United States Patent [19J
`Cunanan
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006024920A
`[11] Patent Number:
`[45] Date of Patent:
`
`6,024,920
`Feb.15,2000
`
`[54] MICROPLATE SCANNING READ HEAD
`
`[75]
`
`Inventor: Chris Cunanan, Moraga, Calif.
`
`[73] Assignee: Bio-Rad Laboratories, Inc., Hercules,
`Calif.
`
`[21] Appl. No.: 09/291,787
`
`[22] Filed:
`
`Apr. 14, 1999
`
`[60]
`
`[51]
`[52]
`
`[58]
`
`[56]
`
`Related U.S. Application Data
`Provisional application No. 60/082,570, Apr. 21, 1998.
`Int. Cl.7 ........................... GOlN 21/01; GOlN 21/59
`U.S. Cl. ........................... 422/65; 422/82.09; 356173;
`356/432; 435/288.7
`Field of Search .................................... 422/65, 82.08,
`422/82.09; 435/288.4, 288.7; 356/73, 432,
`440, 434
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,736,432
`4,240,751
`4,358,203
`5,169,601
`5,244,630
`5,580,524
`5,674,743
`
`5/1973 Sweet.
`12/1980 Linnecke et al. ....................... 422/102
`11/1982 Citrin ...................................... 356/432
`12/1992 Ohta et al. ........................... 422/82.09
`9/1993 Khalil et al. .............................. 422/52
`12/1996 Forrest et al. .
`10/1997 Ulmer.
`
`5,689,110 11/1997 Dietz et al. .
`5,853,666 12/1998 Seaton et al. .
`5,892,577
`4/1999 Gordon ................................ 422/82.09
`
`Primary Examiner-Jeffrey Snay
`Attorney, Agent, or Firm-David G. Beck; Townsend and
`Townsend and Crew, LLP
`
`[57]
`
`ABSTRACT
`
`A scanning head assembly is provided, the scanning head
`suited for use with instruments that characterize the
`absorption, fluorescence, and/or luminescence properties of
`one or more samples contained within a sample plate or
`microplate. The scanning head assembly is coupled to a pair
`of scanning mechanisms, thereby allowing the head assem(cid:173)
`bly to be raster scanned along both the x- and y-axis.
`Although the scanning preferably follows a serpentine
`pattern, other scan patterns can be utilized. Single or mul(cid:173)
`tiple measurements can be made per sample well, multiple
`measurements either being reported individually or aver(cid:173)
`aged together. Although the scanning head assembly can
`utilize a variety of configurations, in the preferred embodi(cid:173)
`ment the scanning head assembly has a C-shape with the
`light source and associated optics mounted in the lower arm
`of the assembly and the detector and associated optics
`mounted in the upper arm. Preferably the optics associated
`with the source include one or more optical filters that
`regulate the wavelength of light radiating the sample.
`
`21 Claims, 4 Drawing Sheets
`
`,101
`
`115
`
`I
`I
`
`Lj-------
`109
`
`103
`
`THERMO FISHER EX. 1019
`
`

`
`U.S. Patent
`
`Feb.15,2000
`
`Sheet 1 of 4
`
`6,024,920
`
`117
`
`j~-25 C5<::=::>;-,~
`c:::::> c:::> c:::>,.... /
`/ /
`- - - - - -
`~ - -
`- - - - - -('
`-
`I
`_,,.""
`I
`.;
`I
`I
`Lj-------------~_,,.
`109
`105
`103 _ _,
`
`1
`,,.
`
`FIG.
`
`I.
`
`211
`
`,203
`
`209
`
`205
`
`207
`~~~~~g_ -- - - -- -- -
`
`000 00000
`000 00000
`0 0 0 101 0 0 0 0 0
`000-00000
`000 00000
`000 00000
`000 00
`0
`
`r 221
`- _.J. __ --...,
`I
`I
`I
`I
`I
`
`217
`
`213
`
`I /
`I
`109 215~ - - - - - - - - - - - - - - - - .J
`FIG. 2.
