Patent Grant
11549959
The technology described herein generally relates to systems and methods for controlling fluid processing operations associated with extracting polynucleotides from samples, particularly multiple biological samples in parallel. The technology more particularly relates to automated pipetting systems that operate in conjunction with reagent containers and carry out various such and dispense operations on various reagents in the containers, thereby bringing about mixing or disposal of those reagents.
The medical diagnostics industry is a critical element of today's healthcare infrastructure. At present, however, diagnostic analyses no matter how routine have become a bottleneck in patient care. There are several reasons for this. First, many diagnostic analyses can only be done with highly specialist equipment that is both expensive and only operable by trained clinicians. Such equipment is found in only a few locations—often just one in any given urban area. This means that most hospitals are required to send out samples for analyses to these locations, thereby incurring shipping costs and transportation delays, and possibly even sample loss or mishandling. Second, the equipment in question is typically not available ‘on-demand’ but instead runs in batches, thereby delaying the processing time for many samples because they must wait for a machine to fill up before they can be run.
Understanding that sample flow breaks down into several key steps, it would be desirable to consider ways to automate as many of these as possible. For example, a biological sample, once extracted from a patient, must be put in a form suitable for a processing regime that typically involves using PCR to amplify a vector of interest. Once amplified, the presence of a nucleotide of interest from the sample needs to be determined unambiguously. Preparing samples for PCR is currently a time-consuming and labor intensive step, though not one requiring specialist skills, and could usefully be automated. By contrast, steps such as PCR and nucleotide detection have customarily only been within the compass of specially trained individuals having access to specialist equipment.
Sample preparation is labor intensive in part because of the number of reagents required, and the need for multiple liquid transfer (e.g., pipetting) operations. Thus, there is a need for an automated pipetting apparatus, particularly one that can operate on multiple samples in parallel.
The discussion of the background herein is included to explain the context of the inventions described herein. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge as at the priority date of any of the claims.
Throughout the description and claims of the specification the word “comprise” and variations thereof, such as “comprising” and “comprises”, is not intended to exclude other additives, components, integers or steps.
The technology herein includes a liquid dispenser, comprising: one or more sensors; a manifold; one or more pumps in fluid communication with the manifold; one or more dispense heads in fluid communication with the manifold; and electrical connections that accept electrical signals from an external controller, wherein the liquid dispenser has no inlet or outlet for fluids, other than through the one or more pumps. The liquid dispenser further has a number of dispense heads, wherein each head is configured to accept a pipette tip.
The technology herein further includes an automated pipetting system that includes a liquid dispenser, the dispenser comprising: one or more sensors; a manifold; one or more pumps in fluid communication with the manifold; one or more dispense heads in fluid communication with the manifold; and electrical connections that accept electrical signals from an external controller, wherein the liquid dispenser has no inlet or outlet for fluids, other than through the one or more pumps.
The technology herein further includes an apparatus for carrying out sample preparation on multiple samples in parallel, the apparatus including an automated pipetting system configured to carry out liquid handling steps associated with sample preparation. The pipetting system includes a liquid dispenser, the dispenser comprising: one or more sensors; a manifold; one or more pumps in fluid communication with the manifold; one or more dispense heads in fluid communication with the manifold; and electrical connections that accept electrical signals from an external controller, wherein the liquid dispenser has no inlet or outlet for fluids, other than through the one or more pumps. The apparatus may further carry out diagnostic analysis on nucleotides put into form ready for amplification after sample preparation, where the automated pipetting system is configured to transfer those samples to a device that can amplify those samples and provide detectable quantities of amplified samples.
The technology herein further includes methods of sample preparation, comprising liquid handling steps that are performed on multiple samples in parallel by an automated pipetting system that includes a liquid dispenser as further described herein.
Like reference numerals in the various drawings indicate like elements.
The automated pipetting apparatus described herein is typically configured for use in a method and apparatus for carrying out sample preparation on biological samples in parallel, with or without PCR and detection on the prepared samples, and preferably with high throughput.
Overview of a Preparatory or Diagnostic Apparatus that Incorporates a Liquid Dispenser
A schematic overview of an apparatus 981 for carrying out automated sample preparation on multiple samples in parallel, according to steps exemplified elsewhere herein, is shown in
A processor 980, such as a microprocessor, is configured to control functions of various components of the system as shown, and is thereby in communication with each such component requiring control, for example via a bus. It is to be understood that many such control functions can optionally be carried out manually, and not under control of the processor. Furthermore, the order in which the various functions are described, in the following, is not limiting upon the order in which the processor executes instructions when the apparatus is operating. A suitable processor 980 can be designed and manufactured according to, respectively, design principles and semiconductor processing methods known in the art.
Processor 980 can be configured to accept user instructions from an input device 984, where such instructions may include instructions to start analyzing the sample, and choices of operating conditions. Processor 980 can be also configured to communicate with a display 982, so that, for example, information about an analysis is transmitted to the display and thereby communicated to a user of the system. Such information includes but is not limited to one or more of: the current status of the apparatus; progress of PCR thermocycling; and a warning message in case of malfunction of either system or cartridge. Additionally, processor 980 may transmit one or more questions to be displayed on display 982 that prompt a user to provide input in response thereto. Thus, in certain embodiments, input 984 and display 982 are integrated with one another.
Processor 980 can be optionally further configured to transmit results of an analysis to an output device 986 such as a printer, a visual display such as display 982 or a second display, a display that utilizes a holographic projection, or a speaker, or a combination thereof. Processor 980 can be still further optionally connected via a communication interface such as a network interface to a computer network 988.
Processor 980 can be further configured to control various aspects of sample preparation and diagnosis, as follows in overview. In
Embodiments of rack 970 are further described in U.S. patent application Ser. No. 12/173,023, filed by ExpressMail on Jul. 14, 2008 (and entitled “Integrated Apparatus for Performing Nucleic Acid Extraction and Diagnostic Testing on Multiple Biological Samples”, in the name of Williams, et al.), and Ser. No. 12/178,584, filed on Jul. 23, 2008, and entitled “Rack For Sample Tubes And Reagent Holders”, in the name of Duffy, et al., both of which are incorporated herein by reference in their entireties. A rack 970 is itself configured to receive a number of biological samples 996, such as nucleic-acid containing samples, in a form suitable for work-up and subsequent diagnostic analysis, and a number of holders 972—as further described herein, such as in connection with
The heating functions of the heater assembly 977 can be controlled by the processor 980. Heater assembly 977 operates in conjunction with a separator 978, such as a magnetic separator, that also can be controlled by processor 980 to move into and out of close proximity to one or more processing chambers associated with the holders 972, wherein particles such as magnetic particles are present. Assembly 977 and separator 978 are further described in U.S. patent application Ser. No. 12/178,586, filed on Jul. 23, 2008, and entitled “Integrated Heater and Magnetic Separator”, in the name of Handique, which is incorporated herein by reference in its entirety.
Processor 980 can be configured to receive data about a sample to be analyzed, e.g., from a sample reader 990, which may be a barcode reader, an optical character reader, or an RFID scanner (radio frequency tag reader). Thus, sample reader 990 is configured to transmit identifying indicia about the sample, and in some instances the holder, to processor 980. In some embodiments, the sample reader is movable from one sample position to another. In some embodiments a sample reader is attached to the liquid dispenser 976 and can thereby read indicia about a sample above which the liquid dispenser is situated. In other embodiments the sample reader is not attached to the liquid dispenser and is independently movable, under control of the processor.
Liquid dispenser 976, which similarly can be controlled by processor 980 and is further described herein, is configured to automatically carry out various pipetting (e.g., suck and dispense) operations on respective samples in rack 970, and fluids and reagents in the holders 972, to achieve extraction of nucleic acid from the samples. Liquid dispenser 976 can carry out such operations on multiple holders simultaneously, and is further described herein.
Liquid dispenser 976 is also configured to take aliquots of fluid containing nucleic acid extracted from one or more samples and direct them to a storage area (not shown in
In the embodiment of a diagnostic apparatus shown in
Embodiments of the apparatus shown in outline in
The apparatus of
The apparatus of
In various embodiments, preparation of a PCR-ready sample for use in subsequent diagnosis using the apparatus as further described herein can include one or more of the following steps: contacting a neutralized polynucleotide sample with a PCR reagent mixture comprising a polymerase enzyme and a plurality of nucleotides (in some embodiments, the PCR reagent mixture can further include a positive control plasmid and a fluorogenic hybridization probe selective for at least a portion of the plasmid); in some embodiments, the PCR reagent mixture can be in the form of one or more lyophilized pellets, as stored in a receptacle on a holder, and the method can further include reconstituting the PCR pellet with liquid to create a PCR reagent mixture solution.
The apparatuses as described herein find application to analyzing any nucleic acid containing sample for any purpose, including but not limited to genetic testing, and clinical testing for various infectious diseases in humans.
The apparatus herein can be configured to run on a laboratory benchtop, or similar environment, and can test approximately 45 samples per hour when run continuously throughout a normal working day. Results from individual raw samples are typically available in less than 1 hour.
Shown in
Reagent Holders
The automated diagnostic apparatus described herein is configured to carry out sample preparation on multiple samples by accessing more than one sample tube, and more than one reagent holder, simultaneously. Thus, the liquid dispense head, further described herein, is configured to extract and dispense volumes of liquid from various positions in one or more reagent holders, the holders being disposed in a suitably configured rack, as also described elsewhere herein.
Described herein are reagent holders for holding and transporting reagents for various purposes, in particular sample preparation in a clinical context, and configured to be received by a rack as described elsewhere herein. The reagent holders also typically provide a container, such as a process tube, in which various reagents can be mixed one with another and/or with a sample, and subjected to heating.
