System, method, and non-transitory computer-readable medium for automated intelligent continuous manufacturing and operation

Abstract

Anon-transitory computer-readable medium for use in a biology laboratory is provided, which includes a script program layer, an interface program layer, a hardware protocol layer, and a connection-type layer. The script program layer controls a sequence flow, an algorithm, and variables during a specific biomedical experiment based on one or more control commands. The interface program layer includes drivers for controlling one or more hardware devices. The hardware protocol layer includes hardware protocols used by the one or more hardware devices. The connection -type layer includes connection types used by the one or more hardware devices. An automated system in the biology laboratory, which is biosafety-level 2 or higher, operates to perform biomedical experiment operations on viruses, bacteria, fungi, or a combination thereof in a negative pressure environment, or to perform biomedical experiment operations for producing cell therapy products and immunological antibodies in a positive pressure environment.

Description

SYSTEM, METHOD, AND NON-TRANSITORY COMPUTER-READABLE MEDIUM FOR AUTOMATED INTELLIGENT CONTINUOUS MANUFACTURING AND OPERATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 563,543, filed March 11, 2024, the entire disclosure of which is incorporated by reference herein.DESCRIPTION OF THE RELATED ART

[0002] Robotic systems have found extensive application in biology laboratories for the purpose of intra-laboratory item transportation. Nevertheless, the utilization of robots for automation remains confined to specific areas within existing biology laboratories. Consequently, biological experiments conducted in laboratories with elevated biosafety levels (e.g., BSL-2 or higher) are either reliant on manual operation by the operator or semi-automation facilitated by individuals with limited automation capabilities. This situation poses an augmented risk to the operator.SUMMARY

[0003] An aspect of the present disclosure provides a non-transitory computer- readable medium for use in a biology laboratory. The non-transitory computer-readable medium includes a script program layer, an interface program layer, a hardware protocol layer, and a connection-type layer. The script program layer is configured to control a sequence flow, an algorithm, and variables during a specific biomedical experiment based on one or more control commands. The interface program layer includes a plurality of drivers for controlling one or more hardware devices. Thehardware protocol layer includes a plurality of hardware protocols that are used by the one or more hardware devices. The connection-type layer includes a plurality of connection types that are used by the one or more hardware devices.

[0004] Another aspect of the present disclosure provides an automated system for use in a biology laboratory, which includes a passing box, a working chamber, a buffer chamber, and an autoclave. The passing box is configured to handle entry and exiting of one or more objects. The working chamber is coupled to the passing box and is configured to conduct biomedical experiment operations using the one or more objects. The buffer chamber is coupled to the working chamber and is configured to process waste and hazardous materials generated by the biomedical experiment operations, as well as to transfer experimental materials to another robot for further experiments. The autoclave is coupled to the buffer chamber and is configured to disinfect the interior space of at least one of the passing box, the working chamber, and the buffer chamber.

[0005] Yet another aspect of the present disclosure provides a method for automating biomedical experiment operations in an automated system for use in a biology laboratory, which includes a passing box, a working chamber, a buffer chamber, and an autoclave. The method includes the following steps: receiving one or more first objects through the passing box; performing biomedical experiment operations using the one or more first objects with the working chamber; processing one or more second objects generated by the biomedical experiment operations using the buffer chamber; and disinfecting the automated system using the autoclave.

[0006] Yet another aspect of the present disclosure provides a method for automating biomedical experiment operations in an automated system for use in a biology laboratory, which includes a passing box, a working chamber, a buffer chamber, and anautoclave. The method includes the following steps: receiving one or more objects through a first room of the passing box; equalizing a first air pressure of the first room and a second air pressure of a second room of the passing box; transporting the one or more objects from the first room to the second room through a convey belt in response to a first affirmative determination from a first check point between the first room and the second room; equalizing the second air pressure of the second room and a third air pressure of the working chamber; transporting the one or more objects from the second room to the working chamber through the convey belt in response to a second affirmative determination from a second check point between the second room and the working chamber; and conducting one or more biomedical experiment operations using a first robotic arm and a second robotic arm disposed within the working chamber.BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Aspects of the present disclosure are best understood from the following detailed description when read with the accompanying figures. It is noted that in accordance with the standard practice in the industry, various features are not drawn to scale. In fact, the dimensions of the various features may be arbitrarily increased or reduced for clarity of discussion.

[0008] FIG. 1 is a floorplan of a biology laboratory with an automated system in accordance with some embodiments.

[0009] FIG. 2 is a floorplan of an automated system in accordance with some embodiments.

[0010] FIG. 3 is a diagram illustrating the hierarchy of a biology laboratory script program in accordance with some embodiments.

[0011] FIG. 4 is a diagram of a composite tool for use in the automated system in accordance with some embodiments.

[0012] FIG. 5Ais a diagram illustrating a collaborative automatic focusing operation between a microscope and a motor in accordance with some embodiments of the present invention.

[0013] FIG. 5B is a diagram illustrating auto-focusing on the well plate using the microscope and motor in FIG. 5A.

[0014] FIG. 6 is a diagram illustrating different pressures in various rooms or chambers within the automated system in accordance with some embodiments.

[0015] FIG. 7 is a diagram of a plate adapter in accordance with some embodiments.

[0016] FIG. 8 is a diagram of a plate holder in accordance with some embodiments.

[0017] FIGs. 9A to 9C are diagrams of different configurations of plate holders within a hanging basket in accordance with some embodiments.

[0018] FIG. 10 is a diagram illustrating a scenario for placing well plates within an automated incubator hotel by a tray machine, in accordance with some embodiments.

[0019] FIG. 11 is a diagram of a positioning machine in accordance with some embodiments.

[0020] FIG. 12 is a flowchart of a method for operating a robotic arm in a biology laboratory using an Al model in accordance with some embodiments.

[0021] Corresponding numerals and symbols in the different figures generally refer to corresponding parts unless otherwise indicated. The figures are drawn to clearly illustrate the relevant aspects of the various embodiments and are not necessarily drawn to scale.DETAILED DESCRIPTION

[0022] FIG. 1 is a floorplan of a biology laboratory with an automated system in accordance with some embodiments. As depicted in FIG. 1, the laboratory 100 includes an automated system, a plurality of clean rooms, and a plurality of dirty rooms. The automated system 200 includes a passing box 115 (including passing rooms 115 A and 115B), a working chamber 128, a buffer chamber 123, and an autoclave 124. The clean rooms may include a buffer room 180 (e.g., buffer room 1), a buffer room 160 (e.g., buffer room 2), a reparation room 110, a waste room 150, and a front room 170. The dirty rooms may include a repair region 120, a culture room 130, and a wash room 140. It should be noted that the automated system 200 can also be disposed within a BSL-3 or BSL-4 laboratory.

[0023] In some embodiments, with the exception of buffer room 180, the remaining other rooms and chambers within the biology laboratory 100 may be constructed within a blocked area. The block area 102 may be biosafety level 2 (BSL-2) or higher. Additionally, a barrier 103 may enclose passing room 1 15B, working chamber 128, buffer chamber 123, autoclave 124, repair region 120, culture room 130, and wash room 140, as depicted in FIG. 1. The region enclosed by the barrier 103 may be at BSL-3 or BSL-4.

[0024] In some embodiments, the automated system 200 is modular, and each chamber can be individually combined and paired. The automated system 200 is portable and suitable for operation in various environments. These includes, but are not limited to, buildings, grasslands, deserts, and polar regions. Additionally, each space or chamber in the automated system 200 is a sterilizable and movable clean space. For example, each chamber of the automated system 200 may be equipped with a sterilizer that can sterilize and disinfect the entire automated system or the individual chamberusing, but not limited to air and liquid. Moreover, each chamber of the automated system may be equipped with an air conditioner, such as a heating, ventilation and air conditioning (HVAC) system or a mechanical ventilation and air conditioning (MVAC) system, capable of adjusting air pressure of the respective chamber. Furthermore, each chamber of the automated system 200 may be equipped with a plurality of sensors, including but not limited to optical sensors (e.g., cameras), air pressure sensors, air flow sensors, temperature sensors, humidity sensors, etc.

[0025] In some embodiments, the automated system 200 may perform multiple functions, such as chamber loading and unloading, and biological experimental operations in the experimental area.

[0026] In some embodiments, the passing box 115 manages the entry and exit of samples, consumables, and reagents to be used by the automated system 200. The passing box 115 may be divided into two distinct sub-boxes, namely, passing rooms 115A and 115B. The consumables may include, but are not limited to, well plates (e.g., for containing sample tubes, pipettes, or tips), tips, V-shaped reservoir, diluents, culture mediums, sample tubes, pipettes, etc. In some embodiments, the well plates can be placed on the plate adapter 700, as shown in FIG. 7. The plate adapter 700 can be placed on a plate holder 800, as shown in FIG. 8. The positioning portion of the plate adapter 700, indicated by the points 701 and 702 in FIG. 7, should align with the alignment portion of the plate holder 800, represented by the points 801 and 802 in FIG. 8. Furthermore, it is possible to place one or more plate holders (e.g., one of plate holders 800A to 800C in FIGs. 9A to 9C) within a hanging basket (e.g., one of hanging baskets 910A to 910C in FIGs. 9A to 9C). Various configurations of this arrangement can be observed in the structure 900A, 900B, and 900C shown in FIGs. 9A, 9B, and 9C.