`
`THERMO FISHER EX. 1019
`
`

`
`N =
`.... = N
`
`\C
`~ ....
`
`0--,
`
`.i;;..
`0 .....,
`N
`~ .....
`'Jl =(cid:173)~
`
`N c c c
`"""" Ul
`?'
`~
`"'!"j
`
`~
`
`~ = ......
`~ ......
`~
`•
`\JJ.
`d •
`
`FIG. 3.
`
`-------
`1
`I
`:
`:
`I
`...c, .. 315
`
`,---j__ -
`
`MONITOR
`POSITION
`Y-AXIS
`
`I
`
`:--x-ix1s --(313
`
`I
`
`_____ _J
`1
`I
`
`MONITOR
`POSITION
`
`L
`I
`
`-_ ~ 317
`
`i
`
`I
`-,
`
`1
`I
`
`L ____ j
`
`INCUBAIDR
`
`1
`I
`
`-
`
`,--
`
`L MECHANIS~ J
`I
`I
`1
`r --1----',. 215
`
`TRANSPORT
`
`PLATE
`SAMPLE
`
`1
`I
`
`1
`
`I
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-,--
`
`-
`
`-
`
`I __ -
`I
`I
`
`L
`I
`
`I
`1
`I
`.-----~-----. 203 :
`
`SYSTEM
`SCANNING
`Y-AXIS
`
`I
`I
`I
`I
`I
`
`SYSTEM
`SCANNING
`X-AXIS
`
`1201
`
`•
`
`,--_____ I
`
`CONTROLLER
`
`DEVICE
`INPUT
`USER
`
`306
`
`I
`I
`I
`303 _ {_ PROCESSOR j
`.-------,
`
`I
`,-----~
`r311
`
`FILTER
`
`~ _S~~TION __ :
`
`I
`
`r3QI
`
`I
`
`I
`
`.r309
`
`~ _D~E~T~R-j
`I
`r-----"i
`
`I
`
`REFERENCE
`
`DETECTOR
`
`SOURCE
`
`/107
`
`103
`
`I
`
`L ____ I
`305 -~--MEMORY--:
`f
`I 1------------
`I
`I
`I
`I __ _J
`
`'
`/307
`
`DEVICE
`OUTPUT
`DATA
`
`THERMO FISHER EX. 1019
`
`

`
`U.S. Patent
`
`Feb.15,2000
`
`Sheet 3 of 4
`
`6,024,920
`
`O') t---lr------+------~
`
`v
`
`,....., O')
`,.....,
`N " ' 'O
`
`ir.>
`
`\
`
`,....,I
`
`I
`~
`I
`~
`
`""",_ .. ~ T _ - 1\
`I-~ - - - -·1-1 ·-.
`~------'1
`t-- - - - - ,I
`1-------'
`1-------,1
`t- - - - - - ..JI
`t- -- - - 'I
`,- -- -- - ...J
`------,1
`I
`r------1
`c===.::-.=-J1
`'------,1
`1--------'1
`r-------.
`______ JI
`I -----,1
`~-----·
`1------,l
`r-----...JI
`-----...,,
`l_ ____ ..J
`L _____ ,I
`1------...J'
`r---- - ,I
`r---- - _JI
`r--- - 'I
`______ ...J
`L------,1
`l_ ____ ...J,
`l---- ---,
`1-- - - - - _.I
`1----- --,1
`r-- - - - ..JI
`1--- - - - -·1
`1--- - -- _J
`------,1
`I
`,------1
`,------,1
`______ ...)
`L _____ ,
`
`I
`
`I
`
`=1
`
`THERMO FISHER EX. 1019
`
`

`
`U.S. Patent
`
`Feb.15,2000
`
`Sheet 4 of 4
`
`6,024,920
`
`123
`
`109
`FIG. 5.
`
`FIG. 6.
`
`123
`
`109
`
`701
`
`-''07 .703 .,,,l
`
`FIG. 7.
