Magnet assembly to prevent extraction particle carryover

Abstract

To provide a fixed magnet assembly that can be implemented into automated platforms for performing polynucleotide extraction from biological samples and preparing the polynucleotides into an amplification-ready form.SOLUTION: The fixed magnet assembly can be used to provide magnetic energy to a container containing magnetic particles and a reaction mixture of polynucleotides, in order to bring about a separation of the magnetic particles from the reaction mixture. This can prevent or reduce magnetic particle carryover in the prepared amplification-ready sample, thereby improving amplification results.SELECTED DRAWING: Figure 8B

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 948,003, filed December 13, 2019, which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates generally to an automated platform for performing polynucleotide extraction from biological samples and preparing the polynucleotides in a PCR-ready form. More specifically, the present disclosure relates to a stationary magnet assembly that can be used with such an automated platform to provide magnetic energy to a vessel containing a reaction mixture of magnetic particles and polynucleotides, thereby resulting in separation of the magnetic particles from the reaction mixture. [Background technology]

[0003] The medical diagnostics industry is a critical component of today's healthcare infrastructure. However, currently, diagnostic analysis is an obstacle to any routine patient care. There are several reasons for this. First, many diagnostic analyses can only be performed using highly specialized equipment that is expensive and can only be operated by a skilled clinician. Such equipment is found in only a few locations, often only one in any given metropolitan area. This means that most hospitals are required to ship samples to these locations for analysis, thereby incurring transportation costs and delays, and potentially even sample loss or mishandling. Second, the equipment in question is typically not available "on demand," but instead runs in batches, thereby slowing processing times as they must wait for the machines to be fully filled before they can run them on many samples.

[0004] Understanding that the sample flow is divided into several critical steps, it would be desirable to consider ways to automate as many of these as possible. For example, once extracted from a patient, a biological sample must be placed in a form suitable for a processing regime that typically involves using an amplification method, including but not limited to polymerase chain reaction (PCR), TMA, SDA, NASBA, LCR, and rolling circle amplification, to amplify the vector of interest. Once amplified, the presence of the nucleotide of interest from the sample must be unambiguously determined. Preparing the sample for PCR is currently a time-consuming and labor-intensive step that does not require specialized skills and could be usefully automated. In contrast, steps such as PCR and nucleotide detection are usually only within the scope of specially trained individuals with access to specialized equipment. Summary of the Invention [Problem to be solved by the invention]

[0005] Sample preparation is labor intensive, in part because most samples must be heated in one or more stages, and in part because the target polynucleotides are typically captured by some type of retention member, which must then be substantially isolated from the surrounding environment. Thus, even though various liquid transfer operations can be optimized and even automated, there remains a need for controlled heat application and efficient capture of extracted polynucleotides in situ. [Means for solving the problem]

[0006] The background discussion herein is included to explain the context of the invention described herein, and is not to be construed as an admission that any of the material mentioned was published, publicly known, or part of the common general knowledge as of the priority date of any of the claims.

[0007] Throughout the description and claims of this specification, the words "comprise" and variations thereof, such as "comprising" and "comprises", are not intended to exclude other additional elements, components, integers or steps.

[0008] Each of the systems, methods, and devices described herein has several aspects, no single one of which is solely critical to its desirable attributes. Without limiting the scope of the present disclosure, some non-limiting features are now briefly discussed below.

[0009] Discussed herein are embodiments of a fixed magnet assembly that can be implemented in an automated platform for performing polynucleotide extraction from biological samples and preparing the polynucleotides in a PCR-ready form. The fixed magnet assembly can be used to provide magnetic energy to a vessel containing the magnetic particles and a polynucleotide reaction mixture to effect separation of the magnetic particles from the reaction mixture. This can prevent or reduce magnetic particle carryover in the prepared PCR-ready sample, thereby improving the PCR results.

[0010] In various embodiments, a system for nucleic acid analysis is contemplated, the system may include a receiving bay configured to receive a plurality of lysis tubes aligned along a lysis axis and a plurality of mixing tubes aligned along a mixing axis substantially parallel to the lysis axis. The receiving bay may include one or more first magnets aligned along a first magnet axis (substantially parallel to the lysis and mixing axis) and one or more second magnets aligned along a second magnet axis (substantially parallel to the first magnet axis). The one or more first magnets may be configured to move between a position below the plurality of lysis tubes to a position adjacent to the plurality of lysis tubes when the plurality of lysis tubes are received in the receiving bay. The one or more first magnets may be configured to apply a first magnetic force to the contents of the plurality of lysis tubes when the plurality of lysis tubes are received in the receiving bay and the one or more first magnets are disposed adjacent to the plurality of lysis tubes. The one or more second magnets can be configured to remain stationary when the multiple mixing tubes are received in the receiving bay, and the one or more second magnets are configured to apply a second magnetic force to the contents of the multiple mixing tubes when the multiple mixing tubes are received in the receiving bay.

[0011] In some embodiments, the one or more second magnets are included in a stationary magnet assembly that may include a mounting plate, a support plate having a height relative to the mounting plate, and a first plurality of fasteners that mechanically couple the support plate to the mounting plate. The first plurality of fasteners may allow the height of the support plate relative to the mounting plate to be user adjustable. In some cases, each of the first plurality of fasteners may include a jack screw.

[0012] In some embodiments, when the plurality of dissolution tubes and the plurality of mixing tubes are received in the receiving bay, a first magnetic force is applied to the contents of each of the plurality of dissolution tubes along a direction that is approximately perpendicular to the dissolution axis, and a second magnetic force is applied to the contents of each of the plurality of mixing tubes along a direction that is approximately parallel to the mixing axis. In some embodiments, when the plurality of dissolution tubes and the plurality of mixing tubes are received in the receiving bay, a first magnetic force is applied to the contents of each of the plurality of dissolution tubes along a direction that is approximately perpendicular to the dissolution axis, and a second magnetic force is applied to the contents of each of the plurality of mixing tubes along a direction that is approximately perpendicular to the mixing axis. In some embodiments, the receiving bay is further configured to receive a processing device comprising the plurality of dissolution tubes and the plurality of mixing tubes. In some embodiments, the first magnet axis is spatially separated from the second magnet axis by a distance such that the one or more first magnets do not exert a first magnetic force on the contents of the multiple mixing tubes when the multiple mixing tubes are received in the receiving bay, and the one or more second magnets do not exert a second magnetic force on the contents of the multiple lysis tubes when the multiple lysis tubes are received in the receiving bay.

[0013] In some embodiments, the system may further include a plurality of second magnets housed within a plurality of housings aligned along a second magnet axis, each housing of the plurality of housings housing two of the plurality of second magnets. In some embodiments, when the plurality of mixing tubes are received in the receiving bay, a first magnet of the two magnets in each housing is configured to apply a second magnetic force to contents of the first mixing tube at a first position of the first mixing tube, a second magnet of the two magnets in each housing is configured to apply a second magnetic force to contents of a second mixing tube adjacent the first mixing tube, and a second magnet of the two magnets is configured to apply a second magnetic force at a second position of the second mixing tube that is about 180 degrees or less than 180 degrees from the first position of the second mixing tube. In some embodiments, when the plurality of mixing tubes are received in the receiving bay, the ratio of mixing tubes to housings is 2 to 1.

[0014] In some embodiments, the system may further include a plurality of first magnets aligned along a first magnet axis, such that when a plurality of lysis tubes are received in the receiving bay, the ratio of lysis tubes to first magnets is 1 to 1. In some embodiments, each housing may include two faces, each inclined at a different angle relative to the second magnet axis, and each of the two second magnets (housed in the housing) is disposed adjacent an inner wall of one inclined face of the housing.

[0015] In some embodiments, the system may further include a unitary structure including the multiple housings, hi some embodiments, the multiple housings are separated by multiple connectors.

[0016] In some embodiments, the system may include one second magnet formed of a magnetic material, the second magnet including a plurality of magnet structures aligned along a second magnet axis. Each magnet structure may include two inclined magnet faces, each inclined at a different angle relative to the second magnet axis. In some embodiments, when the plurality of mixing tubes are received in the receiving bay, the first inclined magnet face of each magnet structure is configured to apply a second magnetic force to the contents of the first mixing tube at a first position of the first mixing tube, and the second inclined magnet face of each magnet structure is configured to apply a second magnetic force to the contents of a second mixing tube adjacent to the first mixing tube. The second inclined magnet face may be configured to apply a second magnetic force at a second position of the second mixing tube that is about 180 degrees or less than 180 degrees from the first position of the second mixing tube.

[0017] In some embodiments, when multiple mixing tubes are received in the receiving bay, the ratio of mixing tubes to magnet structures is 2 to 1. In some embodiments, the system may further include a plurality of first magnets aligned along a first magnet axis, and when multiple lysis tubes are received in the receiving bay, the ratio of lysis tubes to first magnets is 1 to 1. In some embodiments, the receiving bay may further include a support plate disposed between the one or more second magnets and a cover of the receiving bay. In some embodiments, the support plate includes a plurality of recesses each configured to receive a bottom portion of one of the mixing tubes when multiple mixing tubes are received in the receiving bay.

[0018] In some embodiments, the system may further include a plurality of second magnets contained within a plurality of housings aligned along a second magnet axis, the plurality of housings being movable relative to the support plate when the plurality of mixing tubes are not received in the receiving bay. In some embodiments, the system may further include a plurality of lysis tubes and a plurality of mixing tubes received in the receiving bay.

[0019] In various embodiments, a system for nucleic acid analysis is contemplated, the system may include a receiving bay configured to receive a device having a lysis tube and a mixing tube aligned along each of a plurality of parallel processing axes. The receiving bay may include one or more first magnets aligned along a first magnet axis that is generally perpendicular to the plurality of processing axes, and may also include one or more second magnets aligned along a second magnet axis that is generally perpendicular to the first magnet axis. The one or more first magnets may be configured to move between a position below the plurality of lysis tubes to a position adjacent to the plurality of lysis tubes when the device is received in the receiving bay. The one or more first magnets may be configured to apply a first magnetic force to the contents of the plurality of lysis tubes when the device is received in the receiving bay and the one or more first magnets are positioned adjacent to the plurality of lysis tubes. The one or more second magnets may be configured to remain stationary when the plurality of mixing tubes are received in the receiving bay. The one or more second magnets may be configured to apply a second magnetic force to the contents of the plurality of mixing tubes when the device is received in the receiving bay.

[0020] In some embodiments, when the device is received in the receiving bay, a first magnetic force is applied along a respective process axis of each of the plurality of lysing tubes and a second magnetic force is applied at a point offset from a respective process axis of each of the plurality of mixing tubes. In some embodiments, when the device is received in the receiving bay, a first magnetic force is applied along a respective process axis of each of the plurality of lysing tubes and a second magnetic force is applied along a respective process axis of each of the plurality of mixing tubes.

[0021] In some embodiments, the first magnet axis is spatially separated from the second magnet axis by a distance such that the one or more first magnets do not exert a first magnetic force on the contents of the plurality of mixing tubes when the device is received in the receiving bay, and the one or more second magnets do not exert a second magnetic force on the contents of the plurality of lysis tubes when the device is received in the receiving bay.

[0022] In some embodiments, the system may further include a plurality of second magnets housed within a plurality of housings aligned along a second magnet axis, each housing of the plurality of housings housing two of the plurality of second magnets. In some embodiments, a first of the two magnets in each housing is configured to apply a second magnetic force to the contents of the first mixing tube at a first position of the first mixing tube when the device is received in the receiving bay. A second of the two magnets in each housing may be configured to apply a second magnetic force to the contents of a second mixing tube adjacent the first mixing tube, and the second of the two magnets may also be configured to apply a second magnetic force at a second position of the second mixing tube that is about 180 degrees or less than 180 degrees from the first position of the second mixing tube.

[0023] In some embodiments, when the device is received in the receiving bay, the ratio of mixing tubes to housing is 2 to 1. In some embodiments, the system may further include a plurality of first magnets aligned along a first magnet axis, and when the device is received in the receiving bay, the ratio of lysis tubes to first magnets is 1 to 1. In some embodiments, each housing includes two faces, each inclined relative to an adjacent processing axis, and each of the two second magnets is disposed adjacent an inner wall of one of the inclined faces.

[0024] In some embodiments, the system may further include a unitary structure including a plurality of housings. In some embodiments, the receiving bay may further include a support plate disposed between the one or more second magnets and a cover of the receiving bay. In some embodiments, the support plate includes a plurality of recesses, each configured to receive a bottom portion of one mixing tube when the device is received in the receiving bay. In some embodiments, the system may further include a plurality of second magnets housed within a plurality of housings aligned along a second magnet axis, the plurality of housings being movable relative to the support plate before the device is received in the receiving bay. In some embodiments, the system may further include a device received in the receiving bay.

[0025] Further embodiments of the present disclosure are described below with reference to the appended claims which are considered to serve as a further summary of the present disclosure. [Brief description of the drawings]

[0026] [Figure 1A] FIG. 1 shows an image of a device for PCR amplification (e.g., a microfluidics cartridge) that is mechanically blocked by carried-over magnetic extraction particles according to embodiments disclosed herein. [Figure 1B] FIG. 1 is a schematic diagram of an automated diagnostic or preparation device for performing automated sample preparation on multiple samples in parallel according to embodiments disclosed herein. [Figure 2A] FIG. 2 is an isometric view of an exemplary reagent holder according to embodiments disclosed herein. [Figure 2B] FIG. 2 is a side profile view of an exemplary reagent holder according to embodiments disclosed herein. [Figure 2C] FIG. 2 illustrates a top view of an exemplary reagent holder according to embodiments disclosed herein. [Figure 2D] FIG. 2 is a side profile view of an exemplary reagent holder according to embodiments disclosed herein. [Figure 2E]FIG. 2 illustrates a top view of an exemplary reagent holder according to embodiments disclosed herein. [Figure 3A] FIG. 2 is an isometric view of an exemplary heater assembly and magnetic separator according to embodiments disclosed herein. [Figure 3B] 1A-1D are isometric and side profile views of an independently controllable heater unit of a heater assembly according to embodiments disclosed herein. [Figure 3C] FIG. 2 is a side profile view of an independently controllable heater unit of a magnetic separator and heater assembly illustrating the interaction between the magnetic separator and heater unit according to embodiments disclosed herein. [Figure 4A] FIG. 1 is a perspective view of a rack for holding reagent holders according to embodiments disclosed herein. [Figure 4B] FIG. 2 is an isometric view of a rack for holding reagent holders according to embodiments disclosed herein. [Figure 5A] FIG. 2 is an isometric view of an empty loading bay (or receiving bay) of an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 5B] FIG. 1 illustrates a front perspective view of an exemplary automated diagnostics instrument having two loading bays occupied by corresponding sample racks according to embodiments disclosed herein. [Figure 6A] FIG. 2 is a top conceptual diagram of a set of reagent holders in a loading or receiving bay of a diagnostic or preparation device according to embodiments disclosed herein. [Figure 6B] 6B is a top conceptual diagram of the position of certain components of the reagent holder of FIG. 6A relative to a magnet in a diagnostic or preparation device according to embodiments disclosed herein. [Figure 6C] 13 is a top conceptual view of another set of reagent holders in a loading or receiving bay of a diagnostic or preparation device according to embodiments disclosed herein. [Figure 6D] FIG. 6D is a top conceptual diagram of the position of certain components of the reagent holder of FIG. 6C relative to a magnet in a diagnostic or preparation device according to embodiments disclosed herein. [Figure 6E]1 is a schematic side profile diagram of the position of certain components of a reagent holder relative to a magnet in a diagnostic or preparation device according to embodiments disclosed herein. [Figure 7A] FIG. 2 is a perspective view of an embodiment of a stationary magnet assembly that can be implemented in an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 7B] FIG. 2 is a perspective view of an embodiment of a stationary magnet assembly that can be implemented in an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 7C] FIG. 13 is a dimensional side profile view of an embodiment of a fixed magnet assembly disposed between certain components of a reagent holder according to embodiments disclosed herein. [Figure 8A] FIG. 2 is an isometric view of an embodiment of a stationary magnet assembly that can be implemented in an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 8B] FIG. 2 is an isometric view of an embodiment of a stationary magnet assembly secured to a cover of an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 9] FIG. 2 is an isometric view of an embodiment of a stationary magnet assembly that can be implemented in an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 10A] FIG. 2 is an isometric view of an embodiment of a stationary magnet assembly that can be implemented in a diagnostic or preparation device according to embodiments disclosed herein. [Figure 10B] FIG. 13 is a transparent perspective view of a reagent holder interacting with an embodiment of a fixed magnet assembly according to embodiments disclosed herein. [Figure 11] FIG. 2 is an isometric view of the interior of a portion of an embodiment of an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 12A] FIG. 2 is an isometric view of a processing plate used in some embodiments of a diagnostic or preparative device according to embodiments disclosed herein. [Figure 12B]FIG. 2 is a top view of an arrangement of two processing plates received in a receiving bay of some embodiments of a diagnostic or preparation device according to embodiments disclosed herein. [Figure 13A] FIG. 2 is an isometric view of the interior of a portion of an embodiment of a diagnostic or preparation device according to embodiments disclosed herein. [Figure 13B] FIG. 2 is a side profile view of a processing plate and interior of an embodiment of a portion of a diagnostic or preparative device according to embodiments disclosed herein. [Figure 14A] FIG. 2 is a top conceptual view of a processing plate used in some embodiments of a diagnostic or preparative device according to embodiments disclosed herein. [Figure 14B] 1A-1C are top schematic diagrams of the location of certain components of a processing plate relative to a magnet in some embodiments of a diagnostic or preparative device according to embodiments disclosed herein. [Figure 14C] 1A-1C are schematic side profile diagrams of the position of certain components of a processing plate relative to a magnet in some embodiments of a diagnostic or preparative device according to embodiments disclosed herein. [Figure 15A] FIG. 2 is an isometric view of a stationary magnet assembly used in some embodiments of a diagnostic or preparation device according to embodiments disclosed herein. [Figure 15B] FIG. 2 is an isometric view of a stationary magnet assembly used in some embodiments of a diagnostic or preparation device according to embodiments disclosed herein. [Figure 15C] FIG. 2 is an isometric view of a stationary magnet assembly used in some embodiments of a diagnostic or preparation device according to embodiments disclosed herein. [Figure 15D] FIG. 2 is an isometric view of a stationary magnet assembly used in some embodiments of a diagnostic or preparation device according to embodiments disclosed herein. [Figure 16A] FIG. 2 is an isometric view of an embodiment of a stationary magnet assembly for use with an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 16B] FIG. 2 is an isometric view of an embodiment of a stationary magnet assembly for use with an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 16C] FIG. 2 is an isometric view of an embodiment of a stationary magnet assembly for use with an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 16D] FIG. 13 is a perspective view of a fastening mechanism used in an embodiment of a fixed magnet assembly according to embodiments disclosed herein. [Figure 16E] FIG. 13 is a side cutaway view of a fastening mechanism used in an embodiment of a fixed magnet assembly according to embodiments disclosed herein. [Figure 16F] FIG. 2 is an isometric view of an embodiment of a stationary magnet assembly secured to a cover of an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 17A] 1 is an isometric view of an embodiment of a bridge for installing a stationary magnet assembly in an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 17B] 1 is an isometric view of an embodiment of a bridge for installing a stationary magnet assembly in an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 17C] 1 is an isometric view of an embodiment of a bridge for installing a stationary magnet assembly in an automated diagnostic or preparation device according to embodiments disclosed herein. [Figure 17D] 1 is an isometric view of an embodiment of a bridge for installing a stationary magnet assembly in an automated diagnostic or preparation device according to embodiments disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Automated platforms exist for processing biological samples for diagnostic or preparative purposes (which may alternatively be called automated diagnostic or preparative devices). For example, these automated platforms can be used to perform polynucleotide extraction from biological samples and prepare the polynucleotides in a PCR-ready form.

[0028] Some embodiments of these automated platforms perform polynucleotide extraction and preparation by mixing cells in a biological sample with a lysis reagent in a processing tube and heating the processing tube, thereby lysing the cells and releasing the polynucleotides contained in the cells. To isolate the polynucleotides from the remainder of the mixture, magnetic extraction particles (e.g., surface-modified magnetic beads) configured to bind to these polynucleotides can be added to the mixture. The magnetic extraction particles are also referred to as magnetic substrates or magnetically bound particles. The magnetic extraction particles can include beads modified with, for example, PAMAM, dendritic polyamines, poly(allylamine) (PAA), polypropyleneiminetetramine dendrimers (DABAM), or any other suitable material. With the polynucleotides bound to the magnetic extraction particles, a magnetic force can be applied using a magnet to hold the magnetic extraction particles in place and separate them from the remainder of the mixture. Some embodiments of these automated platforms can have a magnetic separator that can move up and down relative to the processing tube to raise the magnetic extraction particles from the remainder of the mixture and remove the remainder of the mixture.

[0029] With the magnetic extraction particles isolated in the processing tube, a chemical eluent can be added to the processing tube to separate the polynucleotides from the magnetic extraction particles. Some embodiments of the automated platform can again use a magnetic separator to collect and hold the magnetic extraction particles in place while the polynucleotides are extracted from the processing tube and transferred to a separate mixing tube. The polynucleotides can then be added to a mixture of primers and probes used for PCR amplification, which can then be loaded into a device (e.g., a microfluidics cartridge) for PCR amplification.

