United States Patent c191
`Bjornson et al.
`
`I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll llllll Ill lllll llll
`US005125748A
`5,125,748
`[11] Patent Number:
`[45] Date of Patent:
`Jun. 30, 1992
`
`Primary Examiner-F. L. Evans
`Attorney, Agent, or Firm-William H. May; Paul R.
`Harder; Wen Liu
`
`ABSTRACT
`[57]
`An automated multi-purpose analytical chemistry pro(cid:173)
`cessing center and laboratory work station having a
`movable table for supporting microtiter plates and other
`fluid receptacles, a movable arm, and a modular mobile
`pod affixed for reciprocal movement along the arm.
`The workstation combines into a single programmable
`system the capabilities for automation of a wide range
`of bioanalytical procedures including, not only sample
`pipetting, serial dilution, reagent additions, mixing, re(cid:173)
`action timing and similar known manual procedures,
`but also programmable spectrophotometric measure(cid:173)
`ments and other physical parameters, further processing
`based on these measurements and automatic data re(cid:173)
`cording. The work station is adapted to transfer, dis(cid:173)
`pense, and aspirate liquid from one location to another
`automatically in accordance with user programmed
`instructions. The work station is capable of measuring
`physical characteristics of selected samples and per(cid:173)
`forming experimental assays in a closed loop manner in
`accordance with those measurements. Fluid is dis(cid:173)
`pensed and aspirated using an interchangeable modules
`having one or a selected plurality of nozzles. Affixed to
`the modules nozzles are disposable pipettor tips, which
`are automatically picked up by the pod and ejected by
`a tip ejector mechanism at the control of the user. Addi(cid:173)
`tional modules may be used to perform Measurement
`Functions. The work station is designed for interactive
`connection with a remote computer.
`19 Claims, 16 Drawing Sheets
`
`(75]
`
`[54] OPTICAL DETECTION MODULE FOR USE
`IN AN AUTOMATED LABORATORY WORK
`STATION
`Inventors: Torleif 0. Bjornson, Milpitas; R.
`Freel Pfost, Los Altos; both of Calif.
`[73] Assignee: Beckman Instruments, Inc.,
`Fullerton, Calif.
`(21] Appl. No.: 698,756
`(22] Filed:
`
`May 10, 1991
`
`Related U.S. Application Data
`
`[60) Division of Ser. No. 383,299, Jul. 20, 1989, Pat. No.
`5,104,621, which is a continuation of Ser. No. 844,374,
`~ar. 26, 1986, abandoned.
`Int. Cl.s ......................... GOlJ 3/51; GOIN 21/27
`[51]
`[52) U.S. Cl . .................................... 356/414; 356/418;
`422/63; 422/82.09
`[58] Field of Search ............... 356/402, 409, 414, 416,
`356/418, 419, 432, 436, 440; 422/63, 67, 82.05,
`82.09; 436/43.50, 164
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,090,791 5/1978 Siddiqi et al. ....................... 356/414
`4,495,149 1/1985 Iwata et al. ........................... 422/65
`
`FOREIGN PATENT DOCUMENTS
`
`136002 4/1985 European Pat. Off ............. 356/432 _
`0138205 4/1985 European Pat. Off ..
`2089034 6/1982 United Kingdom .
`
`22
`
`Agilent Exhibit 1217
`Page 1 of 41
`
`

`

`00
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`
`•
`• en
`c::
`
`U.S. Patent
`
`5,125,748
`
`FIG I
`
`46
`
`39
`
`/
`
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`
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`
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`Agilent Exhibit 1217
`Page 2 of 41
`
`

