[19] The State Intellectual Property Office (SIPO) of the People’s Republic of China
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`[12] Description of Invention Patent Application
` [21] Appl. No. 01116421.2
`
`[51] Int. Cl 7
`G01N 21/64
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`[11] Pub No.: CN 1379236A
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`[43] Pub Date: Nov 13, 2002
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`[21] Application No.: 01116421.2
`[22] Filed on: April 12, 2001
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`[71] Applicant: DAHE THERMO-MAGNETIC AND ELECTRONIC CO., LTD.
`Address: 9F-B Jinjiang Building, 111 Hushu South Rd, Hangzhou, Zhejiang Province
`310005
`
`[72] Inventor(s): Shegang Li, Lixin Mao, Jianfeng Li, Weiping Xiang, Zhihua Liu, Zhihe
`Wu
`[74] Patent firm or Agency: Hangzhou Qiushi Patent Co., Ltd.
`
`Agent: Jiemei Han
`
`Claims 1 page, Description: 4 pages, Drawings: 3 pages
`[54] Tile of Invention
`Fluorescence quantitative PCR analyzing system
`[57] Abstract of Disclosures
`
`A fluorescence quantitative PCR analyzing system is composed of a thermal cycling unit,
`a fluorescence detection unit, and a control circuit, which are all disposed in a housing, and a
`computer disposed outside the housing. The present invention is controlled by the computer and
`a microprocessor. The thermal cycling unit amplifies a target gene, while the fluorescence
`detection unit detects the fluorescence intensities of the test sample and a reference, and then
`computer software compares the fluorescence intensity of the test sample with that of the
`reference. Due to the fact that the concentration of a target gene is proportional to the
`fluorescence intensity of the target gene, the present invention is able to achieve an automatic
`and quick real-time quantitative determination of target gene concentration. In addition, since the
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`entire detection process is carried out in a completely enclosed sample tube, the test sample will
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`Claims
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`01116421.2
`What is claimed is:
`
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`1. A fluorescence quantitative PCR analyzing system, characterized in that the system
`comprises a thermal cycling unit [I], a fluorescence detection unit [II], and a control
`circuit [III], which are all disposed in a housing, and a computer [IV] disposed outside
`the housing, wherein the thermal cycling unit [I] comprises a variable temperature metal
`module [4] with a row of wells [21], a thermoelectric regulator [3] tightly attached to the
`variable temperature metal module [4], a heat sink [2], and a fan [1], which are disposed
`next to the thermoelectric regulator [3], and a tube [5] disposed in the well [21], wherein
`the tube [5] is covered with a heatable lid [6] having a heater, wherein the heatable lid [6]
`and the heat sink [2] are each provided with a temperature sensor [7], and the variable
`temperature metal module [4] is provided with a temperature sensor [8] as well;
`the fluorescence detection unit [II] comprises a belt capable of moving back and forth
`[16] wherein the belt is driven by a stepper motor [17], the belt is located below the
`variable temperature metal module [4], and the belt is directly under and parallel with
`row of wells [21] on the metal module, a housing [22] fixed on the belt [16], wherein a
`position sensor [36] is disposed on the housing, and a hole [19] which is provided on top
`of the housing, a lens [13], a dichroic mirror [12] with an angle of 45 degrees from an
`axis, a horizontal bar [20] perpendicular to the axis and a photomultiplier tube [15] being
`sequentially disposed along a direction from the top hole downwards, wherein the
`horizontal bar [20] passes through two opposing walls of the housing, the horizontal bar
`is capable of moving back and forth along with the housing, and two ends of the
`horizontal bar can hit a positioning plate [18] on the housing to enable horizontal sliding,
`a plurality of filters [14] with various wavelengths disposed on the horizontal bar, an
`excitation light source [9], a filter [10], and a lens [11] disposed above the horizontal bar
`in the housing, wherein a light emitted by the light source travels to the dichroic mirror
`[12] in a horizontal direction via the filter [10], and the lens [11];
`the control circuit [III] comprises a microprocessor [25] that is connected to the external
`computer [IV] via an interface [24], an A/D convertor [26, 27] that converts the output
`signals from the temperature sensor [8] and the photomultiplier tube [15] to
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`corresponding digital signals and then outputs the digital signals to the microprocessor
`[25], a solid state steering bridge [28] for steering voltages, which has an input end
`connected to the microprocessor and an output end electrically connected to the
`thermoelectric regulator [3], a temperature control circuit [30] with an input end
`connected to the temperature sensor [7] and an output end connected to the heater of the
`heatable lid and the fan [1], and a power supply [29] which is connected to the
`microprocessor [25], whose output voltages are respectively provided to the solid state
`steering bridge [28], the temperature control circuit [30], and a stepper motor driver [34],
`wherein a drive signal outputted from the microprocessor is sent to the stepper motor
`driver [34], and an output signal from the position sensor [36] is sent to the
`microprocessor.