[0030] However, some chemical components may be present either in the cell matrix of the sample or in other substances present during sample collection that may prevent the magnetic collection of the magnetic extraction particles sufficient to separate them from the rest of the contents in the processing tube. Some examples of substances present during sample collection may include medical lubricants, antifungal creams, antibacterial creams, contraceptive gels and foams, and vaginal moisturizing creams, etc. Any of the chemical components present may interact with the modified surfaces of the magnetic extraction particles, the cell matrix, the captured polynucleotides, or any combination thereof, and prevent the magnetic collection of the magnetic extraction particles. As a result, when the polynucleotides are extracted from the processing tube and transferred to the mixing tube, there may be magnetic extraction particles that carry over to the mixing tube and end up in the device (e.g., microfluidics cartridge) used for PCR amplification. This magnetic extraction particle "carryover" may result in either mechanical or chemical failure of the PCR amplification inducing an assay failure such as non-reportable (NR). Mechanically, carryover particles may block the loading ports or microfluidics in a PCR amplification device (e.g., a microfluidics cartridge). An example of this blockage is illustrated in FIG. 1A, which shows an image of a device for PCR amplification (e.g., a microfluidics cartridge) that is mechanically blocked by carryover magnetic extraction particles. Chemically, problematic components of cellular matrix or other interfering substances that bind to the carryover magnetic extraction particles can interfere with or prevent the PCR reaction and subsequent detection of the amplified products.

[0031] To reduce and prevent this undesired magnetic extraction particle carryover, various embodiments of stationary magnet assemblies are contemplated and disclosed herein that can be implemented with these automated platforms. In some embodiments, the stationary magnet assembly can include a set of graded magnets in a housing located in close proximity to the mixing tube. In some such embodiments, the individual magnets can be 0.25×0.25×.0625″ N52 grade NdFeB square magnets with a pull force of 1.77 lbs and a magnetic field strength of 3032 Gauss. However, in other embodiments, suitable magnets can include magnets of a variety of different materials, sizes, and / or strengths, so long as the combination of the selected magnet configuration and the placement of the magnet near the mixing tube allows the magnet to collect some or all of the magnetic extraction particles carried over into the mixing tube. The magnet can be located close enough to the mixing tube to generate a magnetic field of sufficient strength to hold or “trap” the carryover magnetic extraction particles within the mixing tube, particularly against the inner wall of the mixing tube. Thus, the fixed magnet assembly of the technology disclosed in this invention can provide a secondary set of magnets (in addition to the first set of magnets in the magnetic separator) that can be placed in a fixed location near the mixing tube to provide a secondary magnetic capture for any undesirable magnetic extraction particles (e.g., extraction particles that were not captured during a previous step in the workflow) carried over into the mixing tube to prevent these magnetic extraction particles from being carried over into the PCR amplification device.

[0032] The embodiments of the technology disclosed in this invention can be advantageously implemented in any device that accepts a holder in a holder receptacle for processing and manipulating a magnetic substrate. The implementation of the fixed magnet assembly according to the technology disclosed in this invention can be placed in a very small predefined volume or envelope that exists between the cover of the receiving bay and the processing device that is received in this bay. As a result, the fixed magnet assembly can be retrofitted to existing diagnostic or preparation equipment with a specific receiving bay configured to accept a specific processing device without the need to redesign the processing device (reagent holder or processing plate) or the components that snap onto it (such as reagent tubes or reagent containers). Despite being retrofitted into equipment that is implemented across many sites and has some variation in components, the magnets of the fixed magnet assembly still effectively and invariably apply a magnetic force to the contents of the processing device that is received by these field-deployed systems. Yet another significant advantage of the technology disclosed in this invention is that the technology disclosed in this invention can be very quickly implemented in field-deployed systems with little downtime for the users or laboratories that employ these equipment.

[0033] The installation of the fixed magnet assembly according to the disclosed techniques can be tailored to site-specific characteristics and constraints. As described in detail below, the fixed magnet assembly can be installed with a shim between it and the cover of the receiving bay, where the height of the shim is selected based on site-specific requirements. This can be particularly advantageous when the fixed magnet assembly is retrofitted into an existing preparation and diagnostic equipment in the field, in view of the very slight dimensional differences and tight tolerances associated with the receiving bay and processing devices implemented in the equipment.

[0034] As another example of the advantageous adjustability and versatility of the disclosed technology, some embodiments of the stationary magnet assembly include a spring-loaded support plate that is movable in the z-direction relative to a mounting plate that is secured to the cover of the receiving bay. The mounting plate can be secured using any suitable mechanism, including but not limited to screws or adhesive tape (including double-sided tape). The support plate can be moved up and down in the z-direction within the receiving bay before and during insertion of the processing device into the receiving bay. This feature can enable the fixed magnet assembly to accurately and consistently position tubes or containers of a processing device relative to magnets in the fixed magnet assembly without the need to accurately and consistently reproduce the exact magnet placement across each of the multiple devices installed therein (e.g., through designing, constructing, and placing the fixed magnet assembly to very tight tolerances).

[0035] As yet another example of the advantageous adjustability and versatility of the disclosed technology, some embodiments of the stationary magnet assembly include a support plate mechanically coupled to the mounting plate using a number of adjustable fasteners, which allow the support plate to be movable in the z-direction relative to the mounting plate by adjusting the fasteners. The support plate can be mechanically coupled to the mounting plate using any suitable fastener that can be adjusted to increase or decrease the distance between the support plate and the mounting plate. For example, the support plate can be mechanically coupled to the mounting plate using a number of jack screws that can be threaded clockwise or counterclockwise, respectively, to increase or decrease the distance between the support plate and the mounting plate (e.g., to raise or lower the height of the support plate in the z-direction). The mounting plate can be secured to the receiving bay cover using any suitable mechanism, including, but not limited to, screws or adhesive tape (including double-sided tape). This feature can allow an installer of the fixed magnet assembly (e.g., including but not limited to a user of the system) to manually adjust the height of the support plate based on the particular apparatus in which the fixed magnet assembly is installed so that tubes or containers of a processing device are precisely and consistently positioned relative to the magnets in the fixed magnet assembly, without having to pre-configure the fixed magnet assembly with the exact magnet placement that should be (e.g., through designing, configuring, and placing the fixed magnet assembly to very tight tolerances), thereby allowing the fixed magnet assembly to be used with a variety of apparatus that may have inconsistent dimensions.

[0036] An embodiment of a stationary magnet assembly according to the disclosed technology may include multiple magnet housings or magnet structures. As described in detail below, the magnet housings or magnet structures may include surfaces that are advantageously oriented to align very closely (e.g., within 1-2 mm) with the tube or container that encloses the magnetic structure while also avoiding interference with the tube (or features surrounding it) when the tube is inserted into the receiving bay. These surfaces may be inclined with respect to the processing axis on which the tube rides while still maintaining extreme closeness to the tube. In the case of magnet housings, the magnets coupled to the inner walls of these surfaces may be advantageously oriented. In the case of magnet structures formed of magnetic material, the inclined surfaces may be advantageously oriented. The shape and dimensions of the magnet housings / structures, as well as the shape and dimensions of the connecting structures connecting the magnet housings / structures, may be advantageously adjusted so that these magnet housings / structures and connecting structures do not interfere with skirts or flanges on the underside of processing devices that receive snap-on reagent tubes or snap-on reagent containers. Thus, the magnet housing / structure can still position the magnet in extreme physical proximity to the tube containing the magnetic substrate, while avoiding undesirable physical interference with the tube containing the magnetic substrate, as well as adjacent tubes that do not contain a magnetic substrate.

[0037] An embodiment of a stationary magnet assembly according to the disclosed technology of the present invention can include a magnet housing / structure configured to simultaneously apply a magnetic force to two different tubes or vessels arranged on parallel processing axes. For example, in the case of a magnet housing containing two magnets, in a situation where a first and a second vessel are arranged on parallel processing axes, one magnet housed in the magnet housing can apply a magnetic force to one side of a first vessel of a processing device, and another magnet housed in the magnet housing can apply a magnetic force to the opposite side of a second vessel of the processing device. In other words, the magnets in the magnet housing can apply a magnetic force to both sides of vessels of adjacent processing axes. In a non-limiting example where the reagent holders are received in a rack inserted into a receiving bay, the magnets in the single magnet housing can apply a magnetic force to both sides of the snap-on vessels of the adjacent reagent holders. Although the magnetic force is applied to different sides of the snap-on vessels depending on which magnet is in the immediate vicinity of the snap-on vessel, the problem of magnetic extraction particle carryover is considered valid and invariant for each of the reagent holders. Advantageously, this implementation can avoid the need to place magnets in very tight spaces (e.g., between a snap-on container containing magnetic particles and another snap-on container aligned along the same process axis.) Instead, the magnets of the disclosed technology can be advantageously positioned at an oblique angle to the process axis of each reagent holder, rather than being positioned on the process axis.

[0038] As mentioned above, the stationary magnet assembly can be designed to be implemented quickly and efficiently even in existing automated diagnostic or preparation equipment without any hardware modifications to those equipment. Various embodiments of the stationary magnet assembly of the technology disclosed in this invention can be designed, configured, and tailored for use with specific embodiments of the automated diagnostic or preparation equipment. Specific examples of some of the various embodiments of the stationary magnet assembly are shown and discussed herein.

[0039] For example, Figures 1B, 2A-2E, 3A-3C, 4A-4B, and 5A-5B provide context for a first embodiment of an automated diagnostic or preparation device. Figures 6A-6C provide a conceptual overview of how a stationary magnet assembly can be configured, arranged, and implemented for this first embodiment of an automated diagnostic or preparation device to reduce or prevent magnetic extraction particle carryover. Figures 7A-7B, 8A-8B, 9, 10A-10B, and 16A-16F show various different embodiments of a stationary magnet assembly illustrating additional features and concepts outlined with respect to Figures 6A-6C. The exemplary stationary magnet assemblies described with reference to Figures 6A-6C can be implemented in the first embodiment of an automated diagnostic or preparation device to prevent magnetic extraction particle carryover. It will be understood that these are non-limiting examples and that other suitable configurations and implementations are not inconsistent with the techniques disclosed in the present invention.

[0040] In addition, Figures 11, 12A-12B, and 13A-13B provide context for a second embodiment of an automated diagnostic or preparation device in which the fixed magnet assembly of the disclosed technology can be implemented. Figures 14A-14C provide a conceptual overview of how the fixed magnet assembly can be configured, arranged, and implemented for this second embodiment of an automated diagnostic or preparation device to prevent magnetic extraction particle carryover. Figures 15A-15D show an embodiment of a fixed magnet assembly that illustrates additional features and concepts outlined with respect to Figures 14A-14C. The exemplary fixed magnet assembly described with reference to Figures 15A-15D can be implemented in the second embodiment of an automated diagnostic or preparation device to prevent magnetic extraction particle carryover. It will be understood that these are non-limiting examples and that other suitable configurations and implementations are not inconsistent with the disclosed technology.

[0041] Exemplary automated devices, reagent holders, and racks of the presently disclosed technology FIG. 1B shows a schematic diagram of an apparatus 181 for performing automated sample preparation on multiple samples in parallel according to steps illustrated elsewhere herein. The geometric arrangement of the components of the system 181 is exemplary and is not intended to be limiting. The apparatus may additionally include a device (not shown in FIG. 1B) in the receiving bay and be configured to perform diagnostic testing on the samples, such as by detecting the presence of amplified polynucleotides in the cartridge. The device may include, for example, a microfluidics cartridge configured to receive polynucleotides in a PCR-ready form. Such additional features are also described in U.S. Patent Application Serial No. 12 / 173,023, filed July 14, 2008, entitled "Integrated Apparatus for Performing Nucleic Acid Extraction And Diagnostic Testing on Multiple Biological Samples" by Williams et al. Unless specifically made clear to the contrary, when the term PCR is used herein, it is intended to encompass any variation of PCR, including but not limited to real-time, quantitative, and any other form of polynucleotide amplification.

[0042] A processor 180, such as a microprocessor, is configured to control the functions of the various components of the illustrated system and is therefore in communication with each such component that requires control. It is to be understood that, optionally, many such control functions can be performed manually rather than under the control of a processor. Furthermore, the order in which the various functions are described below is not limiting with respect to the order in which the processor executes instructions when the device is in operation. Thus, the processor 180 can be configured to accept data regarding the sample to be analyzed from a sample reader 190, which can be, for example, a barcode reader, an optical character reader, or an RFID scanner (radio frequency tag reader).

[0043] The processor 180 may be configured to accept user instructions from an input device 184, where such instructions may include an instruction to start analyzing a sample and a selection of operating conditions. The processor 180 may be further configured to communicate with a display 182, for example, such that information regarding the analysis is transmitted to the display 182 and thereby communicated to a user of the system. Such information may include, but is not limited to, the current status of the device, the progress of PCR thermal cycling, and warning messages in case of malfunction of either the system or the cartridge. Furthermore, the processor 180 may transmit one or more queries that will be displayed on the display 182 prompting the user to respond and provide input. That is, in certain embodiments, the input 184 and the display 182 are integrated with each other. Optionally, the processor 180 may be further configured to transmit the results of the analysis to an output device 186, such as a printer, a visual display, a display utilizing holographic projection, or a speaker, or a combination thereof. The processor 180 may further optionally be connected to a computer network 188 through a communication interface, such as a network interface.

[0044] Processor 180 may be further configured to control various aspects of sample preparation and diagnosis according to the summary. In Fig. 1B, device 181 is configured to cooperate with complementary rack 170. Device 181 may have the capability to accept multiple racks, such as 1, 2, 3, 4, or 6 racks.

[0045] Embodiments of rack 170 are described in detail in U.S. patent application Ser. No. 12 / 173,023, filed Jul. 14, 2008 by Williams et al. and entitled "Integrated Apparatus for Performing Nucleic Acid Extraction And Diagnostic Testing on Multiple Biological Samples," and U.S. patent application Ser. No. 12 / 178,584, filed Jul. 23, 2008 by Duffy et al. and entitled "Rack For Sample Tubes And Reagent Holders," both of which are incorporated herein by reference in their entireties. Rack 170 is itself configured to receive a number of biological samples 196 in a form suitable for workup and diagnostic analysis, and a number of holders 172, as described in more detail herein with respect to Figures 2A-2C and the like, that are equipped with various reagents, pipette tips, and receptacles. The racks are configured such that samples are processed within their respective holders during work-up of the samples, which processing includes providing individual heating and cooling via heater assemblies 177 .

[0046] The heating functionality of heater assembly 177 can be controlled by processor 180. Heater assembly 177 cooperates with separator 178, such as a magnetic separator, which can be further controlled by processor 180 to move particles, such as magnetic particles, into or out of the vicinity of one or more processing chambers associated with holder 172 within which the particles reside. Assembly 177 and separator 178 are described in more detail herein.

[0047] Fluid dispenser 176, which may also be controlled by processor 180, is configured to perform various aspiration and dispensing operations on each sample, fluid, and reagent in holder 172 to achieve extraction of nucleic acid from the sample. Fluid dispenser 176 may perform such operations on multiple holders simultaneously.

[0048] The sample reader 190 is configured to transmit identification indicators for the samples and in some cases the holder to the processor 180. In some embodiments, the sample reader is attached to the liquid dispenser so that it can read indicators for the samples over which the liquid dispenser is placed. In other embodiments, the sample reader is not attached to the liquid dispenser and is independently movable under the control of the processor. The liquid dispenser 176 is further configured to obtain an aliquot of fluid containing nucleic acids extracted from one or more samples and direct it to a storage area 174, which may be a cooler. The storage area 174 encloses, for example, a PCR tube corresponding to each sample. Additionally or alternatively, the liquid dispenser 126 can be configured to obtain an aliquot of fluid containing nucleic acids extracted from one or more samples and direct it to a device configured to receive and amplify the nucleic acids. The device can include, for example, a microfluidics cartridge received in a receiving bay (not illustrated) of the apparatus 181.

[0049] As with the other exemplary embodiments described herein, the embodiment of the device generally shown in Figure 1B is advantageous in that it does not require locations within the device that are configured for storing reagents. Thus, the device of Figure 1B is self-contained and cooperates with a holder 172 that is prepackaged with reagents as in a location therein that is dedicated to storing reagents.

[0050] The devices of FIG. 1B may be configured to perform operation at a single location, such as a laboratory environment, or they may be portable, for example, so that they can be carried by a doctor or other medical personnel who may see patients at various locations. Typically, the devices are provided with a power cord so that they can accept AC power from a mains supply or a generator. The devices may be configured to operate by using one or more batteries, and therefore are typically further equipped with a battery recharging system and various warning devices to alert the user if the battery power becomes too low to reliably initiate or complete a diagnostic analysis.

[0051] In other embodiments, the device of Figure 1B may be further configured for multiple sample analysis and / or analysis of multiple sample batches, where, for example, a single rack holds a single sample batch. Thus, each component shown in Figure 1B may be present in as many instances as there are sample batches, although the various components may be configured within a common housing.

[0052] The devices described herein find use for analyzing any nucleic acid-containing sample for any purpose, including, but not limited to, genetic testing and clinical testing for various human infectious diseases.

[0053] The devices herein can be configured to operate on a laboratory bench or similar environment and can test approximately 45 samples per hour when operated continuously throughout a normal working day. Typically, results from an individual raw sample are available in less than an hour.

[0054] 2A illustrates an isometric view of an exemplary holder described herein (e.g., holder 172 shown in FIG. 1B). The holder described herein is a reagent holder for holding and transporting reagents for various purposes, including but not limited to sample preparation in a clinical setting, and configured to be received by a rack described herein. The reagent holder also typically provides containers in which various reagents can be mixed with each other and / or with a sample. The holder is further configured for use in an automated device that can perform sample preparation on samples in more than one holder simultaneously.

[0055] This exemplary holder is now described, as well as other holders not shown as specific embodiments but not inconsistent with the description herein. Further details of the reagent holder can be found in U.S. patent application Ser. No. 12 / 218,416, filed Jul. 14, 2008 in the names of Wilson et al. (entitled "Reagent Tube, Reagent Holder, and Kits Containing Same"), which is incorporated herein by reference.

[0056] 2A includes a connecting member 210 having one or more of the following characteristics: The connecting member 210 functions to connect the various components of the holder to one another. The connecting member 210 has an upper side 212 and a lower side (not shown) opposite the upper side.

[0057] A reagent holder 200 will now be described below to illustrate certain features of the disclosed technology, with the understanding that the disclosed technology can be practiced with any suitable holder that accepts magnetic substrates, such as magnetically coupled particles. The reagent holder 200 of this particular non-limiting embodiment of FIG. 2A includes a process tube 220 having an opening 222 located in the connecting member, two or more reagent tubes 240 disposed on the underside of the connecting member, each having an inlet opening 242 located in the connecting member, and one or more receptacles 250 located in the connecting member, each configured to accept a complementary container 254, such as a reagent tube, inserted from the upper side 212 of the connecting member. In the embodiment illustrated in FIGS. 2A-2C, the reagent holder 200 includes receptacles 250, each configured to accept a snap-on container 254. In another non-limiting embodiment described below with reference to Figures 2D and 2E, the reagent holder includes three receptacles 250, each configured to receive a snap-on container 254. Implementation of the techniques disclosed in this invention can be implemented in holders with any suitable number of receptacles, as well as holders with containers 254 that are integrally formed rather than snapped into the connecting member. Optionally, the reagent holder 200 can include at least one socket positioned in the connecting member and configured to receive a disposable pipette tip and at least one pipette sheath. In this non-limiting embodiment, the reagent holder includes four sockets and four pipette sheaths. The lanes of the racks described herein are designed to be deep and wide enough to receive the various reagent tubes, receptacles, process tubes, and pipette sheaths of a given reagent holder to place the process tubes in communication with the heater / separator unit.

[0058] The container 254 is already inserted into its corresponding receptacle 250. The one or more receptacles 250 contain a quantity of one or more reagents for performing an extraction of nucleic acids from a sample and are configured to receive a reagent tube for the holder. The reagents can be in solid form, such as in lyophilized form. The receptacles can all be the same size and shape, or can be different sizes and shapes from each other. Although the receptacles 250 are shown as having an open bottom, the receptacles 250 are not limited to such a shape and can be closed except for an inlet 252 on the upper side of the connecting member 210. Preferably, the receptacles 250 are configured to receive containers commonly used in the field of laboratory analysis or configured for use with the holder herein. For example, the containers 254 can be 0.3 ml tubes.

[0059] Illustrated is an embodiment of the reagent holder 200 configured with a waste chamber 260 having an inlet opening 262 on the upper side of the connecting member 210. The waste chamber 260 is optional and, in embodiments where it is present, is configured to receive used liquid reagents. In other embodiments where the waste chamber 260 is not present, the used liquid reagents can be transported and discarded to a location outside the holder, such as, for example, a sample tube that contained the original sample whose contents are being analyzed.

[0060] The process tube 220 can be configured as a snap-on tube, like the container 254, or can be integrally formed with the connection member 210. The process tube 220 can be used for various mixing and reaction processes that occur during sample preparation. For example, cell lysis can occur in the process tube 220, as well as extraction of nucleic acids, such as patient DNA or RNA and pathogen DNA or RNA. The process tube 220 can be advantageously located in a location that generally minimizes pipette head movement operations required for the step of transferring liquid thereto. Furthermore, the process tube 220 is positioned in the holder in a position such that when the holder is inserted into a rack, as described in detail herein, the process tube is exposed and accessible to the heater and separator, as described in detail herein.

[0061] Some of the reagents contained in the holder may be provided as liquids and others as solids, in some embodiments a different type of container or tube is used to store the liquids than that which stores the solids.

