# US 5,609,826 A · Methods and apparatus for the generation of chemical libraries > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,609,826 A - Document ID: US5609826A - Status: Granted - Kind: A - Application number: 08/422,869 - Filed: 1995-04-17 - Granted: 1997-03-11 - Earliest claimed: 1995-04-17 - Assignees: Ontogen Corporation - Inventors: John Cargill; Romaine R. Maiefski - Web page: https://patentgrep.com/patent/US5609826A ## CPC - 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 - 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)} - C07K 1/045: {using devices to improve synthesis, e.g. reactors, special vessels} - B01J 2219/00286: Reactor vessels with top and bottom openings - B01J 2219/00308: interchangeably mounted in racks or blocks - B01J 2219/0031: the racks or blocks being mounted in stacked arrangements - B01J 2219/00315: Microtiter plates - B01J 2219/00335: Septa - B01J 2219/00373: Hollow needles - B01J 2219/00416: Vacuum - B01J 2219/00418: using pressure - B01J 2219/00423: using filtration, e.g. through porous frits - B01J 2219/00454: by chemical cleavage from the solid support - B01J 2219/00484: by shaking, vibrating or oscillating of the reaction vessels - B01J 2219/00495: Means for heating or cooling the reaction vessels - B01J 2219/00497: Features relating to the solid phase supports - B01J 2219/005: Beads - B01J 2219/00542: Alphanumeric characters - B01J 2219/00545: Colours - B01J 2219/00547: Bar codes - B01J 2219/00549: 2-dimensional - B01J 2219/00585: Parallel processes - B01J 2219/0059: Sequential processes - B01J 2219/00596: Solid-phase processes - B01J 2219/00686: Automatic - 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 - C40B 60/14: for creating libraries - C40B 70/00: Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes - G01N 35/028: {having reaction cells in the form of microtitration plates} - C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13) - B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - C40B: COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES (in silico combinatorial libraries of nucleic acids, proteins or peptides G16B35/00; in silico combinatorial chemistry G16C20/60) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## Abstract Methods and apparatus for the generation of chemical libraries are described. The preferred embodiments include a reaction block which uses replaceable reaction chambers supported in the block. Each reaction block is fitted with four sets of 12 reaction chambers, and has fittings that facilitate robotic manipulation. The reaction chambers are preferably fitted with a frit. An s-shaped trap tube snaps into a fitting on the bottom of each reaction chamber. The trap tube runs into a drain tube. The reaction block is fitted with gas (preferably N.sub.2) lines and a septum seal such that gas pressurization empties the reaction chambers into the drain tubes. The drain tubes are arranged so as to mate directly with a standard 96 well microtiter plate for the collection of material. A docking station provides for secure registration of the reaction blocks, and provides for introduction of gases and liquids into the reaction blocks. An inert atmosphere in the reaction block is maintained by a top and (optional) bottom seal. A synthesis support may be introduced into each reaction chamber as a slurry, and the top septum fastened. A needle pipettes reagents from an array of reagent containers into the reaction chambers, and maintains the inert atmosphere. A locking reagent container rack keeps the containers securely in place. ## Claims ### Claim 1 A reaction block comprising: a plurality of reaction chambers; a first side wall and a second side wall, the first and second side walls having a first width and a first height; a first end wall and a second end wall, the first and second end walls having a second width narrower than the first width, and the first height; a first top surface bordered by the first and second side walls and the first and second end walls, the first top surface having: a plurality of generally circular openings for removably receiving the reaction chambers, the reaction chambers each having a circular opening and a second top surface; a gas port; and a plurality of raised beads defining the edges of a plurality of chambers; the raised beads having a third top surface which is in approximately the same plane as the second top surface of the reaction chambers; a flexible septum which seals against the second and third respective top surfaces of the reaction chambers and the raised beads; and a retainer plate which covers the septum. ### Claim 2 (depends on 1) A reaction block as in claim 1 wherein the retainer plate has a plurality of openings which spatially correspond to the openings of the reaction chambers. ### Claim 3 (depends on 2) A reaction block as in claim 2 wherein the retainer plate is held securely against the septum and the reaction block with a plurality of fasteners. ### Claim 4 (depends on 1) A reaction block as in claim 1 wherein the first top surface includes a first, a second, a third, and a fourth, separately controllable gas outlet ports, and wherein the raised beads define a first, a second, a third, and a fourth pressurization chambers. chambers. ### Claim 5 (depends on 4) A reaction block as in claim 4 wherein each pressurization chamber includes an equal number of the reaction chambers. ### Claim 6 (depends on 4) A reaction block as in claim 4 wherein each pressurization chamber includes 12 reaction chambers. ### Claim 7 (depends on 4) A reaction block as in claim 4 wherein the first, second, third, and fourth separately controllable gas outlet ports are in communication with the first, second, third, and fourth pressurization chambers, respectively. ### Claim 8 (depends on 5) A reaction block as in claim 5 wherein each