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`2. The fluorescence quantitative PCR analyzing system as set forth in claim 1, characterized
`in that the solid state steering bridge is formed by two IR2110 integrated blocks and the
`MOSFET tubes [Q1 to Q4].
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`01116421.2
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`Description
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`Fluorescence quantitative PCR analyzing system
`
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`The present invention is a device used in the biological and medical field for quantitative
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`analysis of target gene concentration through polymerase chain reaction (PCR).
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`Prior to the present invention, there has been no device available that is able to perform
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`automatic quantitative detection of polymerase chain reaction (PCR) for target genes. In a
`traditional method, a target gene is placed in the thermal cycling device whose heating and
`cooling are controlled by a circuit that is atomically controlled by a computer, so as to finish the
`processes of denaturing, annealing, and extending to amplify the target gene to millions of
`copies; subsequently, the product of amplification is analyzed in a gel electrophoresis to
`determine whether a target gene is present in the sample. However, due to the very high PCR
`amplification efficiency, both a very slight amount of target gene and a very large amount of
`target gene could be amplified at the same time to reach their respective saturation levels, which
`will result in similar detection results in gel electrophoresis. As a result, the foregoing method
`can only obtain a qualitative result about whether a specific target gene exists, but is unable to
`provide a quantitative result for the specific amount or concentration of the target gene. On the
`other hand, the foregoing method needs to move samples around during its operation process.
`Accordingly, this may result in sample contamination by its environment, and thus leads to an
`inaccurate detection result (false positive or false negative). In addition, it also has a few other
`drawbacks, such as complex operation and long detection time.
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`One object of the present invention is to provide a fluorescence quantitative PCR
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`analyzing system that is able to perform an automatic and quick quantitative detection for a
`target gene and that is free of environmental contamination during the detection process.
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`The technical solution of the present invention is as follows: in the present invention, the
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`fluorescence detection unit detects the fluorescence intensities of a test sample and a reference
`sample, and computer software compares the fluorescence intensity of the test sample with that
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`of the reference sample; due to the fact that the concentration of a gene is proportional to its
`fluorescence intensity, the present invention is able to determine the amount or concentration
`(amount per unit volume) of a specific gene by way of detecting the fluorescence intensity
`generated by it.
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`The overall device of the present invention comprises a thermal cycling unit, a
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`fluorescence detection unit, and a control circuit, which are all disposed in a housing, and a
`computer disposed outside the housing. The thermal cycling unit comprises a variable
`temperature metal module with a row of wells, a thermoelectric regulator tightly attached to the
`variable temperature metal module, a heat sink, and a fan, which are disposed next to the
`thermoelectric regulator, and a tube disposed in the well, wherein the tube is covered with a
`heatable lid having a heater, and wherein the heatable lid, the heat sink, and the variable
`temperature metal module are each provided with a temperature sensor.
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`The fluorescence detection unit comprises a belt capable of moving back and forth,
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`wherein the belt is driven by a stepper motor, the belt is located below the variable temperature
`metal module, and the belt is directly under and parallel with the row of wells on the metal
`module; a housing fixed on the belt, wherein a position sensor is disposed on the housing and a
`hole is provided on top of the housing; a lens; a dichroic mirror with an angle of 45 degrees from
`an axis; a horizontal bar perpendicular to the axis; and a photomultiplier tube provided along a
`direction from the top hole downwards are sequentially disposed, wherein the horizontal bar
`passes through two opposing walls of the housing, the horizontal bar is capable of moving back
`and forth with the housing, two ends of the horizontal bar can hit a positioning plate on the
`housing to enable horizontal sliding; a plurality of filters with various wavelengths disposed on
`the horizontal bar; an excitation light source; a filter; and a lens disposed above the horizontal
`bar in the housing, wherein a light emitted by the light source travels to the dichroic mirror in a
`horizontal direction via the filter and the lens.