[0027] In some embodiments, the working chamber 128 may be used for fully- automated experimental operations by robotic arms RAI and RA2. The working chamber 128 can operate in a negative pressure environment and be applied to pathogen research and detection. The object may include, but is not limited to, virus, bacteria, fungi, etc. It can also operate in a positive pressure environment and be applied to antibody production and cell therapy production.

[0028] In some embodiments, the biomedical experiments, operations, or tests, that can be performed by the automated system 200 operating in the negative pressure environment, may include, but are not limited to cytopathic effect (CPE) experiments, immunofluorescence assay (IF A) experiments, hemadsorption (HAD) tests, enzyme- linked immunosorbent assay (ELISA) tests, immunochromatographic (ICT) tests, IgG / IgM dual detection, nucleic acid extraction reagents operations, high-throughput drug screening, TCID50 (50% tissue culture infectious dose) tests, pathogens or cell lines incubation, pathogen amplification and purification, RNA / DNA extraction for RT-PCR (Reverse Transcription Polymerase Chain Reaction) detection of RNA viruses or PCR detection for DNA viruses (e.g., RG2, RG3, RG4), plaque assay tests, Mycobacterium tuberculosis tests, sputum specimen digestion, liquefied concentration smear, microscopy and primary specimen inoculation (including solid and liquid culture media), strain identification or drug sensitivity testing using cultures suspected or configured to be tuberculosis bacteria, pre-processing of molecular biology tests using Mycobacterium tuberculosis cultures, and other related biological methods operated in the negative pressure environment.

[0029] In some embodiments, the biological experiments, operations, or tests, that can be performed by the automated system 200 operating in the positive pressureenvironment, may include, but are not limited to, antibody purification and mass production, stem cell purification and mass production, CAR-T cell purification and mass production, mass production of protein drugs, mass production of RNA drugs, mass production of DNA drugs, mass production of chemical drugs, and other related biological methods operated in the positive pressure environment.

[0030] In some embodiments, sample-processing operations that can be performed within the working chamber 128 may include, but are not limited to, opening and closing doors, packaging, bottle lid opening, grasping, moving materials / consumables, loading and unloading, barcode scanning, etc. Additionally, liquid-processing operations that can be performed within the working chamber 128 include, but are not limited to, suction, pipetting, mixing, dilution, etc.

[0031] FIG. 2 is a floorplan of an automated system in accordance with some embodiments. In some embodiments, the buffer chamber 123 may serve as a buffer between the working chamber 128, the autoclave 124, and the culture room 130. Additionally, the buffer chamber 123 may include a material stack area 213, a material disposal area 214, and an incubator transfer region 215, as shown in FIG. 2. The material stack area 213 may temporarily receive well plates in a plate rack within a hanging basket. The material disposal area 214 may receive waste liquids or consumables sterilized and disinfected by the autoclave 124. The incubator transfer region 215 may be an entry or exit for biological materials to or from the culture room 130. Moreover, a robotic arm RA3 in the buffer chamber 123 can move consumables or biological materials in the output transfer area 212 within the working chamber 128 and the incubator transfer region 215 within the buffer chamber 123.Delivery Procedure for Consumables

[0032] As depicted in FIG. 2, in some embodiments, the passing room 115A may include a door 231 and a transfer gate 232 A, while the passing room 115B may include two transfer gates 232B and 233A disposed in opposite sides of the passing room 115B. One or more operators can enter the passing room 115 A through door 231. The working chamber 128 may include two transfer gates 233B and 234A, while the buffer chamber 123 may include transfer gates 234B, 235, and 236. In some embodiments, the transfer gates 232A and 232B can be combined into a single transfer gate, known as a paired transfer gate. This paired transfer gate consists of two sides, represented by the transfer gates 232A and 232B. This concept also applies to other paired transfer gates, such as those formed by the transfer gates 233 A and 233B, and 234A and 234B, among others. In some embodiments, when the working chamber 128 operates in a negative-pressure environment (i.e., the air pressure of the working chamber is lower than that of any other chamber of the automated system 200), the entry procedure for the consumables may involve the following steps:(1) The operator manually deploys a hanging basket that holds each corresponding consumable in the passing room 115A.(2) The operator utilizes a human-machine interface (e.g., a touch screen within or outside passing room 115A) to inform the control device (e.g., a server) of the automated system 200 of the type and quantity of consumables, after which the door 231 of passing room 115A is closed to initiate delivery.(3) The control device reduces the air pressure of passing room 115A (e.g., via an HVAC or MVAC system) to equalize with that of passing room 115B. Upon the air pressures of passing rooms 115A and 115B being substantially equal, the control deviceopens the paired transfer gates (e.g., 232Aand 232B) between passing rooms 115A and 115B, and transfers the consumables to the passing room 115B via a conveyor belt 221. Upon the consumables being transferred to the passing room 115B, the control device closes the paired transfer gates (e.g., 232A and 232B) between the passing rooms 115A and 115B.(4) The control device reduces the air pressure of the passing room 115B (e.g., via a HVAC or MVAC system) to balance it with that of the working chamber 128. Upon the air pressures of the passing room 115B and the working chamber 128 being substantially equal, the control device opens the paired transfer gate (e.g., 233A and 233B) between the passing room 115B and the working chamber 128, and transfers the consumables to a positioning machine 203 (e.g., shown in FIG. 11) in the working chamber 128 via the convey belt 221.(5) The positioning machine 203 aligns and positions all incoming objects in a designated orientation. This can be achieved through its roller shaft assembly 2031 , which moves the objects forward and outward. As a result, the objects can be easily retrieved by robotic arm RAI in the working chamber 128.(6) The robotic arm RAI places the majority of the consumables (e.g., diluents, culture mediums, sample tubes, pipettes, etc.) in the sample processing chamber 121 in which it is located, and directly places the same in a designated position within the sample processing chamber 122 based on the material type of the consumables.(7) The robotic arm RAI grasps and positions the hanging basket(s) containing plates, tips, and V-shaped reservoir in the exchange area between the sample processing chamber 121 and the liquid processing chamber 122.(8) The robotic arm RA2 grasps and positions the hanging basket containing the plates, tips, and V-shaped reservoir in a designated position within the liquid processing chamber 122.

[0033] In some embodiments, a plurality of check points are disposed at the transfer gates within the automated system 200. For example, an optical inspection device (e.g., a camera plus a server for image recognition) can be used to determine whether the consumables or biological materials are transferred to the check point of the current chamber or room.Delivery Procedure for Biological Materials

[0034] In some embodiments, the delivery of biological materials, such as cells and viruses, to the working chamber 128 can be conducted in a manner similar to that of consumables. For example, non-infectious biological materials (e.g., cells) are typically placed in sample tubes (or pipettes) and then placed in a hanging basket in batches outside the automated system 200. The hanging basket containing the sample tubes (or pipettes) of the non-infectious biological materials can be manually placed in the passing room 115A, and delivered to the working chamber 128 using a delivery procedure similar to that for consumables.

[0035] In some embodiments, if the biological materials are infectious materials such as RG2, RG3, RG4 viruses, etc., the sampling tubes of these infectious materials are also placed in a confirmed compartment or basket, which is covered with an outer package. Additionally, the outer package should be sterilized and disinfected first before being delivered to the working chamber 128. For example, when the outer package is located in either the passing room 115 A or 115B without any transfer gates beingopened, the outer package of these infectious materials can be sterilized and disinfected using vaporized hydrogen peroxide (VHP) or ultraviolet (UV) light inside the passing room 115A or 115B.

[0036] Once the outer package is transferred to the sample processing chamber 121 via the convey belt 221, the positioning machine 203 secures the outer package, retrieves the sample tubes (or pipettes) from the confirmed compartment within the outer package, and places them in the designated position. In some embodiments, the sample tubes (or pipettes) can be sterilized using UV light before being placed in the designated position.

[0037] Subsequently, the robotic arm RAI grasps and moves the outer package to the exchange area 211 between the sample processing chamber 121 and the liquid processing chamber 122, and then the robotic arm RA2 grasps and moves the outer package to the output transfer area 212, allowing the output package to be removed from the automated system 200 through a disposal or transfer-out procedure. The specific details of this procedure are as follows.Disposal / Transfer-out Procedure for Consumables and Biological Materials

[0038] Once the disposal / transfer-out procedure for the consumables or biological materials in the sample processing chamber 121 starts, all consumables or biological materials should be positioned in their corresponding hanging baskets by the position machine 203 or robotic arm RAI . Subsequently, the robotic arm RAI places the hanging basket(s) in the exchange area 211 between the sample processing chamber 121 and the liquid processing chamber 122, and the robotic arm RA2 moves the hanging basket(s) in the output transfer area 212.