of the pressurization chambers includes a waste basin which is recessed below the level of the second top surfaces of the reaction chambers. ### Claim 9 (depends on 8) A reaction block as in claim 8 wherein each of the four pressurization chambers has 12 of the reaction chambers. ### Claim 10 (depends on 1) A reaction block as in claim 1 wherein each of the generally circular openings on the first top surface have a keying notch, and wherein each of the reaction chambers have a keying protrusion. ### Claim 11 (depends on 1) A reaction block as in claim 1 wherein the block is made of aluminum. ### Claim 12 (depends on 11) A reaction block as in claim 11 wherein the block is made of 6061 aluminum. ### Claim 13 (depends on 11) A reaction block as in claim 11 wherein the aluminum has been anodized. ### Claim 14 (depends on 1) A reaction block as in claim 1 wherein the block is color coded. ### Claim 15 (depends on 1) A reaction block as in claim 1 wherein the block has an identification number. ### Claim 16 (depends on 1) A reaction block as in claim 1 wherein the septum is made from thermoplastic rubber. ### Claim 17 (depends on 16) A reaction block as in claim 16 wherein the septum is die cut with six registration holes and four access holes. ### Claim 18 (depends on 1) A reaction block as in claim 1 wherein the first and second side walls are fitted with one pin each to facilitate securing the block to a work station. ### Claim 19 (depends on 1) A reaction block as in claim 1 wherein the first and second end walls are fitted with two pins each to facilitate handling by a robotic gripper. ### Claim 20 (depends on 7) A reaction block as in claim 7 further including a bottom surface defined by the bottom edges of the first and second side walls and the first and second end walls, the bottom surface being parallel to the first top surface. ### Claim 21 (depends on 20) A reaction block as in claim 20 further including a first, second, third and fourth gas inlet ports in communication with the first, second, third, and fourth gas outlet ports of the first top surface, respectively. ### Claim 22 (depends on 21) A reaction block as in claim 21 wherein the first, second, third and fourth gas inlet ports are in the bottom surface. ### Claim 23 (depends on 22) A reaction block as in claim 22 further including an input port for receiving heating or cooling fluid. ### Claim 24 (depends on 23) A reaction block as in claim 23 wherein the input port for receiving heating or cooling fluid is in the bottom surface. ### Claim 25 (depends on 23) A reaction block as in claim 23 further including an output port for draining heating or cooling fluid. ### Claim 26 (depends on 25) A reaction block as in claim 25 wherein the output port for draining heating or cooling fluid is on the bottom surface. ### Claim 27 (depends on 26) A reaction block as in claim 26 further including a plurality of passages connecting the input port of receiving heating or cooling fluid to the output port for draining heating or cooling fluid. ### Claim 28 (depends on 20) A reaction block as in claim 20 wherein the bottom surface includes a magnet. ### Claim 29 (depends on 28) A reaction block as in claim 28 wherein the magnet is a bar magnet. ### Claim 30 (depends on 20) A reaction block as in claim 20 wherein each of the reaction chambers includes a drain tube. ### Claim 31 (depends on 30) A reaction block as in claim 30 further including a cavity extending upwardly from the bottom surface to a middle surface, the middle surface parallel to the first top surface and the bottom surface. ### Claim 32 (depends on 31) A reaction block as in claim 31 wherein the middle surface has openings for receiving the drain tubes. ### Claim 33 (depends on 32) A reaction block as in claim 32 wherein the cavity includes a machined step to facilitate mating with a microtiter plate. ### Claim 34 (depends on 33) A reaction block as in claim 33 wherein the cavity includes a second machined step to facilitate mating with a bottom seal. ### Claim 35 (depends on 34) A reaction block as in claim 34 wherein the bottom seal includes an o-ring which seals against the second machined step. ### Claim 36 (depends on 34) A reaction block as in claim 34 wherein the bottom seal includes a one-way pressure valve. ### Claim 37 (depends on 22) A reaction block as in claim 22 wherein the first, second, third and fourth gas inlet ports include a quad ring seal. ### Claim 38 (depends on 21) A reaction block as in claim 21 wherein the first, second, third and fourth gas inlet ports include a valve. ### Claim 39 (depends on 38) A reaction block as in claim 38 wherein the valve is a schraeder valve. ### Claim 40 (depends on 38) A reaction block as in claim 38 wherein the valve is a bi-directional elastomeric valve. ### Claim 41 A reaction block comprising: a plurality of reaction chambers; a first side wall and a second side wall, the first and second side walls having a first width and a first height; a first end wall and a second end wall, the first and second end walls having a second width narrower than the first width, and the first height; a first top surface bordered by the first and second side walls and the first and second end walls, the top surface having: a plurality of generally circular openings for removably receiving the reaction chambers, the reaction chambers each having a circular opening and a second top surface; a gas port; and a plurality of raised beads defining the edges of a plurality of chambers; the raised beads having a first top surface which is in approximately the same plane as the second top surface of the reaction chambers; means for sealing against the second and third respective top surfaces of the reaction chambers and the raised beads; and a retainer plate which covers the means for sealing. ### Claim 42 (depends on 41) A