(12)
`
`United States Patent
`Vuong
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,448,089 B1
`Sep. 10, 2002
`
`US006448089B1
`
`(54) MULTIWELL SCANNER AND SCANNING
`METHOD
`
`(75) Inventor: T. Mlnh Vuong, San Diego, CA (US)
`
`(73) Assignee: guroraclittséisances Corporation, San
`1ego,
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(1)) by 0 days.
`
`(21) Appl. No.: 09/417,246
`_
`_
`Oct‘ 12’ 1999
`(22) Flled'
`(51) Int. c1.7 .............................................. .. G01N 21/75
`(52) US. Cl. ..................... .. 436/164; 436/165; 436/171;
`436/172; 422/62; 422/8205
`(58) Field of Search ............................... .. 436/ 164, 165,
`436/171, 172, 805; 422/52, 55, 62, 8205,
`8209; 356/73, 432; 435/2871, 2887
`
`(56)
`
`References Cited
`
`Us‘ PATENT DOCUMENTS
`4,061,543 A 12/1977 Bean et a1_
`4,461,403 A
`7/1984 Kuperstein
`4,626,684 A * 12/1986 Landa ...................... .. 250/328
`4,628,933 A 12/1986 Michelson
`47677989 A * 7/1987 Robblee
`2 13/
`gomel et all‘ """"" " 250M581
`’
`’
`/
`yers et a '
`5024223 A
`6/1991 Chow
`5’187’096 A
`2/1993 G-
`,
`,
`iaever et al.
`5,405,367 A
`4/1995 Schulman et aL
`5,416,329 A
`5/1995 some et a1_
`5,439,440 A
`8/1995 Hofmann
`5,444,239 A * 8/1995 Nacman et al. ........... .. 250/235
`5,512,492 A
`4/1996 Herron etal-
`55457130 A
`8/1996 Hoflnann etaL
`2 18/
`iu?haralet a1‘
`5’571’158 A “£1996 BZIZ 6; 21'
`5,677,196 A 10/1997 Herron et 211.
`5,686,300 A 11/1997 Berndt
`
`6/1998 Berndt
`5,770,440 A
`7/1998 Heffel?nger et 211.
`5,784,152 A
`8/1998 Wood et al.
`5,798,263 A
`(List Continued on next page‘)
`
`FOREIGN PATENT DOCUMENTS
`0 760 478 A2
`3/1997
`EP
`WOW/19339
`5/1997
`W0
`WOW/04228
`1/1999
`W0
`>1 Cited by examiner
`
`Primary Examiner—Jill Warden
`Assistant Examiner—Yelena Gakh
`(74) Attorney, Agent, or Firm—Knobbe, Martens, Olson &
`Bear LLP
`(57)
`
`ABSTRACT
`
`A multiWeH P1ate Scanner Comprises a detector for measur
`ing an attribute of a sample Which is scanned continuously
`over Wells of a multiWell plate. An signal obtained during
`the scan may be sampled and digitized based on detector
`position over the multiWell plate. The scanner is also dis
`closed for scanning microarrays, bio-chips and areas of
`samples not having physical separations. The scanner may
`be used in a high throughput screening system comprising a
`storage and retrieval module, a sample distribution module,
`a reagent distribution module, and a detector Which incor
`porates the scanner. The screening system may further
`comprise a transport module and a data processing and
`integration module for transporting samples betWeen the
`com onents of the s stem and for controllin s stem 0 era
`p
`y
`g y
`p
`tion. Another aspect of the invention is a system and method
`_
`for performmg an assay to detect the effect of a reagent on
`a target. The present invention is also directed to composi
`tions and therapeutics identi?ed by the disclosed methods. A
`further aspect of the present invention is a method of testing
`a therapeutic for therapeutic activity and toxicology by
`identifying a compound using a method of the present
`invention and monitoring the toxicology and ef?cacy of the
`therapeutic in an in vivo model.
`
`19 Claims, 7 Drawing Sheets
`
`/~20
`
`1
`1
`l
`l
`
`1
`1
`
`REABW
`
`244
`
`111mm 1E0
`PLATE ‘
`{210111011
`11000 r
`
`H16
`4
`CAP/101W
`S’ACUAG
`981311
`
`.4
`
`0015105
`
`HT 1100:1180
`ROBCF
`
`4444-1‘ swans AND FEW FVA1 MOEULII
`
`‘it , VLFORMA '1011
`RANSFER
`
`i PLATE
`
`WANSFER
`
`Agilent Exhibit 1236
`Page 1 of 21
`
`

