container for said fluid.  
     
     
         70 . A method according to  claim 67  wherein a wash solution and a reagent for said synthesis are independently directed to said inlet.  
     
     
         71 . A method according to  claim 67  wherein said fluid is an organic solvent.  
     
     
         72 . A method according to  claim 62  wherein said biopolymers are peptides.  
     
     
         73 . 24. A method according to  claim 62  wherein said biopolymers are synthesized on said surface in multiple arrays and said support is subsequently diced into individual arrays of biopolymers on a support.  
     
     
         74 . A method according to  claim 62  wherein reagents for said first step of said synthesis are in separate fluid communication with said first flow cell and reagents for said second step of said synthesis are in separate fluid communication with said second flow cell.  
     
     
         75 . A method according to  claim 62  further comprising exposing the array to a sample and reading the array.  
     
     
         76 . A method according to  claim 75  comprising forwarding data representing a result obtained from a reading of the array.  
     
     
         77 . A method according to  claim 76  wherein the data is transmitted to a remote location.  
     
     
         78 . A method according to  claim 75  comprising receiving data representing a result of an interrogation obtained by the reading of the array.  
     
     
         79 . An apparatus for synthesizing an array of biopolymers on the surface of a support, said apparatus comprising: (a) a plurality of flow cells, (b) one or more fluid dispensing stations in fluid communication with one or more of said plurality of flow cells, (c) a station for monomer addition to said surface of said support, and (d) a mechanism for moving a support to and from said station for monomer addition and a flow cell and from one flow cell to another flow cell.  
     
     
         80 . An apparatus according to  claim 79  further comprising a controller for controlling the movement of said mechanism.  
     
     
         81 . An apparatus according to  claim 79  wherein said mechanism is a robotic arm.  
     
     
         82 . An apparatus according to  claim 79  wherein said flow cells comprise a chamber, a holder for said support, at least one inlet and an outlet.  
     
     
         83 . An apparatus according to  claim 82  wherein said apparatus further comprises a manifold in fluid communication with said inlet.  
     
     
         84 . An apparatus according to  claim 79  wherein said apparatus further comprises a purification system in fluid communication with said outlet.  
     
     
         85 . An apparatus according to  claim 79  wherein said apparatus further comprises a holding chamber in fluid communication with said purification system.  
     
     
         86 . An apparatus according to  claim 85  wherein said apparatus further comprises a sensor in fluid communication with holding chamber.  
     
     
         87 . An apparatus according to  claim 79  wherein said apparatus further comprises a sensor in fluid communication with said outlet.  
     
     
         88 . An apparatus according to  claim 79  wherein reagents for a step of said synthesis are in separate fluid dispensing stations in fluid communication with one of said flow cells and reagents for another step of said synthesis are in separate fluid dispensing stations in fluid communication with another of said flow cells.  
     
     
         89 . A method comprising using an array, prepared by an apparatus according to  claim 79 , by exposing the array to a sample and reading the array.  
     
     
         90 . A method according to  claim 89  comprising forwarding data representing a result obtained from a reading of the array.  
     
     
         91 . A method according to  claim 90  wherein the data is transmitted to a remote location.  
     
     
         92 . A method according to  claim 89  comprising receiving data representing a result of an interrogation obtained by the reading of the array.  
     
     
         93 . An apparatus for synthesizing an array of biopolymers on the surface of a support, said apparatus comprising: (a) a plurality of flow cells wherein said flow cells comprise a chamber, a holder for said support, at least one inlet and an outlet, wherein each of said inlets is in fluid communication with a manifold and wherein said outlet is in controlled fluid communication with one or more purification systems, holding chambers and sensors, (b) one or more fluid dispensing stations in fluid communication with one or more of said plurality of flow cells by means of said manifolds, (c) a station for monomer addition to said surface of said support, (d) a mechanism for moving a support to and from said station for monomer addition and a flow cell and from one flow cell to another flow cell, and (e) a controller for controlling the movement of said mechanism.  
     
     
         94 . An apparatus according to  claim 93  wherein said mechanism is a robotic arm.  
     
     
         95 . An apparatus according to  claim 93  wherein said apparatus further comprises a purification system in fluid communication with said outlet.  
     
     
         96 . An apparatus according to  claim 93  wherein said apparatus further comprises a holding chamber in fluid communication with said purification system.  
     
     
         97 . An apparatus according to  claim 96  wherein said apparatus further comprises a sensor in fluid communication with holding chamber.  
     
     
         98 . An apparatus according to  claim 93  wherein said apparatus further comprises a sensor in fluid communication with said outlet.