Exemplary reagent holders are further described in copending application Ser. No. 12/218,416, filed by ExpressMail on Jul. 14, 2008 (and entitled “Reagent Tube, Reagent Holder, and Kits Containing Same”, in the name of Wilson, et al.) and incorporated herein by reference.
The exemplary holders of
The reagent holder of
The one or more receptacles 550 are configured to accept container 554 that contain, respectively, sufficient quantities of one or more reagents typically in solid form, such as in lyophilized form, for carrying out extraction of nucleic acids from a sample that is associated with the holder. The receptacles can be all of the same size and shape, or may be of different sizes and shapes from one another. Preferably the receptacles 550 are configured to accept commonly used containers in the field of laboratory analysis, or containers suitably configured for use with the holder herein. The containers may be snap-in reagent tubes that maintain a steady position in the holder during pipetting operations thereon.
The containers that contain solid reagents such as lyophilized reagents, can be sealed across their tops by a metal foil, such as a single layer of an aluminum foil, with no plastic lining layer, as further described herein.
The containers containing different reagents may be of different colors, or color-coded for easy identification by the user. For example they may be made of different color material, such as tinted plastic, or may have some kind of identifying tag on them, such as a color stripe or dot. They may also have a label printed on the side, and/or may have an identifier such as a 1-D or a 2-D barcode on the sealing layer on the top, or on the side of the tube. Such a code is useful for identifying the composition of the reagents stored within, and/or a batch number for the preparation thereof, and/or an expiry date. The code may be printed on with, for example, an inkjet or transfer printer.
In one embodiment, the containers 554 containing lyophilized reagents, disposed in the receptacles 550, are 0.3 ml tubes that have been further configured to have a star-shaped pattern on their respective bottom interior surfaces. This is so that when a fluid has been added to the lyophilized reagents (which are dry in the initial package), a pipette tip can be bottomed out in the tube and still be able to withdraw almost the entire fluid from the tube. The design of the star-pattern is further described elsewhere in U.S. patent application Ser. No. 12/178,557, filed on Jul. 23, 2008, and entitled “Reagent Tube”, in the name of Handique et al., which application is incorporated herein by reference. Still other containers used in conjunction with the holder herein may be similarly configured with a start-shaped pattern to increase pipetting efficiency.
The embodiments of reagent holders 804 are shown configured with a waste chamber 560, having an inlet aperture 562 in the upper side of the connecting member. Waste chamber 560 is optional and, in embodiments where it is present, is configured to receive spent liquid reagents. In other embodiments, where it is not present, spent liquid reagents can be transferred to and disposed of at a location outside of the holder, such as, for example, a sample tube that contained the original sample whose contents are being analyzed.
The embodiments of reagent holders 804 are shown having a pipette sheath 570. This is an optional component of the holders described herein. It may be permanently or removably affixed to connecting member 510, or may be formed, e.g., moulded, as a part of a single piece assembly for the holder. Pipette sheath 570 is typically configured to surround the at least one socket and a tip and lower portion of a pipette tip when the pipette tip is stationed in the at least one socket. In some embodiments, the at least one socket comprises four sockets. In some embodiments the at least one socket comprises two, three, five, or six sockets. The sheath and sockets are large enough to accommodate a variety of sizes of pipette tips, such as those having volumes as small as 10 μl to as large as 1 ml.
Pipette sheath 570 typically is configured to have a bottom 576 and a walled portion 578 disposed between the bottom and the connecting member. Pipette sheath 570 may additionally and optionally have one or more cut-out portions 572 in the wall 578, or in the bottom 576. In embodiments of the reagent holder having a pipette sheath, a purpose of the sheath is to catch drips from used pipette tips, and thereby to prevent cross-sample contamination, from use of one holder to another in a similar location, and/or to any supporting rack in which the holder is situated. Typically, then, the bottom 576 is solid and bowl-shaped (concave) so that drips are retained within it. An embodiment having no pipette sheath, could utilize, e.g., a drip tray or a drainage outlet, suitably placed beneath pipette tips located in the one or more sockets, for the same purpose and located under or in the bottom of the rack, as described herein.
Process tube 520 (sometimes referred to as a lysis tube) can also be a snap-in tube, rather than being part of an integrated piece. Process tube 520 is typically used for various mixing and reacting processes that occur during sample preparation. For example, cell lysis can occur in process tube 520, as can extraction of nucleic acids, such as DNA or RNA of a patient, or DNA or RNA of a pathogen. Process tube 520 is then advantageously positioned in a location that minimizes, overall, pipette head moving operations involved with transferring liquids to process tube 520. Process tube 520 is also located in the holder in such a position that, when the holder is inserted in a rack as further described herein, the process tube is exposed and accessible to a heater and separator, as further described herein. The process tube is typically configured to accept a pipette tip during multiple pipetting operations.
The process tube also may have a low binding surface, and allows magnetic beads to slide up and down the inside wall easily without sticking to it. Moreover, it has a hydrophobic surface coating enabling low stiction of fluid and hence low binding of nucleic acids and other molecules.
Some of the reagents contained in the holder are provided as liquids, and others may be provided as solids from which a solution is re-generated, in situ, by adding liquid from a pipette tip. In some embodiments, a different type of container or tube is used to store liquids from those that store the solids.
Reagent tubes 540 are typically configured to hold liquid reagents, one per tube. For example, in reagent holder embodiment 501, three reagent tubes are shown, containing respectively wash buffer, release buffer, and neutralization buffer, each of which is used in a sample preparation protocol, carried out with multiple pipetting operations controlled by, e.g., a pipette head as further described herein.
Reagent tubes 540 that hold liquids or liquid reagents can be sealed with a laminate structure 598. The laminate structure typically has a heat seal layer, a plastic layer such as a layer of polypropylene, and a layer of metal such as aluminum foil, wherein the heat seal layer is adjacent the one or more reagent tubes. The additional plastic film that is used in a laminate for receptacles that contain liquid reagents is typically to prevent liquid from contacting the aluminum.
Two embodiments of a laminate structure, differing in their layer structures, are shown in
The laminates deployed herein make longer term storage of reagents easier because the holder includes both sealed lyophilized reagents and liquids sealed in close proximity, which is normally hard to achieve.
In one embodiment, the tops of the reagent tubes have beveled edges so that when an aluminum foil is heat bonded to the top, the plastic melt does not extend beyond the rim of the tube. This is advantageous because, if the plastic melt reduces the inner diameter of the tube, it will cause interference with the pipette tip during operation. In other embodiments, a raised flat portion 599 on holders 804 facilitates application and removal of laminate 598. Raised surface 599, on the upper side of the connecting member, and surrounding the inlet apertures to the reagent tubes and, optionally, the waste chamber, is an optional feature of the holder.
The manner in which liquid is pipetted out is such that a pipette tip piercing through the foil rips through without creating a seal around the pipette tip, as illustrated in
The reagent holder of embodiments 804 has a connecting member 510 that is configured so that the at least one socket, the one or more receptacles, and the respective apertures of the process tube, and the two or more reagent tubes, are all arranged linearly with respect to one another (i.e., their midpoints lie on the same axis). However, the holders herein are not limited to particular configurations of receptacles, process tube, sockets, reagent tubes, and waste chamber if present. For example, a holder may be made shorter, if some apertures are staggered with respect to one another and occupy ‘off-axis’ positions. The various receptacles, etc., also do not need to occupy positions with respect to one another that are the same as those shown in
In some embodiments, the holder comprises a registration member such as a mechanical key. Typically such a key is part of the connecting member 510. A mechanical key ensures that the holder is accepted by a complementary member in, for example, a supporting rack as described herein or a receiving bay of an apparatus that controls pipetting operations on reagents in the holder. Thus, embodiment 501 has a mechanical key 592 that comprises a pair of rectangular-shaped cut-outs on one end of the connecting member. This feature as shown additionally provides for a tab by which a user may gain a suitable purchase when inserting and removing the holder into a rack or another apparatus. Embodiment 501 also has a mechanical key 590 at the other end of connecting member 510. Key 590 is an angled cutout that eases insertion of the holder into a rack, as well as ensures a good registration therein when abutting a complementary angled cut out in a recessed area configured to receive the holder.
In some embodiments, not shown in
It should also be considered consistent with the description herein that a holder additionally can be configured to accept a sample, such as in a sample tube. Thus, in embodiments described elsewhere herein, a rack accepts a number of sample tubes and a number of corresponding holders in such a manner that the sample tubes and holders can be separately and independently loaded from one another. Nevertheless, in other embodiments, a holder can be configured to also accept a sample, for example in a sample tube. And thus, a complementary rack is configured to accept a number of holders, wherein each holder has a sample as well as reagents and other items. In such an embodiment, the holder is configured so that the sample in a suitably marked tube or container is accessible to a sample identification verifier.
A reagent holder for use with a rack as described herein is typically made of a plastic such as polypropylene. The plastic is such that it has some flexibility to facilitate placement into a rack, as further described herein. The plastic is typically sufficiently rigid, however, so that the holder will not significantly sag or flex under its own weight and will not easily deform during routine handling and transport or pipetting operations as further described herein, and thus will not permit reagents to leak out from it.
The holder is typically such that the connecting member, process tube, the two or more reagent tubes, and the waste chamber (if present) are made from a single piece, made from a material such as polypropylene.
The materials of the various tubes and chambers may be configured to have at least an interior surface smoothness and surface coating to reduce binding of DNA and other macromolecules thereto. Binding of DNA is unwanted because of the reduced sensitivity that is likely to result in subsequent detection and analysis of the DNA that is not trapped on the surface of the holder.