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`The control circuit comprises a microprocessor that is connected to the external computer
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`via an interface, an A/D convertor that functions to convert the output signals from the
`temperature sensor and the photomultiplier tube to corresponding digital signals and then output
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`the digital signals to the microprocessor, a solid state steering bridge for steering voltages, which
`has an input end connected to the microprocessor and an output end electrically connected to the
`thermoelectric regulator, a temperature control circuit with an input end connected to the
`temperature sensor and an output end connected to the heater in the heatable lid and the fan, and
`a power supply which is connected to the microprocessor, wherein its output voltages are
`respectively provided to the solid state steering bridge, the temperature control circuit, and a
`stepper motor driver; a drive signal outputted from the microprocessor is sent to the stepper
`motor driver, and an output signal from the position sensor is sent to the microprocessor.
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`The present invention will be further described in detail in reference to the accompanying
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`drawings.
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`Figure 1 is a schematic view of the fluorescence quantitative PCR analyzing system
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`according to the present invention;
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`circuit;
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`In reference to Figure 1, the fluorescence quantitative PCR analyzing system of the
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`present invention comprises a thermal cycling unit I, a fluorescence detection unit II, and a
`control circuit III, which are all disposed in a housing V, and a computer IV disposed outside the
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`Figure 2 is a schematic view of the thermal cycling unit;
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`Figure 3 is an A-A sectional view of Figure 1;
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`Figure 4 is a block diagram showing the control circuit;
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`Figure 5 is a specific circuit example of the solid state steering bridge in the control
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`Figure 6 is a specific circuit example of the power supply in the control circuit;
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`Figure 7 is a specific circuit example of the temperature control circuit.
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`housing. The fluorescence detection unit is located below the thermal cycling unit. The specific
`structures of the thermal cycling unit and the fluorescence detection unit are shown in Figure 2
`and Figure 3, respectively.
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`The thermal cycling unit I comprises a variable temperature metal module 4 with a row
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`of wells 21, a thermoelectric regulator 3 tightly attached to the variable temperature metal
`module 4, a heat sink 2, and a fan 1, which are disposed next to the thermoelectric regulator 3,
`and a tube 5 for holding reactants, which is disposed in the well 21, wherein the tube 5 is covered
`with a heatable lid 6 with a heater for the purpose of preventing the reactants from evaporating
`from the tube, and wherein the heatable lid 6 and the heat sink 2 are each provided with a
`temperature sensor 7, in addition, a temperature sensor 8 is provided in the variable temperature
`metal module 4. When in use, a plurality of tubes is used to hold standard reactants with known
`concentrations, and the remaining tubes are used to hold the reactants to be detected. A
`fluorescent agent is added to each of the reactants.
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`The fluorescence detection unit II comprises a belt 16 capable of moving back and forth,
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`wherein the belt is driven by a stepper motor 17, the belt is located below the variable
`temperature metal module 4, and the belt is directly under and parallel with the row of wells 21
`in the metal module, a housing 22 fixed on the belt 16, wherein a position sensor 36 is disposed
`on the housing, a hole 19 provided on top of the housing, along a direction from the top hole
`downwards are sequentially disposed a lens 13, a dichroic mirror 12 with an angle of 45 degrees
`from an axis, a horizontal bar 20 perpendicular to the axis, and a photomultiplier tube 15,
`wherein the horizontal bar 20 passes through two opposing walls of the housing, the horizontal
`bar is capable of moving back and forth along with the housing, and two ends of the horizontal
`bar can hit a positioning plate 18 on the housing to enable horizontal sliding, a plurality of filters
`14 with various wavelengths disposed on the horizontal bar, an excitation light source 9, a filter
`10, and a lens 11 disposed above the horizontal bar in the housing. In general, the light source is
`an LED light source. An excitation light emitted from the excitation light source 9 passes
`through the filter 10 and is filtered into a monochromatic light with specific wavelength, which is
`then focused to become a parallel light by the lens 11, and illuminates on the dichroic mirror 12;
`further, the monochromatic light with specific wavelength is reflected by the dichroic mirror and
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`focused by the lens 13 onto the bottom of the tube 5, which enables the reactants at the bottom of
`the tube to emit a fluorescence with specific wavelength. The fluorescence illuminates on the
`dichroic mirror 12 through the lens 13, where the fluorescence whose wavelength is greater than
`a certain value passes through the dichroic mirror 12, and then is filtered by the filter 14 to
`become a monochromatic light with specific wavelength; the foregoing monochromatic light is
`then received by the photomultiplier tube 15, where it is converted to an electronic signal and
`outputted to the control circuit. In addition, the stepper motor 17 is able to make forward and
`backward rotations to drive the belt 16 to make a linear movement. As a result, the housing fixed
`on the belt, which contains an optical detection device, is driven to make a back and forth
`movement to detect the fluorescence from each tube one by one. Moreover, the filter 14 can be
`switched by way of the positioning plate 18 hitting the horizontal bar 20, which is used to filter
`the fluorescence with different wavelengths.