`

`00
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`~ = = (t)
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`~ = '"1'-
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`
`FIG 2
`
`z y X p
`
`SENSORS
`POSITION
`
`CZ-AXIS)
`MOTOR
`. DRIVE
`ARM
`
`(Y-AXIS)
`MOTOR
`DRIVE
`POD
`
`122 (X-AXIS)
`I' MOTOR
`DRIVE
`TABLE
`
`128-..
`
`~
`
`126-..
`
`•
`
`124-...
`
`PUMP
`
`REAGENT
`
`BULK
`
`INTERFACE
`
`,-/34
`
`I
`
`DISPLACEMENT
`
`I
`PUMP
`
`POD MOTOR
`
`DRIVEN
`
`1
`
`132-.....
`
`DETECTOR
`
`TRANSDUCER/
`
`-
`
`/'/40
`
`I
`I
`I
`1""100
`
`f
`
`1
`
`120 .....
`
`~30
`
`MOTOR
`
`POD
`
`MICROPROCESSOR
`
`I
`
`(12
`
`'--138
`
`MODULE ID
`
`IMODULEI
`I
`52-...
`
`REMOTE COMPUTER I
`
`Agilent Exhibit 1217
`Page 3 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 3 of 16
`
`5,125,748
`
`FIG 3A
`
`/68
`
`38
`154
`
`38
`
`FIG 38
`
`22
`
`Agilent Exhibit 1217
`Page 4 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 4 of 16
`
`5,125,748
`
`FIG. 3C
`
`24
`
`183
`
`Agilent Exhibit 1217
`Page 5 of 41
`
`

`

`00
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`...
`U1
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`1-l
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`U1
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`w
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`CONVERTER SLf1IL
`
`V/F
`
`I UP-El~
`
`·202
`
`I
`
`I
`
`.. , SYNCI-RONOUS
`
`CIRCUIT
`DETECTION
`
`I
`
`FIG 4
`
`VREF
`
`CHOPPER
`
`FROM
`
`o.c.
`
`204
`
`B
`
`SIGNAL
`ERROR
`o.c.
`
`196
`
`-Ml
`
`DECODER
`
`EIU-UP
`FROM
`
`·/99
`
`Agilent Exhibit 1217
`Page 6 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 6 of 16
`
`5,125,748
`
`42
`
`+VOLTS
`
`212
`
`CLOCK
`J1.MM
`
`TIMER
`TRIGGER
`
`R S
`
`206
`·•H
`
`C
`
`210
`
`--~--
`
`TIMER
`TRIGGER
`
`S R
`
`213
`
`219
`
`209
`
`FIG. 5
`
`52
`
`Agilent Exhibit 1217
`Page 7 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 7 of 16
`
`5,125,748
`
`J--_
`
`__,__2_:J_4_...._ A
`
`)¢
`
`2~~
`
`B~
`
`FIG 6
`
`241
`
`27'0'
`
`FIG T
`
`Agilent Exhibit 1217
`Page 8 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 8 of 16
`
`5,125,748
`
`24/
`
`240
`
`FIG. 8
`
`Agilent Exhibit 1217
`Page 9 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 9 of 16
`
`5,125,748
`
`241
`
`240
`
`.
`
`I 0
`
`FIG. 9
`
`Agilent Exhibit 1217
`Page 10 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 10 of 16
`
`5,125,748
`
`240~~~~~~------r~---t---....e~,,_.-----..
`1
`282
`LOCK __.i.. UNLOCK
`r--2ii- -------- --27i -Ti . 2J6 '
`1\
`,,. I ·~· .r
`1
`f".:y !--,
`'):'')
`• ...:~
`I -~
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`\,t.,' J
`I U,'
`,
`·-------- -- -------- ______________ ,
`I
`I I
`: I I
`I
`
`11
`
`I
`
`270'
`
`• -
`
`272
`
`FIG 10
`
`Agilent Exhibit 1217
`Page 11 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 11 of 16
`
`5,125,748
`
`EXTERNAL
`VACUUM " 4 - - - - 1 . . . - -C I
`SOURCE
`
`302
`
`VACUUM
`FLASK
`
`300
`
`PINCH
`VALVE
`
`304
`
`290
`
`BULK
`296
`292
`------'---...i DISPENSER 1---------.
`PUMP
`POD
`298
`
`BULK
`RESERVOIR
`
`FIG. /IA
`
`Agilent Exhibit 1217
`Page 12 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`. Sheet 12 of 16
`
`5,125,748
`
`I,
`
`294
`
`FIG. 1/B
`
`476
`
`FIG. /IC
`
`Agilent Exhibit 1217
`Page 13 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 13 of 16
`
`5,125,748
`
`ELIMINATE
`INVALID ANSWERS
`
`OBTAIN
`TEMPLATE VALUE
`
`320
`
`322
`
`326
`
`USE TEMPLATE
`VALUE
`
`328
`
`OBTAIN
`PARAMETER
`FROM USER
`
`327
`
`USE VALID
`PARAMETER
`
`FIG. 12
`
`Agilent Exhibit 1217
`Page 14 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 14 of 16
`
`5,125,748
`
`-
`l
`~ ,_ _____ _
`~ ii------
`~------
`,,, .,_ _____ _
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`~ .-------
`..... r-·-·-·-·-
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`
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`
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`
`Agilent Exhibit 1217
`Page 15 of 41
`
`