Rack
The apparatus outlined herein, and also described in U.S. patent application Ser. No. 12/173,023, filed by ExpressMail on Jul. 14, 2008 (and entitled “Integrated Apparatus for Performing Nucleic Acid Extraction and Diagnostic Testing on Multiple Biological Samples”, in the name of Williams, et al.), incorporated by reference herein, is configured to carry out various liquid transfer operations on samples and various reagents, in parallel. The samples and various reagents are typically held in one or more removable racks 970, positioned in the apparatus (such as one shown in
The racks for use herein are typically configured to be insertable into, and removable from, a diagnostic or preparatory apparatus as further described herein (e.g., in connection with
Two perspective views of an exemplary rack 800, configured to accept 12 sample tubes and 12 corresponding reagent holders, in 12 lanes, are shown in
A rack may accept 2, 4, 6, 8, 10, 12, 16, or 20 samples such as in sample tubes 802, and a corresponding number of reagent holders 804. Thus the embodiment of
Rack 800 is shown with a handle 806, having optionally a hand-grip 808, to facilitate transport, and removal from the apparatus. Rack 800 is also shown with positioning feet 811 that can help stabilize the rack during loading and when resting on, e.g., a bench-top, outside of the apparatus. Rack 800 is also shown as having a structural member 810, typically made of steel, that provides strength and rigidity for the rack, and also ensures that the rack fits tightly into an appropriately configured receiving area of the apparatus. Rack 800 is also shown as having a body 812 configured with a number of slots that accept the reagent holders.
As described elsewhere herein, the holders each comprise a process tube in which reactions, e.g., between reagents and sample, take place, typically with some heating, or cyclical heating and cooling. The location of the reagent holders in the rack typically ensures that the process tubes are effectively located in proximity to the heater units, as shown in
Heater Assembly & Magnetic Separator
The racks as described herein are configured such that the reagent holders placed in the racks are positioned so that the process tubes in the holders are heated by a dedicated heating assembly 977, as may be situated in an apparatus for carrying out sample preparation and analysis on multiple samples in parallel, such as shown in
Yet additionally, the holders herein are configured so that each process tube is in close enough proximity to a magnetic assembly that separation of magnetic particles from reagents in solution in the process tubes can be accomplished. An exemplary magnetic separator is configured to move one or more magnets relative to the one or more process tubes. Typically, the magnet is mounted in such a way that it can be moved in proximity to the process tubes, either in an automated fashion such as under control of a processor, or manually. The magnet can be made of neodymium (e.g., from K & J Magnetics. Inc.) and can have a magnetic strength of 5,000-15,000 Gauss (Brmax). The poles of the magnets can be arranged such that one pole faces the heat blocks and the other faces away from the heat blocks.
Advantageously, the heater assembly and magnetic separator operate together to permit successive heating and separation operations to be performed on liquid materials in the one or more process tubes without transporting either the liquid materials or the process tubes to different locations to perform either heating or separation. An exemplary heater assembly and magnetic separator are further described in U.S. provisional Patent Application Ser. No. 60/959,437, filed Jul. 13, 2008, and 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”, in the name of Williams, et al., and Ser. No. 12/178,586, entitled “Integrated Heater and Magnetic Separator”, in the name of Handique, filed on Jul. 23, 2008, all of which are incorporated herein by reference in their entirety.
The heater assembly and magnetic separator are also configured to operate in conjunction with the liquid dispenser further described herein so that, when appropriate quantities of liquid reagents and/or sample have been dispensed into the process tube adjacent the heater and separator, the heater and separator are controllably activated to accomplish the required heating and/or separating.
Pipetting Operations
Basic pipetting operations, such as may be accomplished with the automated pipetting apparatus described herein, are now described, as follows.
In various embodiments, preparation of a PCR-ready sample for use in subsequent diagnosis using the apparatus as further described herein, can include one or more of the following steps: contacting a neutralized polynucleotide sample with a PCR reagent mixture comprising a polymerase enzyme and a plurality of nucleotides (in some embodiments, the PCR reagent mixture can further include a positive control plasmid and a fluorogenic hybridization probe selective for at least a portion of the plasmid); in some embodiments, the PCR reagent mixture can be in the form of one or more lyophilized pellets, as stored in a receptacle on a holder, and the method can further include reconstituting the PCR pellet with liquid to create a PCR reagent mixture solution. Various, such as one or more, of the liquid transfer operations associated with the foregoing steps can be accomplished by one or more pipette heads on an automated pipetting apparatus that comprises a liquid dispenser, as further described herein.
The automated liquid dispenser can be further configured to dispense a solution (e.g., of a prepared sample, various PCR reagents, and detection tags) into a microfluidic cartridge. Thus, the liquid dispenser is configured to travel from a first set of positions above reagent holders having various containers that hold reagents, etc., to a second set of positions above the inlets of a microfluidic cartridge. The second set of positions is depicted schematically in
Liquid Dispenser
The liquid dispenser, as further described herein, can be configured to carry out pipetting operations in parallel on samples and solutions stored in one or more holders, and in one or more sample tubes, in a rack, as described elsewhere herein. It would be understood, however, that the operation, design, and function of the liquid dispenser is not dependent upon the locations of the samples and various solutions, but that the liquid dispenser could perform similarly in connection with pipetting solutions disposed in other types of receptacles. Thus, a liquid dispenser, as described herein, is an assembly of components that together cooperate to carry out such pipetting operations on solutions. The liquid dispenser thus, typically, can pick up and drop off pipette tips as needed, as well as aspirate quantities of liquid up into, and deposit out those quantities of liquid from, such pipette tips. The motions and operation of the liquid dispenser is typically controlled by a processor such that pipetting operations can be automated.
Advantageously, the liquid dispenser can be configured so that the pumps, sensors (e.g., for pipette tip presence detection, and force sensing during pipetting), sample identification verifier, and other items, move with it, and therefore minimize the number of control lines that move across the instrument during use, and also reduces the likelihood that such control lines will become tangled during motion of the liquid dispenser, as would be the case where pipette dispense heads are the only items undergoing motion, and remain in communication with other components that are fixed at various points within a preparatory or diagnostic apparatus. In such apparatus, where only e.g., dispense heads undergo motion, the need to be able to move freely in three degrees of freedom becomes severely constrained by the need to move a number of cables independently of one another.
Advantageously, as further described herein, also, the dispenser can be configured to align pipette tips, e.g., with cartridge inlet holes, using a motorized alignment plate. Additionally, as also described elsewhere herein, the dispenser can be configured with a scanner that reads information from, e.g., a sample.
Also included within the liquid dispenser 4000 is a sensor 4004 configured to sense when vertical motion of the support or mount is obstructed, and to provide a suitable signal, e.g., via an electrical connection 4020, directly to a processor (not shown), or indirectly (not shown) via printed circuit board 4008. Thus sensor 4004 can be mounted on support 4001, as shown, or on mount 4017, depending on matters of design choice.
Optionally included within the liquid dispenser 4000 is a scanner 4015, connected to, e.g., support 4001 (or, alternatively, to mount 4017) via a connector, such as a mechanical attachment, 4016. Scanner 4015 can be configured to read, e.g., sample and patient information, from one or more of a sample tube, reagent holder, or microfluidic cartridge, as further described elsewhere herein. Scanner 4015 can be electrically connected directly (not shown) to a processor, or indirectly via printed circuit board 4008.
A valve 4005 is associated with each dispense head 4002, and serve to control operation of each dispense head such as by, for example, controlling when to reduce pressure, thereby causing a sucking operation, or to increase pressure, thereby causing a dispense operation. Each valve 4005 is connected to (including being in fluid communication with) manifold 4007 via a connecting tube 4006.
Manifold 4007 is connected to pump 4012 via an air-line 4011, and to valves 4005 via connecting tubes 4006. Manifold 4007 contains a number of independently controllable valves that selectably divert air from pump 4012 to various of valves 4005, and therefore to corresponding dispense heads 4002. In
Manifold 4007 is also typically connected to pump 4012 via a second line 4020 that is configured to permit equilibriation of air between manifold and pump. Line 4020 connects to a vent 4021 on the manifold, and is also controlled by a valve 4022.
Operation of manifold 4007 is typically controlled by printed circuit board (PCB) 4008 to which it is connected via an electrical connection 4009. PCB 4008 additionally can receive electrical input from connection 4010. Thus, the suck and dispense operations can be precisely controlled, by signals from the PCB, so that accurate volumetric control is achieved. In some embodiments, calibration of the liquid dispenser is required so that the amount of time to force or to suck air that is required to dispense or aspirate a desired volume of liquid is known. Thus, the time between, e.g., a valve opening and valve closing, as controlled by signals, is known and can be incorporated into the control software.
Pump 4012 typically also comprises a motor (not shown) controlling its action, e.g., motion of a plunger, which receives electrical signals as input, and an air supply (not shown).