`
`.705
`
`THERMO FISHER EX. 1019
`
`

`
`6,024,920
`
`1
`MICROPLATE SCANNING READ HEAD
`
`CROSS-REFERENCES TO RELATED
`APPLICATIONS
`
`This application claims benefit of U.S. Provisional Patent
`Application Ser. No. 60/082,570, filed Apr. 21, 1998, the
`disclosure of which is incorporated herein by reference for
`all purposes.
`
`FIELD OF THE INVENTION
`
`The present invention relates generally to microplate
`reading systems, and more particularly, to a method and
`apparatus for scanning a microplate in order to determine the
`fluorescence, luminescence, and/or absorption in each
`sample well of the microplate.
`
`BACKGROUND OF THE INVENTION
`
`2
`the plate can be moved at a slower rate and utilize gradual
`start and stop cycles. Additionally, the level of liquid within
`each sample well can simply be sufficiently below the top of
`the sample well to avoid spillage.
`An instrument that provides the benefits of multi-well
`sample plate scanning without the drawbacks associated
`with translating the sample plate along multiple axes is
`desired. The present invention provides such an instrument.
`
`SUMMARY OF THE INVENTION
`
`5
`
`10
`
`The present invention provides a scanning head assembly
`for use in a variety of different instrument types. For
`example, the scanning head assembly of the present inven(cid:173)
`tion can be used to characterize the absorption, fluorescence,
`15 or luminescence properties of one or more samples. Prefer(cid:173)
`ably the instrument is capable of use with various microplate
`sizes and formats, thus providing maximum flexibility to the
`user.
`In one aspect of the invention, the scanning head assem-
`20 bly has a C-shape with the light source mounted in one arm
`of the C-shaped assembly and the detector mounted in the
`other arm of the assembly. Preferably the source and asso(cid:173)
`ciated optics are in the lower arm and the detector and
`associated optics are in the upper arm of the assembly. The
`25 invention can utilize other configurations as well, such as
`having the source in the upper arm and the detector in the
`lower arm. Alternatively, a non-C-shaped configuration can
`be used in which both the source and the detector are
`mounted within the same arm.
`In another aspect of the invention, the scanning head
`assembly is coupled to a pair of scanning mechanisms that
`allow the head assembly to be raster scanned relative to a
`sample microplate along both the x- and y-axis. Although
`the scanning preferably follows a serpentine pattern, other
`scan patterns can be utilized. Single or multiple measure(cid:173)
`ments can be made per sample well, multiple measurements
`either being reported individually or averaged together.
`In another aspect of at least one embodiment of the
`invention, the source is a xenon flash lamp mounted within
`one arm of the head assembly. The light from the xenon
`lamp is conditioned and collimated with a series of apertures
`and lenses. Preferably the source light passes through a filter
`in order to limit the light wavelengths radiating the sample.
`The filter can be any of a variety of different filter types (e.g.,
`bandpass, cutoff, etc.) and is preferably one of a series of
`filters accessible through a filter wheel or other filter selec(cid:173)
`tion system. Prior to irradiating the sample, a portion of the
`source light is separated using a beam splitter, the separated
`portion being used to monitor variations in the output of the
`source. The light from the sample passes through an aperture
`and is collected by a lens that focuses the sample light onto
`the measurement detector.
`In another aspect of at least one embodiment of the
`invention, the scanning head assembly is coupled to a
`controller containing one or more processors. The controller
`is used to monitor and control the position of the scan head
`relative to the sample plate. The controller is also used
`during data collection and processing, lamp source control,
`and filter selection.
`A further understanding of the nature and advantages of
`the present invention may be realized by reference to the
`remaining portions of the specification and the drawings.
`
`Bio-chemical researchers involved in high throughput
`screening and/or drug and chemical development require the
`capability to characterize millions of samples accurately and
`rapidly. Due to this requirement, sample testing is often
`performed in sample plates that may include tens, hundreds,
`or even thousands of individual sample wells. The use of
`such multi-well sample plates simplifies automation of
`sample testing, assuming the necessary test equipment is
`compatible with multi-well sample plates.
`In designing high throughput test apparatus, typically a
`variety of system constraints are considered. The first critical 30
`design parameter is the intended use of the test apparatus.