`

`QC
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`
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`
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`
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`
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`I
`
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`
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`
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`
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`
`LOG
`
`37h
`
`36'6
`
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`
`316
`
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`
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`
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`
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`
`LOG
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`
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`
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`
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`
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`
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`I
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`
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`(INCLUDING TABLE)
`
`PARAMETERS
`REMAINING
`
`344../
`
`342./
`
`----
`
`PARAMETERS
`DESTINATION
`
`-------•
`
`PARAMETERS
`
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`
`---•
`
`I
`
`PARAMETERS
`
`TRANSFER
`
`'
`
`VOLUME
`
`I
`
`'
`
`~
`
`TIP
`I
`
`_,..
`
`-.. WHERE?
`
`TIP TOUCH
`
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`
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`
`TYPE
`
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`
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`
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`
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`
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`
`HEIGHT
`
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`
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`
`Agilent Exhibit 1217
`Page 16 of 41
`
`

`

`U.S. Patent
`
`June 30, 1992
`
`Sheet 16 of 16
`
`5,125,748
`
`412
`
`MICROPROCESSOR
`
`n 2.5 MHz
`
`4/4r
`
`4/6
`
`FREQUENCY
`DIVIDER
`
`(I')
`
`(I')
`::,
`~ ID
`~
`~
`
`(I')
`(I')
`uJ
`
`ls
`0
`ct
`
`nn
`
`IOOKHz
`
`490
`
`\
`
`420
`
`494
`
`496
`
`INTERRUPT
`CONTROLLER
`
`FIG. 158
`
`OTHER MOTOR CONTROLLERS
`
`OUTPUT
`PORT
`
`DIRECTION
`
`GATE
`
`450
`
`430
`
`440
`
`COUNTER
`
`(RATE
`GENERATOR
`MODE)
`
`MOTOR
`CONTROLLER
`
`444
`
`COUNTER
`
`(INTERRUPT
`ON TERMINAL
`COUNT MODE)
`
`MOTOR
`
`FIG. 15A
`
`Agilent Exhibit 1217
`Page 17 of 41
`
`