A perspective side view of an exemplary liquid dispense head is shown in
The gantry 2108 comprises a horizontal rail 2102 to provide movement in the x-direction, controlled by controller 2109, which receives electrical input from cables (not shown). Also not shown is an orthogonally disposed rail to provide movement in the y-direction of the rail and the attached assemblies. The gantry permits, overall, three degrees of translational freedom of the liquid dispenser. (Further embodiments, not herein described, can comprise a gantry having fewer than three degrees of translational freedom.) A suitable gantry comprises three axes of belt-driven slides actuated by encoded stepper motors. The gantry slides can be mounted on a framework of structural angle aluminum or other equivalent material, particularly a metal or metal alloy. Slides aligned in x- and y-directions (directed out of and in the plane of
Assembly 1700 is shown only as an outer housing; internal parts are further shown in
As shown in the various figures, the entire liquid dispenser that moves up and down the z-axis is a self-contained unit having only electrical connections to a processor or controller, and mechanical connections to the gantry. The translational motions in three dimensions of the liquid dispenser can be controlled by a microprocessor, such as processor 980. No fluid handling lines are associated with the dispenser. This design enables simplification of assembly of the instrument, minimizes contamination of the instrument and cross-contamination of samples between different instances of operation of the apparatus, increases efficiency of pumping (minimal dead volume) and enables easy maintenance and repair of the device. This arrangement also enables easy upgrading of features in the dispensing device, such as individual and independent pump control for each dispenser, individual pipette attachment or removal, ability to control the pitch of the pipettes, etc.
A suitable liquid dispenser for use with the apparatus herein comprises: one or more sensors (such as for sensing pipette tips, in
A cross-sectional view of the exemplary liquid dispenser of
Typically, pipette heads 1803 are individually sprung. Shown in
The liquid dispenser can further comprise computer-controlled, motorized, pump 1800 connected to distribution manifold 1802 with related computer-controlled valving. The distribution manifold typically travels with the dispense head, rather than being positioned at a fixed location away from the dispense head while the dispense head moves from one pipetting location to another. Computer-control can be accomplished via a control board 1809, shown in the embodiment of
Also shown in
The liquid dispenser is typically configured to aspirate or dispense fluid in connection with analysis or preparation of solutions of two or more samples. However, that is not to say that any of the features described herein could not also be applied in a device that operates on a single sample. The liquid dispenser is also configured to dispense liquid into a microfluidic cartridge. Typically, the liquid dispenser is configured to accept or dispense, in a single operation, an amount of 1.0 ml of fluid or less, such as an amount of fluid in the range 10 ml-1 ml.
The liquid dispenser is configured such that pump 1800 pumps air in and out of the distribution manifold. The pump can have an air supply and can be as simple in construction as having a plunger that moves back and forward compresses/expands air volume, under control of a motor, whose operation is in turn controlled by electrical signals from a processor. Air can be supplied to pump 1800 and is typically under pressure, such as at 0.1-10 psi. Thus the air supply may ultimately be provided by a compressed air cylinder, located outside of the apparatus. Typically the pump communicates with the manifold via two airways. A first airway, directs pressurized air from the pump to the manifold. A second airway can be for the purpose of equilibriating, where required, between various pipette operations, and connects with a vent on the manifold. When the pump draws air in, it is typical to close off the vents and valves in the manifold.
Further shown in
Fluid distribution manifold 1802, of which an exemplary embodiment is shown in
The distribution manifold comprises a microfluidic network 1829 that distributes air evenly amongst the one or more valves that individually regulate air flow to the dispense heads. Thus, by controlling flow of air through the manifold and various valves, pressure above the pipette heads 1803 can be varied so that liquid is drawn up into or expelled from a pipette tip attached to the respective pipette heads. In this way it is not necessary to supply compressed air via an air hose to the liquid dispenser. Neither is it necessary to provide liquid lines to the dispense head. Furthermore, no liquid reagents or liquid samples from the holders enter any part of the liquid dispenser, including the manifold. The volume of liquid drawn into the pipette is less than the maximum volume of the pipette, and therefore overflows are avoided. This aspect reduces complications that would arise if air bubbles are introduced into samples or liquid reagents. An exemplary configuration of a microfluidic network in a distribution manifold is shown in dashed lines in
Pipette Tip Stripper
The liquid dispenser can also operate in conjunction with a motorized plate configured to strip the pipettes and align the pipettes during dispensing of fluid from multiple pipette tips simultaneously, e.g., into a microfluidic cartridge, as further described herein. Such a device is found to be important because the tolerances for incorrect positioning of a pipette tip are very fine.
In a stripping role, as illustrated in
In an aligning role, shown in
In certain embodiments, the liquid dispenser can also comprise one or more sensors 2001 (e.g., infra-red sensors) each of which detects the presence of a pipette tip 2005 in position beneath the dispense heads, such as in one or more holders in a rack as further described herein. This is important to ensure that the processor knows affirmatively that a pipette tip is present or missing. Since a pipette tip is picked up by application of mechanical force of a head against the pipette, and is also dispensed using mechanical motion of a stripper plate, sensing a pipette tip helps prevent mechanical errors such as having a head descend too far and become damaged. The embodiment in
Such sensors can be mounted in close proximity to the pipette tip stripper described elsewhere herein. In
The embodiment shown in
Sample Identification Verifier
Another aspect of the apparatus relates to a sample identification verifier configured to check the identity of each of the number of samples, and typically mounted on one face of the liquid dispenser, the face and location on the face being determined by other geometric features of the apparatus and its various components, as may be routinely optimized by those of skill in the art. Such sample identification verifiers can be optical character readers, bar code readers, or radio frequency tag readers, or other suitable readers, as available to one of ordinary skill in the art. A sample identification verifier can be mounted on the gantry to which the liquid dispenser is mounted, or attached to the liquid dispenser so that it moves in concert with the liquid dispenser. Alternatively, the sample identification verifier can be separately mounted and can move independently of the liquid dispenser.
In
In the view of
In
The verifier is typically mounted so that freedom of motion along the z-ax is permits it to be readily positioned to read the sample tube, holder, and cartridge barcodes.
Sample identification verifier is configured to communicate details of labels that it has detected or read to a processor 980 or controller in the apparatus, thereby permitting sample identifying information to be associated with diagnostic results and other information relating to sample preparation, and extraction and amplification of nucleic acid therein.
Processor and Control
Control of automated motions of the liquid dispenser of the automated pipetting apparatus is via a suitably configured processor. The processor has been configured to execute instructions that deliver control signals to the various motors, and to receive signals from the various sensors, within the automated pipetting apparatus. Design and manufacture of such a processor is within the capability of one of ordinary skill in the art of laboratory automation systems, or apparatus control systems. The instructions executed by the processor can, similarly, be designed and implemented by one of ordinary skill in the art of computer programming. The instructions can take into account desired protocols of varying natures, depending on numbers of samples, locations of samples, and nature of target nucleotides, and cause motions of the liquid dispense head. The instructions can also take into account signals received from one or more sensors, in order to determine which of one or more next steps to execute, or whether to execute such steps at all or to instead, issue an error notification. The instructions may provide to a user a menu of pre-determined protocols to choose from and to execute, or may permit a user to design a new protocol, or modify an existing one.
Microfluidic Cartridge
As described elsewhere herein, the liquid dispenser can be configured to deliver quantities of solution containing one or more polynucleotide(s) in a form suitable for amplification to a microfluidic cartridge. Typically, such delivery occurs for multiple quantities of solution in parallel. A microfluidic cartridge compatible with such a process typically has a number of inlets, corresponding to a practical number of samples that are to be processed in parallel, for example, 2, 4, 6, 8, 10, 12, 16, or 24. Each inlet is situated in a lane of the cartridge, each lane further having channels that divert the respective samples to respective chambers within which an amplification such as PCR can be performed. The chambers typically can be isolated by one or more valves, during amplification. The chambers are also typically situated so that the progress of amplification can be monitored by one or more detectors. Exemplary configurations and manufactures of cartridges are described elsewhere, including but not limited to U.S. patent application Ser. No. 12/173,023, filed on Jul. 14, 2008, and Ser. No. 11/985,577, filed Nov. 14, 2007, both of which are incorporated herein by reference.
Typically, the inlet separation on the cartridge, or other receiving area, is chosen to correspond to the separation between adjacent pipette tips on the dispense heads of the liquid dispenser, or some convenient fraction or multiple thereof. Thus, for example, for a cartridge having an 8 mm separation between adjacent inlets, used in conjunction with a liquid dispenser having a 24 mm separation between the centers of the tips of adjacent pipette tips, the liquid dispenser can dispense samples into cartridge inlets that are separated by two inlets (e.g., a first and fourth inlets, numbering from a particular end of the cartridge). It would be understood that these dimensions and multiples are not limiting.
The apparatus having been described, it is illustrated by way of the following non-limiting examples.
Chemistry Overview
The chemistry processes typically carried out with the apparatus described herein center around the detection and identification of organisms in a clinical specimen, by virtue of detecting nucleic acids from the organism in question. This involves isolation of nucleic acids from target organisms that are contained in a clinical specimen, followed by a process that will detect the presence of specific nucleic acid sequences. In addition to target detection, an internal positive control nucleic acid can be added to the collection buffer, and can thereby be taken through the entire extraction and detection process along with target nucleic acids. This control will monitor the effectiveness of the entire process and will minimize the risk of having false negative results.
Nucleic Acid Extraction and Purification
Nucleic acid extraction procedures begin with the addition of a clinical specimen to a prepared specimen collection solution. This can be done either at a specimen collection site, or at the testing site. Two collection solution formats can be available: one for body fluids, and one for swab specimens. Collection solutions used at collection sites will serve as specimen transport solutions, and therefore, this solution must maintain specimen and analyte integrity.
The extraction and purification procedure, which is entirely automated using a liquid dispenser as described herein, in conjunction with a suitable heater and separator, proceeds as follows:
Nucleic acids that have been captured by magnetic beads, washed, released in high pH, and neutralized with buffer, are added to a mixture of buffers, salts, and enzymes that have been lyophilized in a tube. The mixture is rapidly rehydrated, and then a portion of the solution is loaded onto a microfluidic cartridge. The cartridge is then loaded into the amplification instrument module, which consists of a heating unit capable of thermal cycling, and an optical detection system. Detection of target nucleic acids proceeds as follows:
Extensive bench-scale testing has been performed to optimize the nucleic acid extraction chemistry, including the collection buffer, the wash buffer formulation, the release solution formulation, and the PCR reagent mixes. The fully automated method of extraction, followed by 12-up PCR, was able to provide very high sensitivity consistently at 150 copies/sample.