`For example, the apparatus may be designed to characterize
`a sample's absorption, luminescence, or fluorescence prop(cid:173)
`erties. Additionally, the test apparatus may be designed to be
`capable of testing more than one property. A second critical 35
`design parameter is the size and format of the sample plate.
`Currently there are a variety of available standard format
`sample plates containing varying numbers of sample wells
`and types. These sample plates typically have different
`external dimensions and may also have different sample well 40
`dimensions. Although most instruments are designed to
`handle only a specific sample plate format, some instru(cid:173)
`ments are designed to handle a range of sample plate
`formats. A third design parameter that is typically taken into
`account is the size and design of the individual sample wells. 45
`For example, sample wells vary in size from microns in
`diameter as utilized in some chip sample plates to millimeter
`sized wells or larger. Additionally, sample wells may be of
`varying depth, comprised of transparent or opaque materials,
`and utilize any of a variety of shapes, e.g., square or round 50
`cross-sections. Sample wells may also include a reflective
`bottom surface. Preferably an instrument is capable of
`handling a range of sample well types.
`In a standard multi-well sample plate testing apparatus the
`sample plate is held within a holding fixture that is coupled 55
`to one or more scanning mechanisms. The scanning mecha(cid:173)
`nisms allow the sample plate to be moved along at least one
`axis relative to the portion of the instrument used to char(cid:173)
`acterize the sample (e.g., an excitation source and a fluo(cid:173)
`rescence detector). Preferably the scanning mechanisms 60
`allow the sample plate to be moved along two axes, thus
`allowing a two-dimensional array of sample wells to be
`analyzed. Although moving the sample plate may cause
`problems such as sample spillage, typically these problems
`are minor in comparison to the difficulties associated with 65
`scanning the test head relative to a fixed sample plate. For
`example, to avoid sample spillage during plate movement,
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 schematically illustrates the basic apparatus
`according to the invention;
`
`THERMO FISHER EX. 1019
`
`

`
`3
`FIG. 2 is an illustration of an instrument utilizing a read
`head assembly according to the invention;
`FIG. 3 schematically illustrates the control system utilized
`in the preferred embodiment of the invention;
`FIG. 4 is a schematic representation of the cross-section 5
`of the preferred embodiment of the read head assembly;
`FIG. 5 is an illustration of the preferred scanning pattern;
`FIG. 6 is an illustration of an alternative scanning pattern;
`and
`FIG. 7 is a cross-sectional view of a single sample well,
`illustrating various interrogation techniques in accordance
`with the present invention.
`
`DESCRIPTION OF THE SPECIFIC
`EMBODIMENTS
`
`FIG. 1 schematically illustrates the basic apparatus
`according to the invention. The system is comprised of a
`read head 101 that is preferably C-shaped. The C-shape of
`read head 101 allows a source 103 radiating light in a
`direction 105 to be mounted within one arm of the head
`assembly and a detector 107 (shown in phantom) to be
`mounted within the second arm of the head assembly. It
`should be understood that although the illustrated configu(cid:173)
`ration is preferred, in at least one embodiment the source and
`the detector are mounted in the same arm of the head
`assembly, thus eliminating the need for the C-shape of the
`assembly. Although placement of source 103 and detector
`107 in opposite arms of read head 101 simplifies the optical
`constraints placed on the system, this configuration requires
`that the bottom surface of the sample well(s) be substantially
`transparent at the wavelengths of interest.
`A sample plate, or microplate, 109 (shown in phantom)
`containing either a single sample well or multiple sample
`wells as shown fits between lower arm 111, upper arm 113,
`and back portion 115 of head assembly 101. Preferably
`source 103 and detector 107 are mounted near the ends of
`arms 111 and 113, respectively. The primary limitation on
`the size of plate 109 that can be read using head assembly
`101 is the distance between the end portions of arms 111 and
`113, i.e., the locations of source 103 and detector 107, and
`a front surface 117 of back portion 115.