`

`OPTICAL DETECTION MODULE FOR USE IN AN
`AUTOMATED LABORATORY WORK STATION
`
`This is a divisional of application Ser. No. 07 /383,299
`filed Jul. 20, 1989, now U.S. Pat. No. 5,104,621, which
`is a continuation of application Ser. No. 06/844,374
`filed Mar. 26, 19,86, now abandoned.
`
`FIELD OF THE INVENTION
`This invention relates to an analytical chemistry pro(cid:173)
`cessing center and clinical and research laboratory
`workstation capable of performing the functions of
`several individual instruments, and, more particularly,
`to an automated laboratory work station useful in the
`performance of numerous chemical, biochemical, and
`biological assays and reactions.
`
`BACKGROUND OF THE INVENTION
`Modern research and clinical laboratory procedures 20
`include biological and chemical analysis of specimen
`substances that require extensive fluid manipulations.
`Many of the routine applications used for analysis are
`bioassays, immunoassays, viral assays, mitogen assays,
`serology, protein assays, lymphokine assays, and sample 25
`aliquoting. Experimental biological and clinical re(cid:173)
`search include the use of photometric analysis of chemi(cid:173)
`cal reactions after the reactions have reached equilib(cid:173)
`rium or a fixed end point. Certain enzyme assays require
`a two-point or multi-point analysis embodying kinetic 30
`assays.
`Standard fluid transfer and manipulative techniques
`include pipetting, diluting, dispensing, aspirating and
`plate washing. Conventional assays may be performed,
`in part, by rapid manipulation of manual pipettors or 35
`conducting assays which are piecemeal automated.
`Heretofore, the measurement portion of the assay, in(cid:173)
`ctuding determining optical or pH parameters, have
`been entirely manual or semi-automated. Common as(cid:173)
`says such as ELISA (enzyme linked immunoassay), 40
`viral, protein, and other biochemical studies and experi(cid:173)
`mentation require liquid handling such as sample prepa(cid:173)
`ration, serial dilution, reagent addition and sample
`transfer to yield results. Bioassays and chemical experi(cid:173)
`mentation which require making use of such liquid han- 45
`dling techniques, when performed manually, are replete
`with potential inaccuracies and error. It is difficult for a
`laboratory technician to accurately dispense the exact
`amount of liquid in each of 96 wells on a plurality of
`microtiter plates. The repetitious nature of liquid han- 50
`dling for experimentation inherently leads to mistakes
`which cannot always be detected. What has not hereto(cid:173)
`fore been within the domain of biotechnology is a sys(cid:173)
`tem which allows a bioassay to be carried out automati(cid:173)
`cally from start to finish with little or no need for 55
`human intervention once the assay has begun.
`Traditionally, the foregoing experimental, clinical,
`and other laboratory procedures require tedious step(cid:173)
`by-step sample and control preparation which are then
`sequenced through a series of operations depending on 60
`the raw measurements, their analysis, and the nature of
`the chemical or biological investigation. As an example,
`the conventional experimental procedure for the pro(cid:173)
`duction of monoclonal antibodies is essentially un(cid:173)
`changed since first reported by Kohler and Milstein in 65
`Nature(Vol. 256, pp. 495-497-1975). Briefly, a mouse or
`rat is injected with an immunogen or antigen. The ani(cid:173)
`mal responds to the antigenic challenge by the produc-
`
`1
`
`5,125,748
`
`2
`tion of antibodies. Mouse spleen cells from immunized
`animals are dissociated and fused with myeloma cells.
`Some of the resulting hybrids will include cells that