Examplary target/sample combinations include: Chlamydia in Urine (50/50); Gonrorrhoea in Urine; GBS in Plasma.
Various detection chemistries such as Taqman, Scorpion, and SYBRg Green work reliably in the microfluidic cartridge.
Sample Pre-Processing
For Urine Sample: Take 0.5 ml of urine and mix it with 0.5 ml of collection buffer. Filter the sample through a pre-filter (containing two membranes of 10 micron and 3 micron pore size).
For Plasma Sample: Take 0.5 ml of plasma and mix it with 0.5 ml of collection buffer.
For GBS swab samples: Take the swab sample and dip it in 1 ml of collection buffer.
For each type of sample, after it is mixed with the appropriate collection buffer (and filtered if applicable), the solution is placed in the external sample tube in the position specified for it in the rack.
The sample collection buffer contains 50 mM Tris pH 7, 1% Triton X-100, 20 mM Citrate, 20 mM Borate, 100 mM EDTA, plus 1,000 copies of positive control DNA.
Loading the Instrument and Starting Sample Processing
The following steps may be performed to initiate an analysis on samples in batch.
The following steps may be performed to carry out sample preparation. Herein the numbering of the pipette tips refers to those pipette tips that are stored in a reagent holder, for example, in a pipette sheath of such a holder. It would be understood that such operations could be performed multiply in parallel by a liquid dispenser as described elsewhere herein. References to a ‘robot’ herein are intended to mean an automated pipetting apparatus, such as embodiments further described herein.
After all the appropriate PCR lanes of the PCR cartridge are loaded with final PCR solution, the tray containing the cartridge moves the cartridge into the PCR Analyzer. The cartridge is pressed by an optical detection read-head against the PCR heater. Heaters activate valves to close either ends of the PCR reactor and the real-time thermocycling process starts. After completing appropriate PCR cycles (˜45 cycles), the analyzer decides whether the sample has the target DNA based on the output fluorescence data, and issues an indication of the same.
An exemplary reagent holder consistent with the description herein has the following dimensions and capacities:
It is to be understood that these dimensions are exemplary. However, it is particularly desirable to ensure that a holder does not exceed these dimensions so that a rack and an apparatus that accommodates the reagent holder(s) does not become inconveniently large, and can be suitably situated in a laboratory, e.g., on a bench-top.
Tubes containing buffers have to be sealed with high moisture vapor barrier materials in order to retain the liquid over a long period of time. Reagent holders may need to have a shelf life of 1-2 years, and as such, they should not lose more than say 10-15% of the liquid volume over the time period, to maintain required volume of liquid, and to maintain the concentration of various molecules present in the solution. Moreover, the materials used for construction of the tube as well as the sealing laminate should not react with the liquid buffer. Special plastic laminates may provide the moisture barrier but they may have to be very thick (more than 300 μm thick), causing the piercing force to go up tremendously, or of special, expensive polymer (such as Aclar). Aluminum foils, even a thin foil of a few hundred angstrom provides an effective moisture barrier but bare aluminum reacts with some liquid buffers, such as sodium hydroxide, even an aluminum foil with a sprayed coating of a non-reactive polymer may not be able to withstand the corrosive vapors over a long time. They may react through tiny pin holes present in the coating and may fail as a barrier over time.
For these reasons, aluminum toils with a laminate structure have been identified as a suitable barrier, exemplary properties of which are described below:
The aluminum laminate containing a plastic film described elsewhere herein serves well for not reacting with corrosive reagents such as buffers containing NaOH, and having the favorable properties of pierceability and acting as a moisture barrier. However, it presents some additional difficulties during piercing. The aluminum foil tends to burst into an irregular polygonal pattern bigger than the diameter of the pipette, whereas the plastic film tends to wrap around the pipette tip with minimal gap between the pipette and the plastic film. The diameter of the hole in the plastic film is similar to the maximum diameter of the pipette that had crossed through the laminate. This wrapping of the pipette causes difficulty in dispensing and pipetting operations unless there is a vent hole allowing pressures to equilibrate between outside of the tube and the air inside of the tube.
A strategy for successful pipetting of fluid is as follows:
The containers of lyophilized reagents provided in conjunction with a holder as described herein are typically sealed by a non-plasticized aluminum foil (i.e., not a laminate as is used to seal the reagent tubes). Aluminum foil bursts into an irregular polygonal pattern when pierced through a pipette and leaves an air vent even though the pipette is moved to the bottom of the tube. In order to save on reagents, it is desirable to dissolve the reagents and maximize the amount withdrawn from the tube. To accomplish this, a star-ridged (stellated) pattern is placed at the bottom of the container to maximize liquid volume withdrawn, and flow velocity in between the ridges.
Exemplary steps for dissolving and withdrawing fluid are as follows:
Travel of the liquid dispenser along the z-axis is regulated by a force-sensor. A force sensor is interfaced with the pipette heads in such a way that any time the pipette head seats against the disposable pipette tip(s) or the picked pipettes are forced through a laminate cover of the reagent holder, or the pipette tip is forced against the bottom of the tubes in the reagent disposable, an upward force acts on the pipette head through the pipette holding nozzle or the pipette tip itself. The entire head is pivoted at a lower point, and any force acting on the head causes a set-screw on the upper part of the head to press against a force sensor. This force sensor is calibrated for vertical displacement of the head against a non-moving surface. Using this calibration, it can be determined when to stop moving the head in the z-direction by detecting whether, for example, a pipette is properly seated or if a pipette tip has hit a tube bottom.
The liquid dispenser is configured so that, when multiple pipette tips are attached simultaneously, the tips can dispense in parallel to multiple inlets on a microfluidic cartridge. In particular, this means that the spacing between the tips is exactly the same as, or the same as to within an acceptable tolerance, the spacing between the inlets on the cartridge. Larger volume pipette tips can be as long as 95 mm (for, e.g., a p1000 pipette). When 4 long pipette tips are sprung from the head, even a 1° misalignment during seating can cause the tip to be off-center by ˜1.7 mm, which is sufficient for that tip to miss the desired inlet on the cartridge. As it is difficult to have perfect alignment all the time during pipetting of the tip both at its top where it is interfaced with the tip holder and its bottom, it becomes necessary to mechanically constrain all the tips at another location closer to the bottom. As described elsewhere herein, a stripper plate having a defined hole structure, can be used to align all the tips. The stripper plate holes clear all the 4 pipette tips when they are picked up. After the tips are properly seated, the stripper plate is moved horizontally, such as in the x-axis direction, using a motor to move all the pipettes against the notches provided in the stripper plate. Now all the pipettes land on the cartridge inlet holes with ease.
Described herein are exemplary specifications for the mechanical design of a system for carrying out PCR on multiple samples. In some embodiments, the system can be about 28.5 inches deep, or less, and about 43 inches wide, or less, and weight about 250 pounds or less. The system can be designed with a useful life of about 5 years (e.g., assuming 16,000 tests per year) and can be designed such that the sound level for this instrument (during operation) does not exceed 50 dB as measured 12 inches from the instrument in all ordinate directions. In some embodiments, the exterior of the system can be white with texture.
Referring to the overall system, in some embodiments, critical components of the system can remain orthogonal or parallel (as appropriate) to within 0.04 degrees. Exemplary critical components can include motion rails, pipettes, nozzles (e.g., axially as individual nozzles, linearly as an array of four nozzle centroids, or the like), lysis heaters, major edges of the installed cartridge holder in the reader drawer, the front face of the separation magnets, and the like.
In the following descriptions as with elsewhere herein, the X-axis (or X direction) refers to the axis extending from left to right when facing the front of the system, the Y-axis (or Y direction) refers to the axis extending from back to front when facing the front of the system, and the Z-axis (or Z direction) refers to the axis extending up from the bottom when facing the front of the system. As viewed from the top of the instrument, the centroid of the leftmost pipette nozzle on the Z-payload (as viewed from the front of the instrument) can be capable of unobstructed travel in the X direction from a point 80 mm from the outermost left baseplate edge to a point 608 mm from the outermost left baseplate edge and can be capable of unobstructed travel in the Y direction from a point 60 mm from the outermost front baseplate edge to a point 410 mm from the outermost front baseplate edge.
Still referring to the system, as viewed from the front of the instrument, the bottom-most face of the pipette nozzles on the Z-payload can be capable of unobstructed travel in the Y direction from a point 156 mm above the top surface of the baseplate to a point 256 mm above the top surface of the baseplate. The 1 ml pipette tips can be capable of penetrating the foil covers included on disposable reagent strips. This penetration may not create contamination, affect the associated chemistries, or damage the pipette tips. Motions can be executed in such a manner as to eliminate mechanical hysteresis, as needed. Gantry motions can be optimized to prevent cross lane contamination and carryover. The rack can align the reagent strips to a tolerance of +/−0.010 inches in the X and Y directions.
Referring now to the gantry, in some embodiments, the gantry can consist of a stepper-motor actuated, belt/screw-driven cartesian robotic system. The gantry can be free to move, with or without attachments, above the modules that are forward of the rear facade and below the bottom-most horizontal face on the Z head, so long as the Z-payload is fully retracted. The gantry can be capable of travel speeds up to about 500 mm/sec in the X and Y directions and up to about 100 mm/sec in the Z direction. The accuracy and precision of the axis motions (e.g., with respect to the X, Y. and Z home sensors) can be 25 mm or better for each axis, and can be retained throughout the maintenance period. The axis drive belts may not leave residue in areas where PCR and samples are processed. The gantry can contain provisions for routing its own and all Z-payload wire harnesses back to the instrument. Belt tension on the X and Y axes can be set at 41.5+/−3.5 pounds.