[0039] Regarding the disposal / transfer-out procedure for the consumables or biological materials in the liquid processing chamber 122, the tips and plates are positioned in the corresponding hanging baskets in the liquid processing chamber 122. After the tips and plates are used, the robotic arm RA2 moves the used tips and plates to the output transfer area 212. After liquid processing, the used plates are covered and transferred to the output hanging basket. If there are multiple used plates, the robotic arm RA2 can stack them in the output hanging basket and move the output hanging basket to the output transfer area 212. Additionally, all consumables placed in the exchange area 211 are moved to the output transfer area 212 by the robotic arm RA2. Waste liquids and tips are also moved to the output transfer area 212 by the robotic arm RA2. Afterwards, all materials and consumables in the output transfer area 212 are moved to the buffer chamber 123 by the robotic arm RA3 disposed in the buffer chamber 123.Transfer Procedure for Biological Materials in the Buffer Chamber

[0040] In some embodiments, the transfer procedure of the biological materials can consist of four stages, such as 1. direct sterilization; 2. stack sterilization; 3. temporary placement; and 4. package removal.

[0041] 1. Direct sterilization: the sample tubes of the biological materials are placed in a single hanging basket in the output transfer area 212, allowing the robotic arm RA3 to move the hanging basket from the output transfer area 212 directly to the autoclave 124 for sterilization and disinfection.

[0042] 2. Stack sterilization: a single used plate is placed in the output transfer area212 by the robotic arm RA2. Then, the robotic arm RA3 moves the single used plate toa stack in a hanging basket placed in the material stack area 213 in the buffer chamber 123. Once the used plates in the stack reaches a preset number, the robotic arm RA3 moves the hanging basket containing the stacked used plates to the autoclave 124 for sterilization and disinfection.

[0043] 3. Temporary placement: the used consumables or processed biological materials are transferred outside from the automated system 200, but they are still within a P3 (protection level 3) region, which generally includes incubators 131. When there is a need to transfer a single used plate out from the automated system 200, the single used plate is placed in a hanging basket or rack to guarantee safe transportation by the robotic arm RA3.

[0044] 4. Package removal: the sample tubes of the biological materials are packaged by the robotic arm RA3 within the buffer chamber 123, and then VHP or UV lights can be applied on the package for sterilization and disinfection. Then, the robotic arm RA3 moves the package to the external chamber (e g., culture room 130 shown in FIG. 1) through the transfer gate 235, and the robotic arm RA4 can pick up the package, and transfer the package out using an RTP (rapid transfer port). For example, an RTP may refer to a 2-component system that allows transferring hazardous or sterile materials between two separated contained areas, in a sterile way without incurring in contamination from the surrounding environment.OPERATIONS FOR LIQUID PROCESSING

[0045] In some embodiments, the operations that can be performed in the liquid processing chamber 122 are listed as follows.

[0046] 1 The robotic arm RAI takes one of the sample tubes, and opens the lid of the sample tube on the lid opener. The robotic arm RA2 transfers the liquid (e.g., contained in pipettes) to the V-shaped reservoir.

[0047] 2. The robotic arm RA2 can perform liquid handling tasks such as pipetting, dispensing, dilution, etc., for standard liquids.

[0048] 3. The final processed plate can be removed to the incubator 131 or discarded.

[0049] 4. Tilted pipetting operations such as waste liquid removal, cleaning, etc., can be performed.

[0050] 5. Operations such as target fixation and staining can be performed.

[0051] 6. The liquid can be moved to the ELISA (Enzyme-linked immunosorbent assay) reader 207 for absorbance reading.

[0052] 7. The liquid can be moved under the microscope 208 for image inspection.

[0053] 8. The processed liquid can be moved to the output transfer area 212 by the robotic arm RA2, and the final disposal process of the processed liquid is performed by the robotic arm RA3, such as moving the processed liquid to the autoclave 124.OPERATIONS FOR SAMPLE PROCESSING

[0054] In some embodiments, the operations that can be performed in the liquid processing chamber 122 are as follows.

[0055] 1. The robotic arm RAI retrieves various materials from the positioning machine 203, and places them in the required positions.

[0056] 2. If there is a need to move some materials to the liquid processing chamber122, the robotic arm RAI moves such materials to the exchange area 211 for the robotic arm RA2 to take over.

[0057] 3. If the sample liquid (e.g., contained in a sample tube or pipette) needs to be centrifuged, the robotic arm RAI places it in the centrifuge 205 for centrifugation, and retrieves it from the centrifuge 205 in the sample processing chamber 121.

[0058] 4. The robotic arm RAI can put the balance weight in the centrifuge 205, and retrieves the balance weight of the centrifuge 205.

[0059] 5. After centrifugation, if the sample liquid needs to be layered, the robotic arm RAI moves it to the lid opener 206 to open its lid.

[0060] 6. Layered liquid aspiration can be performed with the camera (not shown) and the robotic arm RA2’s pipettes.

[0061] In some embodiments, the operations performed by the automated system 200 may include, but not are limited to, material transfer, dilution of virus solution, cell processing, cell pathology examination 1 (e.g., cytopathic effect staining), cell pathology examination 2 (e.g., viability analysis), and decontamination. The steps of each operation are as follows.1. Material transfer:

[0062] 1.1 Reagent consumables: performing surface cleaning and disinfection first.

[0063] 1.2 Virus tubes are packaged with one or more layers.

[0064] 1.3 Cells: pre-treatment is performed on the cells in the culture room 130, such as updating the experimental culture medium, adding antiviral drugs, and scanning barcodes for record.2. Dilution of virus solution

[0065] 2.1 The robotic arm RAI retrieves the virus tube, performs centrifugation on the virus tube at the centrifuge 205, and opens the lid of the virus tube using the lid opener 206.

[0066] 2.2 The robotic arm RAI mixes the virus solution with the culture medium(suction and dispensing). For example, the required amount of the virus and culture medium should be instructed according to the batch requirement, and other dilution ratios need to be optimized according to experimental batches.3. Cell Processing

[0067] 3.1 The robotic arm RAI retrieves the cell culture plate from the plate rack(e.g., pre-treated in the culture room 130).

[0068] 3.2 The robotic arm RA2 retrieves a sample tube of the cells from the plate rack, performs centrifugation on the sample tube at the centrifuge 205, opens the lid of the sample tube using the lid opener 206, and removes the culture medium from the sample tube.

[0069] 3.3 The robotic arm RA2 adds a certain volume (e.g., l OOpI (microliter)) of virus dilution to the 96-well cell plate or another certain volume (e.g., 40pl) of virus dilution to the 384-well cell plate.

[0070] 3.4 The robotic arm RA2 performs sample inspection at the microscope 208(e g., the inspected images are transferred to the server).

[0071] 3.5 The robotic arm RA2 puts the cell plate back into the plate rack.

[0072] 3.6 The robotic arm RA2 puts the plate rack in the output transfer area 212. The robotic arm RA3 moves the plate rack from the output transfer area 212 to the culture room 130, and the robotic arm RA4 moves the plate rack to the cell culture incubator 131 for static cultivation for approximately 3 to 5 days.4. Cell Pathology Examination 1 (e.g., cytopathic effect staining)

[0073] 4.1 The robotic arm RA4 retrieves the plate rack from the cell culture incubator 131 and puts it at the incubator transfer region 215 within the buffer chamber123. The robotic arm RA2 grasps the plate rack and retrieves the 96-well cell plate from the plate rack.

[0074] 4.2 The robotic arm RA2 removes the culture medium from the 96-well cell plate and discards the removed culture medium (e.g., can be transferred to the autoclave by the robotic arm RA3 as described).

[0075] 4.3 The robotic arm RA2 adds a certain volume (e.g., lOOpl) of 10% formalin and let it stand for predetermined period of time (e.g., approximately 24 hours).

[0076] 4.4 VHP is used for surface decontamination of the cell culture plate.

[0077] 4.5 The plate rack (e.g., including the 96-well cell plate) is moved outside the automated system 200 (e.g., a BSL-3 isolator) for staining with crystal violet solution in the culture room 130.5. Cell Pathology Examination 2 (e.g., viability analysis)

[0078] 5.1 The robotic arm RA4 retrieves the plate rack from the cell culture incubator 131 and puts it at the incubator transfer region 215 within the buffer chamber 123. The robotic arm RA2 grasps the plate rack and retrieves the 96-well cell plate from the plate rack.

[0079] 5.2 The robotic arm RA2 removes the culture medium from the 96-well cell plate and discards the removed culture medium (e.g., can be transferred to the autoclave 124 by the robotic arm RA3 as described).

[0080] 5 3 The robotic arm RA2 adds a certain volume (e.g., 50pl) of cell viability reagent to the sample tube on the 96-well cell plate, and puts the cell plate back to the plate rack. The plate rack is moved back to the incubator 131 within the culture room 130 to stand for approximately 30 to 120 minutes through the transfer-out procedure described.

[0081] 5.4 The plate rack is again retrieved from the incubator 131 within the culture room 130 via the procedure described.