`produce only antibodies against one site on the chal-
`5 lenge antigen.
`Hybridoma selection and screening is a biotechnolog(cid:173)
`ical procedure where samples of cell culture superna(cid:173)
`tants of cancerous myeloma cell hybridomas (a hybrid
`of a cancerous myeloma cell and a challenged lympho-
`10 cyte) are tested to create, by manual pipetting, from
`sample volumes from growth plates to assay plates, a
`hybrid for the purpose of producing a single antibody
`with the immortal growth characteristics of the cancer(cid:173)
`ous cell. The number of samples which require testing
`15 are commonly as great as 750. In order to select the
`desired hybrid cell, it is necessary to begin an experi(cid:173)
`mental run starting with a single cell placed into hun(cid:173)
`dreds of microtiter plate compartments or wells. Tradi-
`tionally, the researcher manually analyzes each of the
`specimens after each clone has had a chance to grow
`and then determines whether the desired antibodies
`have been produced by use of optical spectroscopy in
`an immunoassay. Those cell colonies which are produc(cid:173)
`ing the antibody are actively grown for the rapid pro(cid:173)
`duction of a monoclonal antibody, a desired product of
`the hybrid cells for the rapid production of a biochemi-
`cally necessary substance. The cells are also recloned
`back to a single cell stage and grown for expansion for
`the production of additional antibodies.
`The conventional hybridoma process as developed
`by Kohler and Milstein is based on the fusion of an
`antigen stimulated lympocyte (immunocyte) with a
`non-secreting myeloma cell. The myeloma cell which is
`cancerous confers immortality to the fusion partner,
`resulting an an immortal, hybrid cell which secretes the
`antibody conferred by the lymphocyte. The antibody is
`specific to the stimulating or challenge antigen. Per(cid:173)
`forming this process involves five major areas of work.
`They are cell fusion, cell feeding, screening and assay(cid:173)
`ing of hybridomas, cloning and expansion. Each area of
`work can take up to a full eight-hour day requiring basic
`manual pipetting. Briefly, the hybridomas of a cell fu(cid:173)
`sion are dispensed by manual pipetting to over 1000
`wells of a plurality of 96-well tissue culture plates. The
`hybridomas are then nourished every three to five days
`by hand, aspirating the old media and replacing it with
`new cell culture media (this step results in about 2000
`manipulations). Screening of the hybridomas is done to
`locate those hybrids which are secreting the antibody of
`choice. This process requires manually sampling up to
`1000 wells by pipetting the cell culture out of each well
`and placing it into the wells of corresponding assay
`plates. An ELISA is performed on these plates whereby
`all reagents must be manually pipetted from reservoirs
`to the assay plate in proper physical order and time
`sequence. The results of the ELISA are determined by
`a conventional plate reader. These results must be cor(cid:173)
`related to the original growth plates for accurate selec(cid:173)
`tion and cloning. All data correlation has heretofore
`been done by the scientist through known computation
`techniques.
`Selection of positive hybridomas is done based on the
`accurate calculated correlation of the results from the
`ELISA to the growth plates. Those wells which indi(cid:173)
`cated a positive result are the cloned. This can be as
`much as 800 out of 1,000 hybrids. Cloning is done by
`distributing each hybridoma over an entire 96 well
`tissue culture plate. The cloned hybridomas are allowed
`
`Agilent Exhibit 1217
`Page 18 of 41
`
`