`

`US 6,448,089 B1
`Page 2
`
`US. PATENT DOCUMENTS
`
`9/1998 Sugihara er al-
`5,810,725 A
`5,865,975 A * 2/1999 Bishop ..................... .. 204/618
`5,919,712 A
`7/1999 Herron et 211.
`5,935,155 A
`8/1999 Humayun et 211.
`5,957,958 A
`9/1999 Schulman et 211.
`5,965,452 A 10/1999 Kovacs
`5,981,268 A 11/1999 Kovacs et 211.
`
`6,008,038 A 12/1999 Kroger et 211.
`6,009,347 A 12/1999 Hofmann
`6,010,613 A
`1/2000 Walters et 211.
`6,024,920 A * 2/2000 Cunanan ____________________ __ 422/65
`6,043,066 A
`3/2000 Mangano et 211.
`6,066,245 A * 5/2000 Trost ........................ .. 204/461
`6,071,748 A * 6/2000 Modlin et a1.
`436/174
`6,236,456 B1 * 5/2001 Giebeler et a1. ..
`356/318
`6,271,022 B1 * 8/2001 Bochner ................ .. 435/287.3
`
`Agilent Exhibit 1236
`Page 2 of 21
`
`

`

`U.S. Patent
`
`Sep. 10, 2002
`
`Sheet 1 0f 7
`
`US 6,448,089 B1
`
`‘ E
`MO V
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`INFORMATION TRANSFER
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`
`REACTION MODULE <—
`
`FIG. 7
`
`Agilent Exhibit 1236
`Page 3 of 21
`
`

`

`U.S. Patent
`
`Sep. 10, 2002
`
`Sheet 2 0f 7
`
`US 6,448,089 B1
`
`SYSTEM
`
`A5’
`/I/
`
`I ————————— —~+- MANAGEMENT ~¢ ———————————— --j
`I
`MODULE
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`_______>|NFORMATION
`TRANSFER
`
`-__
`
`PLATE
`TRANSFER
`
`Agilent Exhibit 1236
`Page 4 of 21
`
`

`

`U.S. Patent
`
`Sep. 10, 2002
`
`Sheet 3 0f 7
`
`US 6,448,089 B1
`
`L
`50/ 56
`
`0x32
`
`J5
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`45 \y=
`
`45
`
`Agilent Exhibit 1236
`Page 5 of 21
`
`

`

`U.S. Patent
`US. Patent
`
`Sep. 10, 2002
`Sep. 10, 2002
`
`Sheet 4 0f 7
`Sheet 4 0f 7
`
`US 6,448,089 B1
`US 6,448,089 B1
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`Agilent Exhibit 1236
`
`Page 6 of 21
`
`Agilent Exhibit 1236
`Page 6 of 21
`
`

`

`US. Patent
`
`Sep.10,2002
`
`Sheets 0f7
`
`US 6,448,089 B1
`
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`Agilent Exhibit 1236
`
`Page 7 of 21
`
`Agilent Exhibit 1236
`Page 7 of 21
`
`
`
`
`

`

`U.S. Patent
`
`Sep. 10, 2002
`
`Sheet 6 0f 7
`
`US 6,448,089 B1
`
`EEO? w
`
`
`
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`
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`
`Agilent Exhibit 1236
`Page 8 of 21
`
`

`

`U.S. Patent
`
`Sep. 10, 2002
`
`Sheet 7 0f 7
`
`US 6,448,089 B1
`
`
`
`EE .MQZ/NQQQ
`
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`
`Agilent Exhibit 1236
`Page 9 of 21
`
`