[0082] 5.5 The robotic arm RA2 puts the 96-well cell plate on the microplate reader207 (e.g., ELISA reader) absorbance spectrum interpretation.

[0083] 5.6 The robotic arm RA2 retrieves the 96-well cell plate, and moves it to the output transfer area 212 for disposal and decontamination as described in item 6.6. Decontamination

[0084] 6.1 The robotic arm RA3 collects infectious waste liquid in a heat and pressure-resistant container.

[0085] 6.2 The robotic arm RA3 places the infectious waste in a heat and pressureresistant autoclave bag and seals it.

[0086] 6.3 The robotic arm RA3 places the heat and pressure-resistant container and / or bag of items 6.1 and 6.2 into the autoclave 124 with a bottom tray for decontamination.

[0087] 6.4 The robotic arm RA3 places the non-disposable items, such as plate racks, into a heat and pressure-resistant autoclave bag and seal it, and then places the sealed bag into the autoclave 124 for decontamination.

[0088] It should be noted that the items 1 to 6 described can be automatically and continuously performed by the automated system 200 without any personnel entering the automated system 200 (i.e., an unmanned system). Furthermore, the automated system 200 shown in FIG. 2 complies with the Good Manufacturing Practices (GMP) regulations, which is the aspect of quality assurance that ensures that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the product specification.. In other words, alllaboratory activities conducted by the automated system 200 are in accordance with the GMP regulations.

[0089] FIG. 3 is a diagram illustrating the hierarchy of a biology laboratory script program in accordance with some embodiments.

[0090] In some embodiments, all the components, such as transfer gates, convey belts, lights, HVACs, cameras, machines (e.g., including positioning machine 203, centrifuge 205, microscope 208, ELISA reader 207, lid opener 206, autoclave 124, etc.), robotic arms RAI to RA3, etc., in the automated system 200 are controlled by one or more servers, thereby facilitating full automation (including entry procedures, sample processing, liquid processing, disposal procedure, contamination procedures, etc.) within the biological laboratory 100 (e.g., a BSL-2 to BSL-4 laboratory). The one or more servers are controlled by the biology laboratory script program 321 (e.g., BioLab script) proposed in the present invention.

[0091] For example, the control system 300 running the biology laboratory script program BioLab script 321 is shown in FIG. 3. The hierarchy of the control system 300 includes a variety of layers, such as an instruction input layer 310, a script program layer 320, an interface program layer 330, a hardware (HW) protocol layer 340, and a connection type layer 350, which includes a plurality of programs, instructions, and / or micro codes stored in a non-volatile memory (e.g., a non-transitory computer-readable medium). A processor (e.g., a central processing unit) in the control system 300 can execute the plurality of programs, instructions, and micro codes stored in the nonvolatile memory to perform the functions of the layers 310 to 350. Additionally, actual hardware devices 361 to 367 for different usages are also shown in FIG. 3. In some embodiments, the instruction input layer 310 may be implemented using a plug-inprogram 311 (e g., BioLab Chat) and / or a plug-in program 312 (e.g., BioLab Chart). The plug-in program 311 may refer to an artificial intelligence (Al) plug-in program that is configured to generate scripts or flows for experimental operations using a conversational Al model which is similar to ChatGPT. The plug-in program 312 may refer to a graphical-user-interface (GUI)-controlled plug-in program that is configured to generate biological operation flows using the GUI by the operator. The operator can input one or more high-level commands (e.g., name of a desirable biological experiment with or without its limitations) to the plug-in program 311 and / or the plug-in program 312 executed by the control servers, allowing the plug-in program 311 and / or the plugin program 312 to generate one or more control commands corresponding to a given specific biological experiment that can be recognized and translated by the script program 321.

[0092] In some embodiments, the biology laboratory script program 321 (i.e., BioLab Script) is an upper-level master control program, when executed by a processor of the control server, cause the processor to control the flow, algorithm, and variables during the specific biological experiment. The script program 321 may also control a variety of interface drivers, such as an isolator driver 331, a pipette driver 332, an experimental instrument driver 333, a motors driver 334, BioLab robot drivers 335, within the interface program layer 330.

[0093] In some embodiments, each of the drivers 331 to 335 within the interface program layer 330 may correspond to one or more actual hardware devices 361 to 367 using one or more specific hardware protocols and connection types. For example, the isolator drivers 331 may use hardware protocols such as MODBUS 341 and Direct VO 342, but the present disclosure is not limited thereto. The actual hardware devices 361,such as isolators, transfer gates, VHP devices, air pressure calibration devices, air conditioners, lights, image recognition devices, etc., can communicate with the control servers through respective UART (Universal Asynchronous Receiver / Transmitter) interfaces 351, thereby realizing control of the actual hardware devices 361 using the script program 321. In some embodiments, the air pressure calibration devices are configured to calibrate the air pressure of the working chamber 128, passing box 115, and buffer chamber 123 to be within a negative pressure environment or a positive pressure environment.

[0094] Similarly, the pipette device 362 (e.g., INTEGRA™ pipette) can communicate with the control servers through a respective UART interface 352. The experimental instrument 363, such as the centrifuge 205, microscope 208, ELISAreader 207, etc., can communicate with the control servers through the respective interface 353, such as a Universal Serial Bus (USB) interface. The set of machine-moving devices 364 can communicate with the control server through a respective Transmission Control Protocol (TCP) interface 354). The set of machine-moving devices 364 may include an automated slide rail (e.g., tracks 201 in FIG. 2) and a rotary stage (not shown). In some embodiments, the robotic arm RA4 can be attached on the rotary stage, which moves along the automated slide rail, thereby moving the robotic arm RA4. In some embodiments, the automated system 200 includes a plurality of sets of machine-moving devices 364, with each of the robotic arms RAI to RA3 being mounted on the respective sets of machine-moving devices 364 assigned to a specific chamber or area. For example, the robotic arm RA2 can be mounted on the respective set of machine-moving device 364 assigned to the liquid processing chamber 122. This arrangement allows the robotic arm RA2 to retrieve samples, consumables, reagents, and / or a plate rack fromthe output transfer area 212 and the exchange area 215, and place them on the output transfer area 212, exchange area 215, or the corresponding experimental instrument. In some embodiments, the robotic arm RA4 located in the culture room 130 may be accompanied by a respective set of machine-moving devices 364 that is capable of moving along tracks 201 that are constructed within the culture room 130, as depicted in FIG. 2. Furthermore, a tray machine 1010 can be utilized to either place well plates 1030 or culture dishes inside the automated incubator hotel 1020 (as depicted in FIG. 10), or retrieve them from the automated incubator hotel 1020. The automated incubator hotel 1020 includes 4 stacks and can hold a maximum of 100 96-well plates 1030, with each stack holding 25 plates. Additionally, the height between the adjacent well plates 1030 can be adjusted, and distance between adjacent stacks can also be adjusted.

[0095] In some embodiments, the BioLab robot driver 335 may correspond to different robotic arms, such as robotic arms RAI to RA4 shown in FIG. 1. However, different types of robotic arms may have different robot protocols. Here, the BioLab robot protocol 343 shown in the hardware protocol layer 340 in FIG. 3 may be a unified robot protocol that can handles commands received from and sent to different robotic arms. For example, the XARM™ robot (e.g., robotic arm RA4 shown in FIG. 1) uses hardware protocols such as MODBUS and TCP, and it is still capable of communicating with the control servers through a respective hardware built-in protocol translation program (e g., driver 3651) using the Wi-Fi MQTT interface 355.

[0096] Additionally, the STAUBLI™ robot (e g., an implementation of the robotic arm RA3 shown in FIG. 1) uses SRS + VAL3 language, and it is still capable of communicating with the control servers through a respective hardware built-in protocol translation program (e.g., driver 3661) using the UART / TCP / MQTT interface 356.Moreover, the ABB™ robot (e g., another implementation of the robotic arm RA3 shown in FIG. 1) uses RobotStudio + Rapid language, it is still capable of communicating with the control servers through a respective hardware built-in protocol translation program (e.g., driver 3671) using the UART / TCP / MQTT interface 356.

[0097] In some embodiments, the script program layer 320, interface program layer 330, and hardware protocol layer 340 of the script program 321 can provide a unity UI interface 322 that allows the operator to control different types of robotic arms using the same high-level command. In other words, the unity UI interface 322 is capable of providing a unified interface program that supports different hardware protocols and connection types used by different robotic arms. It should be noted that, for purposes of description, robotic arms RAI to RA4 described in the specification are made by specific manufacturers, the present disclosure is not limited thereto. The type or manufacturers of the robotic arms 1 to 4 can be adjusted according to practical needs.

[0098] In some embodiments, the script program 321 can be summarized as follows.

[0099] 1. Aprotocol description for an automated system 200 that is easy to establish, maintain, and update with new definitions.

[0100] 2. It can satisfy the needs of simple standalone devices as well as multimachine, multi -device collaborative operations.

[0101] 3 It uses the MQTT (Message Queuing Telemetry Transport) QsO protocol for network communication.

[0102] 4. The overall system operates based on message-oriented operations, requiring QsO to ensure low latency and reliable transmission over the network.