Referring now to the Z-payload, the fluid head can have 4 pipette attachment nozzles located at 24 mm distances between adjacent centers. Such a distance is chosen to facilitate interfacing the pipette tips and inlets on a microfluidic cartridge, as well as between sample tubes, or reagent tubes, on adjacent holders. Exemplary pipette tips that the pipette nozzles can capture without leakage include Biorobotix tips PN23500048 (50 μL), PN23500049 (1.75 μL), and PN23500046 (1 ml). The Z payload can incorporate a stepper actuated stripper plate capable of removing pipette tips (e.g., the pipette tips described hereinabove). The system can include a pump and manifold system that includes software controlled aspiration, dispensing, and venting of individual fluid volumes within each of the four individual tips and simultaneous dispensing and venting on all tips. The pump and manifold system can have an accuracy and precision of about +/−2 μL per tip for volumes that are less than 20 μL and about +/−10% for volumes greater than or equal to 20 μL (e.g., when aspirating or dispensing in individual tips). The total pump stroke volume can be greater than about 8 μL and less than about 1250 μL. The minimum aspirate and dispense speed can be about 10 μL/sec to about 300 μL/sec. The centroid of the bottom-most face of each pipette tip can be axially aligned with the nozzle centroid of the pipette nozzles within 0.2 mm. The bottom-most pipette tip faces can be co-planar within 0.2 mm. The Z-payload can incorporate a Z axis force sensor capable of feedback to software for applied forces of between about 0 and 4 lbs. The Z-payload can incorporate a downward facing barcode reader capable of reading the system barcodes as described elsewhere herein.
Referring now to racks included in the system, disposable reagent strips (e.g., oriented orthogonally to the front of the instrument) can be contained in 2, 12-lane racks. The 12 reagent strips in a given rack can register and lock into the rack upon insertion by a user. The rack can contain an area for 12 sample lysis tubes and hold the tube bottoms co-planar, allowing the user to orient the bar code to face the rear of the instrument. Certain features, including those listed above, can allow the racks to be inserted and oriented in the instrument by a minimally trained user. Proper rack placement can be confirmed by feedback to the software. In some embodiments, the racks can be black and color fast (e.g., the color may not appreciably degrade with use or washing with a 10% bleach solution) and the rack material can be dimensionally stable within 0.1 mm over the operating temperature range of the system. The rack can be designed with provisions to allow the rack to be carried to and from the instrument and to minimize or eliminate the likelihood that the tubes held by the rack will spill when placed on a flat surface.
In
The foregoing description is intended to illustrate various aspects of the present inventions. It is not intended that the examples presented herein limit the scope of the present inventions. The technology now being fully described, it will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.
This application is a continuation of U.S. patent application Ser. No. 15/160,186, filed on May 20, 2016 and scheduled to issue on Mar. 19, 2019 as U.S. Pat. No. 10,234,474, which is a continuation of U.S. patent application Ser. No. 13/652,368, filed on Oct. 15, 2012 and issued on May 24, 2016 as U.S. Pat. No. 9,347,586, which is a continuation of U.S. patent application Ser. No. 12/212,403, filed on Sep. 17, 2008 and issued as U.S. Pat. No. 8,287,820 on Oct. 16, 2012, which is a continuation-in-part of U.S. patent application Ser. No. 12/173,023, filed Jul. 14, 2008 and issued as U.S. Pat. No. 8,133,671 on Mar. 13, 2012, and a continuation-in-part of U.S. patent application Ser. No. 12/218,498, filed on Jul. 14, 2008 and issued as U.S. Pat. No. 9,186,677 on Nov. 17, 2015, both of which applications claim the benefit of priority to U.S. Provisional Patent Application No. 60/959,437, filed Jul. 13, 2007. The disclosures of all of the above-referenced prior applications, publications, and patents are considered part of the disclosure of this application, and are incorporated by reference herein in their entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| D189404 | Nicolle | Dec 1960 | S |
| 3050239 | Williams | Aug 1962 | A |
| 3905772 | Hartnett et al. | Sep 1975 | A |
| 3985649 | Eddelman | Oct 1976 | A |
| 4018089 | Dzula et al. | Apr 1977 | A |
| 4018652 | Lanham et al. | Apr 1977 | A |
| 4038192 | Serur | Jul 1977 | A |
| 4055395 | Honkawa et al. | Oct 1977 | A |
| D249706 | Adamski | Sep 1978 | S |
| 4139005 | Dickey | Feb 1979 | A |
| D252157 | Kronish et al. | Jun 1979 | S |
| D252341 | Thomas | Jul 1979 | S |
| D254687 | Fadler et al. | Apr 1980 | S |
| 4212744 | Oota | Jul 1980 | A |
| D261033 | Armbruster | Sep 1981 | S |
| D261173 | Armbruster | Oct 1981 | S |
| 4301412 | Hill et al. | Nov 1981 | A |
| 4439526 | Columbus | Mar 1984 | A |
| 4457329 | Werley et al. | Jul 1984 | A |
| 4466740 | Kano et al. | Aug 1984 | A |
| 4472357 | Levy et al. | Sep 1984 | A |
| 4504582 | Swann | Mar 1985 | A |
| 4522786 | Ebersole | Jun 1985 | A |
| D279817 | Chen et al. | Jul 1985 | S |
| D282208 | Lowry | Jan 1986 | S |
| 4599315 | Terasaki et al. | Jul 1986 | A |
| 4612873 | Eberle | Sep 1986 | A |
| 4612959 | Costello | Sep 1986 | A |
| D288478 | Carlson et al. | Feb 1987 | S |
| 4647432 | Wakatake | Mar 1987 | A |
| 4654127 | Baker et al. | Mar 1987 | A |
| 4673657 | Christian | Jun 1987 | A |
| 4678752 | Thorne et al. | Jul 1987 | A |
| 4683195 | Mullis et al. | Jul 1987 | A |
| 4683202 | Mullis | Jul 1987 | A |
| 4698302 | Whitehead et al. | Oct 1987 | A |
| D292735 | Lovborg | Nov 1987 | S |
| 4720374 | Ramachandran | Jan 1988 | A |
| 4724207 | Hou et al. | Feb 1988 | A |
| 4795698 | Owen et al. | Jan 1989 | A |
| 4798693 | Mase et al. | Jan 1989 | A |
| 4800022 | Leonard | Jan 1989 | A |
| 4827944 | Nugent | May 1989 | A |
| 4841786 | Schulz | Jun 1989 | A |
| D302294 | Hillman | Jul 1989 | S |
| 4855110 | Marker et al. | Aug 1989 | A |
| 4871779 | Hat et al. | Oct 1989 | A |
| 4889818 | Gelfand et al. | Dec 1989 | A |
| 4895650 | Wang | Jan 1990 | A |
| 4902624 | Columbus et al. | Feb 1990 | A |
| 4914710 | Ward et al. | Apr 1990 | A |
| 4919829 | Gates et al. | Apr 1990 | A |
| 4921809 | Schiff et al. | May 1990 | A |
| 4935342 | Seligson et al. | Jun 1990 | A |
| 4946562 | Guruswamy | Aug 1990 | A |
| 4948561 | Hinckley et al. | Aug 1990 | A |
| 4949742 | Rando et al. | Aug 1990 | A |
| D310413 | Bigler et al. | Sep 1990 | S |
| 4963498 | Hillman | Oct 1990 | A |
| 4965188 | Mullis et al. | Oct 1990 | A |
| 4967950 | Legg et al. | Nov 1990 | A |
| D312692 | Bradley | Dec 1990 | S |
| 4978502 | Dole et al. | Dec 1990 | A |
| 4978622 | Mishell et al. | Dec 1990 | A |