[0062] Generally, the reagent wells 240 are configured to hold one liquid reagent per well. For example, the reagent holder embodiment 200 illustrates three reagent wells, each containing a wash buffer, a dissociation buffer, and a neutralization buffer, respectively, used in a sample preparation procedure. Other numbers and configurations of reagent wells may be suitably implemented in embodiments of the technology disclosed herein.

[0063] The reagent holder 200 is configured such that at least one socket, one or more receptacles, and respective openings of the process tubes, and two or more reagent tubes are all aligned with each other (i.e., their midpoints lie on the same axis). As will be explained in more detail below with reference to Figures 6A-6B, this axis may be the process axis along which the features of the holder are aligned. It will be understood that in embodiments of the disclosed technology, the holder may be aligned in a substantially linear arrangement such that the midpoints of the features do not lie exactly on a common process axis. Furthermore, the holder herein is not limited to a particular configuration of receptacles, process tubes, sockets, reagent tubes, and waste chambers, if present. For example, the holder may be shorter if some openings are staggered with respect to each other and occupy "off-axis" positions. The various receptacles, etc., need not occupy the same mutual positions as shown in Figure 2A.

[0064] It will be understood that alternative configurations of the various components of the holder 200 result in changes in form only, and that these alternative configurations can be accommodated within other variations of the described apparatus, including, but not limited to, alternative instruction sets for the liquid dispensing pipette head, heater assembly, and magnetic separator described in detail herein. Each such configuration of reagent holder can be accommodated by a corresponding variation in the form of the rack described herein that receives one or more such holders.

[0065] In some embodiments, the holder 200 includes an alignment member, such as a mechanical key. Typically, such a key is part of the connecting member 210. The mechanical key ensures that the holder is received, for example, by a complementary member in a support rack described herein (e.g., rack 170 in FIG. 1B) or a complementary member in a receiving bay of a device that controls dispensing actuation for a reagent in the holder. Thus, the embodiment 200 has a mechanical key 292 that includes a pair of rectangular notches on one end of the connecting member. This illustrated feature further provides a tab that allows a user to properly grip when inserting and removing the holder into and from a rack or another device. The illustrated embodiment of the holder 200 also has a mechanical key 290 on the other end of the connecting member 210. The mechanical key 290 is an angled notch that facilitates insertion of the holder into the rack and also ensures good alignment with the rack when it abuts a complementary angled notch in a recessed area configured to receive the holder.

[0066] Reagent holders for use with the racks described herein are typically manufactured from a plastic, such as polypropylene, that has some flexibility to facilitate placement in the racks described in detail herein, but generally has sufficient rigidity such that the holders do not sag or bend significantly under their own weight, and do not easily deform during routine handling and shipping, thus allowing reagents to leak out of the holder.

[0067] Holder 200 is typically such that connecting member 210, process tube 220, two or more reagent tubes 240, and waste chamber 260 (if present) are manufactured from a single piece made from a material such as polypropylene, although it will be understood that other configurations of holder 200 may be suitably implemented with the techniques disclosed in this invention.

[0068] The illustrated embodiment of the reagent holder 200 has four receptacles 250 and corresponding containers 254. Fig. 2B shows a side profile view of this embodiment of the reagent holder 200, and Fig. 2C shows a top view of this embodiment of the reagent holder 200. It can be seen that the four receptacles 250 (e.g., receptacles 250-1, 250-2, 250-3, and 250-4) are configured to receive corresponding containers 254 (e.g., containers 254-1, 254-2, 254-3, 254-4). Some of the containers 254 can contain a quantity of one or more reagents, typically in solid form, such as in lyophilized form, for performing extraction of nucleic acids from a sample associated with the holder.

[0069] In other embodiments, such as the embodiment of the holder 202 shown in Figures 2D and 2E, there may be a different number of receptacles 250 and containers 254. For example, Figure 2D shows a side profile view of an embodiment of the holder 202, and Figure 2E shows a corresponding top view of this embodiment of the holder 202. In this embodiment of the reagent holder 202, there are three receptacles 250 (e.g., receptacles 250-1, 250-2, and 250-3) configured to receive corresponding containers 254 (e.g., containers 254-1, 254-2, and 254-3). Some of the containers 254 may contain a quantity of one or more reagents, typically in solid form, such as in lyophilized form, for performing extraction of nucleic acids from a sample associated with the holder. Although the exemplary holders 200 and 202 have been described as containing reagents for performing extraction of nucleic acids from a sample, it will be understood that the techniques disclosed in this invention are not limited to holders containing such reagents, but may be suitably implemented on any holder in which a magnetic substrate, such as magnetically bound particles in solution, is manipulated or processed.

[0070] An exemplary heater and magnetic separator assembly capable of applying thermal and magnetic energy to process tubes of multiple holders will now be described with reference to Figures 3A-3C. It will be understood that embodiments of the techniques disclosed in this invention may be suitably implemented in other heater and magnetic separator assemblies. Figure 3A shows an isometric view of an exemplary heater assembly 300 having independently controllable heater units and a magnetic separator 370. Figure 3B provides an isometric view and a side profile view of one of these independently controllable heater units 301. Figure 3C provides a side profile view of the interaction of the magnetic separator 370 with the independently controllable heater units of the heater assembly 300.

[0071] More specifically, the heater assembly 300 shown in Figure 3A can include one or more independently controllable heater units 301, each including a heat block 303. Each of the heat blocks 303 is configured to align with and deliver heat to the process tube 302. Optionally, each heat block 303 can be secured and connected to the remainder of the apparatus using one or more fasteners, such as one or more screws 307 or other adhesive devices. The securing mechanism is not limited to such a configuration.

[0072] In certain embodiments, there are 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 25, 30, 32, 36, 40, 48, or 50 heater units in the heater assembly 300. Still other numbers of heater units, such as any number between 6 and 100, are consistent with the description herein. The one or more heat blocks 303 may be molded from a single piece of metal or other material, or may be manufactured separately from one another and mounted independently of one another or connected to one another in some manner. Thus, the term heater assembly implies an assembly of heater units, but does not require that the heater units or their respective heat blocks be directly or indirectly joined to one another. The heater assembly 300 can be configured such that each heater unit 301 independently heats each of one or more process tubes 302 (e.g., process tubes of a reagent holder, such as process tube 220 of holder 200 shown in FIG. 2A ), for example by enabling each of one or more heat blocks to be independently controllable as described in detail herein.

[0073] In certain embodiments, a magnetic separator 370 may be present. The magnetic separator 370 may be configured to move one or more magnets 304 relative to one or more process tubes 302 and the individual magnetic particles therein. In some embodiments, the magnets 304 may be moved in close proximity to the process tubes 302 (e.g., each magnet 304 has a face that is less than 2 mm, between 2 mm and 1 mm, or less than 1 mm away from the outer surface of the corresponding process tube 302 without contacting the process tube). The magnets 304 of the magnetic separator 370 may be aligned on a common axis (e.g., passing through the midpoint of each of the magnets 304). This common axis may be positioned behind the process tubes 302 and extend parallel to the process tubes 302 (more specifically, extends parallel to a common axis that passes through all of the process tubes 302 when the process tubes 302 are placed in the heat block 303). In some cases, the common axis passing through the magnets 304 of the magnetic separator 370 may be referred to as the first magnet axis, such as the example of first magnet axis 380 shown in FIG. 3B. The magnetic particles may be microparticles, beads, or microspheres that have the ability to bind one or more biomolecules, such as polynucleotides, and that are commonly used as retention members. Separating the particles while in solution generally comprises collecting and concentrating or collecting the particles at one location inside one or more processing tubes 302.

[0074] Structurally, the magnetic separator 370 can include one or more magnets 304 fixed to a support member, a motorized mechanism configured to move the support member such that the magnets move back and forth along a fixed axis and maintain close proximity to one or more receptacles containing magnetic particles in solution during at least a portion of this movement, and control circuitry for controlling the same. The support member and motorized mechanism are not shown in Figure 3A, but are described in more detail with respect to Figure 3C.

[0075] The magnetic separator 370, in cooperation with the heater assembly 300, can enable successive heating and separation operations to be performed on liquid material in one or more process tubes without transporting either the liquid material or the process tubes to a different location to perform any of those operations. Such operations are also advantageous in that they mean that heating and separation functions, which are independent of one another but both utilised in sample preparation, can be performed using a small and efficient device.

[0076] In some embodiments, the heater assembly 300 and the magnetic separator 370 can be controlled by electronic circuitry, such as on a printed circuit board 309. The electronic circuitry can be configured to cause the heater assembly 300 to apply heat independently to the process tube 302 to minimize heating and sensing costs. Additionally, the electronic circuitry can be configured to repeatedly move the magnetic separator 370 relative to the process tube 302. The electronic circuitry can be incorporated into a single printed circuit board (PCB).

[0077] In some cases, the magnetic separator 370 may be integrated with the heater assembly 300, and may be referred to together as an integrated magnetic separator and heater assembly. Thus, the integrated magnetic separator and heater assembly may include a heater assembly including a plurality of independently controllable heater units, each having a heat block configured to receive and heat one of a plurality of process tubes, one or more magnets fixed to a support member, a motorized mechanism configured to move the support member such that the one or more magnets move back and forth along a fixed axis and maintain close proximity to one or more of the process tubes containing magnetic particles within the heater assembly during at least a portion of this movement, and a control circuit for controlling the motorized mechanism and further controlling the heating of the heater units.

[0078] Although not shown in FIG. 3A, an enclosure can cover the magnetic separator 370 and the heater assembly 300 for protection of the subassemblies below and for aesthetic purposes. The enclosure can be designed to keep the heat blocks 303 spaced apart to ensure efficiency of heating and cooling. The enclosure can be configured to allow sufficient air flow around the process tube 302 so as not to significantly inhibit the cooling rate. The enclosure can have a gap between the enclosure and the heat block 303 to facilitate cooling. The magnetic separator 370 and the heater assembly 300 can alternatively be housed by separate enclosures. For example, the heater assembly 300 can optionally be enclosed within an enclosure that surrounds the heater unit 301 and the heat block 303. The one or more enclosures can be manufactured from plastic, but are not so limited. The one or more enclosures can be configured to be aesthetically pleasing to the user.

[0079] In the particular configuration shown in FIG. 3A, the heater assembly 300 includes twelve heat blocks 303 aligned parallel to one another. Each heat block 303 is fabricated from aluminum and has an L-shaped configuration with a U-shaped entrance for receiving the process tube 302. The magnetic separator 370 includes twelve magnets 304 aligned parallel to one another. Each magnet 304 can be a rectangular block of neodymium (or a permanent rare earth material with a magnetic field) mounted on a support member disposed behind each heat block 304. The magnets 304 can be configured to move up and down relative to the process tube 302 within the heater assembly 300. This mechanism is described in more detail with respect to FIG. 3C.

[0080] Certain embodiments of the automated diagnostic or preparation apparatus described herein have more than one independently controlled heater unit 301 in a single heater assembly 300 as described in detail herein. For example, a single heater assembly 300 can be configured to independently heat six or twelve process tubes, and the apparatus can be configured to have two or four such heater assemblies 300. It will be appreciated that embodiments of the techniques disclosed in this invention can be implemented in heater assemblies that do not independently heat each process tube, or that apply heat to a subset of multiple process tubes received within the heater assembly.

[0081] It should be understood that while only a cross-section of one heat block 303 is shown in the right-hand panel of FIG. 3B, this cross-section remains the same when having multiple heat blocks aligned parallel to one another, and thus the geometric midpoints of these heat blocks all lie on a single linear axis (e.g., as in FIG. 3A), but are not so limited in configuration. Thus, one or more heat blocks, either in groups or alternatively individually, can be positioned at different heights relative to one another, or, either in groups or alternatively individually, can be staggered relative to one another from left to right. Furthermore, in other embodiments, the heat blocks are not aligned parallel to one another, but are positioned at angles other than 180° relative to one another. Furthermore, while the heat block 303 shown in FIG. 3B can be one of several that are equally sized, it is consistent with the art herein that one or more heat blocks can be configured to receive and heat process tubes of different sizes.

[0082] The exemplary heat block 303 of FIG. 3B (right hand panel) is configured to have an internal cavity that partially surrounds the lower portion of the process tube 302. In the heat block 303, the internal cavity surrounds the lower portion of the process tube 302 on two sides, but not on the front side (facing away from the magnet 304) and the back side (adjacent to the magnet 304). In other embodiments, the heat block 303 is configured to surround the bottom of the process tube 302 on three sides, including the front side. Still other configurations of the heat block 303 are possible that are consistent with the goal of achieving rapid and uniform heating of the contents of the process tube 302. In certain embodiments, the heat block is molded to closely conform to the shape of the process tube 302 to increase the area of ​​the heat block that contacts the process tube during heating of the process tube. Thus, although an exemplary heat block 303 is shown having a conically curved bottom cavity in which a complementary process tube seats, other embodiments of the heat block 303 have, for example, a cylindrical cavity with a flat bottom. Still other embodiments of the heat block 303 can have a rectilinear interior cavity that would accommodate a cuvette.

[0083] 3B shows heat block 303 as L-shaped to aid in the transfer of heat from heating element 351 and in securing one or more heat blocks to the rest of the apparatus, this need not be the case, as described further herein. For example, in some embodiments, heating element 351 can be located directly below process tube 302.

[0084] In one embodiment, the heat block 303 is configured to heat liquid samples having a mass of ≈10 grams and a volume between 1.2 ml and 10 μl. Heating a 1 ml biological sample from room temperature to 65° C. can be accomplished in less than 3 minutes, and heating a 10 μm aqueous liquid, e.g., dissociation buffer, to 85° C. (from 50° C.) can be accomplished in less than 2 minutes. The heat block 303 can cool from 85° C. to 50° C. in less than 3 minutes. The heat block 303 can be configured to have a temperature uniformity of 65±4° C. for heating a 1 ml sample, and 85±3° C. for heating a 10 μl dissociation buffer. These ranges are exemplary, and the heat block can be appropriately strength-tuned to heat other volumes of liquid at slower and faster rates than those described. This aspect of the present technology is one aspect that contributes to achieving rapid nucleic acid extraction of multiple samples through a combination of liquid handling steps, rapid heating for lysis, DNA capture and release, and magnetic separation, as described in detail herein and in any other publications, such as U.S. Patent Application Nos. 12 / 172,208 and 12 / 172,214, both of which are incorporated herein by reference.

[0085] As shown in FIG. 3B, the independent controller heater unit 301 can further include one or more heating elements (e.g., power resistors) 351, each configured to thermally couple to and dissipate heat to the heat block 303. For example, in one embodiment, the power resistors can dissipate up to 25 watts of power. Although the heating elements 351 are shown positioned at the bottom of the heat block 303, it will be understood that other configurations are contemplated consistent with the assemblies described herein, for example, the heating elements 351 can be positioned on the top or side of each heat block 303 or directly underneath the process tube 302. In other embodiments, the heating elements can have other shapes and be curved, such as spherical or elliptical, rather than rectangular in cross section. Additionally, the heating elements can be molded or shaped to closely or approximately match the shape of the bottom of the process tube.

[0086] 3B, the independently controlled heater unit 301 may further include one or more temperature sensors 352, such as resistive temperature detectors, for sensing the temperature of each of the heat blocks 303. Although the temperature sensors 352 are shown positioned at the bottom of the heat blocks 303, it will be understood that other configurations are contemplated consistent with the assemblies described herein, for example, the temperature sensors could be positioned on the top or sides of each heat block 303, or near the bottom of the process tube 302 but not so close as to inhibit uniform heating of the process tube 302.

[0087] Also shown is a printed circuit board (PCB) 309 that enables the heater assembly 300 to apply heat independently to each process tube 302 upon receipt of appropriate commands.

[0088] FIG. 3C provides a cutaway side profile view of the independently controllable heater unit 301 and magnet 304 of the magnetic separator 370 to illustrate the interaction of the magnetic separator 370 with the independently controllable heater units of the heater assembly 300.

[0089] Although FIG. 3C illustrates magnet 304 as a rectangular block, magnet 304 is not so limited in shape. Additionally, the configuration of FIG. 3C is consistent with either having a single magnet that extends across all heat blocks 303 in heater assembly 300, or having multiple magnets aligned in a common line on a support member, for example, that are aligned to operate in unison to span a subset of heat blocks 303. Magnet 304 can be made of neodymium and can have a magnetic strength (Brmax) of 5,000 to 15,000 Gauss. Exemplary magnets are from K&J Magnetics, Inc. Other suitable magnets can also be implemented. The poles of magnet 304 can be arranged such that one pole faces toward heat block 303 and the other pole faces away from heat block 303.

[0090] The magnets 304 are mounted on a support member 372 that can be raised and lowered with a motorized shaft 305 along a fixed axis. The fixed axis can be vertical. The magnetic separator 370 can have a gear 306 that transfers rotational energy from a motor 375 to the motorized shaft 304 to raise and lower the magnets 304 relative to the heat block. This gear transmission arrangement can allow the motor 375 to be positioned perpendicular to the shaft 305, thereby saving space within the apparatus in which the magnetic separator 370 is placed. In other embodiments, the motor 375 is positioned below the shaft 305. It will be understood that other configurations, including but not limited to moving the magnets 304 side to side or carrying the magnets 304 from top to bottom, are consistent with moving the magnets 304 relative to the process tube 302.

[0091] The motor 375 can be computer controlled to operate at a particular speed, for example a rotational speed that results in vertical movement of the magnets 304 in the range of 1-20 mm / s. Thus, the magnetic separator 370 can be configured to move up and down, left and right, or back and forth repeatedly several times along the same axis. In some embodiments, there is more than one shaft 305 operating under motorized control. The presence of at least a second shaft has the effect of making the motion of the separator 370 smoother and acting as a guiding member. In some embodiments, the support member 372 rests on one or more guiding members to ensure that it does not, for example, tilt, twist, or deflect, or accept other internal movements during movement (other than those of the controlled movement along the axis) and thereby reduce the effectiveness of the separation.

[0092] The support member 372 can be configured to move the magnet 304 between a first position located away from the processing tube 302 (e.g., as in the left hand side of FIG. 3C) and a second position located immediately adjacent to the processing tube 302 (e.g., as in the right hand side of FIG. 3C), and further configured to move around the second position with an amplitude that is smaller than the distance between the first and second positions measured along the shaft 305.

[0093] Figures 4A and 4B show various views of a rack that can hold multiple reagent holders (e.g., holder 200 shown in Figure 2A) in a defined position to ensure that the process tubes of the reagent holders (e.g., process tube 220 of holder 200 shown in Figure 2A) are accurately positioned within a heater block of a heater assembly (e.g., heater block 303 of heater assembly 300 shown in Figure 3A) when the rack is loaded into an automated diagnostic or preparation device described herein. More specifically, Figure 4A shows a perspective view of the rear of the rack, whereas Figure 4B shows an isometric view of the rack. Figures 4A and 4B are described together.

[0094] An embodiment of a rack 400 is shown that is configured to be insertable into and removable from a loading bay (alternatively, a receiving bay) of an automated device, such as an automated diagnostic or preparation device described herein. An example of a loading bay of an automated device is shown in FIG. 5A. Further details regarding such devices are provided in U.S. Patent Application Serial No. 12 / 173,023, filed July 14, 2008, entitled "Integrated Apparatus for Performing Nucleic Acid Extraction And Diagnostic Testing on Multiple Biological Samples" by Williams et al., which is incorporated herein by reference. The automated device can have multiple loading bays that allow for simultaneous processing of samples in multiple racks.

[0095] Each rack can be configured to receive multiple reagent holders. In some examples, the rack is also configured to receive multiple sample tubes. The device is configured to receive multiple reagent holders and multiple sample tubes such that the reagent holders are in one-to-one correspondence with the sample tubes, each of which contains sufficient reagents to extract polynucleotides from the sample and make it PCR-ready. In implementations in which the rack receives multiple sample tubes, the rack can receive any number of sample tubes (e.g., 2, 4, 6, 8, 10, 12, 16, or 20 sample tubes) that contain samples, and a corresponding number of reagent holders. The rack can be configured to hold the reagent holders in place and either allow access to the reagents stored in these holders on the laboratory bench or to allow access to these holders in a dedicated area of ​​the device for one or more other functions of the device, such as automated dispensing, heating of processing tubes, and magnetic separation of affinity beads. The reagent holders can include at least one process tube and a container for one or more reagents. These reagent holders are described in more detail herein (e.g., with respect to Figures 2A-2E) and further details are provided in U.S. patent application Ser. No. 12 / 218,416 (entitled "Reagent Tube, Reagent Holder, and Kits Containing Same" to Wilson et al.), filed Jul. 14, 2008, and incorporated herein by reference.

[0096] For example, in the embodiment illustrated in FIGS. 4A and 4B, the rack 400 is configured to receive twelve sample tubes 416 and twelve corresponding reagent holders 404 in twelve lanes 402. A lane 402, as used herein in the context of the rack 400, is a dedicated area of ​​the rack 400 designed to receive a sample tube and a corresponding reagent holder 404. In some cases, the reagent holder 404 may be a reagent holder 200 having a process tube 220 at one end as shown in FIG. 2A. The lanes 402 of the rack 400 may be configured to receive the reagent holders 404 in a certain orientation. For example, in order to slide each reagent holder 404 into the lane 402, the end of the reagent holder 404 having a process tube may need to be oriented toward the lane 402.