`Due to the compact design of head assembly 101, it can
`easily be moved relative to sample plate 109 along both
`x-axis 119 and y-axis 121. Moving head assembly 101 rather
`than the sample plate allows plate 109 to remain motionless
`during characterization, thereby providing several benefits.
`First, limiting the motion of plate 109 limits the possibility
`of liquid within an individual sample well 123 from splash- 50
`ing out of the well. Loss of liquid through splashing can alter
`the chemical reaction not only of the sample well from
`which liquid was lost, but also in adjacent sample wells that
`may receive some of the splashed liquid. Second, by not
`requiring movement of plate 109 during a reading, the 55
`amount of mixing within sample wells 123 can be con(cid:173)
`trolled. For example, it may be desirable to provide no
`additional mixing after each of the components of a multi(cid:173)
`component sample has been placed within a sample well.
`Alternatively, it may be desirable to provide mixing by 60
`controllably shaking plate 109 for a specific period of time
`with a specific vibrational amplitude and frequency. In this
`instance plate 109 can be coupled to a vibration table or
`other mechanism.
`Depending upon the design, location, and output charac- 65
`teristics of source 103; the design, location, and detection
`characteristics of detector 107; and the transmission char-
`
`6,024,920
`
`20
`
`4
`acteristics of the bottom surface of sample wells 123; head
`assembly 101 can be used in a variety of different testing
`schemes. In the preferred embodiment of the invention, light
`105 from source 103 passes through the bottom surface of
`the sample well, through the sample within an individual
`sample well, and is detected by detector 107, thereby
`providing a measure of the absorption characteristics of the
`sample. Alternatively, the locations of source 103 and detec(cid:173)
`tor 107 can be exchanged, thus locating source 103 in upper
`arm 113 and detector 107 in lower arm 111. The head
`10 assembly can also be used in instruments designed to
`determine the fluorescence or luminescence of a sample.
`FIG. 2 is an illustration of an instrument 200 utilizing read
`head assembly 101. Head assembly 101 is coupled to an
`15 x-axis scanning system 201 and a y-axis scanning system
`203, thus allowing the source and detection portions of the
`head assembly to be used to analyze the samples contained
`in every sample well 123 of sample plate 109. As shown,
`x-axis scanning system 201 is comprised of a belt and pulley
`system 205 and a drive motor 207. Similarly, y-axis scan(cid:173)
`ning system 203 is comprised of a belt and pulley system
`209 and a drive motor 211. Although belt and pulley systems
`are used in the preferred embodiment of the invention, it
`should be apparent to one of skill that other scanning
`25 systems could be used such as gear drive systems, etc.
`In at least one embodiment of the invention, sample 109
`is held on a sample plate carrier 213. Plate carrier 213
`preferably uses a sample holding fixture that is either
`adjustable or can be used with various sample plate adaptors,
`30 thus allowing a variety of different sample plates (e.g., 6, 12,
`24, 48, 96, and 384 well microplates, etc.) to be used with
`instrument 200. Although plate carrier 213 can be designed
`to accommodate any size sample plate, preferably it is
`designed to accommodate at least a standard 96 well sample
`35 plate (i.e., 130 millimeters by 95 millimeters).
`Plate carrier 213 can be coupled to a second x-axis
`transport mechanism 215, mechanism 215 using either a belt
`and pulley system 217 and drive motor 219 as shown, or
`another type of transport mechanism. System 215 is used to
`40 move plate carrier 213, and thus sample plate 109, into
`position for characterization by assembly 101. System 215
`can also be used to move sample plate 109 into another
`preparation and/or testing region 221. In the preferred
`embodiment, region 221 is an incubator that can be used to
`45 control the temperature and/or humidity of the sample plate.
`Preferably the incubator is programmable from ambient to
`42° C. in 0.2° C. increments and maintains a temperature
`variation across the sample plate of less than or equal to 0.5°
`c.
`FIG. 3 schematically illustrates the control system utilized
`in the preferred embodiment of the invention. A controller
`301 is used to control the various functions of the
`instrument, ranging from sample scanning to data process(cid:173)
`ing. Controller 301 may utilize one or more processors 303
`and contain memory 305 for storing instructions and data.