`

`US 6,448,089 B1
`
`1
`MULTIWELL SCANNER AND SCANNING
`METHOD
`
`BACKGROUND OF THE INVENTION
`
`2
`largely independent of changes in the sensitivity of the
`detector, provided that is that these changes are the same for
`the detection efficiency at both Wavelengths. This combina
`tion of advantages makes ?uorescence based ratiometric
`assays highly attractive for high throughput screening
`systems, Where day to day, and, assay to assay reproduc
`ibility are important.
`Traditionally, there are tWo general Ways to read ?uores
`cence from a multi-Well plate. In one arrangement, a read
`head is moved from Well to Well and at each Well, there is
`a dWell time during Which the ?uorescence signal is digi
`tiZed and stored into memory. Optically, this scheme is the
`simplest. There is only one optical assembly, one set of
`?lters and one detector. HoWever, depending on hoW many
`Wells there are in the plate, the read time can be unaccept
`ably long. It is not just the dWell times that contribute to the
`total read time. Every time the read head is moved from Well
`to Well, it takes time to accelerate and decelerate the stage
`used in moving the setup.
`In the other arrangement, some sort of parallelism is
`employed. Either a picture is taken of the plate, using a CCD
`camera or some other imaging arrangement, or multiple
`optical read heads are employed. The advantage of this
`arrangement is a signi?cant reduction in the read time.
`HoWever, a neW difficulty is introduced, namely that of
`normaliZation. When several Wells are read at the same time
`by several read heads, the question that arises is hoW to make
`sure that these heads behave in the same Way in terms of
`collection ef?ciency, detector sensitivity, ?lter quality and
`the like. In the case of a CCD camera, the analogous issue
`is one of ?at-?elding. Accordingly, improved methods and
`systems for rapidly and accurately measuring ?uorescence
`signals in high throughput screening environments are
`needed.
`
`SUMMARY OF THE INVENTION
`
`A multiWell plate scanner comprises a detector Which is
`scanned continuously over Wells of a multiWell plate. The
`scanner may also be used for scanning microarrays, bio
`chips and areas of samples not having physical separations.
`In one embodiment, the invention is directed to a method
`of detecting light emitting molecules in Wells of a multiWell
`plate. The method comprises positioning a light collector to
`one side of a ?rst Well of the multiWell plate continuously
`moving the light collector relative to the multiWell plate
`such that the light collector passes a ?rst edge of the ?rst
`Well, passes over the ?rst Well, and passes a second edge of
`the ?rst Well. Fluorescent light intensity is measured during
`at least a portion of the time the light collector is over the
`?rst Well.
`The scanner may be used in a high throughput screening
`system comprising a storage and retrieval module, a sample
`distribution module, a reagent distribution module, and a
`detector Which incorporates the scanner. One embodiment of
`the invention thus comprises a high throughput drug dis
`covery method comprising retrieving chemicals from a
`chemical storage and retrieval module, placing the chemi
`cals into Wells of multi-Well plates, scanning the multi-Well
`plates in a substantially continuous raster scan pattern so as
`to detect a chemical or biological activity of one or more of
`the chemicals. Alternatively, the scan pattern could be in a
`spiral, concentric circle, or any other suitable mathematical
`function, depending on the shape of the sample or sample
`container.
`The present invention is also directed to compositions and
`therapeutics identi?ed by the disclosed methods. One such
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`1. Field of the Invention
`The present invention generally relates to devices and
`methods for rapidly identifying chemicals With biological
`activity in liquid samples, particularly automated screening
`of loW volume samples for neW medicines, agrochemicals,
`or cosmetics.
`2. Description of the Related Art
`Drug discovery is a highly time dependent and critical
`process in Which signi?cant improvements in methodology
`can dramatically improve the pace at Which a useful chemi
`cal becomes a validated lead, and ultimately forms the basis
`for the development of a drug. In many cases the eventual
`value of a useful drug is set by the timing of its arrival into
`the market place, and the length of time the drug enjoys as
`an exclusive treatment for a speci?c ailment.
`A major challenge for pharmaceutical companies is to
`improve the speed and ef?ciency of this process While at the
`same time maintaining costs to an absolute minimum. One
`solution to this problem has been to develop high throughput
`screening systems that enable the rapid analysis of many
`thousands of chemical compounds per 24 hours. To reduce
`the otherWise prohibitive costs of screening such large
`numbers of compounds, typically these systems use minia
`turiZed assay systems that dramatically reduce reagent costs,
`and improve productivity. To ef?ciently handle large num
`bers of miniaturiZed assays it is necessary to implement
`automatic robotically controlled analysis systems that can
`provide reliable reagent addition and manipulations. Pref
`erably these systems and the invention herein are capable of
`interacting in a coordinated fashion With other systems
`sub-components, such as a central compound store to enable
`rapid and ef?cient processing of samples.
`MiniaturiZed high throughput screening systems require
`robust, reliable and reproducible methods of analysis that
`are sensitive enough to Work With small sample siZes. While
`there are a large number of potential analysis methods that
`can successfully be used in macroscopic analysis, many of
`these procedures are not easily miniaturiZable, or lack suf
`?cient sensitivity When miniaturiZed. This is typically true
`because absolute signal intensity from a given sample
`decreases as a function of the siZe of the sample, Whereas
`background optical or detector noise remains more or less
`constant for large or small samples. Preferred assays for
`miniaturiZed high throughput screening assays have high
`signal to noise ratios for very small sample siZes.
`Fluorescence based measurements have high sensitivity
`and perform Well With small samples, Where factors such as
`inner ?ltering of excitation and emission light are reduced.
`Fluorescence based measurements therefore exhibit good
`signal to noise ratios even With small sample siZes. A
`55
`particularly preferred method of using ?uorescence based
`signal detection is to generate a ?uorescent (emission) signal
`that simultaneously changes at tWo or more Wavelengths. A
`ratio can be calculated based on the emission light intensity
`at the ?rst Wavelength divided by the emitted light intensity
`at a second Wavelength. This ratiometric measurement of a
`?uorescent assay has several important advantages over
`other non-ratiometric types of analysis. Firstly, the ratio is
`largely independent of the actual concentration of the ?uo
`rescent dye that is emitting ?uorescence. Secondly, the ratio
`is largely independent of the intensity of light With Which the
`?uorescent compound is being excited. Thirdly, the ratio is
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`Agilent Exhibit 1236
`Page 10 of 21
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`