[0097] For example, in the embodiment shown, at least the first and second lanes are in a configuration that enhances dispensing efficiency by being parallel to one another. Typically, when parallel to one another, pairs of adjacent sample lanes 402 are separated by 24 mm at their respective midpoints. Other distances such as 18 mm apart or 27 mm apart are possible. As explained further herein, the distance between the midpoints depends on the pitch of the nozzles in the fluid dispensing head. Keeping this spacing to a multiple of 9 mm allows for easy loading from the rack into a 96 well plate (where wells are typically spaced 9 mm apart). Typically, the rack is also such that multiple reagent holders in multiple lanes are maintained at the same height relative to one another.

[0098] The lanes 402 of the rack 400 can be configured to receive a reagent holder 404 such that the reagent holder 404 is reversibly snapped or locked into place, thereby remaining stable while the reagents are accessed within a given reagent holder 404 and while the rack 400 is being transported from one location to another or inserted into or removed from a diagnostic or preparation device. The lanes 402 of the rack 400 can be configured to align for proper pipette tip pick-up with a liquid dispenser, as described in more detail herein, when the reagent holder 404 is placed in the rack 400. Additionally, in instances where the reagent holder accommodates one or more pipette tips, the second location of each lane can be deep enough to receive one or more pipette tips contained within, for example, a pipette tip sheath.

[0099] The rack 400 may include a sample tube holder 410 configured to receive a number of sample tubes 416, one for each lane 402. Thus, in the embodiment illustrated in Figures 4A and 4B, the sample tube holder 410 may be configured to receive up to 12 sample tubes 416. For each sample tube 416 that the sample tube holder 410 is configured to hold, the sample tube holder 410 may have a first slot 412 and a second slot 414 through which the sample tube 416 is inserted. Each first slot 412 may have a corresponding second slot 414, and each first slot 412 and corresponding second slot 414 may be positioned to receive and hold the sample tube 416 adjacent to one of the lanes 402 (e.g., in the same axis as the lane 402 such that a holder 404 inserted into the lane 402 aligns with the sample tube 416). It will be understood that the practice of the techniques disclosed in this invention is not limited to racks including sample tube holders 410 as shown in Figures 4A-4B, but may be suitably practiced with racks that do not include sample tube holders 410 and do not accept sample tubes 416.

[0100] FIG. 5A shows an isometric view of an empty loading bay 500 (or receiving bay) of an automated diagnostic or preparation device.

[0101] The loading bay 500 may be a recessed area of ​​the device configured to receive a rack, such as the exemplary rack 400 of FIGS. 4A and 4B. The device may have a corresponding number of loading bays 500 to receive any number of racks 400. For example, FIG. 5A illustrates an embodiment of the device having two loading bays 500 positioned side-by-side to allow for simultaneous loading of two separate racks 400. FIG. 5A further illustrates a first magnet axis 580, which may be a common axis on which the magnets of the magnetic separator are aligned (e.g., a common axis passing through the magnets of the magnetic separator). The first magnet axis 580 (similar to the first magnet axis 380 shown in FIG. 3B) may be positioned behind the process tubes of the reagent holder in the rack 400 when the rack 400 is inserted into the loading bay 500 and may extend parallel to the process tubes (more specifically, parallel to a common axis passing through the process tubes).

[0102] 5B shows a front perspective view of an exemplary automated diagnostics instrument having two loading bays 500 occupied by corresponding sample racks 400. These loading bays 500 are shown in the context of two microfluidic cartridges 510 that may be configured to perform amplification on appropriately prepared samples, as described in detail in U.S. Patent Application Serial No. 12 / 173,023, filed July 14, 2008, entitled "Integrated Apparatus for Performing Nucleic Acid Extraction And Diagnostic Testing on Multiple Biological Samples" by Williams et al. Other recessed areas suitably configured to receive other racks differing in shape, appearance, and form but not function are consistent with the description herein.

[0103] Also illustrated is a liquid dispensing head 520, which may be an automated pipette head used to perform liquid processing operations. An exemplary automated pipette head is described in U.S. patent application Ser. No. 12 / 173,023, filed Jul. 14, 2008, entitled "Integrated Apparatus for Performing Nucleic Acid Extraction And Diagnostic Testing on Multiple Biological Samples" by Williams et al.

[0104] The liquid dispensing head 520 can pick up a pipette tip (e.g., from one or more sockets in a reagent holder, such as one of the reagent holders 404 in the rack 400) and return it (e.g., to such socket in the reagent holder after use), peel off the pipette tip from the pipette head and discard it after use or when an error is encountered, as well as move the pipette tip from one location to another in a given holder with high precision so that liquid reagents can be positioned and added to solid reagents, for example, to compound solutions, and also so that various liquid reagents can be mixed with each other during a sample preparation procedure. Moreover, such a liquid dispensing head 520 can desirably operate on several (e.g., 2, 3, 4, or 6) holders in the rack 400, thereby performing certain operations in parallel. The liquid dispensing head 520 can move in three degrees of freedom.

[0105] Exemplary Fixed Magnet Assembly According to the Present Disclosed Technology 6A-6E show various schematic diagrams associated with implementing a fixed magnet assembly to prevent extracted particle carryover according to the techniques disclosed in this invention. These schematic diagrams provide contextual details that are helpful in understanding how the provision of a fixed magnet assembly prevents extracted particle carryover in the practice of the techniques disclosed in this invention.

[0106] FIG. 6A is a top view concept of a set of three reagent holders 602 within a loading bay or receiving bay 600 of a diagnostic or preparation device. FIG. 6A shows how the reagent holders 602 are arranged relative to a first magnetic axis 612 (e.g., out of the magnetic separator) and a second magnetic axis 614 (of the fixed magnet assembly according to the technology disclosed in the present invention). As will be described below, one or more of the magnets of the magnetic separator described above with reference to FIGS. 3A - 3C can be aligned along the first magnetic axis 612. Further, a set of three sample tubes 604 related to the reagent holder 602 are shown adjacent to the reagent holder 602. In fact, it is contemplated that there can be more than three reagent holders 602 (and more than three corresponding sample tubes 604) such as the twelve reagent holders held within the rack 400 within the receiving bay 600. A portion of the associated components of each reagent holder 602 including a processing tube 606 (e.g., the processing tube 220 shown in FIG. 2A) and a set of containers 608 (e.g., the containers 254 shown in FIG. 2A) are illustrated for each reagent holder 602. Each reagent holder 602 and its corresponding sample tube 604 can be aligned along a processing axis 610, and the diagnostic or preparation device is configured to perform processing and operations (e.g., liquid transfer) along each processing axis 610. Thus, a total of n processing axes 610 can be conceptualized, one for each reagent holder 602 and its corresponding sample tube 604.

[0107] In some embodiments, it will be understood that the processing axis 610 does not include the sample tube 604 (e.g., when the sample tube 604 is received within a different part of the device not related to the reagent holder 602). In such an example, the processing axis 610 can be defined by the location of the processing tube 606 and the location of a container (container 608 - 3 in the illustrated embodiment) that receives magnetic energy from a magnet aligned along the second magnetic axis 614.

[0108] In some embodiments, each of the reagent holders 602 may be similar to the reagent holder 200 shown in FIGS. 2A-2C. In other words, the reagent holder 602 may be an embodiment having four snap-on containers 608 (e.g., containers 254 in FIG. 2A) including containers 608-1, 608-2, 608-3, and 608-4 (numbered in order from closest to the processing tube 606 to furthest). In such cases, the processing tube 606 may alternatively be referred to as either a reaction tube or a lysis tube, the container 608-1 may alternatively be referred to as an extraction tube, and the container 608-3 may alternatively be referred to as a mixing tube. It will be appreciated that alternative reagent holders 602 may be implemented in embodiments of the techniques disclosed herein. For example, multiple reagent holders 602 may be joined or formed as a single monolithic processing device configured to be received in a receiving bay. In another example, a single device including multiple reagent holders 602 may be received in a receiving bay.

[0109] The first magnet axis 612 can extend horizontally behind the process tube 606 of the reagent holder 602. The first magnet axis 612 can be the axis along which the magnets of the magnetic separator ride (magnets 304 of magnetic separator 370 shown in FIGS. 3A and 3C). The first magnet axis 612 can be positioned such that the magnets of the magnetic separator are in close proximity to the process tube 606 (e.g., within 2 mm of the process tube 606) when the magnetic separator is raised.

[0110] According to an embodiment of the stationary magnet assembly of the present disclosure, the second magnet axis 614 can extend horizontally through the vessel 608-3 of the reagent holder 602. Alternatively, the second magnet axis 614 can extend sufficiently proximate to the vessel 608-3, whether behind or in front of the vessel 608-3, to exert a magnetic force on the contents of the vessel 608-3. The second magnet axis 614 can be the axis along which the magnets of the stationary magnet assembly ride. The second magnet axis 614 can be positioned such that the magnets of the stationary magnet assembly are sufficiently proximate to the vessel 608-3 (e.g., a mixing tube) of the reagent holder 602 to exert a magnetic force on the contents of the vessel 608-3. The magnetic force can be strong enough to hold magnetically coupled particles in a solution in the vessel 608-3 against the inner wall of the vessel 608-3 while the solution is being transferred from the vessel 608-3 during, for example, a dispense operation. Additionally, the second magnet axis 614 can be spaced sufficiently from the first magnet axis 612 such that the magnets of the stationary magnet assembly do not interfere with the magnets of the magnetic separator. For example, the first magnet axis 612 can be spatially separated from the second magnet axis 614 by a distance "D" such that one or more magnets aligned along the first magnet axis 612 do not exert a magnetic force on the contents of the vessel 608-3 and one or more magnets aligned along the second magnet axis 614 do not exert a magnetic force on the contents of the process tube 606.

[0111] The first magnet axis 612 and the second magnet axis 614 are further illustrated in FIG. 6B, which is a top view schematic diagram of the arrangement of certain components of the reagent holder 602 relative to the magnets on the first magnet axis 612 and the magnets on the second magnet axis 614.

[0112] More specifically, Figure 6B illustrates four reagent holders including the location of the process tubes 606, snap-on containers 608-3, and process axis 610 for each reagent holder. It can be seen that the magnetic separator 620 includes a plurality of magnets 622 aligned on a first magnet axis 612, with each magnet 622 positioned adjacent to a process tube 606 of the reagent holder. In this exemplary implementation, the magnets 622 are in one-to-one correspondence with the process tubes 606. In fact, when the magnetic separator 620 is raised to bring the magnets 622 into close proximity with the process tubes 606, the magnets 622 exert a magnetic force (shown as a vertical vector in Figure 6B) on the contents of the process tubes 606.

[0113] 6B further illustrates a magnet 632 of a stationary magnet assembly according to the disclosed technology. In this exemplary implementation, a single magnet 632 exerts a magnetic force on two vessels 608-3, and thus the magnet 632 does not have a one-to-one correspondence with the vessels 608-3. In some embodiments, the magnets 632 of the stationary magnet assembly can be arranged in pairs. Each pair of magnets 632 can be positioned in a housing or structure 630. The stationary magnet assembly can include multiple housings 630. In one non-limiting embodiment, multiple housings 630 are formed in a single structure, each housing configured to house or accommodate two magnets 632. In another non-limiting embodiment, the stationary magnet assembly includes a single structure formed of a magnetic material, the single structure including multiple magnetic structures 630 configured to exert a magnetic force on the vessels 608-3. The pairs of magnets 632 can be arranged in the diagnostic or preparation device such that each pair of magnets 632 is positioned (in the manner shown) between the vessels 608-3 of two adjacent reagent holders when the reagent holders are in the receiving bay of the diagnostic or preparation device. There can be a magnet 632 for each reagent holder, and each magnet 632 can be in the immediate vicinity of the vessel 608-3 of the reagent holder when the reagent holders are in the receiving bay of the diagnostic or preparation device. All of the magnets 632 of the stationary magnet assembly can be aligned (or substantially aligned) on the second magnet axis 612. Each of the magnets 632 can exert a magnetic force (shown as a horizontal vector in FIG. 6B ) on the contents of the adjacent vessel 608-3.

[0114] Implementations of the stationary magnet assembly according to the presently disclosed technology can include any suitably configured magnet. In one non-limiting example, the individual magnets 632 are 0.25×0.25×.0625″ N52 grade NdFeB square magnets with a pull force of 1.77 lbs and a magnetic field strength of 3032 Gauss. It will be understood that these materials, dimensions, and pull forces are not limited to this particular example of the presently disclosed technology. Suitable magnets can include magnets of a variety of different materials, sizes, and / or strengths, so long as the combination of the selected magnet configuration and the placement of the magnet by the mixing tube allows the magnet to adequately capture the magnetic extraction particles in the mixing tube.

[0115] Figure 6C is similar to Figure 6A in that it shows a top conceptual view of a set of three reagent holders 602 in a loading or receiving bay 600 of a diagnostic or preparation device. However, in the embodiment shown in Figure 6C, the second magnet axis 614 does not extend through the midpoint of each of the containers 608-3 in the reagent holders 602. Instead, the second magnet axis 614 extends off the centerline of each of the containers 608-3. This embodiment may correspond to the embodiment shown in Figure 6D.

[0116] Figure 6D is similar to Figure 6B in that it shows a top view schematic of the position of certain components of the reagent holder 602 relative to the magnets on the first magnet axis 612 and the magnets on the second magnet axis 614. However, in the embodiment shown in Figure 6D, the second magnet axis 614 does not extend through the midpoint of each of the vessels 608-3 of the reagent holder 602. This second magnet axis 614 is distinct from the mixing axis 616, which passes through the midpoint of each of the vessels 608-3 of the reagent holder 602. The magnet 632 is aligned along the second magnet axis 614, which is generally parallel to the first magnet axis 612 and also generally parallel to the mixing axis 616 (but not coincident with the mixing axis 616). However, the second magnet axis 614 may be sufficiently close to the mixing axis 616 that the magnet 632 (riding on the second magnet axis 614) may be considered to apply a magnetic force to the contents of each of the containers 608-3 along a direction generally parallel to the mixing axis 616. The function of the magnet 622 of the magnetic separator 620 and the magnet 632 of the fixed magnet assembly may be better understood with the additional context provided by FIG. 6E, which is a side profile schematic diagram showing the position of the reagent holder 602 and corresponding sample tube 604 relative to the first magnet 622 (e.g., from the magnetic separator) and the second magnet 632 (e.g., from the fixed magnet assembly) when the reagent holder 602 and corresponding sample tube 604 are in a receiving bay of a diagnostic or preparation device.

[0117] More specifically, Figure 6E illustrates a reagent holder 602 having a process tube 606, a set of four snap-on containers 608 (e.g., containers 608-1, 608-2, 608-3, and 608-4), a set of reagent tubes (e.g., reagent tubes 640, 642, and 644), a waste chamber 646, and a set of pipette tips (e.g., pipette tips 648, 650, 652, and 654) disposed within a pipette sheath. It should be noted that although this illustrated embodiment of the reagent holder 602 has four snap-on containers 608, embodiments of the technology disclosed herein may be suitably implemented with the three snap-on containers 608 (e.g., container 608-4 is absent) described with reference to Figures 2D-2E.

[0118] The process tube 606 (similar to the process tube 220 shown in FIG. 2A) can be generally used during sample preparation for lysis of cells and extraction of nucleic acids such as DNA or RNA of the patient and DNA or RNA of the pathogen. The process tube 606 can be positioned at the distal end of the reagent holder 602 in a location that minimizes the overall pipette head movement actuation required for the step of transferring liquid to the process tube 606 when the reagent holder 602 is in the receiving bay of the diagnostic or preparation device. The process tube 606 is also positioned such that the process tube 606 is positioned in the heater block 660 of the heater assembly (e.g., shown in FIGS. 3A and 3B) when the reagent holder 602 is in the receiving bay of the diagnostic or preparation device. The first magnet 622 of the magnetic separator can be raised to the immediate vicinity of the process tube 606 to exert a magnetic force on the contents of the process tube 606.

[0119] Some of the containers 608 may contain lyophilized reagents (e.g., dry reagents) to which fluids may be added. In some embodiments, container 608-1 may alternatively be referred to as an extraction tube. In some embodiments, container 608-3 may alternatively be referred to as a mixing tube. In some embodiments, containers 608-2 and 608-4 may alternatively be referred to as master mix tubes. Reagent tubes 640, 642, and 644 may contain liquid reagents, one per tube. In some embodiments, reagent tube 640 may contain a wash buffer. In some embodiments, reagent tube 642 may contain an elution buffer. In some embodiments, reagent tube 644 may contain a neutralization buffer. Each of the wash buffer, dissociation buffer, and neutralization buffer may be used in the sample preparation procedure. The used liquid reagents may be transferred to a waste chamber 646 where they may be subsequently discarded.

[0120] A set of four pipette tips (e.g., pipette tips 648, 650, 652, and 654) can be disposed within a pipette sheath. The pipette tips can be used by a diagnostic or preparation device (e.g., through liquid dispensing head 520) to perform processes and operations (e.g., transfer of liquids). The pipette sheath can function to capture droplets from used pipette tips, thereby preventing inter-sample contamination from use of one holder to use of another holder in a similar location and / or to any support rack in which the holder is placed. The pipette sheath can be permanently or removably fixed to the reagent holder 602, or can be formed, e.g., molded, as part of a single-piece assembly for the holder 602.

[0121] Preparation of a sample using this additional fixed magnet assembly can proceed as follows. It should be noted that the following exemplary workflow description is provided to provide context for understanding that the roles and steps of the fixed magnet assembly are not applicable to all assays that may use other workflows with different processing steps or sequences of operation. In some embodiments, the liquid dispensing head of the diagnostic or preparation device can first pick up the first pipette tip 648 and use it to penetrate (e.g., gain access to) various components of the reagent holder 602, including the container 608-1, the waste chamber 646, and the reagent tubes 640, 642, and 644 (containing wash buffer, dissociation buffer, and neutralization buffer, respectively).

[0122] The liquid dispensing head of the diagnostic or preparation device can transfer a portion of the raw sample from the sample tube 604 using the first pipette tip 648 and add it to the processing tube 606. The amount of raw sample transferred may depend on the type of assay or procedure. A portion of the sample (e.g., the remainder of the sample that was not transferred into the processing tube 606) can be added to a container 608-1 (e.g., an extraction tube) that can contain magnetic particles (e.g., beads), a freeze-dried extraction reagent (e.g., a dried lysis reagent), and an internal control. The magnetic particles can be configured to bind to specific molecules (e.g., DNA / RNA) in the sample. The contents of the container 608-1 are rehydrated with the added sample and a given time to dissolve in solution. The liquid dispensing head can then transfer the contents of the container 608-1 using the first pipette tip 648 into the processing tube 606 (containing the remainder of the sample transferred from the sample tube 604) and mix the contents of the processing tube 606. The fluid dispensing head can then return the first pipette tip 648 to its pipette sheath.

[0123] The contents of a process tube 606 disposed in a heater block 660 of a heater unit of a heater assembly of a diagnostic or preparation device (e.g., the process tube 606 is received within the heater block 660) are heated by the heater block 660. The temperature and duration of heating are determined by the type of assay or procedure. The heat and lysis reagents cleave cells from the sample and a portion of the target nucleic acid (e.g., DNA or RNA) and internal control contained in the cells can be attached or bound to magnetic particles (e.g., magnetically coupled particles or beads).

[0124] The first magnet 622 of the magnetic separator can be raised until it is in close proximity to the processing tube 606. The magnet 622 can exert a magnetic force on the magnetic particles in the processing tube 606, drawing the magnetic particles and attached nucleic acid to the side of the processing tube 606. The liquid dispensing head can extract liquid from the processing tube 606 with the first pipette tip 648 while the magnet 622 is still drawing the magnetic particles and attached nucleic acid to the side of the processing tube 606. Under normal operation, ideally this liquid should be free of the magnetic particles and attached nucleic acid that were held against the inner wall of the processing tube 606 as it was being extracted. The liquid dispensing head can dispense the extraction liquid into the waste chamber 646 and return the first pipette tip 648 to its pipette sheath.

[0125] The first magnet 622 of the magnetic separator can be lowered, which can remove the magnetic force that holds the magnetic particles and attached nucleic acid to the side of the processing tube 606. The liquid dispensing head can transfer the wash buffer from the reagent tube 640 to the processing tube 606 using the second pipette tip 648. The second pipette tip 650 can be used to mix the added wash buffer with the magnetic particles bound to the nucleic acid in the processing tube 606. The first magnet 622 of the magnetic separator can then be raised again until it is in close proximity to the processing tube 606. The magnet 622 can exert a magnetic force on the magnetic particles in the processing tube 606, attracting the magnetic particles and attached nucleic acid to the side of the processing tube 606 again.

[0126] With the magnetic particles moving to the side of the processing tube 606, the liquid dispensing head can use the second pipette tip 650 to extract the liquid contents of the processing tube 606 (e.g., mainly added wash buffer) and transfer this liquid to the waste chamber 646. Under normal operating conditions, this liquid should ideally be free of the magnetic particles and attached nucleic acid that were held against the inner wall of the processing tube 606 as it was being extracted. The liquid dispensing head can then return the second pipette tip 650 to its pipette sheath and lower the first magnet 622 of the magnetic separator, which can remove the magnetic force that holds the magnetic particles and attached nucleic acid to the side of the processing tube 606.