`Controller 301 preferably controls all aspects of head assem-
`bly 101 including source 103, detector 107, and x- and
`y-axis scanning systems 201 and 203, respectively. The user
`inputs any required system operation parameters (e.g.,
`sample plate type, well size and number, well spacing, scan
`mode, number of measurements to be made per sample well,
`whether or not to average readings, etc.) using a user input
`device 306 such as a keyboard, touchscreen, etc. Controller
`301 outputs the data with a data output device 307, e.g., a
`printer, plotter, or monitor.
`In addition to controlling the instrument as outlined
`above, controller 301 can also be used to control other
`
`THERMO FISHER EX. 1019
`
`

`
`6,024,920
`
`10
`
`15
`
`5
`aspects o~ the instrument. For example, if read head assem(cid:173)
`bly 101 mcludes a reference detector 309, controller 301
`preferably receives the output from detector 309 thus allow(cid:173)
`ing relative i:neasurements to be made. Additiodally, assem(cid:173)
`bly 101 can mclude one or more filter wheels 311 to control 5
`the wavelength of radiation from source 103 impinging upon
`the samples and/or the wavelengths detected by detector
`107: .control~er 301 can also be coupled to x- and y-axis
`pos1t10n momtors 313 and 315, respectively, these monitors
`providing sample plate carrier location feedback to the
`con~ro system. Lastly, if the instrument includes multiple
`1
`testmg and/or preparation regions as briefly described
`above, controller 301 can be used to control sample plate
`transp.ort me~hanism 215 as well as the additional region
`(e.g., mcubat10n chamber humidity and temperature control
`317).
`FIG. 4 is a cross-sectional view of the preferred embodi(cid:173)
`ment of read head assembly 101. In this embodiment read
`~ead assembly.1~1 is designed to analyze a samples absorp(cid:173)
`tion charactenstics. Assembly 101 includes source 103,
`preferably a xenon flash lamp. Other types of sources (e.g.,
`laser sources) can also be used with the invention, either
`mounted within assembly 101 as in the preferred embodi(cid:173)
`ment or mounted separately from assembly 101 and opti(cid:173)
`cally coupled to the assembly using optical fibers or other
`~ea?s .. The radiation from source 103 is conditioned prior to
`impmgmg upon a sample, thus insuring that the beam has a
`sufficiently narrow beam diameter. In the illustrated
`embodiment, the output of source 103 passes through an
`aperture 401 and a lens 403 prior to being reflected by mirror 30
`405 along path 105. A second lens 407 further conditions the
`beam prior to its emergence from head assembly 101. In the
`preferred embodiment lens 401 is a convex-convex lens with
`a diameter of 20 millimeters and a focal length of 20
`millimeters and lens 407 is a collimating plano-convex lens 35
`with a diameter of 10 millimeters and a focal length of 20
`millimeters. This embodiment also includes apertures
`409-412 with 2, 1.5, 1.5, and 0.3 millimeter diameter
`apertures, respectively.
`In at least one embodiment of the invention, the output of
`source 103 is tunable using a filter 413 such as a bandpass
`filter, a cutoff filter, etc. Filter 413 is selected from a series
`of filters, preferably contained in a filter wheel 415. The
`selection of filter 413 from filter wheel 415 is preferably
`automated using a filter wheel motor 417 coupled to pro(cid:173)
`cessor 301. Source wavelength selection can also be accom(cid:173)
`plished using a diffraction grating either mounted within
`head assembly 101 or, for the case of an externally mounted
`source, mounted separate from the head assembly.
`Prior to exiting from lower arm 111, output beam 105
`preferably passes through a beam splitter 419, reflecting a
`portion of light 421 towards reference detector 309. Prefer(cid:173)
`ably beam splitter 419 is a quartz plate, reflecting approxi(cid:173)
`mately 20 percent of the incident light and transmitting
`approximately 80 percent of the incident light. Detector 309 55
`is preferably a photodiode. Detector 309 is used to monitor
`variations in the output of source 103.