[0103] 5. Multiple hierarchical MQTT servers can be deployed, with message forwarding done through the MQTT Gateway program.

[0104] 6. MQTT Clients can be divided into hardware drivers, collaboration, overall command, database processing, etc. based on its sub-functionality.

[0105] 7 It generates messages in a simple format of "command parameterl, parameter2, comment" .

[0106] 8 Client programs of the script program 321 can be developed in various languages or methods, as long as they include the MQTT protocol.

[0107] 9. The upper-level command program can be further integrated into a higher- level Al-directed program for overall planning.

[0108] 10. The database MQTT Client can passively or actively exchange messages with programs at different levels to modify data.

[0109] 11. It can be used for listening and recording (logging) with a listening client, as well as performing corresponding graphical control operations.

[0110] In some embodiments, the operations of the MQTT messages of the script program 321 are described using items 1 to 11 as follows.

[0111] 1. In principle, it operates in a master-slave mode, which means that the client and server communicate with each other. The server only responds when called upon.

[0112] 2. If the server can respond immediately, such as when a balance or temperature sensor returns the current reading, it will directly respond with ">Q 0012.3445 gram" or ">Q <37.22 degree C".

[0113] 3 If the server is an action device that can respond immediately, such as the centrifuge 205, it will respond with a single response: ">RPM 3000" to set the RPM to 3000, "<C" to indicate the setting is complete, and ">Q <1024 (rpm)" to read the current speed.

[0114] 4. If the server is an action device like a robotic arm that requires movement, it will respond in two stages: ">mv 100,200,.." to initiate the movement, "<O" to indicate the start of the action, and "<C" to indicate the end of the action. Between ”<O" and "<C", ">EMGSTOP <C" can be used to immediately stop the current motion, equivalent to an emergency stop.

[0115] 5 If the server has batch execution capability, "<C" should be sent at the end of the batch.

[0116] 6. If the client calls the server and does not receive a response within 0.1 seconds (maximum 1 second), it should consider whether there is a problem with the network connection.

[0117] In some embodiments, a precise balance (e.g., one of the hardware devices 363 in FIG. 3) can be used in the working chamber 128 of the automated system 200. The precise balance may be an MQTT client driven by the script program 321 using an RS232 connection with a baud rate of 9600. The precise balance operates in a read mode capable of continuously outputting current read values. External hardware can be attached on the precise balance for zeroing operation. The MQTT client command of the precise balance are listed as follows. 1. “0”: return current read value; 2.continuously return read values; and 3. “Z”: zeroing (tare) operation. The main program of the script program 321 commands other devices based on the obtained read values.

[0118] In some embodiments, an electronic pipette 362 can be used in the working chamber 128 of the automated system 200. The electronic pipette 362 (e.g., INTEGRA™ pipette) may be an MQTT client driven by the script program 321 using an RS485 connection with a baud rate of 115200. The operation of the electronic pipette is two-stage, and requires return with a set time. The MQTT client commands of theelectronic pipette are listed as follows. 1. “Asp[ire] volume( l)”: Aspirate liquid; 2. “Disp[ose] volume( l)” : dispense liquid; 3. “Mix volume( l), times”', mix liquid; and 4. “VS speed(l-lO)”: set operation speed. An example of the MQTT command of the electronic pipette 362 is provided as follows: “>Asp 100 ' O <C”.

[0119] In some embodiments, the robotic arm RAI shown in FIG. 1 can be implemented using a gripper (not shown). The gripper (e.g., TOYO™ CHY2 gripper) may be an MQTT client driven by the script program 321 using an RS485 connection with a baud rate of 115200. The operation of the gripper is two-stage, and requires return with a set time. The MQTT client commands of the gripper are listed as follows. 1. “Gopen 120(mm)”: open the gripper to 120mm; 2. “Gelose 10(mm)”: close the gripper to 10mm; and 3. “Force 20”: set the gripping force to 20%. An example of the MQTT command of the gripper is provided as follows: “>Gopen 100 <0 <C”.

[0120] FIG. 4 is a diagram of a composite tool for use in the automated system in accordance with some embodiments.

[0121] In some embodiments, the robotic arm RA2 shown in FIG. 1 can be implemented using the composite tool 400 shown in FIG. 4. The composite tool 400, which includes a gripper 410 and a liquid processing device 420, may be an MQTT client driven by the script program 321 using an RS485 connection with a baud rate of 115200. The operation of the composite tool 400 is two-stage, and requires return with a set time. The MQTT client commands of the composite tool 400 are listed as follows. 1. “Sei 1~4”: set next communication channel; 2. “Mx 1, 0\100(mm)” select pipette position; 3. “Asp, Disp volume (pl)” dispense, aspirate liquid; and 4. “Gopen / close space(mm)” : operate the gripper 410. An example of the MQTT command of the gripper 410 is provided as follows: “>Asp 100 <0 <C”.

[0122] In some embodiments, a barcode reader (e g., one of the hardware devices 363) can be used in the working chamber 128 of the automated system 200. The barcode reader may be an MQTT client driven by the script program 321 using a TTL-UART (Transistor-Transistor Logic Universal Asynchronous Receiver / Transmitter) connection with a baud rate of 115200. The operation of the barcode reader is two-stage, and requires return with a set time. The MQTT client commands of the barcode reader are listed as follows. 1. “Q <code"'. read the barcode once; and 2. “QC <multi code"'. read the barcode multiple times. An example of the MQTT command of the barcode reader is provided as follows: “> > <12345678" .

[0123] In some embodiments, each of the auto-guided vehicles (AGV) for use in the automated system 200 can be implemented using the integrated closed-loop stepper motor driver array (e.g., an MKS™ motor). The integrated closed-loop stepper motor driver array may be an MQTT client driven by the script program 321 using an RS485 connection with a baud rate of 115200. The operation of the integrated closed-loop stepper motor driver array is two-stage, and requires return with a set time. The MQTT client commands of the integrated closed-loop stepper motor driver array are listed as follows. 1. “A v xl, x2, x3" move to a specific position; 2. “Mxr axis, dValue"'. move a relative distance along a single axis; 3. “KS’AT axis, speed", rotate along a single axis with the set speed; 4. “US' axis, speed(rpm)" : set the moving speed toward a designated position; and 5. “ e batch.sop.txf '. execute the batch file. An example of the MQTT command of the integrated closed-loop stepper motor driver array is provided as follows: “>mvx 1,100 <0 <C”.

[0124] In some embodiments, the robotic arm RA4 shown in FIG. 1 may be implemented using an xArm robotic arm. The robotic arm RA4 may be an MQTT clientdriven by the script program 321 using a MODBUS™-TCP connection. The operation of the robotic arm RA4 is two-stage, and requires return with a set time. The MQTT client commands of the robotic arm are listed as follows. 1. “A v xl, x2, x3” rmove to a specific position; 2. “Mj jl, j2, move with axis joints; 3. “VS speed( 1-100)”-. set the motion speed ratio; 4. “Srvmv xl,x2,x3”'. operate in a tracking mode; and 5. “Be batch.sop. txt” : execute the batch file. An example of the MQTT command of the robotic arm RA4 is provided as follows: “>mv 100, 150,100,.. <0 <C”.

[0125] In some embodiments, the robotic arm RA3 shown in FIG. 1 may be implemented using a STAUBLI™ robotic arm or an ABB™ robotic arm, but the present invention is not limited thereto. The robotic arm RA3 may be an MQTT client driven by the script program 32 It using a TCP-IP connection in a client-server operation mode. The host of the robotic arm RA3 has a complete controller, its own development environment, and language. For example, the STAUBLI™ robotic arm and its host use the SRS + VAL3 language, and the ABB™ robotic arm and its host use the ROBOTSTUDIO™ + Rapid language. The unified communication protocol is developed to communicate with external devices, such as BioRobot™, TCP / IP connection. The commands of the robotic arm RA4 are listed as follows. 1. “$RXS xl,x2,x3,...” move to a specific position; 2. “SVSM vxl,vx2, motion along each axis based on the respective set speeds; 3. “$VS speed(l-lOO)”-. set the motion speed ratio; and 4. “$RXR <xl,x2,x3,...,st”-. read current coordinate values and status. An external MQTT client (e.g., an MQTT robot program) is used to translate the aforementioned commands of the robotic arm into MQTT commands. After translation, the MQTT commands are the same as the embodiment of the robotic arm RAI (e.g., xArm robotic arm), to achieve consistency in operation commands.

[0126] In some embodiments, the ELISA reader 207 can be used in the working chamber 128 of the automated system 200. The ELISA reader 207 may be an MQTT client driven by the script program 321 using a USB (Universal Serial Bus) connection with an API. The operation of the ELISA reader 207 is two-stage, and requires return with a set time. The MQTT client commands of the ELISA reader 207 are listed as follows. 1. “GetData target filename”, retrieve data; 2. “GetSpectra filename” : retrieve the spectrum; and 3. “LightSel Light” -, set the light source. An example of the MQTT command of the ELISA reader 207 is provided as follows: “> GetData d: \ELISA 1 test! data” .