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`The operation and information transmission of both the thermal cycling unit and the
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`fluorescence detection unit are controlled by the control circuit.
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`As shown in Figure 4, the control circuit comprises a microprocessor 25 that is connected
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`to the external computer IV via an interface 24, an A/D convertor 26, 27 that functions to convert
`the output signals from the temperature sensor 8 and the photomultiplier 15 tube to
`corresponding digital signals and then send the digital signals to the microprocessor 25, a solid
`state steering bridge 28 for steering voltages, which has an input end connected to the
`microprocessor and an output end electrically connected to the thermoelectric regulator 3, a
`temperature control circuit 30 with an input end connected to the temperature sensor 7 and an
`output end connected to the heater of the heatable lid and the fan 1, and a power supply 29 which
`is connected to the microprocessor 25, wherein its output voltages are respectively provided to
`the solid state steering bridge 28, the temperature control circuit 30, and a stepper motor driver
`34; a drive signal outputted from the microprocessor is sent to the stepper motor driver 34, and
`an output signal from the position sensor 36 is sent to the microprocessor.
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`In operation, the instruction signal sent by the computer IV is converted to a control
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`signal by the microprocessor 25. The control signal from the microprocessor is then sent to the
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`solid state steering bridge 28, which is able to steer and adjust the voltage from the power supply
`29; wherein the voltage is used by the thermoelectric regulator 3 to heat, cool or maintain a
`constant temperature, so as to meet the temperature requirements for PCR amplification; in
`addition, a control signal from the microprocessor will be sent to the stepper motor driver 34 for
`controlling the stepper motor to achieve a linear back and forth movement, so as to finish
`detecting the fluorescence intensities of all reactants (including standard reactant and reactant to
`be detected) in the tubes under different wavelengths. On the other hand, the temperature signal
`outputted by the temperature sensor 8 in the thermal cycling unit and the electrical signal
`outputted by the photomultiplier tube 15 in the fluorescence detection unit are respectively
`converted to corresponding digital signals by the A/D convertor 26, 27. Further, the digital
`signals and the position signal outputted by the position sensor 36 will be sent to the computer by
`the microprocessor, where these signals will be processed by computer software. The computer
`sends out control instruction to the microprocessor, where the control instruction is converted to
`a control signal. The computer also compares the fluorescence intensity of the reactant to be
`detected with the fluorescence intensity of the standard reactant, which are inputted to the
`computer during the amplification process. The result is then processed into intuitive curves or
`graphs that are easy to understand and shown on a display. In this way, a quantitative detection
`for the target gene has been accomplished. The temperature control circuit 30 in the control
`circuit receives the temperature signal sent from the temperature sensor 7. An output signal from
`the temperature control circuit is able to operate the heatable lid heater and the fan, so as to
`control the temperatures of the heatable lid and its environment within a desired range.
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`Figure 5 is a specific circuit example of the solid state steering bridge in the control
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`circuit.
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`In the foregoing example, the solid state steering bridge is formed by two IR2110
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`integrated blocks and MOSFET tubes Q1 to Q4. As shown in the figure, the TE+ end and TE-
`end are connected to the thermoelectric regulator. The COOL, HEAT, and PWM ends are the
`CPU interface signals from the microprocessor. The circuit shown here has achieved a non-
`contact electronic switch.
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`Figure 6 is a specific circuit example of the power supply in the control circuit.
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`Figure 7 is a specific circuit example of the temperature control circuit.