[0127] The liquid dispensing head can then use the third pipette tip 652 to transfer the dissociation buffer from the reagent tube 642 to the processing tube 606 containing the magnetic particles and attached nucleic acid. The dissociation buffer can separate the magnetic particles from the nucleic acid and the internal control. The liquid dispensing head can then use the third pipette tip 652 to transfer the neutralization buffer from the reagent tube 644 to the now empty snap-on container 608-3 (e.g., a mixing tube). The liquid dispensing head can then return the third pipette tip 652 to its pipette sheath. At this point, the processing tube 606 will contain the magnetic particles, the extracted nucleic acid (e.g., DNA / RNA extracted from cells and attached to the magnetic particles), and the internal control. The snap-on container 608-3 (e.g., a mixing tube) contains the neutralization buffer.

[0128] The heater block 660 is again activated to heat the contents of the processing tube 606. The temperature and duration of the heating will depend on the assay or procedure being performed. The first magnet 622 of the magnetic separator can be further raised again until it is in close proximity to the processing tube 606. The magnet 622 can exert a magnetic force on the magnetic particles in the processing tube 606 to attract these magnetic particles (no longer nucleic acids, e.g., DNA / RNA molecules, which are attached to magnetic particles) to the inner wall of the processing tube 606. While the magnetic particles are attracted and held by the magnet 622 to the inner wall of the processing tube 606, the liquid dispensing head can extract the liquid contents (e.g., nucleic acid mixture) from the processing tube 606 without extracting the magnetic particles using the third pipette tip 652. The nucleic acid mixture can be transferred to a vessel 608-3 (e.g., a mixing tube) which now contains a neutralization buffer. The neutralization buffer is configured to reduce the pH of the nucleic acid mixture to a neutral pH. The third pipette tip 652 can be returned to the pipette sheath and the first magnet 622 of the magnetic separator can be lowered.

[0129] In an embodiment of the reagent holder 602 having four snap-on containers 608, the liquid dispensing head may now pierce (e.g., gain access to) container 608-2 and / or container 608-4 with the fourth pipette tip 654. Containers 608-2 and 608-4 may alternatively be referred to as master mix tubes, and which of these containers is used may depend on the assay or procedure being performed. A first master mix tube (e.g., container 608-2) may contain primers and probes for testing on a first analyte of interest, and a second master mix tube (e.g., container 608-4) may contain primers and probes for testing on a second analyte of interest.

[0130] As a very specific example, in some embodiments, reagent holder 602 may be used to perform an enterobacteria assay, and both container 608-2 and container 608-4 may be used. In such a case, container 608-2 may be referred to as an enterobacteria panel master mix tube containing an enterobacteria panel master mix for identifying one set or panel of enterobacteria, and container 608-4 may be referred to as an extended bacterial panel master mix tube containing an extended bacterial panel master mix for identifying a second set or panel of enterobacteria. Thus, a portion of the neutral DNA / RNA mix from container 608-3 could be transferred to both master mix tubes.

[0131] In some embodiments, the reagent holder 602 can be used to extract polynucleotides (e.g., DNA or RNA) from a sample into a PCR-ready form. In such a case, either the snap-on container 608-4 or the snap-on container 608-2 can serve as a PCR master mix tube containing a PCR master mix (e.g., primers, probes, and other PCR reagents for a PCR reaction). For example, if the snap-on container 608-2 is a PCR master mix tube containing a PCR master mix, the liquid dispensing head can first pierce (e.g., achieve access to) the container 608-2 with the fourth pipette tip 654. The liquid dispensing head can then extract the neutral nucleic acid mixture in the container 608-3 (e.g., a mixing tube) and transfer it to the container 608-2. This container 608-3 can be in close proximity to a second magnet 632 (e.g., of a stationary magnet assembly) when the reagent holder 602 is inserted for processing by a diagnostic or preparation device. Additional context regarding possible locations and orientations of the second magnet 632 is provided in FIG. 6B. The second magnet 632 can exert a magnetic force on the contents of the vessel 608-3 as the liquid dispensing head extracts the neutral nucleic acid mixture from the vessel 608-3. In particular, despite attempts to prevent the magnetic particles (e.g., beads) from transferring from the processing tube 606 into the vessel 608-3 (e.g., using the first magnet 622 to keep the magnetic particles in the processing tube 606), some magnetic particles may be transferred. The second magnet 632 can be used as part of an additional filtering step to remove any residual magnetic particles (e.g., "carryover" magnetic particles) carried over from the processing tube 606 as the neutral nucleic acid mixture is extracted from the vessel 608-3.

[0132] The extracted neutral nucleic acid mixture is then transferred to container 608-2 (e.g., a PCR master mix tube). In some embodiments, the PCR master mix in container 608-2 can be in the form of a lyophilized pellet. The PCR master mix pellet can be dissolved by adding the neutral RNA / DNA mixture. The PCR master mix pellet can continue to dissolve, and the liquid dispensing head can mix the contents of container 608-2 using the fourth pipette tip 654. The liquid dispensing head can then remove the mixed solution (now an amplification-ready sample) from container 608-2 using the fourth pipette tip 654 and transfer it to a storage device that stores the sample or a microfluidic cartridge that amplifies the sample (e.g., microfluidic cartridge 510 shown in FIG. 5B).

[0133] It should be noted that this sample preparation process for extracting and preparing polynucleotides into a PCR-ready form can be used with other embodiments of the reagent holder, such as a reagent holder having only three snap-on containers (e.g., reagent holder 202 shown in Figures 2D and 2E). In the event that there is no fourth snap-on container available (e.g., container 608-4), the second snap-on container (e.g., container 608-2) will be used as a master mix tube to hold the prepared PCR ready solution that will be transferred to a storage device or microfluidic cartridge.

[0134] Figures 7A and 7B are two perspective views of an embodiment of a fixed magnet assembly according to the presently disclosed technology that may be implemented into an automated diagnostic or preparation device, and Figure 7C shows a side profile view of the dimensions of the fixed magnet assembly 700 of Figures 7A-7B relative to the dimensions of a snap-on container of a reagent holder received within the diagnostic or preparation device.

[0135] In particular, magnets 732 of stationary magnet assembly 700 are illustrated positioned proximate to a third snap-on container 708-3 of a reagent holder received within a diagnostic or preparation device (e.g., a third snap-on container such as container 608-3 of FIGS. 6A-6E). In this non-limiting example, for each reagent holder, magnets 732 are positioned behind the third snap-on container 708-3 (e.g., between the third snap-on container 708-3 and where the second snap-on container would be located in the illustrated case). Furthermore, in this embodiment of stationary magnet assembly 700, magnets 732 are oriented at an angle that makes them parallel to the angled walls of snap-on container 708-3 (e.g., resulting in a magnetic force perpendicular to the angled walls).

[0136] As shown in FIG. 7A, when the fixed magnet assembly 700 is installed and a rack with loaded reagent holders is received in the receiving bay of a diagnostic or preparation device, the fixed magnet assembly 700 (and its magnet 732) can be configured to fit between a second snap-on container (not shown) and a third snap-on container (e.g., between container 608-3 and container 608-2 in FIG. 6E). The fixed magnet assembly 700 can be configured to fit within the very small volume between these snap-on containers, despite dimensional variations across diagnostic or preparation devices and differences in the exact placement of each fixed magnet assembly 700 within the receiving bay of the diagnostic or preparation device. In one non-limiting example, the fixed magnet assembly 700 can be positioned such that the magnet is only a small distance away from the sloping wall of the container, such as 0.01 inches, and can have dimensions that allow the fixed magnet assembly 700 itself to be positioned in the space between the containers. For example, the fixed magnet assembly 700 can have a width ranging between 0.15 and 0.3 inches and a height of less than 0.4 inches. The ability to fit the fixed magnet assembly 700 into such a small volume advantageously allows the fixed magnet assembly 700 to be retrofitted into existing diagnostic or preparation equipment without having to redesign the reagent holder or snap-on container, while also allowing the magnet 732 of the fixed magnet assembly 700 to effectively and invariably apply a magnetic force to the snap-on container 708-3.

[0137] This advantageous aspect of the fixed magnet assembly 700 is more clearly seen in side profile view FIG. 7C of the fixed magnet assembly 700 positioned between the third snap-on container 708-3 and the second snap-on container 708-2. In some embodiments, the distance 750 between the angled wall of the third snap-on container 708-3 and the magnet 732 of the fixed magnet assembly 700 can be 0.011 inches or less, the horizontal distance 752 between the wall of the third snap-on container 708-3 and the wall of the second snap-on container 708-2 of the reagent strip can be 0.152 inches or less, and the length 754 of the angled wall of one of the snap-on containers can be about 0.407 inches. The fixed magnet assembly 700 can be sized and shaped to fit into this space between the third snap-on container 708-3 and the second snap-on container 708-2 of the reagent strip when the reagent strip is loaded into a rack received in a receiving bay of a diagnostic or preparation device.

[0138] Although the exemplary fixed magnet assemblies 700 in Figures 7A and 7B are shown as being configured to exert a magnetic force on a third snap-on container, it will be understood that these fixed magnet assemblies 700 may be suitably positioned to exert a magnetic force on any other snap-on container depending on the particular assay or process being performed and which containers are likely to contain carryover particles.

[0139] It should be noted that the magnet 732 of the embodiment of the fixed magnet assembly 700 shown in Figures 7A and 7B can be considered to be arranged along a single linear axis (e.g., an axis perpendicular to the longitudinal axis of the reagent holder and also perpendicular to the processing axis of the reagent holder). Thus, even though the magnet 732 of the fixed magnet assembly 700 is arranged in a different manner than the magnet 632 shown in Figure 6B, the second magnet axis 614 shown in Figures 6A and 6B is still considered applicable when adjusted to extend between the second snap-on container and the third snap-on container (the magnet 732 is considered to ride on the same axis as the magnet 622 on the first magnet axis 612 and to exert a magnetic force on the third snap-on container that is considered to be best represented as a vertical vector in Figure 6B).

[0140] FIGURE 8A shows an isometric view of an embodiment of a fixed magnet assembly that can be implemented in an automated diagnostic or preparation device in accordance with the techniques disclosed herein. More specifically, FIGURE 8A illustrates an embodiment of a fixed magnet assembly that has a fixed height when implemented in a diagnostic or preparation device. FIGURE 8B shows the fixed magnet assembly of FIGURE 8A implemented in a receiving bay of a diagnostic or preparation device, such as in receiving bay 500 described with reference to FIGURES 5A-5B.

[0141] The stationary magnet assembly 800 can include a support plate 802 that can have dimensions suitable for the particular diagnostic or preparation device in which it is implemented. In some embodiments, the support plate 802 can be a machined aluminum plate. The support plate 802 can include a set of recesses or holes 806 each configured to receive a bottom end of a vessel (e.g., a mixing tube), such as the vessel 708-3 shown in FIGS. 7A-7B or the vessel 608-3 shown in FIGS. 6A-6E. For example, the indicated location of the vessel 608-3 shown in the conceptual diagram of FIG. 6B can match the location of the holes 806 on the support plate 802.

[0142] The stationary magnet assembly 800 can also include a magnet holder 804, which can also have dimensions suitable for the particular diagnostic or preparation device in which it is implemented. In some embodiments, the magnet holder 804 can be manufactured from a material that is chemically resistant to cleaning agents. The magnet holder 804 can include a pair of magnet housings 812 and a connector 814. The magnet housings 812 and the connector 814 can be integrally formed as a single monolithic part. In another example, the magnet housings 812 and the connector 814 are joined to form the magnet holder 804. Other configurations can also be suitably implemented. In some embodiments, each magnet housing 812 can have a trapezoidal shape when viewed from above. In this example, each magnet housing 812 houses two magnets (not shown) positioned adjacent its first and second faces 820 and 822, respectively. This arrangement can be similar to the way that FIG. 6B shows, where a pair of magnets 632 are arranged in the housing 630.

[0143] In one non-limiting example, the stationary magnet assembly 800 is a single monolithic component including multiple magnet housings 812 separated by connectors 814. In some cases, the stationary magnet assembly is a unitary structure including multiple magnet housings 812. The single stationary magnet assembly 800 can be formed, for example, of a magnetic material. In another non-limiting example, the single stationary magnet assembly 800 is formed of one or more non-magnetic materials with a magnetic material bonded to the inner walls of the housing adjacent the first side 820 and the second side 822 of each magnet housing 812. Other configurations are possible.

[0144] The magnet holder 804 may have mounting holes 816 for attaching it to the support plate 802 (e.g., in the connector 814). For example, fasteners (e.g., screws) may be inserted into the mounting holes 816 to secure the magnet holder 804 to the support plate 802 to form the fixed magnet assembly 800. The support plate 802 of the fixed magnet assembly 800 may then be installed in (e.g., secured to) the diagnostic or preparation apparatus using any suitable mechanism. In some embodiments, the fixed height (e.g., up / down position) of the magnet holder 804 relative to the support plate 802 and the rest of the diagnostic or preparation apparatus may be adjusted by adding a shim of a desired height measured in the z-direction between the magnet holder 804 and the support plate 802. Installation of the fixed magnet assembly 800 may include selecting one of a number of shims of different heights from an installation kit, installing the selected shim in a receiving bay, and installing the fixed magnet assembly 800 above the shim in the z-direction. This can be particularly advantageous when the fixed magnet assembly is retrofitted into existing preparation and diagnostic equipment in the field, in view of the very slight dimensional variations and tight tolerances associated with the receiving bays and racks implemented in these equipment.

[0145] That is, a mixing tube of a reagent holder (e.g., vessel 608-3 or vessel 708-3) can be received in a hole 806 of the support plate 802 such that each mixing tube is in close proximity to a magnet in an adjacent magnet housing 812 (e.g., a magnet positioned behind either a first face 820 or a second face 822 of the adjacent magnet housing 812). In some embodiments, the first face 820 and the second face 822 of each magnet housing 812 can be oriented at an angle that makes them parallel to the inclined wall of the mixing tube (e.g., vessel 608-3 or vessel 708-3) when the mixing tube is placed in the hole 806. Thus, the magnets positioned behind each of the first face 820 or second face 822 of the magnet housing 812 can also be oriented to be parallel to the inclined wall of the adjacent mixing tube, resulting in a magnetic force perpendicular to the inclined wall of the mixing tube.

[0146] The shape and dimensions of the magnet housing 812 and the connector 814 connecting the magnet housing 812 can be advantageously adjusted so that the magnet housing 812 and the connector 814 do not interfere with a skirt or flange of a receptacle (e.g., receptacle 250) of a reagent holder receiving a second or third snap-on container (e.g., containers 608-2 and 608-3, respectively) when the fixed magnet assembly 800 is installed in a diagnostic or preparation device and a rack enclosing the reagent holder is loaded into a receiving bay of the diagnostic or preparation device. For example, the connector 814 can have a depth (measured in the y-direction) and height (measured in the z-direction) near the hole 806 that are selected to fit into the very small space between the second and third snap-on containers of a reagent holder stored in a rack inserted into the receiving bay. This allows the magnet housing 812 to apply a magnetic force to the third snap-on container without physically interfering with the second snap-on container, which would otherwise be pushed through the receptacle and out the top of the reagent holder when the rack storing the reagent holder is inserted into the receiving bay if the dimensions of the magnet housing 812 and connector 814 were not properly configured.

[0147] As in the illustrated embodiment, the fixed magnet assembly 800 can advantageously include a magnet housing 812 configured to simultaneously apply a magnetic force to the snap-on containers of two different reagent holders (e.g., as with the magnet housing 630 of FIG. 6B). More specifically, the magnet housing 812 of the fixed magnet assembly 800 can include two magnets (not shown), one of which can apply a magnetic force to one side of a snap-on container of a reagent holder and the other of which can apply a magnetic force to the opposite side of another snap-on container of a different reagent holder. In other words, the magnets in the magnet housing 812 can apply a magnetic force to opposing sides between the snap-on tubes of adjacent reagent holders, and adjacent magnets in the fixed magnet assembly 800 apply a magnetic force to opposing sides between the snap-on tubes of adjacent reagent holders. Although the magnetic force is applied to different sides of the snap-on containers depending on which magnet is in the immediate vicinity of the snap-on container (as shown in FIG. 6B), the problem of magnetic extraction particle carryover is considered valid and invariant for each of the reagent holders. This implementation can avoid the need to place magnets in a very tight space (e.g., between the third snap-on container and the second snap-on container of the reagent holder as in the example of Figures 7A-7B). Instead, the magnets can be positioned at an angle to the process axis of each reagent holder, rather than being positioned on the process axis. An example of this is illustrated by the placement of each pair of magnets 632 in magnet housing 630 shown in Figure 6B.

[0148] In some embodiments, the fixed magnet assembly 800 can be mounted to a particular diagnostic or preparation device by fastening the support plate 802 to a cover 850 of those devices using fasteners such as very strong adhesive tape. While this method can allow the fixed magnet assembly 800 to be inexpensively and quickly mounted in the field (e.g., at the location of the diagnostic or preparation device) into a particular device, there may be unknown component variations between different devices and even variations between all the personnel who may install the fixed magnet assembly 800 into the different devices. Figure 8B shows the same fixed magnet assembly 800 (including the support plate 802 and magnet holder 804) as shown in Figure 8A fastened to the cover 850 of the diagnostic or preparation device.

[0149] More specifically, Fig. 8B illustrates how the fixed magnet assembly 800 can be mounted in a receiving bay of a diagnostic or preparation device, such as the receiving bay 500 of the diagnostic or preparation device shown in Figs. 5A-5B, such that when the receiving bay receives a rack with reagent holders inserted therein, the process tubes of these reagent holders are received in the holes 806 of the support plate 802 of the fixed magnet assembly 800. Furthermore, one or more movable magnets of a magnetic separator (not shown in this figure, but described above with reference to Figs. 3A-3C) can apply a magnetic force to each process tube of the reagent holders in the rack. Furthermore, with the fixed magnet assembly 800 installed in this position, a constant and unchanging magnetic force from the magnets of the fixed magnet assembly 800 (e.g., magnets in magnet housing 812) is also applied to each third snap-on receptacle of the reagent holders in the rack.

[0150] 9 shows an isometric view of an embodiment of a stationary magnet assembly according to the presently disclosed technology that can be implemented into an automated diagnostic or preparation device. More specifically, FIG. 9 illustrates an embodiment of a stationary magnet assembly 900 that is z-compliant (e.g., can move up and down in the z direction when implemented into a receiving bay of a diagnostic or preparation device).

[0151] The stationary magnet assembly 900 can include a support plate 902 that can have dimensions suitable for the particular diagnostic or preparation device in which it is implemented. In some embodiments, the support plate 902 can be a machined aluminum plate. The support plate 902 can include a set of recesses or holes 908, each configured to receive a bottom end of a vessel (e.g., a mixing tube), such as the vessel 708-3 shown in FIGS. 7A-7B or the vessel 608-3 shown in FIGS. 6A-6E. For example, the indicated location of the vessel 608-3 shown in the conceptual diagram of FIG. 6B can correspond to the location of the holes 908 on the support plate 902.

[0152] The stationary magnet assembly 900 may further include a magnet holder 904, which may also have dimensions suitable for the particular diagnostic or preparation device in which it is implemented. In some embodiments, the magnet holder 904 may be made of a material that is chemically resistant to cleaning agents. The magnet holder 904 may include a pair of magnet housings 912 and a connector 914. In some embodiments, each magnet housing 912 may have a trapezoidal shape when viewed from above. In this example, each magnet housing 912 houses two magnets (not shown) positioned adjacent its first and second faces 920 and 922, respectively. This arrangement may be similar to the manner shown in FIG. 6B, where a pair of magnets 632 are arranged within the housing 630.

[0153] The fixed magnet assembly 900 includes a mounting plate 906 disposed below the support plate 902. The fixed magnet assembly includes a set of springs 924 (not visible in this view) with one end of each spring attached to the mounting plate 906 and the opposite end of each spring attached to the magnet holder 904 and / or support plate 902. Other biasing mechanisms can be implemented in addition to or in place of the springs 924 as appropriate. The springs 924 exert a biasing force against the support plate 902 when they are in an uncompressed state to create a desired spacing between the mounting plate 906 and the support plate 902. To assemble the fixed magnet assembly 900 of this non-limiting embodiment, the magnet holder 904 is secured to the support plate 902. In some embodiments, the magnet holder 904 can be mechanically coupled to the support plate 902 using fasteners 919 that can be received in the mounting holes 918 of the magnet holder 904 and corresponding mounting holes (not shown) in the support plate 902. The support plate 902 is then secured to the mounting plate 906. The support plate 902 can be secured using a spring 924 coupled to it and to the mounting plate 906, which allows the support plate 902 to move up and down in the z-axis relative to the mounting plate 906 (e.g., by compressing or expanding the spring 924). In some embodiments, the support plate 902 can be further mechanically coupled to the mounting plate 906 through fasteners 919. The fasteners 919 can be inserted through mounting holes (e.g., mounting holes 918) in the magnet holder 904 and through corresponding mounting holes (not shown) in the support plate 902 to secure the support plate 902 to the mounting plate 906. In some embodiments, the fasteners 919 can be screws or shoulder bolts and can limit the maximum spacing between the mounting plate 906 and the support plate 902. The fasteners 919 can impose an upward limit on the upward movement of the support plate 902 in the z direction away from the mounting plate 906, but do not limit the downward movement of the support plate 902 in the z direction towards the mounting plate 906. In some embodiments, the fasteners 919 can further constrain movement of the support plate 902 in the x and y axes.The stationary magnet assembly 900 can then be secured to a receiving bay of the diagnostic or preparation equipment, such as by fastening the mounting plate 906 to a cover of the diagnostic and preparation equipment using fasteners, such as very strong bonding tape or fasteners received within the mounting plate 906. Other fasteners can be suitably implemented in accordance with the techniques disclosed in this invention.

