# US 5,770,157 A · Methods and apparatus for the generation of chemical libraries

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- Number: US 5,770,157 A
- Document ID: US5770157A
- Status: Granted
- Kind: A
- Application number: 08/718,105
- Filed: 1996-09-18
- Granted: 1998-06-23
- Earliest claimed: 1995-04-17
- Assignees: Ontogen Corporation
- Inventors: John Cargill; Romaine R. Maiefski
- Web page: https://patentgrep.com/patent/US5770157A

## 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 chamber comprising:
a generally cylindrical upper body having a top opening with a rounded edge, an inner surface, an outer surface, an inside diameter, and a gas inlet port connecting the inner surface of the upper body to the outer surface of the upper body;
a generally cylindrical lower body coaxial with the upper body;
the lower body having an inner surface, an outer surface, and an inside diameter smaller than the inside diameter of the upper body;
a tapered section connecting the upper body to the lower body;
a drain tube having an inside surface and connected to the lower body with a funnel-shaped section; and
an s-shaped trap tube having an inlet opening and an outlet opening, the inlet opening of the trap tube connected to the drain tube.

### Claim 2 (depends on 1)

A reaction chamber as in claim 1 wherein the drain tube has an annular bead on its inside surface to facilitate sealing with the inlet opening of the s-shaped trap tube.

### Claim 3 (depends on 2)

A reaction chamber as in claim 2 wherein the s-shaped trap tube is welded to the drain tube.

### Claim 4 (depends on 1)

A reaction chamber as in claim 1 wherein the s-shaped trap tube extends upwardly along the length of the upper body.

### Claim 5 (depends on 4)

A reaction chamber as in claim 4 wherein the outlet port of the s-shaped trap tube points downward.

### Claim 6 (depends on 5)

A reaction chamber as in claim 5 wherein the outlet port of the s-shaped trap tube is connected to a second cylindrical drain tube.

### Claim 7 (depends on 6)

A reaction chamber as in claim 6 wherein the second cylindrical drain tube is of a larger diameter than the trap tube.

### Claim 8 (depends on 7)

A reaction chamber as in claim 7 wherein the s-shaped trap tube and the second cylindrical drain tube are made from extruded polypropylene or teflon.

### Claim 9 (depends on 1)

A reaction chamber as in claim 1 wherein the upper body, the lower body, the tapered section, the funnel shaped section, and the drain tube are made from a single piece of injection-molded polymer.

### Claim 10 (depends on 9)

A reaction chamber as in claim 9 wherein the polymer is polypropylene or teflon.

### Claim 11 (depends on 1)

A reaction chamber as in claim 1 wherein the upper body has a volume of approximately 2 ml.

### Claim 12 (depends on 1)

A reaction chamber as in claim 1 wherein the upper body further includes a keying protrusion on its outer surface.

### Claim 13 (depends on 1)

A reaction chamber as in claim 1 wherein the lower body further includes a frit having a diameter smaller than the inside diameter of the lower body portion.

### Claim 14 (depends on 13)

A reaction chamber as in claim 13 wherein the frit is press fit into the lower body portion.

### Claim 15 (depends on 14)

A reaction chamber as in claim 14 wherein the frit is made of polyethylene.

### Claim 16

A reaction chamber comprising:
a generally cylindrical upper body having a top opening, an inner surface, an outer surface, and an inside diameter;
a generally cylindrical lower body coaxial with the upper body;
the lower body having an inner surface, an outer surface, and an inside diameter smaller than the inside diameter of the upper body;
means for connecting the upper body to the lower body;
a drain tube having an inside surface;
means for connecting the drain tube to the lower body; and
an s-shaped trap tube having an inlet opening and an outlet opening, the inlet opening of the trap tube connected to the drain tube.

### Claim 17 (depends on 16)

A reaction chamber as in claim 16 wherein the means for connecting the drain tube to the lower body is a funnel-shaped section.

### Claim 18 (depends on 16)

A reaction chamber as in claim 16 wherein the means for connecting the upper body to the lower body is a tapered section.

### Claim 19 (depends on 16)

A reaction chamber as in claim 16 wherein the top opening of the upper body has a rounded edge to facilitate sealing against a septum.

### Claim 20 (depends on 16)

A reaction chamber as in claim 16 wherein the upper body includes a means for connecting the inner surface of the upper body to the outer surface of the upper body.

### Claim 21 (depends on 20)

A reaction chamber as in claim 20 wherein the means for connecting the inner surface of the upper body to the outer surface of the upper body port is a gas inlet port.

### Claim 22 (depends on 16)

A reaction chamber as in claim 16 wherein the drain tube has an annular bead on its inside surface to facilitate sealing with the inlet opening of the s-shaped trap tube.

### Claim 23 (depends on 22)

A reaction chamber as in claim 22 wherein the s-shaped trap tube is welded to the drain tube.

### Claim 24 (depends on 16)

A reaction chamber as in claim 16 wherein the s-shaped trap tube extends upwardly along the length of the upper body.

### Claim 25 (depends on 24)

A reaction chamber as in claim 24 wherein the outlet port of the s-shaped trap tube points downward.

### Claim 26 (depends on 25)

A reaction chamber as in claim 25 wherein the outlet port of the s-shaped trap tube is connected to a second cylindrical drain tube.

### Claim 27 (depends on 26)

A reaction chamber as in claim 26 wherein the second cylindrical drain tube is of a larger diameter than the trap tube.

### Claim 28 (depends on 27)

A reaction chamber as in claim 27 wherein the s-shaped trap tube and the second cylindrical drain tube are made from extruded polypropylene or teflon.

### Claim 29 (depends on 16)

A reaction chamber as in claim 16 wherein the upper body, the lower body, the tapered section, the funnel shaped section, and the drain tube are made from a single piece of injection-molded polymer.

### Claim 30 (depends on 29)

A reaction chamber as in claim 29 wherein the polymer is polypropylene or teflon.

### Claim 31 (depends on 16)

A reaction chamber as in claim 16 wherein the upper body has a volume of approximately 2 ml.

### Claim 32 (depends on 16)

A reaction chamber as in claim 16 wherein the upper body further includes a keying protrusion on its outer surface.

### Claim 33 (depends on 16)

A reaction chamber as in claim 16 wherein the lower body further includes means for retaining a frit.

### Claim 34 (depends on 33)

A reaction chamber as in claim 33 wherein the frit is press fit into the lower body portion.

### Claim 35 (depends on 34)

A reaction chamber as in claim 34 wherein the frit is made of polyethylene.

### Claim 36

A reaction chamber comprising:
a generally cylindrical upper body having a top opening with a rounded edge to facilitate sealing against a septum, an inner surface, an outer surface, a gas port connecting the inner surface with the outer surface, and an inside diameter;
a generally cylindrical lower body coaxial with the upper body;
the lower body having an inner surface with an annular bead for retaining a frit, an outer surface, and an inside diameter smaller than the inside diameter of the upper body;
a tapered section connecting the upper body to the lower body;
a drain tube having an inside surface;
a funnel shaped section connecting the drain tube to the lower body; and
an s-shaped trap tube having an inlet opening and an outlet opening, the inlet opening of the trap tube connected to the drain tube.