Fluent material handling – with receiver or receiver coacting mea – Processes
Reexamination Certificate
1999-06-14
2001-04-03
Maust, Timothy L. (Department: 3751)
Fluent material handling, with receiver or receiver coacting mea
Processes
C141S009000, C141S094000, C141S100000, C141S129000, C141S130000, C141S279000, C222S071000, C250S222200, C377S010000
Reexamination Certificate
active
06209589
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to chemical synthesis, and more particularly to an improved apparatus and method for distributing microscopic beads of the kind used as substrates in combinatorial chemistry.
BACKGROUND OF THE INVENTION
In combinatorial synthesis, it is often desirable to be able to distribute beads into a two-dimensional array, so that each variant in a combinatorial library can be identified by its position in the array. The array can consist of a set of plates, each having rows and columns of wells, with one bead, or some other predetermined number of beads, in each well. The beads are typically made of polystyrene, and serve as substrates for different compounds produced in the process of split and combine synthesis. Ultimately, the synthesized compounds are stripped from the beads and tested for activity. The identity of an active compound is determined by spectrographic analysis, in the light of the information available concerning the reaction histories of the beads being distributed.
The beads are spherical and of extremely small size, e.g. 300 mm in diameter. Consequently, they are difficult to handle, and it has been very difficult to separate a single bead from a mixture of beads.
SUMMARY OF THE INVENTION
The principle object of this invention is to provide an apparatus and method for selecting individual beads, or preselected numbers of beads from a mixture of beads, and distributing the selected beads into a two-dimensional array.
A further object of the invention is to provide a bead distribution apparatus which is both simple and highly reliable.
This apparatus utilizes a head similar to that of a “Coulter” counter, a device used to count and size particles in a liquid. For example, it is used in the petroleum industry to assess engine wear by counting particles in lubricating oil. The principle on which the Coulter counter operates is that electrical resistance of a conductive fluid, measured by electrodes on both sides of a small aperture, increases momentarily as a solid particle passes through the aperture. The passage of particles through the aperture is detected as a electrical pulses, which can be counted electronically. The Coulter counter is described in detail in U.S. Pat. No. 2,656,508, issued Oct. 20, 1953, and the disclosure of that patent is here incorporated by reference.
The preferred embodiment of this invention takes advantage of the principle of the Coulter counter, but uses the principle in a different way and for a different purpose.
In accordance with the invention, beads, from a mixture of beads, preferably of substantially uniform size, are distributed into an array having multiple locations, so that a predetermined number of beads is deposited at each location in the array. This is carried out by forming a suspension of the mixture of beads in a carrier liquid; causing a part of the liquid to flow through an aperture of a size such that the beads can pass through the aperture only one at a time; detecting the passage of a predetermined number of the beads through the aperture; and, in response to the detection of the passage of the predetermined number of the beads through the aperture, depositing them at a predetermined location of the array.
In one embodiment of the invention, the selection of beads to be deposited is carried out by discontinuing the flow through the aperture upon detection of the passage of the predetermined number of the beads through the aperture. In an alternative embodiment, flow takes place continuously through the aperture, and is diverted in response to a detection signal to effect bead deposition.
The carrier liquid is electrically conductive, and is stirred to keep the beads in suspension. In a first embodiment, to deposit a single bead, a syringe is operated to produce a steady flow of liquid through an aperture in the side wall of a tube extending through the container for the carrier liquid. Eventually, a bead will pass through the aperture along with the liquid. When the passage of a bead is detected electrically, the operation of the syringe is discontinued and the flow of liquid through the aperture stops. This prevents other beads from passing through the aperture. After its passage through the aperture is detected, the bead is flushed out of the tube by a pumped liquid, and deposited at its location in the array, preferably into a well in a well plate. Preferably, while the syringe is causing liquid to flow into the tube through the aperture, liquid is withdrawn from the upper end of the tube by a pump at the same rate at which it flows into the tube through the aperture. This prevents liquid from passing through the lower end of the tube. Normally only one bead will be deposited at each location in the array. However, multiple beads can be deposited at each location. This is done by counting the electrical pulses corresponding to peaks in resistance. When the desired number of beads is counted, the flow of the suspension liquid is discontinued.
In a second embodiment, the aperture at which detection takes place is at the end of a tube through which liquid flows continuously. When a bead is detected at the aperture, a signal is produced causing the flow of liquid to be diverted so that the bead is carried to the location at which it is to be deposited.
In a preferred embodiment of the invention, a stack of empty well plates is initially placed in the apparatus. The lowermost well plate in the stack is automatically moved to a position underneath the head with a first row of wells positioned underneath, and parallel to a linear path of movement of the head. The head moves successively from one well to the next, depositing a bead in each well of the column. The well plates are indexed laterally to position successive rows of wells underneath the path of the head. When a plate is filled, i.e. it has one bead in each of its wells, it is moved into a new stack and the apparatus retrieves a new plate from the supply stack and begins to distribute beads to the new plate.
REFERENCES:
patent: 2656508 (1953-10-01), Coulter
patent: 3710933 (1973-01-01), Fulwyler et al.
patent: 4170699 (1979-10-01), Wright
patent: 4818492 (1989-04-01), Shimizu
patent: 5076097 (1991-12-01), Zarrin et al.
patent: 5245530 (1993-09-01), Taki
patent: 5290707 (1994-03-01), Wood
patent: 5415051 (1995-05-01), Rokugawa et al.
patent: 5649576 (1997-07-01), Kirk et al.
patent: WO 91/17823 (1991-11-01), None
Hare John Francis
James Philip John
Marlow John Barry
Payne Richard C.
Maust Timothy L.
SmithKline Beecham Plc
Venetianer S.
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