`Shown in phantom in FIG. 4 is a representative sample
`plate 109 and representative sample wells 123. In this
`embodiment of the invention, light beam 105, exiting lower 60
`arm 111 after passing through beam splitter 417, passes
`~hrough the sampl~ well 123 being characterized. The light
`m beam 105 that is not absorbed by the sample within the
`well, or by the bottom surface of the well, passes through an
`aperture 423 and is focussed by a lens 425 onto detector 107. 65
`Preferably aperture 423 is 4.5 millimeters in diameter lens
`425 is a 6 millimeter diameter ball lens, and detector l07 is
`
`6
`a. silicon photodiode. In addition to monitoring output varia(cid:173)
`tions from source 103, the ratio of the output of reference
`detector 309 to the output of measurement detector 107 can
`be used to determine the relative absorption of a sample. In
`the preferred embodiment of the invention, the instrument is
`capable of measuring optical densities (i.e., OD) between
`0.000 and 4.000, outputting this information via data output
`device 307.
`As noted, an instrument designed in accordance with the
`present invention can be used to determine various sample
`characteristics such as fluorescence and luminescence
`although in the preferred embodiment it is used to determin~
`the absorption of samples. Additionally, the instrument can
`be designed to scan a sample plate in a number of ways. In
`the preferred embodiment, read head assembly 101 raster
`scans sample plate 109 in a serpentine pattern 501 as
`illustrated in FIG. 5. This is the preferred scan mode as it
`allows each sample to be characterized rapidly and effi(cid:173)
`ciently. Alternatively as shown in FIG. 6, all of the rows (or
`20 columns) can be scanned in the same direction 601. In a third
`alternative, the user can program controller 301 to move
`head assembly 101 to specific sample wells (e.g., a subset of
`all of the samples) and/or to interrogate the sample wells in
`a specific order.
`FIG. 7 is a cross-sectional view of a single sample well
`701, representative of one of a plurality of sample wells in
`a sample plate. In accordance with the present invention,
`s~mple ~ell 701 can be interrogated in a variety of ways.
`First, a smgle measurement can be made at a single location
`703. The volume of the sample within well 701 that is
`interrogated in this measurement depends upon the diameter
`of light beam 105 as it passes through the sample. It should
`be understood that although location 703 is shown in the
`cente.r of well 701, other locations can also be used (e.g.,
`locat10n 705) that are off-center. Second, multiple locations
`707 can be interrogated. It should be understood that both
`fewer and greater numbers of locations 707 can be used with
`the invention and that the locations shown are only meant to
`be illustrative. Preferably the user can preset the number of
`40 locations as well as the pattern of locations (e.g., circular or
`square pattern). The measured value (e.g., OD) for each
`location can be reported or an average value can be deter(cid:173)
`~ined and reported. Preferably in either sample interroga(cid:173)
`t~on mode, controller 301 causes source 103 to flash a single
`45 time for each measurement being performed. Those of skill
`in the art will understand that other methods of controlling
`source 103 are equally applicable to the present invention.
`As will be understood by those familiar with the art the
`present invention may be embodied in other specific f~rms
`without departing from the spirit or essential characteristics
`thereof. Accordingly, the disclosures and descriptions herein
`are intended to be illustrative, but not limiting, of the scope
`of the invention which is set forth in the following claims.
`What is claimed is:
`1. A sample plate scanning system, comprising:
`a head assembly with a first arm portion, a second arm
`portion, and a connecting portion rigidly coupling said
`first and second arm portions;
`a first transport system coupled to said head assembly for
`scanning said head assembly along a first axis;
`a second transport system coupled to said head assembly
`for scanning said head assembly along a second axis
`said second axis substantially orthogonal to said firs~
`axis;
`a sample plate holder for holding a sample plate in a
`sample reading position, wherein said sample plate is
`
`25
`
`50
`
`THERMO FISHER EX. 1019
`
`

`
`6,024,920
`
`7
`interposed between said first arm portion and said
`second arm portion when said sample plate is in said
`sample reading position;
`a source of radiation coupled to said first arm portion,
`wherein said radiation is directed along a first optical 5
`path from said first arm portion towards said second
`arm portion; and
`a detector coupled to said second arm portion, wherein
`said detector detects radiation along said first optical
`path, said detector outputting a signal corresponding to 10
`an amplitude associated with said detected radiation.