[0154] Advantageously, the springs 924 allow movement of the support plate 902 in the z-direction relative to the mounting plate 906 secured to the cover, so that the support plate 902 of the installed fixed magnet assembly 900 can move up and down in the z-direction within the receiving bay before and during insertion of the rack into the receiving bay. This feature can allow the fixed magnet assembly to properly position the mixing tubes of the reagent holder (e.g., vessel 608-3 or vessel 708-3) relative to the magnets in the magnet holder 904 without requiring precise and consistent reproduction of the exact magnet placement (e.g., by designing, constructing, and placing the fixed magnet assembly to very tight tolerances) across each of the multiple devices installed therein. For example, the bottom surface of the rack can contact the top surface of the magnet holder 904 as the rack is inserted into the receiving bay. In one non-limiting example, this contact occurs between the bottom surface of the rack and one or more magnet housings 912. This contact can cause the magnet holder 904 and support plate 902 to move down in the z-direction, thereby compressing a spring 924 positioned between the support plate 902 and the mounting plate 906. As the rack continues to be inserted into the receiving bay, the magnet holder 904 and support plate 902 continue to move down in the z-direction until they reach a position that precisely positions the magnet housing 912 relative to the mixing tube of the reagent holder and precisely positions the mixing tube of the reagent holder within the hole 908 of the support plate 902. In one non-limiting embodiment, as the spring 924 is compressed, the support plate 902 moves down relative to the mounting plate 906 until it reaches a point where the rack has reached its lowest position within the receiving bay, where the bottom portion of the mixing tube of the reagent holder will be securely and precisely positioned within the hole 908 of the support plate 902. As a result of this arrangement, each mixing tube is in close proximity to an adjacent magnet housing 912 (e.g., behind either the first face 920 or the second face 922 of the adjacent magnet housing 912) regardless of the inherent dimensional variations of the rack used to insert the holder into the receiving bay and also regardless of the inherent dimensional variations of the receiving bay that receives the holder.Therefore, this arrangement for supplying magnetic energy to mixing tubes of multiple holders using a support plate 902 adjustable in the z-direction can be reliably and accurately reproduced across many different machines regardless of dimensional and tolerance variations between the receiving bays and racks of the machine.

[0155] In some embodiments, the first side 920 and second side 922 of each magnet housing 912 can be oriented at an angle that makes them parallel to the slanted wall of a mixing tube (e.g., vessel 608-3 or vessel 708-3) when the mixing tube is placed in the bore 908. Thus, the magnets positioned adjacent each of the first side 920 or second side 922 of the magnet housing 812 can also be oriented to be parallel to the slanted wall of the adjacent mixing tube, resulting in a magnetic force perpendicular to the slanted wall of the mixing tube.

[0156] Advantageously, embodiments of the fixed magnet assembly 900 according to the technology disclosed in this invention may enable the fixed magnet assembly 900 to be implemented in-situ (e.g., at the location of the diagnostic and preparation equipment) within a particular diagnostic and preparation equipment using a nominal magnet arrangement.

[0157] FIG. 10A shows an isometric view of an embodiment of a fixed magnet assembly that can be implemented in an automated diagnostic or preparation device according to the technology disclosed in the present invention. More specifically, FIG. 10A illustrates an embodiment of a fixed magnet assembly 1000 that is z-compatible (e.g., can move up and down in the z-direction when implemented in the receiving bay of the diagnostic or preparation device). FIG. 10B shows a perspective view of a reagent holder interacting with the fixed magnet assembly 1000 of FIG. 10A to illustrate how a third snap-on container 1030 of the reagent holder can be seated in a hole 1008 of a support plate 1002 of the fixed magnet assembly 1000 after the fixed magnet assembly 1000 is installed and a rack enclosing the reagent holder is loaded into the receiving bay of the diagnostic or preparation device.

[0158] The stationary magnet assembly 1000 can include a support plate 1002 that can have dimensions suitable for the particular diagnostic or preparation device in which it is implemented. In some embodiments, the support plate 1002 can be a machined aluminum plate. The support plate 1002 can include a set of recesses or holes 1008 each configured to receive a bottom end of a vessel (e.g., a mixing tube), such as vessel 708-3 shown in FIGS. 7A-7B or vessel 608-3 shown in FIGS. 6A-6E. For example, the indicated location of vessel 608-3 shown in the conceptual diagram of FIG. 6B can correspond to the location of the holes 1008 on the support plate 1002.

[0159] The stationary magnet assembly 1000 may also include a pair of magnet housings 1012. In some embodiments, the magnet holders 1012 may be made of a material that is chemically resistant to cleaning agents. The magnet housings 1012 may have a trapezoidal shape when viewed from above. In this example, each magnet housing 1012 houses two magnets (not shown in FIG. 10A but visible in FIG. 10B) positioned adjacent its first and second faces 1020 and 1022, respectively. This arrangement may be similar to the manner shown in FIG. 6B, where a pair of magnets 632 are arranged within the housing 630.

[0160] The fixed magnet assembly 1000 includes a mounting plate 1006 disposed below a support plate 1002. The fixed magnet assembly 1000 includes a set of springs 1024 with one end of each spring attached to the mounting plate 1006 and an opposite end of each spring attached to the magnet housing 1012 and / or the support plate 1002. Other biasing mechanisms may be suitably implemented in addition to or in place of the springs 1024. A gap may exist between the support plate 1002 and the mounting plate 1006 when the springs 1024 are in an uncompressed state.

[0161] The spring 1024 exerts a biasing force against the support plate 1002 when it is in an uncompressed state to create a desired spacing between the mounting plate 1006 and the support plate 1002. In some embodiments, the support plate 1002 may further be mechanically coupled to the mounting plate 1006 through fasteners 1019. The maximum spacing between the mounting plate 1006 and the support plate 1002 may be limited by fasteners 1019 (e.g., screws or shoulder bolts) inserted through mounting holes 1018 in the support plate 1002. These fasteners 1019 are inserted into the mounting holes 1018 to secure the support plate 1002 to the mounting plate 1006 to form the fixed magnet assembly 1000. In this example, the heads of the fasteners 1019 inserted into the mounting holes 1018 impose an upward limit on the upward movement of the support plate 1002 in the z direction away from the mounting plate 1006, but do not limit the downward movement of the support plate 1002 in the z direction towards the mounting plate 1006. In some embodiments, the fasteners 1019 may further constrain the movement of the support plate 1002 in the x and y axes. The fixed magnet assembly 1000 may then be secured to the diagnostic or preparation apparatus, such as by securing the mounting plate 1006 to the cover of the diagnostic and preparation apparatus with fasteners such as very strong bonding tape or other suitable fasteners.

[0162] Advantageously, the springs 1024 allow movement of the support plate 1002 in the z direction relative to the mounting plate 1006 secured to the cover, so that the spring-loaded support plate 1002 of the installed fixed magnet assembly 1000 can move up and down in the z direction within the receiving bay before and during insertion of the rack into the receiving bay. This feature can allow the fixed magnet assembly to properly position a mixing tube of a reagent holder (e.g., vessel 608-3 or vessel 708-3) relative to a magnet within the magnet housing 1012 without requiring precise and consistent reproduction of the exact magnet placement across each of multiple devices installed therein. For example, a mixing tube of a reagent holder can be received within a hole 1008 in the support plate 1002, and the mixing tube (or another portion of the rack in contact with the flexible support plate 1002) can press down on the support plate 1002 in the z direction, compressing the springs 1024 positioned between the support plate 1002 and the mounting plate 1006. When the spring 1024 is compressed, the support plate 1002 descends relative to the mounting plate 1006 until it reaches a point where the rack has reached its lowest position in the receiving bay, at which point the bottom portion of the mixing tube of the reagent holder will be reliably and accurately located in the hole 1008 of the support plate 1002. As a result of this arrangement, each mixing tube will be in close proximity to the adjacent magnet housing 1012 (e.g., behind either the first face 1020 or the second face 1022 of the adjacent magnet housing 1012) regardless of the inherent dimensional variations of the rack used to insert the holder into the receiving bay and regardless of the inherent dimensional variations of the receiving bay that receives the holder. Thus, this arrangement for providing magnetic energy to mixing tubes of multiple holders using the z-adjustable support plate 1002 can be reliably and accurately reproduced across many different instruments regardless of the dimensional and tolerance variations between the receiving bay and the rack of the instrument.

[0163] In some embodiments, the first side 1020 and second side 1022 of each magnet housing 1012 can be oriented at an angle that makes them parallel to the slanted wall of a mixing tube (e.g., vessel 608-3 or vessel 708-3) when the mixing tube is placed in the bore 1008. Thus, the magnets positioned adjacent each of the first side 1020 or second side 1022 of the magnet housing 1012 can also be oriented to be parallel to the slanted wall of the adjacent mixing tube, resulting in a magnetic force perpendicular to the slanted wall of the mixing tube.

[0164] This can be more easily understood from the perspective view 10B of the fixed magnet assembly 1000 to more easily illustrate the features of the technology disclosed in this invention. The embodiments of the fixed magnet assembly, mixing tube, and holder do not need to be transparent. The mixing tube 1030 of the holder (e.g., a container at a third position from a processing tube at the distal end of the holder) is illustrated seated in the bore 1008 of the fixed magnet assembly 1000. In this position, the mixing tube 1030 is disposed immediately adjacent to a magnet housing 1012 having a first face 1020 and a second face 1022. From FIG. 10B, it can be seen that a magnet 1040 is disposed behind the first face 1020, and a magnet 1042 is disposed behind the second face 1022. It can be seen that the magnet 1042 is in close proximity (within about 2 mm) of the mixing tube 1030 when the mixing tube 1030 is seated in the hole 1008 of the fixed magnet assembly 1000, and the magnet 1042 has an inclined orientation at an angle that matches the inclined wall of the mixing tube 1030.

[0165] Advantageously, the magnet housing 1012 is dimensioned so as not to interfere with a second snap-on container (not shown, but similar to container 608-2 shown in Fig. 6E) of the reagent holder. Furthermore, the magnet housing 1012 can be advantageously dimensioned so as not to interfere with any skirt or flange of a second or third receptacle that receives the second or third snap-on container 1030, respectively.

[0166] It will be appreciated that embodiments of the disclosed technology are not limited to applying a fixed magnetic force to a holder as described above with reference to Figures 2A-10B. Likewise, it will be appreciated that embodiments of the disclosed technology are not limited to applying a fixed magnetic force to a holder in an automated diagnostic or preparation device as discussed above with reference to Figure 1B. The disclosed technology can be advantageously implemented in any device that accepts a holder for processing and manipulating the magnetic substrate in the holder's receptacle. To further illustrate certain advantageous features of the disclosed technology, non-limiting examples of automated devices configured to apply a fixed magnetic force to non-limiting examples of holders in accordance with the disclosed technology are now described below with reference to Figures 11-15D. Figure 11 is an isometric view of the interior 1100 of some embodiments of a diagnostic or preparation device.

[0167] This illustrated embodiment of a diagnostic or preparative device can similarly be used to extract polynucleotides from a sample and prepare them in a PCR-ready form. This diagnostic or preparative device can be similar to that disclosed in PCT Patent Application No. WO2017 / 184244, filed February 17, 2017 (entitled "Automated Diagnostic Analyzer and Method for its Operation").

[0168] Notably, this embodiment of the diagnostic or preparation devices may not use reagent holders containing prepackaged reagents used for sample preparation, such as the reagent holders in the form shown in Figures 2A-2C, that are loaded into racks to be received by these devices. Instead, these diagnostic or preparation devices receive processing plates 1140 that do not contain prepackaged reagents, and reagents for sample preparation can be stored separately in different locations on the processing deck 1116. The processing plate 1140 is described in more detail with respect to Figures 12A-12B.

[0169] For example, there can be a dry reagent plate 1150 that includes multiple dry reagent compartments sealed by a pierceable membrane disposed on each. In some embodiments, there can be a total of 96 dry reagent compartments in the dry reagent plate 1150, and each reagent compartment in the same plate 1150 is loaded with the same reagents so that the reagent plate is assay-specific. However, depending on the assay or procedure, multiple dry reagent plates 1150 can be used, and individual reagent plates can be utilized, each having reagents specific to the assay. For example, to prepare samples in a PCR-ready form, there can be a first dry reagent plate (e.g., extraction reagent plate) that contains a lysis buffer and magnetic particles (e.g., extraction beads) and a second dry reagent plate (e.g., amplification reagent plate) that contains a master mix reagent. In other embodiments, various reagents can be combined on a single dry reagent plate 1150 (e.g., an extraction reagent plate and an amplification reagent plate can be combined).

[0170] The device may also include a liquid reagent plate 1160. The liquid reagent plate 1160 may include a plurality of reagent compartments organized into four processing lines, each of which may include four compartments, each of which holds a reagent for a sample processing step. For example, each processing line may include a first compartment for a reconstitution buffer, a second compartment for a wash buffer, a third compartment for an elution buffer, and a fourth compartment for a neutralization buffer. The compartments may be arranged in the order in which they are used. However, it is contemplated that the compartments may be arranged in other ways. Furthermore, each compartment holds enough reagent to process an entire sample batch, for example, a batch of 24 samples in total. A pierceable membrane (not shown) is disposed over each of these compartments and sealed to the liquid reagent plate 1160 such that when the membrane is pierced, the remaining compartments remain sealed with respect to access to one compartment. This allows the liquid reagent plate 1160 to be stored until needed for another sample batch.

[0171] In some embodiments, the processing plate 1140 can have holes into which pipette tips can be temporarily placed, and there can be elongated openings 1117 on the processing deck 1116 that allow reusable pipette tips that are temporarily placed in the processing plate 2040 to extend therethrough. In some embodiments, the processing deck 1116 can include a pipette tip chute 1135 into which used pipette tips can be discarded. In some embodiments, the interior 1100 of the diagnostic or preparation device can include a bay configured to receive an amplification cartridge 1170 that includes microfluidic channels and an amplification chamber for performing amplification of the processed samples.

[0172] FIG. 12A is an isometric view of an exemplary processing plate 1240 used in some embodiments of the diagnostic or preparation device described with reference to FIG. 11. FIG. 12B is a top view of an arrangement of two processing plates 1240 when inserted into a receiving bay of some embodiments of the diagnostic or preparation device for use. This arrangement of processing plates 1240 can allow for processing 24 samples (12 from each processing plate 1240). FIG. 12A and FIG. 12B are described together. Processing plate 1240 can be the same as or substantially similar to processing plate 1140 described above with reference to FIG. 11. It will be understood that the techniques disclosed in the present invention are not limited to the particular features of the exemplary processing plate 1240, and other suitably configured processing plates can be implemented in the techniques disclosed in the present invention.

[0173] The processing plate 1240 can include a plate body 1241 that can partially define a plurality of processing tubes 1244, mixing tubes 1246, and a pipette tip holding station 1247. The plate body 1241 can have circular openings for each of the processing tubes 1244, mixing tubes 1246, and pipette tip holding station 1247. The processing tubes 1244 can have a tube body 1245 that extends from the bottom of the plate body 1241, and the tube body 1245 can have a conical surface of revolution. The mixing tubes 1246 can also have a tube body (not shown, but visible in FIG. 13B) that extends from the bottom of the plate body 1241 and can also have a conical surface of revolution. The pipette tip holding station 1247 can have a sleeve (not shown, but visible in FIG. 13B) that extends from the bottom of the plate body 1241. The sleeve can keep a temporarily placed pipette tip stable in the pipette tip holding station 1247 even if the processing plate 1240 is moved while the pipette tip is located in the holding station 1247.

[0174] In some embodiments, the processing tube 1244 may alternatively be referred to as an extraction tube or a lysis tube. In some embodiments, the mixing tube 1246 may alternatively be referred to as a mixing well. The processing tube 1244 may be positioned closer to the center of the plate body 1241 than the mixing tube 1246, which may be positioned closer to the center of the plate body 1241 than the pipette tip holding station 1247. Other configurations may be suitably implemented with the techniques disclosed herein.

[0175] In some embodiments, the processing plate 1240 may include two rows of processing tubes 1244, mixing tubes 1246, and pipette tip holders 1247 arranged parallel to one another. In the illustrated embodiment, the processing plate 1240 includes two rows of six processing tubes 1244, two rows of six mixing tubes 1246, and two rows of six pipette tip holding stations 1247. However, more or less is contemplated (e.g., the processing plate 1240 may include two rows of twelve processing tubes 1244, mixing tubes 1246, and pipette tip holding stations 1247, or even a single row of the like). Processing of a single sample may only require one of the processing tubes 1244 and the corresponding mixing tube 1246 and pipette tip holding station 1247 aligned in the same row. Thus, a single processing plate 1240 may allow for processing of twelve samples therein.

[0176] In some embodiments, the processing plate 1240 can include an engagement member 1249 on its upper surface. The engagement member 1249 can include an engagement notch 1242. The engagement member 1249 and the engagement notch 1242 can allow a feature of a diagnostic or preparation device (e.g., a robotic arm) to grasp and move the processing plate 1240 for sample processing.

[0177] Figure 13A is an isometric view of the interior of an embodiment of a portion of a diagnostic or preparative device. Figure 13B is a side profile view of the interior of an embodiment of a portion of a diagnostic or preparative device with a processing plate in position for sample processing. Figures 13A and 13B are described together.

[0178] As can be seen in FIG. 13A, the first extractor 1340 and the second extractor 1350 can be seen as part of a single assembly that can include, among other things, a housing 1342, a printed circuit board 1347 ("PCB"), a motor 1344, several heater assemblies 1348, and several magnetic separators 1341. There can be any number of heating assemblies 1348 and magnetic separators 1341. In some embodiments, the heater assemblies 1348 and magnetic separators 1341 can be controlled by electronic circuitry such as on the PCB 1347 (e.g., to cause the heater assemblies 1348 to apply heat independently to multiple process tubes of a process plate). The electronic circuitry can be configured to move the magnetic separator 1341 up and down relative to the process tubes of the process plate.

[0179] 3A-3C, the heater assembly 1348 may include one or more independently controllable heater units, each including a heat block 1349. The heat blocks 1349 may be molded from a single piece of metal or other material, or may be manufactured separately from one another and mounted independently of one another or connected to one another in some manner. That is, the heater assembly 1348 may include a collection of heater units, but does not require that the heater units or their respective heat blocks 1349 be directly or indirectly attached to one another. Each of the heat blocks 1349 can be configured to align with and deliver heat to a process tube 1314 of the process plate 1310 (similar to the process tube 1244 of the process plate 1240 shown in FIG. 12A ), and the heater assembly 1348 can be configured such that each heater unit independently heats each of one or more process tubes 1314 of the process plate 1310, for example, by enabling each of one or more heat blocks 1349 to be independently controllable as described in detail herein. There can be any number of independently controllable heater units in one of the heater assemblies 1348. In various embodiments, there can be 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24, 25, 30, 32, 36, 40, 48, or 50 independently controllable heater units in the heater assembly 1348. There may be any number of heating assemblies 1348 used in a diagnostic or preparation device.

[0180] 3A-3C, the magnetic separator 1341 can be configured to move one or more magnets 1354 relative to one or more process tubes 1314 (similar to process tubes 1244 of process plate 1240) of the process plate 1310. The magnetic separator 1341 can move the magnets into close proximity to the process tubes 1314 (e.g., each magnet 1354 of the magnetic separator 1341 has a face that is less than 2 mm, between 2 mm and 1 mm, or less than 1 mm away from the outer surface of an adjacent process tube without contacting the process tube).

[0181] Structurally, the magnetic separator 1341 can include one or more magnets 1354 fixed to a support member 1352, a motorized mechanism configured to move the support member 1352 such that the magnets move back and forth along a fixed axis (see, e.g., motor 1344) and maintain close proximity to one or more processing tubes 1314 containing magnetic particles in solution during at least a portion of this motion, and control circuitry (e.g., PCB 1347) for controlling it. The magnetic separator 1341 can cooperate with a heater assembly 1348 to enable successive heating and separation operations to be performed on liquid material in one or more processing tubes 1314 without transporting either the liquid material or the processing tubes to different locations to perform any of these operations. Such operations are also advantageous in that they mean that heating and separation functions, which are independent of each other but both utilized in sample preparation, can be performed using a small and efficient device.

[0182] In the illustrated embodiment, there are four heating assemblies 1348, each with six independently controllable heater units, each with a heater block 1349. Up to two processing plates 1310 can be used at a time, with each processing plate 1310 requiring the use of a heating assembly 1348 with a magnetic separator 1341 between these two heating assemblies 1348. The magnetic separator 1341 can have two rows of six magnets (e.g., a row of six magnets on each side of the magnetic separator 1341) to form six adjacent magnet pairs facing the two heating assemblies 1348 that span the magnetic separator 1341. This side-by-side pair of magnets can enhance the magnetic attraction of the magnetic extraction particles in the processing tubes 1314 of the processing plate 1310 over that of a single magnet. Each magnet in the magnetic separator 1341 can be positioned adjacent to the heat block 1349 of one of the two heating assemblies 1348 when the magnetic separator 1341 is in the raised position. Each of the twelve heat blocks 1349 in these two heating assemblies 1348 can be specifically positioned to receive one of the twelve process tubes 1314 (e.g., the two rows of six process tubes 1244 shown in FIG. 12A ) of the process plate 1310. When the motor 1344 is activated, the row of magnets in the magnetic separator 1341 can be moved upward into the space between the two rows of heat blocks 1349 so that they are immediately adjacent to the process tubes 1314 located in the space.