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`In the foregoing example, the AC power source is protected by TVS tube. The electricity
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`enters an isolated DC/DC converter module PH300F through a rectifier and a fuse. A DC voltage
`with relatively high safety feature is then outputted from the HV+ end and HV- end. The DC
`voltage is provided for the solid state steering bridge to drive the thermoelectric regulator, and is
`also provided for the stepper motor as its driving voltage. At the same time, a 12 V DC is
`provided for the temperature control circuit to control temperatures of the heatable lid and the
`heat sink. In addition, the CNT and SG in the PH300F are connected to a power supply interface
`of the microprocessor.
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`The temperature signal from the temperature sensor in the heatable lid is inputted via the
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`SEN6 and OUT6 ends, and is then subjected to amplification and comparison in the integrated
`circuit U5 (TLC2202) with the temperature setting point determined by the resistances R7 and
`R8, so as to drive the on/off state of Q5 and thus achieve an automatic temperature control for
`the heating membrane of the heatable lid connected to the HOTL10 end. Similarly, the
`temperature signal from the temperature sensor in the heat sink is inputted via the SEN7 and
`OUT7 ends, and is then subjected to an amplification and comparison in the integrated circuit U6
`(TLC2202) with the temperature setting point determined by the resistance R12, so as to drive
`the on/off state of Q6 to directly control the operation of the fan connected to the FAN end, and
`thus achieve an automatic temperature control on the heat sink. Both U3 and U4 are sources of
`constant current, which offer the function of stabilizing the temperature signal to be detected.
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`RS232.
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`The fluorescence quantitative PCR analyzing system of the present invention is
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`controlled by the computer and a microprocessor. The thermal cycling unit amplifies a target
`gene, while the fluorescence detection unit detects fluorescence intensities of a test sample and a
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`The microprocessor in the control circuit can be 80C196, and the interface may adopt
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`reference, and the computer software compares the fluorescence intensity of the test sample with
`that of the reference. Due to the fact that the concentration of a target gene is proportional to its
`fluorescence intensity, the present invention is able to achieve an automatic and quick real-time
`quantitative detection for target gene concentration. In addition, since the entire detection process
`is carried out in a completely enclosed tube, the test sample will not be contaminated.
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`01116421.2
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`Drawings
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`Figure 1
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`Figure 2
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`Figure 3
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`Interface 24
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`Computer IV
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`Microprocessor 25
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`A/D converter 27
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`Photomultiplier tube 15
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`A/D converter 26
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`Temp sensor 8
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`Solid state steering
`bridge 28
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`Thermoelectric regulator 3
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`Power supply 29
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`Temp ctrl circuit 30
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`Temp sensor 7
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`Heatable lid heater
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`Fan 1
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`Stepper motor driver 34
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`Position sensor 36
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`Figure 4
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`Figure 5
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`Figure 6
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`Figure 7
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`Morflingsidé
`
`The Leader in Global lP Solutions
`
`Date: October 9, 2016
`
`To whom it may concern:
`
`I, Qiang Li, a translator fluent in the Chinese and English languages, on behalf of
`
`Morningside Translations, do solemnly and sincerely declare that the following is, to the
`best of my knowledge and belief, a true and correct translation of the document(s)
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`listed below in a form that best reflects the intention and meaning of the original text.
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`I understand that willful false statements and the like are punishable by fine or
`
`imprisonment, or both (18 U.S.C. 1001), and all statements made of my own knowledge
`are true and all statements made on information and belief are believed to be true.
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`The documents are designated as:
`0
`Publication No.2 CN 1379236A
`
`Signature of Qiang Li
`
`NEW YORK
`450 Seventh Avenue
`10th Floor
`New York, NY 10323, USA
`P; L717.) 6-H—3.%(lO
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`SAN FRANClSCO
`ill Pine Street
`Suite ‘I815
`53
`rzmcisco, Cfi 9»’i‘;?l,
`1?’. W53) S8C‘i—(,a%C»L)
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`KENT
`Com Exchange House
`4?: The Pantiles
`TL:nbridgeWi:-E35
`Kent'T'N2 5
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`F’: J /M l:O]l8{-)2 Sat}/'84
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`HAMBURG
`Kurze Mtiizren l
`End F-‘loo:
`l4lan1burg,G:asn:-my 20095
`P: +49 ii)‘; 407 (379 6500
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`JERUSALEM
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`Emrarice B
`Jerusalem 9«3lrllG4, israel
`P: +972 (023 56.234728
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`inforfstmorningsideip.com l www.momingsidelP.com
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`16 OF 16
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`THERMO FISHER EX. 1040