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`US 6,448,089 B1
`
`3
`embodiment comprises a medicament made by a process
`comprising identifying a pharmacologically active chemical
`by a process comprising retrieving chemicals from a chemi
`cal storage and retrieval module, placing the chemicals into
`Wells of multi-Well plates, and scanning the multi-Well
`plates in a substantially continuous ploWman’s fashion so as
`to detect a pharmacological activity of one or more of the
`chemicals. FolloWing identi?cation, an effective amount of
`at least one of the pharmacologically active chemicals is
`incorporated into a biocompatible carrier.
`A further aspect of the present invention is a method of
`testing a therapeutic for therapeutic activity and toxicology
`by identifying a compound using a method of the present
`invention and monitoring the toxicology and ef?cacy of the
`therapeutic in an in vivo model.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a block diagram of a high throughput chemical
`screening system in acccordance With the present invention.
`FIG. 2 is a block diagram of another high throughput
`chemical screening system in accordance With the present
`invention.
`FIG. 3 is a schematic of a ?uorescence excitation and
`emission detection system Which may be part of the reaction
`module of the system of FIG. 1 or part of the reader of the
`system of FIG. 2.
`FIG. 4 is a diagram of the trifurcated ?ber optic bundle of
`FIG. 3.
`FIG. 5 is a diagram of one embodiment of a light detector
`scan path in accordance With the invention.
`FIG. 6 is a schematic of the data acquisition control
`electronics in one embodiment of the invention.
`FIG. 7 is a plot of collected light intensity as a function
`of position during a portion of a scan of Wells containing an
`aqueous chemical solution including ?uorescent species.
`FIG. 8 is a plot of collected light intensity as a function
`of position during a scan of Wells containing a ?uorescent
`cell suspension.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Embodiments of the invention Will noW be described With
`reference to the accompanying Figures, Wherein like numer
`als refer to like elements throughout. The terminology used
`in the description presented herein is not intended to be
`interpreted in any limited or restrictive manner, simply
`because it is being utiliZed in conjunction With a detailed
`description of certain speci?c embodiments of the invention.
`Furthermore, embodiments of the invention may include
`several novel features, no single one of Which is solely
`responsible for its desirable attributes or Which is essential
`to practicing the inventions herein described.
`Unless otherWise de?ned, all technical and scienti?c
`terms used herein have the same meaning as commonly
`understood by one of ordinary skill in the art to Which the
`invention belongs. Generally, the nomenclature used herein
`and many of the automation, computer, detection, chemistry
`and laboratory procedures described beloW are those Well
`knoWn and commonly employed in the art. Standard tech
`niques are usually used for engineering, robotics, optics,
`molecular biology, computer softWare and integration.
`Generally, chemical reactions, cell assays and enZymatic
`reactions are performed according to the manufacture’s
`speci?cations Where appropriate. The techniques and pro
`cedures are generally performed according to conventional
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`methods in the art and various general references. The reader
`may see generally LakoWicZ, J. R. Principles of Fluores
`cence Spectroscopy, NeW York:Plenum Press (1983), and
`LakoWicZ, J. R. Emerging Applications of Fluorescence
`Spectroscopy to Cellular Imaging: Lifetime Imaging, Metal
`ligand Probes, Multi-photon Excitation and Light
`Quenching, Scanning Microsc. Suppl VOL. 10 (1996) pages
`213—24, for ?uorescent techniques, Sambrook et al Molecu
`lar Cloning: A laboratory manual, 2”“ ed. (1989) Cold
`Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
`for molecular biology methods, Optics Guide 5 Melles
`Griot® Irvine Calif. for general optical methods, Optical
`Waveguide Theory, Snyder & Love, published by Chapman
`& Hall, and Fiber Optics Devices and Systems by Peter