[0127] In some embodiments, the microscope 208 shown in FIG. 2 may be a phase inversion microscope. The microscope 208 may be an MQTT client driven by the script program 321 using a USB connection with an API. The operation of the microscope 208 is one-stage, with a timeout extended to 1 second. The MQTT client commands of the microscope 208 are listed as follows. 1 . “Photo target filename” : take a photo and save it; 2. “LED r,g,b(0-l00)” -. set the brightness of the lighting; and 3. “Exp 50(ms)” set the exposure time. An example of the MQTT command of the microscope 208 is provided as follows: “> Photo d:\image\testl image” .

[0128] FIG. 5A is a diagram illustrating a collaborative automatic focusing operation between a microscope and a motor in accordance with some embodiments of the present invention. FIG. 5B is a diagram illustrating auto-focusing on the well plate using the microscope and motor in FIG. 5A.

[0129] In some embodiments, referring to FIG. 5A, in scenario 500, the microscope 540 (e.g., microscope 208 shown in FIG. 2) can operate with a motor 530 (e.g., integrated closed-loop stepper motor driver array), and they can be managed by an auto-focus program 520, which is managed by an upper-level program 510 (e.g., script program 321 in FIG. 3) executed by the control server 502 through the MQTT protocol. The auto-focus program 520 can control the motor 530 and the microscope 540 through the MQTT protocol. The control server 502 can communicate with the motor 530 and microscope 540 through the RS485 and USB connections, respectively.

[0130] An example of the auto-focus program 520’s commands for controlling the motor 530 and microscope 540 is listed as follows. 1. “ Auto ocus <O”: start AutoFocus program; 2. “A / xr z, +200”: move the focusing axis; 3. “Photo pid”: take a photo and analyze the image; 4. “Mxv z,+100”,' move again; 5. “Photo pic2”,’ take another photo; 6. “PhotopicN”: obtain a clear image; and 7. “<C”: operation completed. Accordingly, the auto-focus program 520 can control the motor 530 to move the well plate 535 placed thereon in directions X, Y, and Z for auto-focusing by the microscope 540, thereby taking images of a reagent in one or more wells on the well plate 535.

[0131] Attention now is directed to FIG. 3 again. In some embodiments, the automated system 200 shown in FIG. 2 is also an MQTT client driven by the script program 321 using a MODBUS™-TCP connection. The operation of the automated system 200 is two-stage, and requires return with a set time. The MQTT client commands of the automated system 200 are listed as follows. 1. “Q <datal,data2, query global data; 2. “Door doorid,open close" : control single door; 3. “Pressure Roomid, target _press”: set the target pressure of the designated room; and 4. “VHP Roomid, action” activate VHP in a single room. An example of the MQTT command of the automated system 200 is provided as follows: “>Door main in, open <0 <C”, which can open the entrance gate (e.g., gate 233B shown in FIG. 2) of the working chamber 128.

[0132] FIG. 6 is a diagram illustrating different pressures in various rooms or chambers within the automated system in accordance with some embodiments of the present disclosure.

[0133] In some embodiments, the automated system 200 operates in a negative press environment, and the air pressure (e.g., PA3) of the working chamber 128 is lower than that of any other room or chamber within the automated system 200, such as air pressure PAI in the passing room 115A, air pressure PA2 in the passing room 115B, and air pressure PA4 in the buffer room 123. In some embodiments, the air pressure PA2 is lower than the air pressure PAI . The control server can query the pressure in each room or chamber using the command, such as “Q < pA, pB, pMain, pBuffer”, through the MODBUS™-TCP connection. The pressure information of each room or chamber within the automated system 200 can be displayed on a touch screen of the control server or disposed outside the passing room 115 A. Moreover, the GUI rendered on the touch screen may include a door control button corresponding to each gate within the automated system 200, and the operator can manually open a specific gate by pressing the corresponding button on the GUI. In some embodiments, the automated system 200 further includes a mixed reality (MR) function, a virtual reality (VR) function, and / or an augmented reality (AR) function. The operator can also manually control a specific gate within the automated system by pressing the corresponding button on the virtual UI shown in the MR, VR, or AR scene observed by the operator (e.g., through a smartphone, a wearable device, a pair of smart glasses, a head-mounted display, etc.).

[0134] In some embodiments, an example of initiating a biological experiment using the conversation between the user and the plug-in program 311 (e.g., BioLab Chat, which is a conversational Al model) is shown in Table 1 as follows.Table 1

[0135] After the conversation, the plug-in program 311 can generate high-level commands that can be recognized by the script program 321, allowing the script program 321 to generate control commands of the drivers within the interface program layer 330 to control respective hardware devices 361 to 367 through respective hardware protocols 341 to 343 and connection types 351 to 356.

[0136] The automated system 200 has the following advantages: 1. enabling highly efficient and precise operations, and reducing personnel operation time and risk; 2. enhancing the consistency and reproducibility of operations; 3. ensuring the cleanliness and safety of the experimental environment; 4. automatically disinfecting the system, ensuring hygiene; 5. automatically transports the apparatus, improving transportation efficiency; 6. enabling interactions with Al, and enabling more efficient operations and management. 7. being enabled to handle RG2, RG3 and RG4 pathogens in a negative pressure environment. 8. enabling to produce therapeutic cells, stem cells, or CAR-T cells in a positive pressure environment.

[0137] Attention now is directed back to FIG. 3 again. In some embodiments, the control system 300 (e.g., BioLab Script) incorporates a modular workflow. On thesoftware side, it establishes a biomedical experiment action library, supporting flexible combinations of actions, parameter adjustments, and contextual decision-making. The script program 321 is designed to function as a virtual lab technician with expertise in biological experiments, capable of receiving professional experiment descriptions and generating command sequences executable by the automated system 200.

[0138] In some embodiments, the working principle of the control system 300 leverages the programming capabilities of conversational Al models, such as the plugin program 311 (e.g., BioLab Chat). By utilizing a pre-established biomedical experiment action library and a syntax documentation (e.g., including BioLab-Script syntax rules), the Al model utilized by the plug-in program 311 can convert user- provided natural language descriptions into executable automation commands.

[0139] Specifically, the Al model utilized by the plug-in program 311 first analyzes the user's experimental requirements, identifying key actions (such as pipetting, moving, and gripping) and related parameters (such as position, volume, and speed). The Al model utilized by the plug-in program 311 then maps these actions to a batch command file in a particular syntax (e.g., BioLab-Script syntax) using the pre-established biomedical experiment action library and syntax rules. This process is similar to programming, where the Al model utilized by the plug-in program 311 structures different commands while considering sequence, transitions, and special parameters (e g., speed adjustments and smooth movements) to ensure that the generated command set can be correctly executed by automated equipment (e.g., actual hardware devices 361 to 367).

[0140] Ultimately, the Al model utilized by the plug-in program 311 outputs a complete script command set, which users can directly apply to robotic arms or liquidhandling systems, achieving efficient and precise biomedical experiment automation.System Setup and User action Steps of Control System 300

[0141] The building-up and actions of the control system 300 includes three main stages, such as a system deployment stage, Al retraining stage, and a user action stage.1. System Deployment Stage

[0142] The control system 300 can be deployed using one or more large language models (LLMs), such as ChatGPT, Claude, Perplexity, DeepSeek, etc., via an application program interface (API), online / cloud versions, or local installations. If necessary, a retrieval-augmented generation (RAG) technology can be applied to enhance Al response accuracy.2. Al Retraining Stage

[0143] In some embodiments, to equip the Al model of the plug-in program 311 with specialized knowledge in biomedical experiment automation, the control system 300 undergoes retraining (or enhancement) through the following steps:

[0144] (A) Providing manuals and command syntax: feeding the conversational Al model with BioLab- Script syntax documentation to ensure it understands and correctly applies robotic arm movement commands.

[0145] (B) Enhancing semantic understanding and command generation: using example scenarios and test data, the Al model learns to convert natural language inputs into corresponding BioLab-Script batch commands.

[0146] (C) Handling unknown information: when the user’s experiment description contains action details the Al model cannot determine, the control system 300 promptsthe Al model to ask the user for additional information before generating the complete command set, ensuring accuracy and executability.3. User action Stage

[0147] In some embodiments, once the control system 300 is set up and trained, users can operate it through the following steps:

[0148] (A) Input experiment requirements: the user describes the biomedical experiment, e.g., “Use an eight-channel pipette to aspirate liquid from a reagent reservoir and dispense it into the first three rows of a 96-well plate, 500 pL per well.”

[0149] (B) Analyze requirements using the Al model: the Al model analyzes sentences in the conversation (e.g., natural language description) provided by the user or operator to identify key actions (e.g., aspirating, moving, dispensing), parameters (e g., liquid volume, plate position), and sequence flow of the biomedical experiment.

[0150] (C) Command generation and confirmation: the Al model generates a corresponding batch command file based on BioLab-Script syntax and prompts the user to confirm the action details. If any information is unclear, the Al model will ask for clarification.

