Chemical apparatus and process disinfecting – deodorizing – preser – Control element responsive to a sensed operating condition
Reexamination Certificate
1998-10-30
2004-02-10
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Control element responsive to a sensed operating condition
C422S063000, C422S081000, C422S105000, C436S180000, C073S863320, C073S864720
Reexamination Certificate
active
06689323
ABSTRACT:
BACKGROUND
This invention relates to transferring liquids from one container to another, and more particularly the invention relates to methods and apparatus for transferring small quantities of liquids from a multiplicity of depots to a multiplicity of receptacles.
Continuing rapid advances in chemistry, particularly in biochemistry and molecular biology, demand improved capabilities for carrying out large numbers of reactions using small quantities of materials.
In screening patients for genetic disease and susceptibility, for example, the number of conditions for which associated mutations are known is growing, and the numbers of mutant alleles known to be associated with these conditions is increasing. An adequate genetic screen for one or even a few of these conditions can require testing a sample from the patient against a very large number of genetic probes.
Enormous and rapidly increasing numbers of critical biomolecules have been identified and characterized, and an understanding of their various roles in cellular processes is vastly improving. Consequently, for example, the number of potential targets for pharmacologic intervention is very large. Techniques for parallel chemical synthesis, such as combinatorial chemistries, can efficiently produce libraries of large numbers of synthetic compounds that may be screened against selected targets in a rational drug design approach.
Considerable effort has been directed to developing better approaches to handling large numbers of samples, reagents and analytes. Automated laboratory workstations and robotics-based systems have been brought to routine use for some chemical manipulations in screening and synthesis, and dedicated computer applications have been developed both for controlling processes and for manipulating data. And a number of approaches have been proposed for miniaturizing systems for carrying out chemical processes, to reduce the quantities of the various components. Some of these approaches have found use. Particularly, for example, array technologies for binding pair assays use components immobilized in arrays of features on a surface; and microfluidics technologies employ networks of interconnected capillaries to move and combine components on a very small scale.
There is significant and growing interest in employing array technologies for conducting biomolecular manipulations. In array techniques certain of the components are immobilized in a pattern of array features on a surface of a solid support, and permitted to interact with other components. Arrays of binding agents, in which such binding agents as oligonucleotides or peptides are deposited onto a support surface in the form of an array or pattern, can be useful in a variety of applications, including gene expression analysis, drug screening, nucleic acid sequencing, mutation analysis, and the like. For example, information about the nucleotide sequence of a target nucleic acid may be obtained by contacting the target with an array of different surface-bound DNA probes under conditions that favor hybridization of nucleic acids having complementary sequences, and determining at what sites on the array nucleic acid duplexes are formed. Hybridization to surface-bound DNA probe arrays can provide a relatively large amount of information in a single experiment. And, for example, array technology can be useful in differential gene expression analysis.
Such arrays may be prepared in any of a variety of different ways. For example, DNA arrays may be prepared manually by spotting DNA onto the surface of a substrate with a micro pipette. See, Khrapko et al. (1991), DNA Sequence 1:375-388. Or, a dot-blot approach or a slot-blot approach may be employed in which a vacuum manifold transfers aqueous DNA samples from a plurality of wells to a substrate surface. Or, an array of pins can be dipped into an array of fluid samples and then contacted with the substrate surface to produce the array of sample materials. Or, an array of capillaries can be used to produce biopolymeric arrays, as described for example in International Patent Publication WO 95/35505.
U.S. patent applications Ser. Nos. 09/150,504 and 09/150,507 describe forming biomolecular arrays by adaptations of devices employed in the printing industry and, particularly, of inkjet print heads and of automated devices for moving a print head over a print surface and for depositing the inks at desired locations on the surface. These references and others cited herein, above and below, are incorporated herein in their entirety by reference. Other uses of inkjet printing devices to dispense biochemical agents such as proteins and nucleic acids are suggested or disclosed in, for example, U.S. Pat. Nos. 5,658,802; 5,338,688; 5,700,637; 5,474,796; 4,877,745; and 5,449,754.
Whether the miniaturized system is a microfluidic device or an array, or is of some other design, at least some of the various biomolecules to be introduced to the system are typically prepared in depots remote from the receptacles by which they are introduced to the system. These depots may take the form of a multiwell plate (conventionally providing 96 wells in a 12×8 format), for example, or a microtiter plate (conventionally providing 384 wells in a 16×24 format, or 1536 wells in a 32×48 format). A technical challenge is presented by the step of transferring the liquids containing the various biomolecules from the depots to the specific receptacles. In an array system constructed using an inkjet printing technique, for example, a technical challenge is presented by the need to transfer the liquids from the depots to the specific reservoirs in the print head.
Conventionally a pipet may be employed to transfer a liquid dropwise from a depot to a receptacle (such as a reservoir in a microfluidics device or a reservoir in a print head). The tip of the pipet is first dipped into the liquid in the depot and some of the liquid is drawn into the pipet; then the pipet is moved to the receptacle and a quantity of the liquid is expelled into the receptacle. Several pipets may be ganged and used to transfer several different liquids at once, to reduce the number of repetitions, but problems of small dimension may make such an approach impractical. In any event the transfer step results in contamination of pipets, which accordingly must be either discarded and replaced or decontaminated (for example by rinsing) before they are used to transfer different liquids. Where a large number of different liquids are to be moved, the transfer apparatus becomes mechanically unwieldy, and the cost of minimizing the risk of contamination is increased.
SUMMARY OF THE INVENTION
In one general aspect the invention features a method for transferring liquids from a plurality of wells to one or more receptacles, by displacing liquid contained in each well so that a convex meniscus swells from the opening of the well, and contacting a receptacle with the swollen meniscus to draw at least a portion of the liquid into the receptacle. According to the invention, the liquid transfer is effected directly from the depots to the corresponding receptacles without contact between depots and the receptacles, and without interposition of any transfer device between depots and the receptacles. And, according to the invention, the flow of the liquid into the receptacle following contact of the receptacle with the meniscus is at least initially a result of capillary interaction, and ordinarily is principally so.
In preferred embodiments the wells are arranged in a specified pattern in a depot member, so that where different wells contain different liquids or contain liquids containing different constituents, the different liquid contents are associable with the positions of the wells in the pattern. And, in some embodiments where liquids from different wells are to be transferred to specified different receptacles, the receptacles are arranged in a corresponding or complementary pattern, so that a specified plurality of the wells may be aligned with a corresponding
Caren Michael P.
Fisher William D.
Tella Richard P.
Agilent Technologies
Bex Kathryn
Stewart Gordon M.
Warden Jill
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