`

`5,125,748
`
`40
`
`3
`to grow and are re-nourished as with the original plates.
`All wells with hybridomas growing in them are again
`assayed for the production of antibody by the ELISA
`method. Data is obtained and correlated as before and
`those positive clones are expanded in numbers.
`Each clone is manually pipetted from the 96 well
`tissue culture plate and transferred to the wells of a 24
`well tissue culture and allowed to grow until an ex(cid:173)
`panded cell number is reached. Subsequently, all clones
`are aliquoted (pipetted) manually into special freezing
`containers and frozen until needed.
`Since the basic procedures of manual pipetting, data
`determination, and collection are common to all the
`applications described and since these applications are
`common to disciplines from biochemistry to virology,
`any system which can combine liquid handling, pipet(cid:173)
`ting and plate reading will have broad applicability into
`many scientific disciplines which utilize these basic
`procedures.
`As promising to biological research as the use of 20
`monoclonal antibodies appears to be (see, U.S. Pat. No.
`4,376,110 issued Mar. 8, 1983 to Gary S. David et al.,
`entitled "IMMUNOMETRIC ASSAYS USING
`MONOCLONAL ANTIBODIES"), conventionally,
`the practicality of using monoclonal antibodies has been 25
`heretofore limited. Compared with conventional antise(cid:173)
`rum (derived from polyclonal antibodies by known
`immunoassay techniques), hybridomas required a rela(cid:173)
`tively high cost to prepare. Hybridoma production has
`been restricted by the limited variety of parental cells 30
`available for hybridization.
`To produce large amounts of monoclonal antibodies,
`the hybridomas are grown as mass culture in vitro. Mass
`production of such antibodies requires improvement in
`the antibody concentration in the spent medium. Con(cid:173)
`ventionally, the time required from the start of the in
`vivo immunization procedure to preliminary character(cid:173)
`ization of hybridomas is three months. The most labor
`intensive procedures are the maintenance of hybrids in
`culture and the assaying for antibody production.
`It is the inevitable consequence of monoclonal anti(cid:173)
`body development that constant monitoring of the
`planned protocol of the experimental assay be con(cid:173)
`ducted with a meticulous concern for detail and accu(cid:173)
`racy. As this biotechnological method for producing 45
`monoclonal antibodies is practiced, error resulting from
`tedious experimental repetition is likely. The conven(cid:173)
`tional art simply lacked an instrument which could aid
`in reducing the time for practicing the ordered steps of
`protocol needed for antibody production, while, at the 50
`same time, increasing the relative purity of concentra(cid:173)
`tion of the isolated monoclonal al}tibodies without the
`introduction of increased error that normally accompa(cid:173)
`nies stepped up production.
`Other biological procedures and assays include inves(cid:173)
`tigative methods such as serial dilution which are con(cid:173)
`ventionally performed by beginning with a plurality of
`separate samples of a substance at high (i.e. nearly
`100%) concentration. These samples are then diluted to
`lower known (e.g. approximately 50%) strengths when 60
`mixed with diluent according to known methods of
`serial dilution, where successively increasing propor(cid:173)
`tions of a diluent is added thereby obtaining a series of
`respectively decreasing concentrations of a sample. The
`various sample concentrations can then be assayed at a 65
`useful concentration to determine a particular property.
`For example, the sample might be a. serum and the assay
`may employ a serial dilution which will demonstrate the
`
`4
`relative concentration of the serum component to be
`measured which exhibits the greatest activity when
`reacted with a particular substance (such as a minimum
`inhibitory concentration (MIC) assay). U.S. Pat. No.
`5 4,478,094, issued to Salomaa and assigned to Cetus Cor(cid:173)
`poration of Emeryville, Calif., is an example of a liquid
`sample handling system which performs predetermined
`serial dilution by means of an automatic liquid transfer
`system operating within the framework of a fixed open
`10 loop system.
`Conventionally, pipettors and micropipettors are
`operated manually by suction created through the user's
`mouth (an undesirable activity due to likely contamina(cid:173)
`tion) or with an automatic hand-operated pump or sy-
`15 ringe. Such methods of pipetting can be long and te(cid:173)
`dious, susceptible to cross-contamination, as well as
`prone to measurement inaccuracies, and harmful to the
`scientist, where, for example, a given chemical or bio-
`logical assay requires repetitious use of a pipettor for
`the introduction of a dissolved sample in hundreds of
`microtiter receptacle wells.
`Another attempt at automating liquid sample han-
`dling is U.S. Pat. No. 4,422,151 issued to Gilson. The
`Gilson liquid handling apparatus discloses an open-loop
`system for fractional collection, sampling, dispensing,
`and diluting. The Gilson apparatus uses a microproces-
`sor and three stepping motors to move a liquid handling
`tube suitable for dispensing or sampling in horizontal or
`vertical directions with respect to an array of test tubes
`or similar containers. No indication of the degree of
`precision and accuracy of liquid transfer is indicated in
`the disclosure of Gilson. The pattern of movement of
`the liquid handling tube may be selected according to a
`predetermined mode of operation which the operator
`35 desires. Once an operation is selected, it is fixed, and the
`liquid handling apparatus automatically carries out the
`instructions. The control means of the device described
`in the Gilson patent is used to selectively energize the
`drive motors for moving the carriage holding the liquid
`handling dispenser into positions corresponding to re(cid:173)
`ceptacle location positions and moving the holder de-
`vice in three dimensions so that liquid may be trans(cid:173)
`ferred from one receptacle of a microtiter plate to an(cid:173)
`other. Once the command is entered into the Gilson
`device, it is automatically carried out as instructed.
`Although such a device substantially reduces the need
`for manual effort in precisely measuring the pipetting or
`dispensing to be done for each of hundreds of recepta(cid:173)
`cles, in particular bioassay or chemical assay, the Gilson
`device operates strictly in an open loop environment,
`performing fixed, predetermined liquid transfers.
`Chemical and biological assays may be accomplished
`by the application of human judgment at every stage of
`the assay to control the course of experimentation. For
`55 example, the initial primary samples may be prepared
`manually or by an automated pipettor diluter as dis(cid:173)
`closed in the Gilson and Salommaa patents. Conven(cid:173)
`tionally, other instruments, such as an optical plate
`reader or a spectrophotometer, must be independently
`used to analyze a physical or chemical characteristic of
`each sample receptacle in the microtiter plate. After this
`tedious analysis is undertaken, the experimenter then
`selects to further analyze and subject to chemical or
`biological reactions only those sample plates which
`indicate a desired or optimum range characteristic. For
`example, in the hybridoma procedure as described here-
`inbefore, only those cell colonies which are producing
`monoclonal antibodies of the desired specificity are
`
`Agilent Exhibit 1217
`Page 19 of 41
`
`