[0151] (D) Output executable commands: finally, the Al model produces a completeBioLab-Script batch file, ready to be executed by robotic arms (e.g., RAI to RA4) in the automated system 200 or its digital twins.4. Implementation ExampleExample 1 : Liquid Handling in a 96-Well Plate.

[0152] In some embodiments, the script program 321 (e.g., BioLab Script) is a specialized automation language for biological experiments, similar to assembly language, designed to describe robotic arm liquid-handling actions. The robotic arm(e g., robotic arm RAI) is equipped with a gripper (e.g., gripper 410) and an eightchannel pipette (e.g., pipette 420). In some embodiments, the robotic arm can also perform liquid-handling actions according to the commands input by the user.

[0153] In some embodiments, the syntax includes the following structure: “ACTION PARAMETER(S); COMMENT! Each command must be on a new line.

[0154] In some embodiments, the syntax for defining the point location of the end terminal of the robotic arm is as follows. point p3000, +293.90, +140.80, +003.34, +180.00, +000.00, -180.00; restocking position

[0155] In the aforementioned syntax, “point” represents the definition of a specific point; “p3000” represents the point name followed by its endpoint coordinates x, y, z, rx, ry, and rz, where x, y, and z in units of mm; and “restocking position ” represents the comment of the syntax.

[0156] In some embodiments, the syntax for setting the moving speed to 40 is as follows: vs 40. The syntax for moving the end terminal of the robotic arm to point p3000 is as follows: mvp p3000. The syntax for moving the end terminal of the robotic arm to 3cm above point p3000 is as follows: mvp p3000, 0, 0, +30. The syntax for smoothly passing through point p3000 is as follows: qmvp p3000. The syntax for delaying 1 second is as follows: delay I. The syntax for aspirating 500 pL using the 8-channel pipette (e.g., 8 channels are aspirated simultaneously) is as follows: PipAspire 500. The syntax for dispensing 500 pL using the 8-channel pipette (e.g., 8 channels are dispensed simultaneously) is as follows: PipDesp 500. The syntax for closing the gripper to position 30 is as follows: GripClose 30. The syntax for opening the gripper to position 90 is as follows: GripOpen 90.

[0157] In some embodiments, a combination of these syntaxes may constitute a file, which is regarded as a batch file to be executed by the script program 321. The batch file may include definitions of necessary points, a complete sequence of action syntaxes (e g., executable automation commands), and conclude with “end”. The script program 321 can control the robotic arm to perform a variety of actions using different combinations of the actions defined by the aforementioned action syntaxes.

[0158] An example scenario is described as follows: “The location (160, 580.00, 20.00, -180.00, 000.00, 000.00) is the position of a 96-well plate placed on the positioning device. The target position for the 96-well plate is (680.00, -20.00, 20.00,- 180.00, +000.00, +000.00). For any pick-up action, always first move 30 mm above the target location, then move down to the target point to grip, lift back up 30 mm above the target, then move to 30 mm above the next destination. Place the item following the same steps in reverse.”

[0159] An example of a user’s input for the aforementioned example scenario is as follows: “Write a BioLab-Script batch, using an 8-channel pipette, aspirate an appropriate volume of solution from the reservoir (one aspiration for all 8 channels) and dispense 500 microliters into each well of the first three rows of a 96-well plate.”

[0160] The batch file output by the Al model for the user’s input is illustrated in Table 2.Table 2Example 2: Main Control Experiment Flow

[0161] In some embodiments, the script program 321 (e.g., BioLab Script) includes "Main Control" commands that run on a master program, controlling various client devices (e.g., hardware devices 361 to 367) to execute high-level experimental workflows.

[0162] The main control program is configured to select appropriate pre-established equipment batches, assign them appropriate parameters, and arrange and combine them to complete the user’s experimental action requirements.

[0163] The syntax of the main control command are described as follows. mqttsend MACHINE _NAME MSG CONTENT ' ; instruct equipment MACHINE NAME to execute the MSG CONTENT command.mqttwait MACHINE NAME END CMD Wait for the END_CMD command from equipment MACHINE NAME, and perform the command in next row.

[0164] In some embodiments, the mqttwait command is applicable when there is a need to execute two commands in sequence. However, it does not need to be used for consecutive instructions to the same device, because the program itself will automatically determine that the device to be operated has completed its previous instruction.

[0165] In some embodiments, a combination of these syntaxes may constitute a file, which is regarded as a batch file to be executed by the script program 321. The batch file may include definitions of necessary points, a set of all actions, and conclude with “end”. A variety of actions can be performed by the robotic arm using different combinations of the actions defined by the aforementioned syntaxes.

[0166] The names of the equipment used and the pre-established equipment batches include:

[0167] (a) stau2, arm2 JEariablesDef. define all necessary spatial points for the robotic arm (staubli arm 2, stau2). This is executed at the very beginning.

[0168] (b) stau2, InstallTip8. control the robotic arm to insert the pipettor at the end point into the tip box to install tips. A parameter is required afterward (separated by a comma): the row number where the tips are located in the box, for example, the first row is 0, the second row is -9, the third row is -18, and so on (default value starts at 0). When installing tips multiple times, you need to switch to the next row each time.

[0169] (c) stau2, DiscardTip8'. control the robotic arm to move to the mechanism to discard the tips. No parameters are needed.

[0170] (d) stau2, SerialDilution. serial dilution, as referred to in typical biological experimental actions. The given parameters include: the position of the plate where the action is performed (default is p320), the volume of liquid to be moved (based on dilution concentration, default is 1 / 10, thus 20), the volume of liquid to be aspirated during mixing (all liquid in the well, default is 200), and the number of rows to be executed (default is 12 rows).

[0171] (e) when giving commands, the parameters that follow cannot be omitted. If the user does not mention them, please fill them in according to your common knowledge of biological experiments. If you cannot decide on your own, then ask the user.

[0172] In some embodiments, an example of a main control batch file, which includes picking up tips, performing actions, and discarding tips, to conduct a complete serial dilution experiment, is shown in Table 3.Table 3

[0173] An example of a user’s input for the aforementioned example scenario is as follows: “The first row of the 96 well plate is at p320, and the first row has already been mixed with the virus. Please draft a batch to accomplish the following requirement: tenfold serial dilution.”

[0174] The batch file output by the Al model for the user’s input is illustrated in Table 4.Table 4

[0175] FIG. 12 is a flowchart of a method for operating a robotic arm in a biology laboratory using an Al model in accordance with some embodiments. Please refer to FIG. 3 and FIG. 12 simultaneously. The method 1200 may include at least steps 1210 to 1230. It should be noted that steps 1210 to 1230 do not need to be performed in a specific order, and their sequence can be rearranged. Furthermore, additional steps may be incorporated into method 1200 either before or after any of the steps 1210 to 1230.

[0176] Step 1210: Training an artificial intelligence (Al) model with a pre- established biomedical experiment action library and a syntax documentation of a biomedical experiment automation operation language, wherein the syntax documentation comprises a plurality of syntaxes for performing a plurality of biomedical experiment operations by a robotic arm. In some embodiments, the biomedical experiment automation operation language may be the script program 321 (e.g., BioLab Script) shown in FIG. 3, and step 1210 is performed to ensure that the Al model can realize and correctly applies robotic arm movement commands.

[0177] Step 1220: Enhancing the Al model using a plurality of example scenarios and corresponding test data. In some embodiments, step 1220 is performed to ensure that the Al model learns to convert natural language inputs into corresponding BioLab Script batch commands.

[0178] Step 1230: Converting a natural language description of a biomedical experiment using the Al model to generate a batch file with a plurality of executable automation commands for controlling the plurality of biomedical experiment operations of the robotic arm. In some embodiments, the batch file may include definitions of necessary points (e.g., operation points), a complete sequence of action syntaxes, and conclude with “end”. The script program 321 can control the robotic arm to perform a variety of actions using different combinations of the actions defined by the aforementioned action syntaxes.

[0179] The scope of the present disclosure is not intended to be limited to the particular embodiments of the process, machine, manufacture, and composition of matter, means, methods, steps, and operations described in the specification. As those skilled in the art will readily appreciate from the disclosure of the present disclosure, processes, machines, manufacture, composition of matter, means, methods, steps, or operations presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present disclosure. Accordingly, the appended claims are intended to include within their scope processes, machines, manufacture, and compositions of matter, means, methods, steps, or operations. In addition, each claim constitutes a separate embodiment, and the combination of various claims and embodiments are within the scope of the disclosure.

[0180] The methods, processes, or operations according to embodiments of the present disclosure can also be implemented on a programmed processor. However, the controllers, flowcharts, and modules may also be implemented on a general purpose or special purpose computer, a programmed microprocessor or microcontroller and peripheral integrated circuit elements, an integrated circuit, a hardware electronic or logic circuit such as a discrete element circuit, a programmable logic device, or the like. In general, any device on which resides a finite state machine capable of implementing the flowcharts shown in the figures may be used to implement the processor functions of the present disclosure.