[0183] As mentioned above, in some cases, the magnetic separator 1341 may be integrated with the heater assembly 1348 (e.g., one magnetic separator 1341 with two spanning heating assemblies 1348), which may be referred to together as an integrated magnetic separator and heater assembly. Additionally, although not shown in Figures 13A and 13B, an enclosure may cover the interior of the diagnostic or preparation device (including the magnetic separator 1341 and heater assembly 1348) for purposes of protection of the subassemblies and aesthetics.

[0184] FIG 14A shows a top conceptual view of a processing plate used in some embodiments of a diagnostic or preparation device. More specifically, FIG 14A illustrates an exemplary processing plate 1400 (similar to processing plate 1240 shown in FIGS. 12A and 12B) that can be used with some embodiments of an automated diagnostic or preparation device (e.g., those described in FIGS. 11, 13A, and 13B). Processing plate 1400 can have two rows of processing tubes 1442, two rows of mixing tubes 1444, and two rows of pipette tip holding stations 1446.

[0185] Each process tube 1442 may be associated with a mixing tube 1444 and a pipette tip holding station 1446, which may be aligned along a process axis 1410, and diagnostic or preparative devices may be configured to perform processes and operations (e.g., transfer of liquids) along each process axis 1410. Thus, n process axes 1410 may be conceptualized, one for each process tube 1442 in the process plate 1400.

[0186] When the processing plate 1400 is in use by an automated diagnostic or preparation device, a magnetic separator having two magnet rows (e.g., magnetic separator 1341) can be positioned between two rows of processing tubes 1442. This arrangement can be seen in FIG. 13B. Each magnetic row of the magnetic separator can be aligned on a common axis (e.g., a common axis passing through the midpoints of the magnets in that row), which may be referred to as a first magnet axis. Thus, a magnetic separator having two magnet rows can have a first magnet axis, represented by first magnet axis 1412 in FIG. 14A, for each of the two rows. Each first magnet axis 1412 can extend horizontally parallel to an adjacent row of processing tubes 1442. Each first magnet axis 1412 can be positioned such that when the magnetic separator is raised, the magnets of the magnetic separator aligned on the first magnet axis 1412 are in close proximity to the processing tubes 1442 in an adjacent row of processing tubes 1442 (e.g., within 2 mm of each processing tube 1442 in the row).

[0187] In some embodiments, two separate fixed magnet assemblies can be implemented in an automated diagnostic or preparation device. Each fixed magnet assembly can include a set of magnets in a row that can be aligned on a common axis (e.g., a common axis that passes through the midpoint of all magnets). This common axis associated with the fixed magnet assemblies may be referred to as the second magnet axis. In FIG. 14A, the second magnet axis for both fixed magnet assemblies is represented by the second magnet axis 1414. The two fixed magnet assemblies can be positioned such that each of the second magnet axes 1414 is near one of the two rows of the mixing tube 1444 and is sufficiently close to the adjacent row of the mixing tube 1444 that the magnets of the fixed magnet assembly exert a magnetic force on any magnetic extraction particles contained within the mixing tube 1444. The magnetic force can be strong enough to hold the magnetic extraction particles in the solution in the mixing tube 1444 against the inner wall of the mixing tube 1444 while the solution is transferred from the mixing tube 1444 during a dispensing operation, for example. When two separate fixed magnet assemblies are used, each second magnet axis 1414 can extend horizontally through one of the two rows of mixing tubes 1444. Alternatively, the second magnet axis 1414 can extend close enough to either behind or in front of the row of mixing tubes 1444 to exert a magnetic force on the contents of the mixing tubes 1444 and collect any magnetic extraction particles contained within the mixing tubes 1444. Additionally, each second magnet axis 1414 can be spaced far enough from the nearest first magnet axis 1414 so that the magnets of the fixed magnet assembly do not interfere with the magnets of the magnetic separator. For example, the first magnet axis 1412 can be spatially separated from the corresponding second magnet axis 1414 by a distance “D” such that one or more magnets aligned along the first magnet axis 1412 do not exert a magnetic force on the contents of the mixing tube 1444, and one or more magnets aligned along the second magnet axis 1414 do not exert a magnetic force on the contents of the processing tube 1442.

[0188] The first and second magnet axes 1412, 1414 are further shown in Figure 14B, which can provide additional context for understanding the first and second magnet axes 1412, 1414. Figure 14B shows a top conceptual view of the location of certain components of the processing plate relative to the magnet in some embodiments of a diagnostic or preparation apparatus with one configuration of a stationary magnet assembly.

[0189] More specifically, the location of two rows of processing tubes 1442 and mixing tubes 1444 on the processing plate is shown along with a processing axis 1410 associated with each of the processing tubes 1442. A magnetic separator 1420 having two rows of magnets 1422 is positioned between the two rows of processing tubes 1442. It can be seen that there are two different first magnet axes 1412 corresponding to each of the two rows of magnets 1422 of the magnetic separator 1420. In this exemplary implementation, the magnets 1422 are in one-to-one correspondence with the processing tubes 1442. Indeed, when the magnetic separator 1420 is raised to bring the magnets 1422 into close proximity with the processing tubes 1422, the magnets 1422 exert a magnetic force (shown as a vertical vector in FIG. 14B ) on the contents of the processing tubes 1442.

[0190] FIG. 14B further illustrates two separate fixed magnet assembly magnets 1432 according to the disclosed technology. In some embodiments, the fixed magnet assembly magnets 1432 can be arranged in pairs. Each pair of magnets 1432 can be positioned within a housing 1430. The fixed magnet assembly can include multiple housings 1430. The pairs of magnets 1432 can be arranged within the diagnostic or preparation device such that each pair of magnets 1432 is positioned (in the manner shown) between two adjacent mixing tubes 1444 of the processing plate when the processing plate is in the receiving bay of the diagnostic or preparation device. There can be a magnet 1432 for each mixing tube 1444 in the processing plate, and each magnet 1432 can be in close proximity to the adjacent mixing tube 1444 when the processing plate is in the receiving bay of the diagnostic or preparation device. All of the fixed magnet assembly magnets 1432 can be aligned (or substantially aligned) on the second magnet axis 1414. When two separate stationary magnet assemblies are used, there are two separate second magnet axes 1414, each corresponding to a row of magnets 1432 in one of the two stationary magnet assemblies. In this exemplary implementation, the magnets 1432 are in one-to-one correspondence with the mixing tubes 1444, and each of the magnets 1432 can exert a magnetic force (shown as a horizontal vector in FIG. 14B) on the contents of an adjacent mixing tube 1444.

[0191] FIG. 14C shows a schematic side profile view of the position of certain components of the processing plate relative to the magnet in some embodiments of a diagnostic or preparative device according to embodiments disclosed herein.

[0192] More specifically, FIG. 14C illustrates a processing tube 1442, a mixing tube 1444, and a pipette tip holding station 1446 associated with one processing axis 1410 of the processing plate 1400. The processing tube 1442 can be used during sample preparation for cell lysis and extraction of nucleic acids such as patient DNA or RNA and pathogen DNA or RNA. The processing tube 1442 can be positioned such that the processing tube 1442 is located in a heater block 1460 of a heater assembly (e.g., heater assembly 1348 shown in FIG. 13A) when the processing plate 1400 is in a receiving bay of a diagnostic or preparation device. The first magnet 1422 of the magnetic separator can be raised to be in close proximity to the processing tube 1442 to exert a magnetic force on the contents of the processing tube 1442. The mixing tube 1444 can be positioned in close proximity to the second magnet 1432 of the stationary magnet assembly such that the second magnet 1432 exerts a magnetic force on the contents of the mixing tube 1444 .

[0193] Preparation of the sample using this additional fixed magnet assembly can proceed as follows. In some embodiments, the diagnostic or preparation device can pierce the extraction tube of the extraction plate (e.g., the sealed dry reagent compartment of the dry reagent plate 1150) containing the extraction reagent, which can include magnetic extraction particles and a freeze-dried extraction reagent (e.g., a dry lysis reagent) and an internal control. The magnetic particles can be configured to bind to specific molecules (e.g., DNA / RNA) in the sample. The diagnostic or preparation device can pierce the corresponding reagent compartment of the liquid reagent plate 1160. The diagnostic or preparation device can then transfer a portion of the raw sample into the processing tube 1442. The amount of raw sample transferred may depend on the type of assay or procedure. The diagnostic or preparation device can move a portion of the extraction reagent (e.g., extraction buffer) from the extraction tube of the extraction plate to the processing tube 1442.

[0194] The process tube 1442, which is placed in a heater block 1460 of the heater unit, is then heated by the heater block 1460. The temperature and duration of the heating are determined by the type of assay or procedure. The heat and lysis reagents cleave cells from the sample, and portions of the target nucleic acids (e.g., DNA or RNA) and internal controls contained in the cells can be attached or bound to magnetic particles (e.g., magnetically bound particles or beads).

[0195] The first magnet 1422 of the magnetic separator can be raised until it is in close proximity to the processing tube 1442. The magnet 1422 can exert a magnetic force on the magnetic particles in the processing tube 1442, drawing the magnetic particles and attached nucleic acid to the side of the processing tube 1442. The diagnostic or preparation device can extract liquid from the processing tube 1442 while the magnet 1422 is still drawing the magnetic particles and attached nucleic acid to the side of the processing tube 1442. Under normal operation, ideally this liquid should be free of the magnetic particles and attached nucleic acid that were held against the inner wall of the processing tube 1442 as it was being extracted. The diagnostic or preparation device can dispense the extracted liquid.

[0196] The first magnet 1422 of the magnetic separator can be lowered, which can remove the magnetic force that holds the magnetic particles and attached nucleic acid to the side of the processing tube 1442. The diagnostic or preparation device can transfer a wash buffer into the processing tube 1442 (e.g., from the reagent compartment of the liquid reagent plate 1160) that is mixed with the magnetic particles bound to the nucleic acid in the processing tube 1442. The first magnet 1422 of the magnetic separator can then be raised again until it is in close proximity to the processing tube 1442. The magnet 1422 can exert a magnetic force on the magnetic particles in the processing tube 1442, attracting the magnetic particles and attached nucleic acid to the side of the processing tube 1442 again.

[0197] With the magnetic particles migrating to the side of the processing tube 1442, the liquid contents (e.g., primarily the added wash buffer) can be extracted from the processing tube 1442 and discarded. Under normal operation, ideally this extraction liquid should be free of the magnetic particles and attached nucleic acids that were held against the inner wall of the processing tube 1442 as they were being extracted. The first magnet 1422 of the magnetic separator can then be lowered, which can remove the magnetic force that holds the magnetic particles and attached nucleic acids to the side of the processing tube 1442.

[0198] An elution or dissociation buffer (e.g., from the reagent compartment of the liquid reagent plate 1160) can be added to the processing tube 1442 containing the magnetic particles and attached nucleic acid. The dissociation buffer can separate the magnetic particles from the nucleic acid and the internal control. The diagnostic or preparation device can transfer a neutralization buffer (e.g., from the reagent compartment of the liquid reagent plate 1160) to the mixing tube 1444, which was empty up to this point. At this point, the processing tube 1442 will contain the magnetic particles, the separated nucleic acid (e.g., DNA / RNA), and the internal control. The mixing tube 1444 contains the neutralization buffer.

[0199] The heater block 1460 is again activated to heat the contents of the processing tube 1442. The temperature and duration of the heating may depend on the assay or procedure being performed. The first magnet 1422 of the magnetic separator may still be raised again until it is in close proximity to the processing tube 1442. The magnet 1422 may exert a magnetic force on the magnetic particles in the processing tube 1442 to attract these magnetic particles (no longer nucleic acids, e.g., DNA / RNA molecules, attached to magnetic particles) to the inner wall of the processing tube 1442. While the magnetic particles are attracted and held by the first magnet 1422 to the inner wall of the processing tube 1442, the liquid contents (e.g., nucleic acid mixture with added dissociation buffer) are extracted from the processing tube 1442 without extracting the magnetic particles. The nucleic acid mixture may be transferred to a mixing tube 1444 containing a neutralization buffer. The neutralization buffer is configured to reduce the pH of the nucleic acid mixture to a neutral pH. The first magnet 1422 of the magnetic separator may be lowered.

[0200] In some embodiments, the dried reagent compartment of the amplification reagent plate containing the PCR master mix reagent containing the probes and primers used for PCR amplification can be accessed. The PCR master mix reagent can be in the form of lyophilized beads. The diagnostic or preparation device can transfer the contents of the mixing tube 1444 into the compartment of the amplification reagent plate containing the PCR master mix reagent, and the neutral nucleic acid mixture from the mixing tube 1444 can dissolve the PCR master mix pellet. However, the second magnet 1432 of the stationary magnet assembly can exert a magnetic force on the contents of the mixing tube 1444 when the contents are extracted from the mixing tube 1444. In particular, there may be some magnetic particles that are transferred despite methods that attempt to prevent the event of magnetic particles (e.g., beads) being transferred from the processing tube 1442 into the mixing tube 1444 (e.g., keeping the magnetic particles in the processing tube 1442 using the first magnet 1422). The second magnet 1432 can be used as part of an additional filtering step to remove any residual magnetic particles (e.g., "carryover" magnetic particles) carried over from the processing tube 1442 when the neutral nucleic acid mixture is extracted from the mixing tube 1444.

[0201] The resulting mixture solution in the dry reagent compartment of the amplification reagent plate containing the rehydrated PCR master mix reagents and the neutral nucleic acid mixture can be transferred to a storage device that stores the sample or to a microfluidic cartridge that amplifies the sample (e.g., microfluidic cartridge 1170 shown in FIG. 11).

[0202] 15A-15D show isometric views of a stationary magnet assembly in accordance with the presently disclosed technology for use in some embodiments of a diagnostic or preparative device.

[0203] 15 illustrates an embodiment of a stationary magnet assembly 1500 that can be implemented for the embodiments of the diagnostic or preparation apparatus depicted and described in FIGS. 11, 13-13B, and 14A-14C. Four separate stationary magnet assemblies 1500 can be installed as shown, each of which can include a support plate 1502 that can have dimensions suitable for the particular diagnostic or preparation apparatus in which the stationary magnet assembly 1500 is implemented. In some embodiments, the support plate 1502 can be a machined aluminum plate. The support plate 1502 can include a set of recesses or holes 1508 each configured to receive a bottom end of a mixing tube 1546 of a processing plate 1540 (similar to the mixing tube 1316 shown in FIG. 13B or the mixing tube 1444 shown in FIGS. 14A-14C).

[0204] The stationary magnet assembly 1500 may also include a pair of magnet housings 1512. The magnet housings 1512 may be integrally formed as a single monolithic part. The magnet holder 1500 may include a pair of magnet housings 1512 and a connector 1514. The magnet housings 1512 and the connector 1514 may be integrally formed as a single monolithic part. In another example, the magnet housings 1512 and the connector 1514 are joined to form the magnet holder 1500. Other configurations may also be suitably implemented. In some embodiments, each magnet housing 1512 may have a trapezoidal shape when viewed from above. In this example, each magnet housing 1512 houses two magnets (not shown) positioned adjacent its first and second faces 1520 and 1522, respectively. This arrangement may be similar to how FIG. 14B shows a pair of magnets 1432 arranged within the housing 1430. The fixed magnet assembly 1500 may include mounting holes 1518 for attaching the magnet housing 1512 to the support plate 1502. For example, fasteners (e.g., screws) may be inserted into the mounting holes 1518 to secure the magnet housing 1512 to the support plate 1502 to form the fixed magnet assembly 1500. The support plate 1502 of the fixed magnet assembly 1500 may then be placed into (e.g., secured to) a diagnostic or preparation device using any suitable mechanism.

[0205] In one non-limiting example, the stationary magnet assembly 1500 is a single monolithic piece including multiple magnet housings 1512 separated by connectors 1514. In some cases, the stationary magnet assembly is a unitary structure including multiple magnet housings 1512. The single stationary magnet assembly 1500 can be formed, for example, of a magnetic material. In another non-limiting example, the single stationary magnet assembly 1500 is formed of one or more non-magnetic materials with a magnetic material bonded to the inner walls of the housing adjacent the first side 1520 and the second side 1522 of each magnet housing 1512. Other configurations are possible.

[0206] In some embodiments, the magnet housing 1512 of each fixed magnet assembly 1500 can have a fixed height (e.g., up / down position) relative to the support plate 1502 and the rest of the diagnostic or preparation equipment. This fixed height can be adjusted by adding a shim of the desired height measured in the z-direction between the magnet housing 1512 and the support plate 1502. Installation of the fixed magnet assembly 1500 can include selecting one of a number of shims of different heights from an installation kit, installing the selected shim in a receiving bay, and installing the fixed magnet assembly 1500 above the shim in the z-direction. This can be particularly advantageous in view of the very slight dimensional differences and tight tolerances associated with receiving bays and racks implemented in existing preparation and diagnostic equipment when the fixed magnet assembly is retrofitted into these equipment in the field. In some other embodiments, a spring-utilized mechanism as shown in FIGS. 9 and 10A-10B can be used for the fixed magnet assembly 1500 to allow the support plate 1502 of the installed fixed magnet assembly 1500 to move up and down in the z-direction.

[0207] That is, the mixing tubes 1546 of the processing plate 1540 can be received in the holes 1508 of the support plate 1502 such that each mixing tube 1546 is in close proximity to a magnet in an adjacent magnet housing 1512 (e.g., a magnet positioned behind either the first face 1520 or the second face 1522 of the adjacent magnet housing 1512). In some embodiments, the first face 1520 and second face 1522 of each magnet housing 1512 can be oriented at an angle that renders them parallel to the angled walls of the mixing tube 1546 when the mixing tube is placed in the hole 1508.

[0208] 16A-16B show isometric views of another embodiment of a fixed magnet assembly that can be implemented in an automated diagnostic or preparation device in accordance with the techniques disclosed herein. More specifically, FIGS. 16A-16B illustrate an embodiment of a fixed magnet assembly 1600 having a user adjustable height. FIG. 16C shows the fixed magnet assembly of FIGS. 16A-16B with the magnet housing 1612 and connector 1614 removed for illustrative purposes only. FIG. 16D shows a perspective view of a fastening mechanism implemented by the fixed magnet assembly of FIGS. 16A-16C, while FIG. 16E shows a side cutaway view of the fastening mechanism. FIG. 16F shows an isometric view of the fixed magnet assembly of FIGS. 16A-16C implemented in a receiving bay of a diagnostic or preparation device, such as receiving bay 500 described with reference to FIGS. 5A-5B.

[0209] The fixed magnet assembly 1600 can include a mounting plate 1602, a support plate 1606, and a magnet holder 1604. The mounting plate 1602 can have dimensions suitable for the particular diagnostic or preparation device in which the fixed magnet assembly 1600 is implemented. In some embodiments, the mounting plate 1602 can be a machined aluminum plate. In some embodiments, the mounting plate 1602 can include multiple mounting brackets 1640 on one side. For example, in the embodiment shown in these figures, there are two mounting brackets 1640 disposed on the front side of the mounting plate 1602 and extending upward (e.g., in the z-axis) from the mounting plate 1602. Each mounting bracket 1640 can have a vertical slot 1644 through which a fastener 1642 can be disposed. The fastener 1642 can be disposed through the vertical slot 1644 into a corresponding recess (not shown) present in the support plate 1606 and configured to receive the fastener 1642. In some cases, to resist repositioning of the support plate 1606, the fasteners 1642 can be screws and the fasteners 1642 can be tightened to fasten the mounting bracket 1640 between the fasteners 1642 and the support plate 1606, thereby mounting the support plate 1606 to the mounting bracket 1640. In some embodiments, the mounting plate 1602 can also include fastener housings 1630 and a fastener 1632 can be disposed in each fastener housing 1630. In the embodiment shown in these figures, there are three fastener housings 1630 spaced along the length of the mounting plate 1602, two of the fastener housings 1630 at each longitudinal end of the mounting plate 1602. It will be understood that other numbers, spacings, and configurations of fastener housings 1630 are possible. Each fastener 1632 may be positioned through a recess in fastener housing 1630, which in turn may be positioned through a corresponding recess in support plate 1606 (as shown in FIG. 16E).In some cases, the fasteners 1632 can be screws, and tightening the fasteners 1632 can thread the screws deeper through the recesses in the support plate 1606 to raise the support plate 1606 relative to the mounting plate 1602.

[0210] As described in more detail herein, the mounting bracket 1640 (and its vertical slot 1644), fastener 1642, fastener housing 1630, and fastener 1632 may be some of the components configured to cooperate to allow a user to adjust the height (relative to the mounting plate 1602) of the support plate 1606 and / or magnet holder 1604 of the stationary magnet assembly 1600. With the mounting plate 1602 fixed in place, the user-adjustable height feature allows the support plate 1606 and / or magnet holder 1604 to move up and down (e.g., along the z-axis) relative to the stationary mounting plate 1602 within a limited range. In some embodiments, the support plate 1606 may be a component that moves up and down (e.g., along the z-axis) relative to the mounting plate 1602 when the user-adjustable height feature is used, for example, when the fastener 1632 (located in the fastener housing 1630) is rotated clockwise and / or counterclockwise.