| 4989626 | Takagi et al. | Feb 1991 | A |
| 4994373 | Stavrianopoulos et al. | Feb 1991 | A |
| 4997772 | Sutton et al. | Mar 1991 | A |
| 5001417 | Pumphrey et al. | Mar 1991 | A |
| 5004583 | Guruswamy et al. | Apr 1991 | A |
| 5048554 | Kremer | Sep 1991 | A |
| 5053199 | Keiser et al. | Oct 1991 | A |
| 5060823 | Perlman | Oct 1991 | A |
| 5061336 | Soane | Oct 1991 | A |
| 5064618 | Baker et al. | Nov 1991 | A |
| 5071531 | Soane | Dec 1991 | A |
| 5089233 | DeVaney, Jr. et al. | Feb 1992 | A |
| 5091328 | Miller | Feb 1992 | A |
| D324426 | Fan et al. | Mar 1992 | S |
| 5096669 | Lauks et al. | Mar 1992 | A |
| D325638 | Sloat et al. | Apr 1992 | S |
| 5126002 | Iwata et al. | Jun 1992 | A |
| 5126022 | Soane et al. | Jun 1992 | A |
| D328135 | Fan et al. | Jul 1992 | S |
| D328794 | Frenkel et al. | Aug 1992 | S |
| 5135627 | Soane | Aug 1992 | A |
| 5135872 | Pouletty et al. | Aug 1992 | A |
| 5147606 | Charlton et al. | Sep 1992 | A |
| 5147777 | Sutton et al. | Sep 1992 | A |
| 5155166 | Danielson et al. | Oct 1992 | A |
| 5169512 | Wiedenmann et al. | Dec 1992 | A |
| 5173269 | Mon et al. | Dec 1992 | A |
| D333522 | Gianino | Feb 1993 | S |
| 5186339 | Heissler | Feb 1993 | A |
| 5192507 | Taylor et al. | Mar 1993 | A |
| 5208163 | Charlton et al. | May 1993 | A |
| 5217694 | Gibler et al. | Jun 1993 | A |
| 5223226 | Wittmer et al. | Jun 1993 | A |
| 5229297 | Schnipelsky et al. | Jul 1993 | A |
| 5231015 | Cummins et al. | Jul 1993 | A |
| D338275 | Fischer et al. | Aug 1993 | S |
| 5234809 | Boom et al. | Aug 1993 | A |
| 5250263 | Manz | Oct 1993 | A |
| 5252743 | Barrett et al. | Oct 1993 | A |
| 5256376 | Callan et al. | Oct 1993 | A |
| 5273716 | Northrup et al. | Dec 1993 | A |
| 5275787 | Yuguchi et al. | Jan 1994 | A |
| 5282950 | Dietze et al. | Feb 1994 | A |
| 5296375 | Kricka et al. | Mar 1994 | A |
| 5304477 | Nagoh et al. | Apr 1994 | A |
| 5304487 | Wilding et al. | Apr 1994 | A |
| D347478 | Pinkney | May 1994 | S |
| 5311896 | Kaartinen et al. | May 1994 | A |
| 5311996 | Duffy et al. | May 1994 | A |
| 5316727 | Suzuki et al. | May 1994 | A |
| 5327038 | Culp | Jul 1994 | A |
| 5334499 | Burdick et al. | Aug 1994 | A |
| 5338671 | Ice et al. | Aug 1994 | A |
| 5339486 | Persic, Jr. | Aug 1994 | A |
| D351475 | Gerber | Oct 1994 | S |
| D351913 | Hieb et al. | Oct 1994 | S |
| 5364591 | Green et al. | Nov 1994 | A |
| 5372946 | Cusak et al. | Dec 1994 | A |
| 5374395 | Robinson | Dec 1994 | A |
| 5384499 | Pedersen et al. | Jan 1995 | A |
| 5389339 | Petschek et al. | Feb 1995 | A |
| D356232 | Armstrong et al. | Mar 1995 | S |
| 5397709 | Berndt | Mar 1995 | A |
| 5401465 | Smethers et al. | Mar 1995 | A |
| 5411708 | Moscetta et al. | May 1995 | A |
| 5414245 | Hackleman | May 1995 | A |
| 5415839 | Zaun et al. | May 1995 | A |
| 5416000 | Allen et al. | May 1995 | A |
| 5422271 | Chen et al. | Jun 1995 | A |
| 5422284 | Lau | Jun 1995 | A |
| 5427946 | Kricka et al. | Jun 1995 | A |
| 5443791 | Cathcart et al. | Aug 1995 | A |
| 5466574 | Liberti et al. | Nov 1995 | A |
| 5474796 | Brennan | Dec 1995 | A |
| 5475487 | Mariella, Jr. et al. | Dec 1995 | A |
| D366116 | Biskupski | Jan 1996 | S |
| 5486335 | Wilding et al. | Jan 1996 | A |
| 5494639 | Grzegorzewski | Feb 1996 | A |
| 5498392 | Wilding et al. | Mar 1996 | A |
| 5503803 | Brown | Apr 1996 | A |
| 5516410 | Schneider et al. | May 1996 | A |
| 5519635 | Miyake et al. | May 1996 | A |
| 5529677 | Schneider et al. | Jun 1996 | A |
| 5559432 | Logue | Sep 1996 | A |
| 5565171 | Dovichi et al. | Oct 1996 | A |
| 5569364 | Hooper et al. | Oct 1996 | A |
| 5576218 | Zurek et al. | Nov 1996 | A |
| 5578270 | Reichler et al. | Nov 1996 | A |
| 5578818 | Kain et al. | Nov 1996 | A |
| 5579928 | Anukwuem | Dec 1996 | A |
| 5580523 | Bard | Dec 1996 | A |
| 5582884 | Ball et al. | Dec 1996 | A |
| 5582988 | Backus et al. | Dec 1996 | A |
| 5585069 | Zanucchi et al. | Dec 1996 | A |
| 5585089 | Queen et al. | Dec 1996 | A |
| 5585242 | Bouma et al. | Dec 1996 | A |
| 5587128 | Wilding et al. | Dec 1996 | A |
| 5589136 | Northrup et al. | Dec 1996 | A |
| 5593838 | Zanzucchi et al. | Jan 1997 | A |
| 5595708 | Berndt | Jan 1997 | A |
| 5599432 | Manz et al. | Feb 1997 | A |
| 5599503 | Manz et al. | Feb 1997 | A |
| 5599667 | Arnold, Jr. et al. | Feb 1997 | A |
| 5601727 | Bormann et al. | Feb 1997 | A |
| 5603351 | Cherukuri et al. | Feb 1997 | A |
| 5605662 | Heller et al. | Feb 1997 | A |
| 5609910 | Hackleman | Mar 1997 | A |
| D378782 | LaBarbera et al. | Apr 1997 | S |
| 5628890 | Carter et al. | May 1997 | A |
| 5630920 | Friese et al. | May 1997 | A |
| 5631337 | Sassi et al. | May 1997 | A |
| 5632876 | Zanzucchi et al. | May 1997 | A |
| 5632957 | Heller et al. | May 1997 | A |
| 5635358 | Wilding et al. | Jun 1997 | A |
| 5637469 | Wilding et al. | Jun 1997 | A |
| 5639423 | Northrup et al. | Jun 1997 | A |
| 5639428 | Cottingham | Jun 1997 | A |
| 5643738 | Zanzucchi et al. | Jul 1997 | A |
| 5645801 | Bouma et al. | Jul 1997 | A |
| 5646039 | Northrup et al. | Jul 1997 | A |
| 5646049 | Tayi | Jul 1997 | A |
| 5647994 | Tuunanen et al. | Jul 1997 | A |
| 5651839 | Rauf | Jul 1997 | A |
| 5652141 | Henco et al. | Jul 1997 | A |
| 5652149 | Mileaf et al. | Jul 1997 | A |
| D382346 | Buhler et al. | Aug 1997 | S |
| D382647 | Staples et al. | Aug 1997 | S |
| 5654141 | Mariani et al. | Aug 1997 | A |
| 5658515 | Lee et al. | Aug 1997 | A |
| 5667976 | Van Ness et al. | Sep 1997 | A |
| 5671303 | Shieh et al. | Sep 1997 | A |
| 5674394 | Whitmore | Oct 1997 | A |
| 5674742 | Northrup et al. | Oct 1997 | A |
| 5681484 | Zanzucchi et al. | Oct 1997 | A |
| 5681529 | Taguchi et al. | Oct 1997 | A |
| 5683657 | Mian | Nov 1997 | A |
| 5683659 | Hovatter | Nov 1997 | A |
| 5699157 | Parce et al. | Dec 1997 | A |
| 5700637 | Southern | Dec 1997 | A |
| 5705813 | Apffel et al. | Jan 1998 | A |
| 5720923 | Haff et al. | Feb 1998 | A |
| 5721136 | Finney et al. | Feb 1998 | A |
| 5725831 | Reichler et al. | Mar 1998 | A |
| 5726026 | Wilding et al. | Mar 1998 | A |
| 5726404 | Brody | Mar 1998 | A |
| 5726944 | Pelley et al. | Mar 1998 | A |
| 5731212 | Gavin et al. | Mar 1998 | A |
| 5744366 | Kricka et al. | Apr 1998 | A |
| 5746978 | Bienhaus et al. | May 1998 | A |
| 5747666 | Willis | May 1998 | A |
| 5750015 | Soane et al. | May 1998 | A |
| 5755942 | Zanzucchi et al. | May 1998 | A |
| 5762874 | Seaton et al. | Jun 1998 | A |
| 5763262 | Wong et al. | Jun 1998 | A |
| 5770029 | Nelson et al. | Jun 1998 | A |
| 5770388 | Vorpahl | Jun 1998 | A |
| 5772966 | Maracas et al. | Jun 1998 | A |
| 5779868 | Parce et al. | Jul 1998 | A |
| 5783148 | Cottingham et al. | Jul 1998 | A |
| 5787032 | Heller et al. | Jul 1998 | A |
| 5788814 | Sun et al. | Aug 1998 | A |
| 5800600 | Lima-Marques et al. | Sep 1998 | A |
| 5800690 | Chow et al. | Sep 1998 | A |
| 5804436 | Okun et al. | Sep 1998 | A |
| D399959 | Prokop et al. | Oct 1998 | S |