[0181] An alternative embodiment preferably implements the methods, processes, or operations according to embodiments of the present disclosure on a non-transitory, computer-readable storage medium storing computer programmable instructions. The instructions are preferably executed by computer-executable components preferably integrated with a network security system. The non-transitory, computer-readable storage medium may be stored on any suitable computer readable media such as RAMs, ROMs, flash memory, EEPROMs, optical storage devices (CD or DVD), hard drives, floppy drives, or any suitable device. The computer-executable component is preferably a processor, but the instructions may alternatively or additionally be executed by any suitable dedicated hardware device. For example, an embodiment of the present disclosure provides a non-transitory, computer-readable storage medium having computer programmable instructions stored therein.

[0182] While the present disclosure has been described with specific embodiments thereof, it is evident that many alternatives, modifications, and variations may be apparent to those skilled in the art. For example, various components of theembodiments may be interchanged, added, or substituted in the other embodiments. Also, all of the elements of each figure are not necessary for operation of the disclosed embodiments. For example, one of ordinary skill in the art of the disclosed embodiments would be able to make and use the teachings of the present disclosure by simply employing the elements of the independent claims. Accordingly, embodiments of the present disclosure as set forth herein are intended to be illustrative, not limiting. Various changes may be made without departing from the spirit and scope of the present disclosure.

[0183] Even though numerous characteristics and advantages of the present disclosure have been set forth in the foregoing description, together with details of the structure and function of the invention, the disclosure is illustrative only. Changes may be made to details, especially in matters of shape, size, and arrangement of parts, within the principles of the invention to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed.

Claims

CLAIMSWhat is claimed is:

1. A non-transitory computer-readable medium, for automating biomedical experiment operations in an automated system for use in a biology laboratory, the non-transitory computer- readable medium comprising: a script program layer, configured to control a sequence flow, an algorithm, and variables during a specific biomedical experiment based on one or more control commands; an interface program layer, configured to provide a plurality of drivers for controlling one or more hardware devices; a hardware protocol layer, comprising a plurality of hardware protocols that are used by the one or more hardware devices; and a connection-type layer, comprising a plurality of connection types that are used by the one or more hardware devices.

2. The non-transitory computer-readable medium of Claim 1, further comprising: an instruction input layer, configured to generate the one or more control commands using a conversational artificial intelligence (CAI) model or a graphical-user-interface (GUI)-based program.

3. The non-transitory computer-readable medium of Claim 2, wherein the conversational Al model generates the one or more control commands based on a conversation, regarding the specific biomedical experiment, between an operator of the automated system and the conversational Al model.

4. The non-transitory computer-readable medium of Claim 2, wherein the GUI-based program generates the one or more control commands based on one or more inputs performed on a GUI rendered on a display screen of the automated system.

5. The non-transitory computer-readable medium of Claim 3, wherein the Al model is trained with a pre-established biomedical experiment action library and a syntax documentation of a biomedical experiment automation operation language.

6. The non-transitory computer-readable medium of Claim 5, wherein the syntax documentation comprises a plurality of syntaxes for performing a plurality of biomedical experiment operations of the specific biomedical experiment by a robotic arm and other associated hardware devices.

7. The non-transitory computer-readable medium of Claim 5, wherein the Al model is further enhanced using a plurality of example scenarios and corresponding test data.

8. The non-transitory computer-readable medium of Claim 6, wherein the instruction input layer is further configured to organize the one or more control commands into a batch file to be executed by the script program layer, and the batch file comprises a plurality of operation points, a complete sequence of action syntaxes, and an ending.

9. The non-transitory computer-readable medium of Claim 6, wherein the conversational Al model analyze sentences in the conversation regarding the specific biomedical experiment to identify key actions, the variables, and the sequence flow of the specific biomedical experiment.

10. The non-transitory computer-readable medium of Claim 1, further comprising: a unity UI interface, arranged across the script program layer, the interface program layer, and the hardware protocol layer, and configured to control robotic arms of different types using a same high-level command.

11. An automated system for use in a biology laboratory, the automated system comprising: a passing box, configured to handle entry and exiting of one or more objects; a working chamber, coupled to the passing box, and configured to conduct biomedical experiment operations using the one or more objects; a buffer chamber, coupled to the working chamber, and configured to process waste and hazardous materials generated by the biomedical experiment operations, and transfer experimental materials to a robot for further experiment; and an autoclave, coupled to the buffer chamber, and configured to disinfect interior space of at least one of the passing box, the working chamber, and the buffer chamber.

12. The automated system of Claim 11, wherein the one or more objects comprise at least one of biomedical samples, consumables, and reagents.

13. The automated system of Claim 11, wherein the biology laboratory is biosafety-level 2 or higher.

14. The automated system of Claim 11, wherein the automated system operates in a negative pressure environment.

15. The automated system of Claim 14, wherein the biomedical experiment operations are performed on viruses, bacteria, fungi, or a combination thereof.

16. The automated system of Claim 11, wherein the automated system operates in a positive pressure environment.

17. The automated system of Claim 16, wherein the biomedical experiment operations are for producing cell therapy products and immunological antibodies.

18. The automated system of Claim 11, wherein the passing box comprises: a first passing room, including an entry gate and a first transfer gate; and a second passing room, including a second transfer gate and a third transfer gate, wherein the second transfer gate is paired with the first transfer gate of the first passing room.

19. The automated system of Claim 18, wherein the working chamber comprises: a first robotic arm and a second robotic arm configured to automate operations on experimental instrument in the working chamber.

20. The automated system of Claim 19, wherein the experimental instrument comprises a centrifuge, an ELISA (Enzyme-linked immunosorbent assay) reader, a microscope, and a lid opener.

21. The automated system of Claim 19, wherein the buffer chamber comprises a third robotic arm configured to automatically transfer waste and hazardous materials generated by the biomedical experiment operations to the autoclave for disinfection.

22. The automated system of Claim 21, further comprising: a mobile robot for transporting any one of the passing box, the working chamber, the buffer chamber, and the autoclave to another biology laboratory.

23. The automated system of Claim 22, further comprising: a control server configured to control operations of the passing box, the working chamber, the buffer chamber, and the autoclave.

24. The automated system of Claim 23, wherein an interactive artificial intelligence (Al) program is running on the control server, and the interactive Al program comprises an instruction input layer, a script program layer, an interface program layer, a hardware protocol layer, and a connection type layer.

25. The automated system of Claim 24, wherein the instruction input layer comprises: a conversational Al model, configured to generate scripts or flows for the biomedical experiment operations based on a conversation between an operator and the conversational Al model; and a GUI (graphical user interface)-controlled program, configured to generate an operation flow of the biomedical experiment operations based on one or more inputs on a GUI displayed on a touch screen within the automated system.

26. The automated system of Claim 25, wherein the interactive Al program comprises a unified UI interface for communicating with the first robotic arm, the second robotic arm, and the third robotic arm that use different robot languages, hardware protocols, and connection types.

27. The automated system of Claim 11, wherein each of the passing box, the working chamber, the buffer chamber, and the autoclave is a sterilizable and movable clean space.

28. The automated system of Claim 11, wherein each of the passing box, the working chamber, the buffer chamber, and the autoclave is modular, and is capable of being individually combined and paired.

29. The automated system of Claim 23, wherein the control server initiates a decontamination process performed on the automated system or any one of the passing box, the working chamber, the buffer chamber, and the autoclave.

30. The automated system of Claim 11, wherein the automated system complies with Good Manufacturing Practices (GMP) regulations.

31. A method for automating biomedical experiment operations in an automated system for use in a biology laboratory, wherein the automated system comprises a passing box, a working chamber, a buffer chamber, and an autoclave, the method comprising: receiving one or more first objects through the passing box; performing biomedical experiment operations using the one or more first objects with the working chamber; processing one or more second objects generated by the biomedical experiment operations using the buffer chamber; and disinfecting the automated system using the autoclave.

32. The method of Claim 31, wherein the one or more first objects comprises at least one of biomedical samples, consumables, and reagents.

33. The method of Claim 31, wherein the one or more second objects comprises at least one of waste and hazardous materials generated by the biomedical experiment operations.

34. The method of Claim 31, further comprising: automating the biomedical experiment operation using a first robotic arm and a second robotic arm disposed within the working chamber; and monitoring and controlling the automated system using an interactive artificial intelligence (Al) program.

35. A method for automating biomedical experiment operations in an automated system for use in a biology laboratory, wherein the automated system comprises a passing box, a working chamber, a buffer chamber, and an autoclave, the method comprising: receiving one or more objects through a first room of the passing box; equalizing a first air pressure of the first room and a second air pressure of a second room of the passing box; transporting the one or more objects from the first room to the second room through a convey belt in response to a first affirmative determination from a first check point between the first room and the second room; equalizing the second air pressure of the second room and a third air pressure of the working chamber; transporting the one or more objects from the second room to the working chamber through the convey belt in response to a second affirmative determination from a second check point between the second room and the working chamber; and conducting one or more biomedical experiment operations using a first robotic arm and a second robotic arm disposed within the working chamber.

36. The method of Claim 35, wherein the one or more objects comprises at least one of biomedical samples, consumables, and reagents.

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