`

`5
`selected for further experimentation. Those cell colo(cid:173)
`nies may be identified by spectrophotometric immuno(cid:173)
`assays which indicate an optimum optical density. Once
`the optimum samples are identified, only those samples
`are used in the latter stages of experimentation. Conven- 5
`tional manual methods of pipettor dilution and titration,
`as well as the devices disclosed in the Gilson and Salom(cid:173)
`maa patents, do not provide for any input by the opera(cid:173)
`tor to the direction of the assay on a real time basis once
`the experimentation has commenced. Being an open 10
`loop system, the conventional art is not able to execute
`the judgmental decisions preprogrammed by the re(cid:173)
`searcher which respond to experimental data as the
`assay progresses.
`U.S. Pat. Nos. 4,488,241 and 4,510,684 assigned to 15
`Zymark Corporation disclose a robot system with inter(cid:173)
`changeable hands and a module system; these patents
`are directed at a robot system for manipulating a series
`of discrete devices used in the field of analytical chemis(cid:173)
`try. These patents teach the use of a robotic arm to 20
`open, touch and manipulate discrete laboratory devices
`in an emulation of manual methods. These patents teach
`the use of a robot system to control these conventional
`laboratory instruments by their automatic manipulation;
`the techniques of the laboratory remain discrete and are 25
`not integrated into an intelligent and co-ordinated sys(cid:173)
`tem.
`Also, in the conventional art, even automated open
`loop pipettors did not provide for an integrated and
`flexible fluid dispensing system. Generally, the movable 30
`dispenser, as disclosed in the Gilson and Salomaa pa(cid:173)
`tents, has either a single nozzle or a multiple nozzle.
`In the conventional art, such as the Gilson and Salo(cid:173)
`maa patents, the user had a limited menu and selection
`of programming available for liquid dispensing. What is 35
`needed is a flexible software operating system which
`will allow the researcher to tailor his use of the work
`station to the needs of his particular research project.
`Additionally, the conventional art required the use of
`specialized motor controller integrated circuits dedi- 40
`cated to controlling robotic movement for discrete
`motor operation, such as the CY512 Stepper Controller
`IC chip, manufactured by Cybernetic Micro Systems of
`San Gregorio, Calif. 94074. A flexible motor control
`system is needed which is adaptable for variable loads 45
`and which is programmable to avoid collisions and
`improper interaction between components of the ro(cid:173)
`botic system.
`Fulfilling the foregoing needs is the goal of the sub(cid:173)
`ject invention.
`
`SUMMARY OF THE INVENTION
`This invention relates to a multi-purpose laboratory
`work station which combines the operation of a number
`of existing discrete instruments, as well automating the 55
`performance of heretofore manual analytical chemistry
`and biological experimental assay procedures. The mul(cid:173)
`ti-purpose laboratory work station has a plurality of
`movable interactive components for the controlled dis(cid:173)
`pensing, aspirating, and transferring of liquid from a 60
`first microtiter plate well or other fluid receptacle to a
`second microtiter plate well or other second fluid re(cid:173)
`ceptacle. The instrument of the invention also functions
`with test tubes, freezing vials, reservoirs and other wet
`chemistry containers. All fluid receptacles, such as mi- 65
`crotiter plates, tip support plates, and troughs are sup(cid:173)
`ported in a movable support table attached to a labora(cid:173)
`tory work station base. The movable support table pro-
`
`5,125,748
`
`6
`vides support for the microtiter plates and movement of
`the table is provided by a motor means, causing the
`table to reciprocally move in at least one axis.
`Suspended above the table is a modular pod which is
`capable of reciprocal movement along the length of an
`elongated arm. The arm is attached at one end for
`movement up and down a vertically extending elevator
`tower rising from the base of the laboratory work sta(cid:173)
`tion. The pod is capable of motion along the arm in at
`least a second axis which is perpendicular to the first
`axis of movement of the support table. The arm in turn
`moves up and down the elevator tower in a third direc(cid:173)
`tion which is perpendicular to both the first and second
`directions.
`The pod may connect with and support a fluid dis(cid:173)
`pensing, aspirating and transferring means. A displace(cid:173)
`ment pump may be connected to the pod by fluid con(cid:173)
`duits to provide pipetting, dispensing, and aspirating
`capability. Interchangeable manipulative component
`modules containing the pump may be affixed to the pod
`and suspended above the movable table. The inter-
`changeable modules may be uniquely identified by pas(cid:173)
`sive electronic means housed within each module. The
`interchangeable modules may have from one to eight or
`more nozzles in order to prepare samples for the recep(cid:173)
`tacle wells of a microtiter plate or other fluid recepta-
`cle. The interchangeable modules may be designed to
`conform to a disposable pipettor tip. Some interchange(cid:173)
`able modules may also be provided with a mechanism
`for ejecting disposable tips after completion of their use.
`The disposable pipettor tips may be sealed to the inter-
`changeable manipulative modules by use of a friction
`fit.
`The coordinated operation of the automated analyti(cid:173)
`cal processing center and workstation is directed by a
`microprocessor control means. The multi-purpose labo(cid:173)
`ratory work station is capable of a wide variety of sam-
`ple preparation and may be used for serial dilution,
`chemical and biological assays. The multi-purpose labo(cid:173)
`ratory work station may, for example, be programmed
`for serial dilution sample preparation.
`The multi-purpose laboratory work station addition-
`ally is provided with a transducer means housed within
`a module for performing spectrophotometric analysis.
`Optical fibers in the base of the laboratory work station
`provide an optical source beam which may be transmit-
`ted through transparent microtiter plates and the sam(cid:173)
`ples contained therein. The amount of optical radiation
`absorbed by the samples may be detected by the trans-
`50 ducer means within an optical densitometer component.
`The pod may be connected to such an interchangeable
`-optical densitometer module which houses a set of
`lenses, a rotatable filter means, and a transducer. This
`optical densitometer module is designed to mechani(cid:173)
`cally interact with the same plunger mechanism which
`operates the fluid transport components, so that the
`same stepper motor which controls fluid dispensing of
`the fluid dispenser can be used to control optical filter
`selection. The source of light may be a chopper modu(cid:173)
`lated light beam with an independent selection of source
`filters to accommodate a wide variety of optical experi-
`mentation, such as absorption or fluorometric data. This
`information is provided to the microprocessor by a
`specialized modulation technique and may form the
`basis of a closed loop system where the programmed
`instructions provided to the microprocessor require
`that the microprocessor control the operation of the
`laboratory work station, including the motor drive
`
`Agilent Exhibit 1217
`Page 20 of 41
`
`