[0211] The support plate 1606 can be seated on the mounting plate 1602 and fastened between the mounting plate 1602 and the magnet holder 1604. The magnet holder 1604 can include a pair of magnet housings 1612 and connectors 1614. The magnet housings 1612 and connectors 1614 can be integrally formed as a single monolithic part or can be combined to form the magnet holder 1604. Other configurations can be implemented as appropriate. The dimensions of the support plate 1606 and magnet holder 1604 can be adapted to the particular diagnostic or preparation device in which the stationary magnet assembly 1600 is implemented. In some embodiments, the magnet holder 1604 can be manufactured from a material that is chemically resistant to cleaning agents. In some embodiments, each magnet housing 1612 can have a trapezoidal shape when viewed from above. In this example, each magnet housing 1612 can house two magnets (not shown) positioned adjacent its first and second faces 1620 and 1622, respectively. This arrangement can be similar to the way that FIG. 6B shows, where a pair of magnets 632 are arranged within a housing 630.

[0212] In one non-limiting example, the stationary magnet assembly 1600 is a single monolithic piece including multiple magnet housings 1612 separated by connectors 1614. In some cases, the stationary magnet assembly is a unitary structure including multiple magnet housings 1612. The single stationary magnet assembly 1600 can be formed, for example, of a magnetic material. In another non-limiting example, the single stationary magnet assembly 1600 is formed of one or more non-magnetic materials with magnetic material bonded to the inner walls of the magnet housings 1612 adjacent the first side 1620 and the second side 1622 of each magnet housing 1612. Other configurations are possible.

[0213] The magnet holder 1604 can have mounting holes 1616 (e.g., in the connector 1614) to mechanically couple it to the mounting plate 1602. For example, in some embodiments, fasteners 1617 (e.g., screws or shoulder bolts) can be inserted into the mounting holes 1616 (and through corresponding mounting holes, not shown, in the support plate 1606) to mechanically couple the magnet holder 1604 to the support plate 1606 and / or the mounting plate 1602. In some embodiments, the fasteners 1617 can limit the maximum spacing between the support plate 1606 and the mounting plate 1602. The fasteners 1617 can impose an upward limit on the upward movement of the support plate 1606 in the z-direction away from the mounting plate 1602, but do not limit the downward movement of the support plate 1606 in the z-direction towards the mounting plate 1602. In some embodiments, fasteners 1617 may further constrain movement of support plate 1606 in the x and y axes. Once in place, these fasteners 1617 may be used to secure magnet holder 1604 to support plate 1606 such that the two can move together as a single unit. These fasteners 1617 inserted through mounting holes 1616 are not to be confused with fasteners 1632 located in fastener housings 1630 which may serve a different purpose (e.g., allowing a user to adjust the height of fixed magnet assembly 1600, e.g., the z-axis position of magnet holder 1604 and support plate 1606 relative to mounting plate 1602). With magnet holder 1604, support plate 1606, and mounting plate 1602 mechanically coupled to one another, mounting plate 1602 of fixed magnet assembly 1600 may then be installed (e.g., secured to) in a diagnostic or preparation device using any suitable mechanism. In some embodiments, the fixed magnet assembly 1600 can be secured to certain diagnostic or preparation devices by fastening the mounting plate 1602 to the cover 1650 of those devices using fasteners such as very strong adhesive tape.

[0214] In some embodiments, the fixed height (e.g., up / down position) of the magnet holder 1604 and / or support plate 1606 relative to the mounting plate 1602 and the rest of the diagnostic or preparation apparatus can be adjusted by a user, such as by using the following technique or procedure: First, the fasteners 1642 in the mounting bracket 1640 can be loosened (e.g., by turning the fasteners 1642 counterclockwise). The fasteners 1642 can function to fix the height (e.g., by rigidly fastening the magnet holder 1604 to the mounting bracket 1640) after the correct height has been determined, allowing the height to be adjusted by loosening the fasteners 1642. The fasteners 1642 can remain loose during the height adjustment, and can then be tightened to ensure that the support plate 1606 remains in the correct position.

[0215] After the fasteners 1642 are loosened, the fasteners 1632 in the fastener housing 130 can be adjusted individually or in unison to adjust the height of the support plate 1606. For example, in some cases, each of the fasteners 1632 can be a jackscrew that is disposed through a recess in the fastener housing 1630 and engages through a recess in the support plate 1606. Thus, as the jackscrew is threaded deeper into or unthreaded from the support plate 1606, the support plate 1606 can move up or down accordingly. For example, by turning the jackscrew in a clockwise direction, the jackscrew can be threaded deeper into the support plate 1606, moving that portion of the support plate 1606 relative to the fastener housing 130, thereby raising that portion of the support plate 1606. By turning the jackscrew counterclockwise, the jackscrew can unscrew from the support plate 1606 and move that portion of the support plate 1606 away from the fastener housing 130, thereby allowing that portion of the support plate 1606 to be lowered.

[0216] In some embodiments, when the fixed magnet assembly 1600 is installed in a particular diagnostic or preparation apparatus and a height adjustment is performed, there may be an alignment fixture (a separate device not shown in these figures) that can be loaded into the same holes that the receptacles of the rack will occupy when the rack is placed in the receiving bay of the apparatus. The alignment fixture can be used as a guide during the height adjustment to determine when the support plate 1606 and / or magnet holder 1604 are at the correct height for the particular diagnostic or preparation apparatus. Advantageously, the height adjustment described above is a one-time adjustment that is performed once and is not repeated once the system is returned to operation.

[0217] Once the support plate 1606 and / or magnet holder 1604 are adjusted to the desired height, the fasteners 1642 can be tightened to maintain these heights. In some embodiments, there can be an additional fixture (e.g., a separate device not shown in these figures) that can check the height of the support plate 1606 and / or magnet holder 1604 to ensure that they are within ±1 mm of the expected standard position and notify if the height needs to be readjusted during this installation procedure. This particular configuration of the fixed magnet assembly 1600 can allow the fixed magnet assembly 1600 to be inexpensively and quickly implemented in the field (e.g., at the location of the diagnostic or preparation device) into a particular device despite any unknown component variations that may exist between various devices. FIG. 16F shows the same fixed magnet assembly 1600 (including the mounting plate 1602 and magnet holder 1604) as shown in FIGS. 16A-16C secured to the cover 1650 of the diagnostic or preparation device.

[0218] More specifically, Fig. 16F illustrates how the fixed magnet assembly 1600 can be mounted in a receiving bay of a diagnostic or preparation device, such as the receiving bay 500 of the diagnostic or preparation device shown in Figs. 5A-5B, such that when the receiving bay receives a rack with reagent holders inserted therein, the process tubes of these reagent holders are on the mounting plate 1602 of the fixed magnet assembly 1600 next to the magnets in the magnet holders 1604. Furthermore, one or more movable magnets of a magnetic separator (not shown in this figure, but described above with reference to Figs. 3A-3C) can apply a magnetic force to each process tube of the reagent holders in the rack. Furthermore, with the fixed magnet assembly 1600 installed in this position, a constant and unchanging magnetic force from the magnets of the fixed magnet assembly 1600 (e.g., the magnets in the magnet holders 1604) is also applied to each third snap-on container of the reagent holders in the rack.

[0219] 17A-17D show isometric views of an exemplary structure for installing and mounting a fixed magnet assembly 1710 in an automated diagnostic or preparation device. More specifically, FIG. 17A illustrates an embodiment of a bridge 1700 used to support the fixed magnet assembly 1710. FIGs. 17B-17D show how the bridge 1700 and fixed magnet assembly 1710 of FIG. 17A may be installed or mounted in a receiving bay of an automated diagnostic or preparation device according to this non-limiting embodiment. It will be understood that the present disclosure is not limited to installing a fixed magnet assembly according to this embodiment, and other structures may be suitably implemented.

[0220] In one non-limiting example, the bridge 1700 can include multiple portions, such as a first bridge portion 1702 and a second bridge portion 1706, that can be used to support a fixed magnet assembly 1710. For example, the first bridge portion 1702 can be configured to support a first end of the fixed magnet assembly 1710, and the second bridge portion 1706 can be configured to support an opposing second end of the fixed magnet assembly 1710, thereby forming a bridge.

[0221] In some embodiments, bridge 1700 can have mirror images of first and second bridge portions 1702 and 1706. First and second bridge portions 1702 and 1706 can be configured to engage slots on either side of a cover 1720 in a receiving bay of the automated diagnostic or preparation device such that bridge 1700 straddles cover 1720, as shown in FIG.

[0222] This engagement can be seen more clearly in Figures 17C and 17D, which show a first bridge portion 1702 mounted on one end of the cover 1720. A second bridge portion 1706 is not shown, but would be on the opposite end of the cover 1720. The opposite ends of a fixed magnet assembly 1710 may be seated on the first bridge portion 1702 and the second bridge portion 1706, respectively, which hold the fixed magnet assembly 1710 above the cover 1720 and position the fixed magnet assembly 1710 in the correct location to precisely exert a magnetic force on magnetic particles present in corresponding tubes of a rack located in the receiving bay.

[0223] In some embodiments, the first bridge portion 1702 and the second bridge portion 1706 can have recesses that allow the bridge portions to fit neatly over the ends of the cover 1720 without interfering with any components of the diagnostic or preparation apparatus that may be present underneath the cover 1720. For example, Figures 17C and 17D illustrate a first bridge portion 1702 having a recess 1704 that is shaped and sized to receive a component (e.g., a printed circuit board) of the diagnostic or preparation apparatus.

[0224] Many variations and modifications can be made to the above-described embodiments, with elements to be understood as being among the permissible alternatives. All such modifications and modifications are intended to be included in the disclosure of the present invention herein. The above description details certain embodiments. However, no matter how detailed the above description appears in text, it will be understood that the above-described systems and methods can be implemented in many ways. As also indicated above, it should be noted that the use of a particular term when describing a certain feature or aspect of the system and method should not be understood to imply that the term is redefined to be limited to include any of the features or aspects of the system and method to which the term relates.

[0225] Conditional language such as "may," "could," "may," or "might," among others, is generally intended to convey that certain embodiments include certain features, elements, and / or steps whereas other embodiments do not, unless otherwise expressly stated or otherwise understood in the context of their use. Thus, such conditional language is generally not intended to suggest that the features, elements, and / or steps are in any way required for one or more embodiments, or that one or more embodiments necessarily include logic for determining whether or not any particular embodiment includes or performs those features, elements, and / or steps, with or without user input or prompting.

[0226] The term "substantially" when used in conjunction with the term "real time" forms a phrase that will be readily understood by those of ordinary skill in the art. For example, it will be readily understood that such language will include speeds where there is no or little noticeable delay or wait, or where such delay is short enough that it does not cause confusion, annoyance, or otherwise annoyance to the user.

[0227] Conjunctive language such as the phrases "at least one of X, Y, and Z" or "at least one of X, Y, or Z" should be understood to be used to convey that, depending on the context, an item, term, etc., can generally be either X, Y, or Z, or combinations thereof, unless expressly stated otherwise. For example, when the term "or" is used to connect, for example, listed elements, these terms are used in an inclusive sense (not a limiting sense) to mean one, some, or all of the listed elements. Thus, in general, such conjunctive language is not intended to suggest that a given embodiment requires that at least one X, at least one Y, and at least one Z each be present.

[0228] The term "a" as used herein is to be given an inclusive interpretation rather than a limiting one. For example, unless expressly stated otherwise, whether used in the claims or anywhere else in this specification, and notwithstanding the use of quantifiers such as "at least one," "one or more," or "plurality" in the claims or anywhere else in this specification, the term "a" should be understood to mean "one or more" or "at least one" referent, and not "exactly one" or "one and only one" referent.

[0229] The term "comprises" as used herein should be given an inclusive interpretation rather than a limiting one: for example, a general-purpose processor comprising one or more processors should not be interpreted as excluding other computer components, and can potentially include components such as memory, input / output devices, and / or network interfaces, among others.

[0230] Although the foregoing detailed description illustrates, describes, and points out novel features applicable to various embodiments, it can be understood that various omissions, substitutions, and changes can be made in the form and details of the illustrated devices or processes without departing from the spirit of the disclosure of the present invention. As will be recognized, certain features can be used or practiced separately from other features, and therefore certain embodiments of the present invention described herein can be practiced in forms that do not provide all of the features and advantages set forth herein. The scope of certain inventions disclosed herein is set forth in the claims, rather than the foregoing description. All changes that come within the meaning and range of equivalency of the claims are intended to be embraced within their scope.

Claims

1. 1. A system for nucleic acid analysis, comprising: a receiving bay configured to receive a plurality of melting tubes aligned along a melting axis and a plurality of mixing tubes aligned along a mixing axis generally parallel to the melting axis; The receiving bay comprises: one or more first magnets aligned along a first magnet axis generally parallel to the melting axis and the mixing axis, the one or more first magnets configured to move between a position below the plurality of melting tubes to a position adjacent to the plurality of melting tubes when the plurality of melting tubes are received in the receiving bay, and configured to apply a first magnetic force to contents of the plurality of melting tubes when the plurality of melting tubes are received in the receiving bay and the one or more first magnets are positioned adjacent to the plurality of melting tubes; one or more second magnets aligned along a second magnet axis generally parallel to the first magnet axis, the one or more second magnets configured to remain stationary when the plurality of mixing tubes are received in the receiving bay and configured to apply a second magnetic force to contents of the plurality of mixing tubes when the plurality of mixing tubes are received in the receiving bay; Equipped with A system for nucleic acid analysis.

2. The one or more second magnets include A mounting plate and a support plate having a height relative to the mounting plate; a first plurality of fasteners mechanically coupling the support plate to the mounting plate such that the height of the support plate relative to the mounting plate is user adjustable; and A fixed magnet assembly including: The system of claim 1 .

3. The system of claim 2 , wherein each of the first plurality of fasteners comprises a jackscrew.

4. 2. The system of claim 1, wherein when the plurality of dissolution tubes and the plurality of mixing tubes are received in the receiving bay, the first magnetic force is applied to the contents of each of the plurality of dissolution tubes along a direction that is generally perpendicular to the melting axis, and the second magnetic force is applied to the contents of each of the plurality of mixing tubes along a direction that is generally parallel to the mixing axis.

5. 2. The system of claim 1, wherein when the plurality of dissolution tubes and the plurality of mixing tubes are received in the receiving bay, the first magnetic force is applied to the contents of each of the plurality of dissolution tubes along a direction that is generally perpendicular to the melting axis, and the second magnetic force is applied to the contents of each of the plurality of mixing tubes along a direction that is generally perpendicular to the mixing axis.

6. The system of claim 1 , wherein the receiving bay is further configured to receive a processing device comprising the plurality of dissolution tubes and the plurality of mixing tubes.

7. 2. The system of claim 1, wherein the first magnet axis is spatially separated from the second magnet axis by a distance such that the one or more first magnets do not exert the first magnetic force on the contents of the plurality of mixing tubes when the plurality of mixing tubes are received in the receiving bay, and the one or more second magnets do not exert the second magnetic force on the contents of the plurality of dissolution tubes when the plurality of dissolution tubes are received in the receiving bay.

8. a plurality of second magnets contained within a plurality of housings aligned along the second magnet axis; each housing of the plurality of housings houses two of the plurality of second magnets; The system of claim 1 .

9. a first of the two magnets in each housing configured to apply the second magnetic force to contents of a first mixing tube at a first location of the first mixing tube when the plurality of mixing tubes are received in the receiving bay; a second of the two magnets in each housing configured to apply the second magnetic force to contents of a second mixing tube adjacent the first mixing tube, the second of the two magnets configured to apply the second magnetic force at a second position of the second mixing tube that is about 180° or less than 180° from a first position of the second mixing tube; The system of claim 8.

10. 9. The system of claim 8, wherein when said plurality of mixing tubes are received in said receiving bay, a mixing tube to housing ratio is 2:

1.

11. a plurality of first magnets aligned along the first magnet axis; a ratio of lysis tubes to first magnets is one to one when the plurality of lysis tubes are received in the receiving bay; The system of claim 10.

12. each housing having two faces each inclined at a different angle relative to the second magnet axis; Each of the two second magnets is disposed adjacent to an inner wall of one of the inclined surfaces. The system of claim 8.

13. The system of claim 8 comprising a unitary structure comprising said plurality of housings.

14. The system of claim 8 , wherein the multiple housings are separated by multiple connectors.

15. a second magnet formed of a magnetic material; the second magnet comprises a plurality of magnet structures aligned along the second magnet axis, each magnet structure comprising two inclined magnet faces, each inclined at a different angle relative to the second magnet axis; The system of claim 1 .

16. a first angled magnetic surface of each magnetic structure configured to apply the second magnetic force to contents of a first mixing tube at a first location of the first mixing tube when the plurality of mixing tubes are received in the receiving bay; a second angled magnet surface of each magnetic structure configured to apply the second magnetic force to the contents of a second mixing tube adjacent the first mixing tube, the second angled magnet surface configured to apply the second magnetic force at a second position of the second mixing tube that is about 180° or less than 180° from a first position of the second mixing tube; The system of claim 15.

17. 17. The system of claim 16, wherein when the plurality of mixing tubes are received in the receiving bay, the ratio of mixing tubes to magnetic structures is 2:

1.

18. a plurality of first magnets aligned along the first magnet axis; a ratio of lysis tubes to first magnets is one to one when the plurality of lysis tubes are received in the receiving bay; 20. The system of claim 17.

19. The system of claim 1 , wherein the receiving bay further comprises a support plate disposed between the one or more second magnets and a cover of the receiving bay.

20. 20. The system of claim 19, wherein the support plate comprises a plurality of recesses each configured to receive a bottom portion of one of the plurality of mixing tubes when the plurality of mixing tubes are received in the receiving bay.

21. a plurality of second magnets contained within a plurality of housings aligned along the second magnet axis; the plurality of housings are movable relative to the support plate when the plurality of mixing tubes are not received in the receiving bay; 20. The system of claim 19.

22. The system of claim 1 further comprising the plurality of dissolution tubes and the plurality of mixing tubes received in the receiving bay.

23. The system of claim 1 , wherein the receiving bay further comprises a support plate disposed between the one or more second magnets and a cover of the receiving bay.

24. 24. The system of claim 23, wherein the support plate comprises a plurality of recesses each configured to receive a bottom portion of one of the mixing tubes when the device is received in the receiving bay.

25. a plurality of second magnets contained within a plurality of housings aligned along the second magnet axis; the plurality of housings are movable relative to the support plate before the device is received in the receiving bay; 24. The system of claim 23.

26. 1. A system for nucleic acid analysis, comprising: a receiving bay configured to receive a device including a dissolution tube and a mixing tube aligned along each of a plurality of parallel processing axes; The receiving bay comprises: one or more first magnets aligned along a first magnet axis generally perpendicular to the plurality of process axes, the one or more first magnets configured to move between a position below the plurality of lysis tubes to a position adjacent to the plurality of lysis tubes when the device is received in the receiving bay, and configured to apply a first magnetic force to contents of the plurality of lysis tubes when the device is received in the receiving bay and the one or more first magnets are positioned adjacent to the plurality of lysis tubes; one or more second magnets aligned along a second magnet axis generally perpendicular to the first magnet axis, the one or more second magnets configured to remain stationary when the plurality of mixing tubes are received in the receiving bay and configured to apply a second magnetic force to contents of the plurality of mixing tubes when the device is received in the receiving bay; Equipped with A system for nucleic acid analysis.

27. The one or more second magnets include A mounting plate and a support plate having a height relative to the mounting plate; a first plurality of fasteners mechanically coupling the support plate to the mounting plate such that the height of the support plate relative to the mounting plate is user adjustable; and A fixed magnet assembly including:

27. The system of claim 26.

28. 30. The system of claim 27, wherein each of the first plurality of fasteners comprises a jackscrew.

29. 27. The system of claim 26, wherein when the device is received in the receiving bay, the first magnetic force is applied along the respective process axis of each of the plurality of dissolution tubes and the second magnetic force is applied to a point offset from the respective process axis of each of the plurality of mixing tubes.

30. 27. The system of claim 26, wherein when the device is received in the receiving bay, the first magnetic force is applied along the respective process axis of each of the plurality of dissolution tubes and the second magnetic force is applied along the respective process axis of each of the plurality of mixing tubes.

31. 27. The system of claim 26, wherein the first magnet axis is spatially separated from the second magnet axis by a distance such that the one or more first magnets do not exert the first magnetic force on the contents of the plurality of mixing tubes when the device is received in the receiving bay, and the one or more second magnets do not exert the second magnetic force on the contents of the plurality of lysis tubes when the device is received in the receiving bay.

32. a plurality of second magnets contained within a plurality of housings aligned along the second magnet axis; each housing of the plurality of housings houses two of the plurality of second magnets; 27. The system of claim 26.

33. a first of the two magnets in each housing configured to apply the second magnetic force to the contents of a first mixing tube at a first location of the first mixing tube when the device is received in the receiving bay; a second of the two magnets in each housing configured to apply the second magnetic force to contents of a second mixing tube adjacent the first mixing tube, the second of the two magnets configured to apply the second magnetic force at a second position of the second mixing tube that is about 180° or less than 180° from a first position of the second mixing tube; 33. The system of claim 32.

34. 33. The system of claim 32, wherein when the device is received in the receiving bay, the mixing tube to housing ratio is 2:

1.

35. a plurality of first magnets aligned along the first magnet axis; a ratio of lysis tubes to first magnets is 1:1 when the device is received in the receiving bay; 35. The system of claim 34.

36. each housing having two faces each inclined relative to an adjacent processing axis; Each of the two second magnets is disposed adjacent to an inner wall of one of the inclined surfaces.

33. The system of claim 32.

37. 33. The system of claim 32, comprising a unitary structure comprising the plurality of housings.

38. 27. The system of claim 26, further comprising the device received in the receiving bay.

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