`Cheo, published by Prentice-Hall for ?ber optic theory and
`materials.
`As employed throughout the disclosure, the folloWing
`terms, unless otherWise indicated, shall be understood to
`have the folloWing meanings:
`“MultiWell plate” refers to a tWo dimensional array of
`sample Wells located on a substantially ?at surface. Multi
`Well plates may comprise any number of separate sample
`Wells, and comprise sample Wells of any Width or depth.
`Common examples of multiWell plates include 96 Well
`plates, 384 Well plates and 3456 Well plates, such as those
`disclosed in commonly assigned US. patent application Ser.
`No. 09/028,283, entitled “LoW Fluorescence Assay Plat
`forms Having Greater Than 864 Wells and Related Methods
`for Drug Discovery,” the content of Which is hereby incor
`porated by reference in its entirety.
`“Pharmaceutical agent or drug” refers to a chemical
`compound or composition capable of inducing a desired
`therapeutic effect When properly administered to a patient.
`As used herein, “optical property” refers to a measurable
`attribute of a sample, such as the intensity of emitted light
`at a particular Wavelength, the intensity or degree of light
`polariZation, the transmittance of a compound or
`composition, or the re?ectance of a compound or composi
`tion.
`“Ball lens” refers to a sphere, truncated sphere, cylinder,
`or truncated cylinder of suitable transparent refractive mate
`rial and is usually a sphere.
`“Operably linked” refers to a juxtaposition Wherein the
`components so described are in a relationship permitting
`them to function in their intended manner.
`“Hit” refers to a sample identi?ed as having signi?cant
`interest or identi?ed as shoWing that a reagent has had a
`signi?cant effect on a target.
`“Raster scan” refers to a scan pattern in Which an area is
`scanned from side to side in lines succeeding from roW to
`roW or column to column, or any combination thereof.
`The present invention is directed to improving the speed
`and accuracy of detection and measurement of light emitted
`from the sample Wells of a multiWell plate. The invention
`?nds especially advantageous application to high throughput
`screening systems (HTSS) Where large numbers of com
`pounds are tested for biological or chemical activity, pref
`erably as quickly as possible.
`Typically, a system utiliZing aspects of the present inven
`tion Would include most or all of components used in
`processing liquid samples to identify a useful chemical,
`starting With a large store of different reagents (usually
`liquid) through the later stage processing steps, such as
`chemical reactions and detection of an analyte or measure
`ment of a physical property of a sample, as Well as a
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`Agilent Exhibit 1236
`Page 11 of 21
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`US 6,448,089 B1
`
`5
`component to collect information resulting from such a
`process. Such a system, as shoWn in FIG. 1, usually includes
`the following components:
`(1) a storage and retrieval module 10 for storing and
`retrieving very large numbers (at least about 100,000)
`of different reagents in containers,
`(2) a sample distribution module 11 to handle (e.g.,
`aspirate samples from containers and dispense samples
`into sample containers) small volumes of liquids at a
`high rate of speed,
`(3) a sample transporter 12 to transport reagents from a
`selected component to another at a compatible through
`put rate,
`(4) a reaction module 14 (e.g., a reagent dispenser and a
`detector) for chemical reactions or physical measure
`ments at high throughput rates, and
`(5) a data processing and integration module 16 that can
`control module operation.
`If desired, each separate module is integrated and pro
`grammably controlled to facilitate the rapid processing of
`liquid samples, as Well as being operably linked to facilitate
`the rapid processing of liquid samples. One such system is
`described in US. patent application Ser. No. 08/858,016
`entitled “Systems and Methods for Rapidly Identifying
`Useful Chemicals in Liquid Samples. The content of appli
`cation Ser. No. 08/858,016 is hereby incorporated by refer
`ence in its entirety.
`FIG. 2 shoWs another high throughput screening system
`18 according to the present invention. Like the system