reaction block as in claim 41 wherein the retainer plate has a plurality of openings which spatially correspond to the openings of the reaction chambers. ### Claim 43 (depends on 42) A reaction block as in claim 42 further including means for fastening the retainer plate to the means for sealing the reaction block. ### Claim 44 (depends on 41) A reaction block as in claim 41 wherein the first top surface includes a first, a second, a third, and a fourth, separately controllable gas outlet ports, and wherein the raised beads define a first, a second, a third, and a fourth pressurization chambers. ### Claim 45 (depends on 44) A reaction block as in claim 44 wherein each of the four pressurization chambers includes an equal number of the reaction chambers. ### Claim 46 (depends on 45) A reaction block as in claim 45 wherein the first, second, third, and fourth separately controllable gas outlet ports are in communication with the first, second, third, and fourth pressurization chambers, respectively. ### Claim 47 (depends on 45) A reaction block as in claim 45 wherein each of the four pressurization chambers includes a waste basin which is recessed below the level of the top surfaces of the reaction chambers. ### Claim 48 (depends on 45) A reaction block as in claim 45 wherein each of the four chambers has 12 of the reaction chambers. ### Claim 49 (depends on 41) A reaction block as in claim 41 wherein each of the generally circular openings on the first top surface have a keying notch, and wherein each of the reaction chambers have a keying protrusion. ### Claim 50 (depends on 41) A reaction block as in claim 41 wherein the block is made of aluminum. ### Claim 51 (depends on 50) A reaction block as in claim 50 wherein the block is made of 6061 aluminum. ### Claim 52 (depends on 50) A reaction block as in claim 50 wherein the aluminum has been anodized. ### Claim 53 (depends on 41) A reaction block as in claim 41 wherein the block is color coded. ### Claim 54 (depends on 41) A reaction block as in claim 41 wherein the block has an identification number. ### Claim 55 (depends on 41) A reaction block as in claim 41 wherein the block has a bar code. ### Claim 56 (depends on 41) A reaction block as in claim 41 wherein the first and second side walls are fitted with one pin each to facilitate securing the block to a work station. ### Claim 57 (depends on 41) A reaction block as in claim 41 wherein the first and second end walls are fitted with two pins each to facilitate handling by a robotic gripper. ### Claim 58 (depends on 46) A reaction block as in claim 46 further including a bottom surface defined by the bottom edges of the first and second side walls and the first and second end walls, the bottom surface being parallel to the first top surface. ### Claim 59 (depends on 58) A reaction block as in claim 58 further including a first, second, third and fourth gas inlet ports in communication with the first, second, third, and fourth gas outlet ports of the first top surface, respectively. ### Claim 60 (depends on 59) A reaction block as in claim 59 wherein the first, second, third and fourth gas inlet ports are in the bottom surface. ### Claim 61 (depends on 60) A reaction block as in claim 60 further including an input port for receiving heating or cooling fluid. ### Claim 62 (depends on 61) A reaction block as in claim 61 wherein the input port for receiving heating or cooling fluid is in the bottom surface. ### Claim 63 (depends on 62) A reaction block as in claim 62 further including an output port for draining heating or cooling fluid. ### Claim 64 (depends on 63) A reaction block as in claim 63 wherein the output port for draining heating or cooling fluid is on the bottom surface. ### Claim 65 (depends on 64) A reaction block as in claim 64 further including a plurality of passages connecting the input port for receiving heating or cooling fluid to the output port for draining heating or cooling fluid. ### Claim 66 (depends on 58) A reaction block as in claim 58 wherein the bottom surface includes a magnet. ### Claim 67 (depends on 66) A reaction block as in claim 66 wherein the magnet is a bar magnet. ### Claim 68 (depends on 58) A reaction block as in claim 58 wherein each of the reaction chambers includes a drain tube. ### Claim 69 (depends on 68) A reaction block as in claim 68 further including a cavity extending upwardly from the bottom surface to a middle surface, the middle surface parallel to the first top surface and the bottom surface. ### Claim 70 (depends on 69) A reaction block as in claim 69 wherein the middle surface has openings for receiving the drain tubes. ### Claim 71 (depends on 70) A reaction block as in claim 70 wherein the cavity includes a machined step to facilitate mating with a microtiter plate. ### Claim 72 (depends on 71) A reaction block as in claim 71 wherein the cavity includes a second machined step to facilitate mating with a bottom seal. ### Claim 73 (depends on 72) A reaction block as in claim 72 wherein the bottom seal includes an o-ring which seals against the second machined step. ### Claim 74 (depends on 72) A reaction block as in claim 72 wherein the bottom seal includes a one-way pressure valve. ### Claim 75 (depends on 59) A reaction block as in claim 59 wherein the first, second, third and fourth gas inlet ports include a quad ring seal. ### Claim 76 A reaction block comprising: a plurality of raised beads on a first top surface, the raised beads defining a plurality of chambers; a plurality of reaction chambers; a plurality of openings in the first top surface for receiving the reaction chambers; and the first top surface having a gas port and each reaction chamber having a second top surface; wherein the raised beads and the second top surfaces of the reaction chambers are in the same plane and sealed with means for sealing.