`

`25
`
`7
`means and the pumping means, in accordance with
`experimental deterµiinations made by the spectrophoto(cid:173)
`metric transducer means. For example, if a biological
`assay is to be conducted, the laboratory work station
`will be instructed by the microprocessor to measure the 5
`optical density of a plurality of individual specimens on
`a microtiter plate. The microprocessor can be pro(cid:173)
`grammed to conduct subsequent testing, after a selected
`spectrometric measurement is determined, only on
`those samples which indicate an optical density within 10
`desired ranges. Such a closed loop system relies upon
`real time information provided by the transducer means
`and can automatically execute subsequent steps re(cid:173)
`quired in chemical and biological experimentation.
`Interacting with the microprocessor is a remote user- 15
`controlled computer or other interactive device by
`which a variety of menus, options, or questions seeking
`limited parameter answers are presented to the user,
`each menu having a plurality of choices or instructions
`for conducting particular biological and chemical assay 20
`experiments. The operating system and software is de(cid:173)
`signed to accommodate a wide variety of experimental
`techniques in accordance with a pre-programmed hier(cid:173)
`archy of experimentation. A "template" program is
`used to focus the instructions for tailoring user need to
`the laboratory work station's capabilities. The user may
`program through a remote computer a complete set of
`instructions for conducting a biological or chemical
`assay. The instructions may include the time and 30
`method for undertaking the experimentation, as well as
`having the multi-purpose laboratory work station deter(cid:173)
`mine the chemical characteristics of the samples being
`tested by the transducer means. Further instructions
`may be given the laboratory wo