`2. The sample plate scanning system of claim 1, wherein
`said source of radiation comprises a xenon lamp.
`3. The sample plate scanning system of claim 2, wherein
`said xenon lamp is mounted within said first arm portion.
`4. The sample plate scanning system of claim 1, said
`radiation source further comprising at least one collimating
`lens and at least one aperture, said radiation from said source
`passing through said at least one collimating lens and said at
`least one aperture prior to exiting said first arm portion 20
`towards said second arm portion along said first optical path.
`5. The sample plate scanning system of claim 3, further
`comprising:
`a first lens mounted within said first arm portion, wherein
`said radiation traveling along a second optical path 25
`passes through said first lens;
`a turning mirror mounted within said first arm portion,
`wherein said radiation passing through said first lens
`along said second optical path is directed along said
`first optical path by said turning mirror; and
`a second lens mounted within said first arm portion,
`wherein said radiation directed by said turning mirror
`along said first optical path passes through said second
`lens prior to exiting said first arm portion towards said
`second arm portion along said first optical path.
`6. The sample plate scanning system of claim 5, wherein
`said first lens is a convex-convex lens with a first focal
`length of 20 millimeters and said second lens is a plano(cid:173)
`convex lens with a second focal length of 20 millimeters.
`7. The sample plate scanning system of claim 5, further
`comprising:
`a first aperture interposed between said first and second
`lenses; and
`a second aperture following said second lens, wherein
`radiation passes through said second aperture prior to
`exiting said first arm portion towards said second arm
`portion along said first optical axis.
`8. The sample plate scanning system of claim 1, further
`comprising an optical filter, wherein radiation from said
`source passes through said optical filter prior to exiting said
`first arm portion towards said second arm portion long said
`first optical path, wherein said optical filter limits said
`radiation to a predetermined wave length band.
`9. The sample plate scanning system of claim 1, further 55
`comprising:
`a plurality of optical filters, wherein each of said plurality
`of optical filters passes a predetermined band of wave(cid:173)
`lengths; and
`an optical filter transport system coupled to said plurality 60
`of optical filters and mounted to said first arm portion,
`wherein said optical filter transport system interposes a
`selected one of said plurality of optical filters between
`said radiation source and a first arm portion exit aper(cid:173)
`ture.
`10. The sample plate scanning system of claim 1, further
`comprising:
`
`8
`a beam splitter mounted within said first optical path,
`wherein a first portion of radiation passes through said
`beam splitter and continues along said first optical path
`and exits said first arm portion; and
`a reference detector, wherein a second portion of radiation
`is reflected by said beam splitter along a second optical
`path, wherein said reference detector detects radiation
`along said second optical path, said reference detector
`outputting a reference signal corresponding to a refer(cid:173)
`ence amplitude of said radiation detected along said
`second optical path.
`11. The sample plate scanning system of claim 1, further
`comprising:
`a beam splitter mounted within said first arm portion,
`wherein a first portion of said radiation from said
`source is reflected and directed along said first optical
`path; and
`a reference detector, wherein a second portion of radiation
`is transmitted by said beam splitter along a second
`optical path, wherein said reference detector detects
`radiation along said second optical path, said reference
`detector outputting a reference signal corresponding to
`a reference amplitude of said radiation detected along
`said second optical path.
`12. The sample plate scanning system of claim 1, wherein
`said detector is a photodiode mounted within said second
`arm portion.
`13. The sample plate scanning system of claim 1, further
`comprising a lens mounted within said second arm portion,
`30 wherein said lens collects at least a portion of said radiation
`passing along said first optical path, and wherein said lens
`focuses said collected radiation onto said detector.
`14. The sample plate scanning system of claim 1, further
`comprising an aperture m