`shoWn in FIG. 1, the HTSS 18 comprises a storage and
`retrieval module 19. The HTSS 18 further comprises a
`sample distribution module 22, a reagent dispensing module
`23, an automated plate replication module 24, a reaction
`module 25, a reader 26, a hit pro?ling robot 27, high
`capacity stacking system 28, and a transport system 20
`Which operably links each of the modules. A system man
`agement module 29 is operably linked to each of the
`components and modules to provide system operation con
`trol and integration and data management.
`The storage and retrieval module 19 fully automates
`storage and delivery of reagents in plates (such as multiWell
`plates) for assay procedures. The storage and retrieval
`module 19 is contemplated to include robotics,
`instrumentation, electro-mechanical devices, computer
`equipment and related softWare that fully automates reagent
`storage and retrieval and delivery from the storage and
`retrieval module 19 to the transport system 20. The storage
`and retrieval module may be substantially as described in
`application Ser. No. 08/858,016 referenced above.
`The transport system 20 comprises apparatus and controls
`for managing and moving plates betWeen each of the HTSS
`18 modules. The transporter system 20 may be substantially
`as described in application Ser. No. 08/858,016 referenced
`above.
`The hit pro?ling robot 27 formats plates that are generated
`from consolidation of hits from separate plates having Wells
`that have been assayed. In operation of the HTSS 18 to
`perform assays on a number of multiWell plates, Wells
`exhibiting screening hits are typically sparsely distributed
`among numerous of multiWell plates. Of course, a plate may
`contain none, one or more than one hit identi?ed by a
`speci?c assay. The hit pro?ling robot 27 gathers the hits and
`groups them together into neW destination multi-Well plates.
`The automated plate replication module 24 reformats
`samples betWeen multiWell plates. For eXample, the auto
`mated plate replication module 24 can dispense samples
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`from a 384-Well plate into a set of four 96-well plates.
`Alternatively, the automated plate replication module 24
`may be con?gured to dispense samples from the Wells of
`several different 384-Well plates into a single 384-Well plate.
`In addition to formatting plates for use in performing
`automated assays, the automated plate replication module 24
`can perform several other useful tasks. For example, it can
`be used to format sample plates for input into the storage and
`retrieval module 19. It can also be used to format assay
`plates for assays performed independent of the HTSS 18.
`The sample distribution module 22 dispenses samples
`from multiWell sample plates into assay plates to be tested.
`The sample plates Will typically be multiWell plates directly
`from the storage and retrieval module 19 or they may be
`reformatted plates from the automated plate replication
`module 24. The sample plates are transported from the
`storage and retrieval module 19 and/or the automated plate
`replication module 24 to the sample distribution module 22
`on the transport system 20. The assay plates may be very
`high density plates such as 3456-Well plates. Suitable
`sample distribution modules 22 are disclosed in commonly
`assigned, co-pending US. application Ser. No. 09/210,260,
`the disclosure of Which is hereby incorporated by reference
`in its entirety.
`The reagent dispensing module 23 dispenses reagent into
`multiWell plates Which have been previously formatted With
`samples by the sample distribution module 22. The reagent
`dispensing module 23 may be substantially the same as the
`corresponding apparatus disclosed in pending U.S. applica
`tion Ser. No. 08/858,016 referenced above.
`The high capacity stacking system 28 provides a buffer for
`short term, temporary storage and retrieval of plates. The
`high capacity stacking system 28 can be used for bulk
`loading and unloading of sample plates, storage plates, assay
`plates and empty plates. Pending US. application Ser. No.
`08/858,016 describes one such high capacity stacking sys
`tem.
`The reaction module 25 provides a temporary repository
`With controllable environmental cond