| 5819749 | Lee et al. | Oct 1998 | A |
| 5827481 | Bente et al. | Oct 1998 | A |
| 5842106 | Thaler et al. | Nov 1998 | A |
| 5842787 | Kopf-Sill et al. | Dec 1998 | A |
| 5846396 | Zanzucchi et al. | Dec 1998 | A |
| 5846493 | Bankier et al. | Dec 1998 | A |
| 5849208 | Hayes et al. | Dec 1998 | A |
| 5849486 | Heller et al. | Dec 1998 | A |
| 5849489 | Heller | Dec 1998 | A |
| 5849598 | Wilson et al. | Dec 1998 | A |
| 5852495 | Parce | Dec 1998 | A |
| 5856174 | Lipshutz et al. | Jan 1999 | A |
| 5858187 | Ramsey et al. | Jan 1999 | A |
| 5858188 | Soane et al. | Jan 1999 | A |
| 5863502 | Southgate et al. | Jan 1999 | A |
| 5863708 | Zanzucchi et al. | Jan 1999 | A |
| 5863801 | Southgate et al. | Jan 1999 | A |
| 5866345 | Wilding et al. | Feb 1999 | A |
| 5869004 | Parce et al. | Feb 1999 | A |
| 5869244 | Martin et al. | Feb 1999 | A |
| 5872010 | Karger et al. | Feb 1999 | A |
| 5872623 | Stabile et al. | Feb 1999 | A |
| 5874046 | Megerle | Feb 1999 | A |
| 5876675 | Kennedy | Mar 1999 | A |
| 5880071 | Parce et al. | Mar 1999 | A |
| 5882465 | McReynolds | Mar 1999 | A |
| 5883211 | Sassi et al. | Mar 1999 | A |
| 5885432 | Hooper et al. | Mar 1999 | A |
| 5885470 | Parce et al. | Mar 1999 | A |
| 5895762 | Greenfield et al. | Apr 1999 | A |
| 5900130 | Benvegnu et al. | May 1999 | A |
| 5911737 | Lee et al. | Jun 1999 | A |
| 5912124 | Kumar | Jun 1999 | A |
| 5912134 | Shartle | Jun 1999 | A |
| 5914229 | Loewy | Jun 1999 | A |
| 5916522 | Boyd et al. | Jun 1999 | A |
| 5916776 | Kumar | Jun 1999 | A |
| 5919646 | Okun et al. | Jul 1999 | A |
| 5919711 | Boyd et al. | Jul 1999 | A |
| 5922591 | Anderson et al. | Jul 1999 | A |
| 5927547 | Papen et al. | Jul 1999 | A |
| 5928161 | Krulevitch et al. | Jul 1999 | A |
| 5928880 | Wilding et al. | Jul 1999 | A |
| 5929208 | Heller et al. | Jul 1999 | A |
| D413391 | Lapeus et al. | Aug 1999 | S |
| 5932799 | Moles | Aug 1999 | A |
| 5935401 | Amigo | Aug 1999 | A |
| 5939291 | Loewy et al. | Aug 1999 | A |
| 5939312 | Baier et al. | Aug 1999 | A |
| 5942443 | Parce et al. | Aug 1999 | A |
| 5944717 | Lee et al. | Aug 1999 | A |
| D413677 | Dumitrescu et al. | Sep 1999 | S |
| D414271 | Mendoza | Sep 1999 | S |
| 5948227 | Dubrow | Sep 1999 | A |
| 5948363 | Gaillard | Sep 1999 | A |
| 5948673 | Cottingham | Sep 1999 | A |
| 5955028 | Chow | Sep 1999 | A |
| 5955029 | Wilding et al. | Sep 1999 | A |
| 5957579 | Kopf-Sill et al. | Sep 1999 | A |
| 5958203 | Parce et al. | Sep 1999 | A |
| 5958349 | Petersen et al. | Sep 1999 | A |
| 5958694 | Nikiforov | Sep 1999 | A |
| 5959221 | Boyd et al. | Sep 1999 | A |
| 5959291 | Jensen | Sep 1999 | A |
| 5935522 | Swerdlow et al. | Oct 1999 | A |
| 5964995 | Nikiforov et al. | Oct 1999 | A |
| 5964997 | McBride | Oct 1999 | A |
| 5965001 | Chow et al. | Oct 1999 | A |
| 5965410 | Chow et al. | Oct 1999 | A |
| 5965886 | Sauer et al. | Oct 1999 | A |
| 5968745 | Thorp et al. | Oct 1999 | A |
| 5972187 | Parce et al. | Oct 1999 | A |
| 5973138 | Collis | Oct 1999 | A |
| D417009 | Boyd | Nov 1999 | S |
| 5976336 | Dubrow et al. | Nov 1999 | A |
| 5980704 | Cherukuri et al. | Nov 1999 | A |
| 5980719 | Cherukuri et al. | Nov 1999 | A |
| 5981735 | Thatcher et al. | Nov 1999 | A |
| 5985651 | Hunicke-Smith | Nov 1999 | A |
| 5989402 | Chow et al. | Nov 1999 | A |
| 5992820 | Fare et al. | Nov 1999 | A |
| 5993611 | Moroney, III et al. | Nov 1999 | A |
| 5993750 | Ghosh et al. | Nov 1999 | A |
| 5997708 | Craig | Dec 1999 | A |
| 6001229 | Ramsey | Dec 1999 | A |
| 6001231 | Kopf-Sill | Dec 1999 | A |
| 6001307 | Naka et al. | Dec 1999 | A |
| 6004450 | Northrup et al. | Dec 1999 | A |
| 6004515 | Parce et al. | Dec 1999 | A |
| 6007690 | Nelson et al. | Dec 1999 | A |
| 6010607 | Ramsey | Jan 2000 | A |
| 6010608 | Ramsey | Jan 2000 | A |
| 6010627 | Hood, III | Jan 2000 | A |
| 6012902 | Parce | Jan 2000 | A |
| D420747 | Dumitrescu et al. | Feb 2000 | S |
| D421130 | Cohen et al. | Feb 2000 | S |
| 6024920 | Cunanan | Feb 2000 | A |
| D421653 | Purcell | Mar 2000 | S |
| 6033546 | Ramsey | Mar 2000 | A |
| 6033880 | Haff et al. | Mar 2000 | A |
| 6043080 | Lipshutz et al. | Mar 2000 | A |
| 6043880 | Andrews et al. | Mar 2000 | A |
| 6046056 | Parce et al. | Apr 2000 | A |
| 6048734 | Burns et al. | Apr 2000 | A |
| 6054034 | Soane et al. | Apr 2000 | A |
| 6054277 | Furcht et al. | Apr 2000 | A |
| 6056860 | Amigo et al. | May 2000 | A |
| 6057149 | Burns et al. | May 2000 | A |
| 6062261 | Jacobson et al. | May 2000 | A |
| 6063341 | Fassbind et al. | May 2000 | A |
| 6063589 | Kellogg et al. | May 2000 | A |
| 6068751 | Neukermans | May 2000 | A |
| 6068752 | Dubrow et al. | May 2000 | A |
| 6071478 | Chow | Jun 2000 | A |
| 6074725 | Kennedy | Jun 2000 | A |
| 6074827 | Nelson et al. | Jun 2000 | A |
| D428497 | Lapeus et al. | Jul 2000 | S |
| 6086740 | Kennedy | Jul 2000 | A |
| 6096509 | Okun et al. | Aug 2000 | A |
| 6100541 | Nagle et al. | Aug 2000 | A |
| 6102897 | Lang | Aug 2000 | A |
| 6103537 | Ullman et al. | Aug 2000 | A |
| 6106685 | McBride et al. | Aug 2000 | A |
| 6110343 | Ramsey et al. | Aug 2000 | A |
| 6117398 | Bienhaus et al. | Sep 2000 | A |
| 6123205 | Dumitrescu et al. | Sep 2000 | A |
| 6123798 | Gandhi et al. | Sep 2000 | A |
| 6130098 | Handique et al. | Oct 2000 | A |
| 6132580 | Mathies et al. | Oct 2000 | A |
| 6132684 | Marino | Oct 2000 | A |
| 6133436 | Koster et al. | Oct 2000 | A |
| D433759 | Mathis et al. | Nov 2000 | S |
| 6143250 | Tajima | Nov 2000 | A |
| 6143547 | Hsu | Nov 2000 | A |
| 6149787 | Chow et al. | Nov 2000 | A |
| 6149872 | Mack et al. | Nov 2000 | A |
| 6156199 | Zuk | Dec 2000 | A |
| 6158269 | Dorenkott et al. | Dec 2000 | A |
| 6167910 | Chow | Jan 2001 | B1 |
| 6168948 | Anderson et al. | Jan 2001 | B1 |
| 6171850 | Nagle et al. | Jan 2001 | B1 |
| 6174675 | Chow et al. | Jan 2001 | B1 |
| 6180950 | Olsen | Jan 2001 | B1 |
| D438311 | Yamanishi et al. | Feb 2001 | S |
| 6190619 | Kilcoin et al. | Feb 2001 | B1 |
| 6194563 | Cruickshank | Feb 2001 | B1 |
| D438632 | Miller | Mar 2001 | S |
| D438633 | Miller | Mar 2001 | S |
| D439673 | Brophy et al. | Mar 2001 | S |
| 6197595 | Anderson et al. | Mar 2001 | B1 |
| 6203759 | Pelc | Mar 2001 | B1 |
| 6211989 | Wulf et al. | Apr 2001 | B1 |
| 6213151 | Jacobson et al. | Apr 2001 | B1 |
| 6221600 | MacLeod et al. | Apr 2001 | B1 |
| 6228635 | Armstrong et al. | May 2001 | B1 |
| 6232072 | Fisher | May 2001 | B1 |
| 6235175 | Dubrow et al. | May 2001 | B1 |
| 6235313 | Mathiowitz et al. | May 2001 | B1 |
| 6235471 | Knapp et al. | May 2001 | B1 |
| 6236456 | Giebeler et al. | May 2001 | B1 |
| 6236581 | Foss et al. | May 2001 | B1 |
| 6238626 | Higuchi et al. | May 2001 | B1 |
| 6251343 | Dubrow et al. | Jun 2001 | B1 |
| 6254826 | Acosta et al. | Jul 2001 | B1 |
| 6259635 | Khouri et al. | Jul 2001 | B1 |
| 6261431 | Mathies et al. | Jul 2001 | B1 |
| 6267858 | Parce et al. | Jul 2001 | B1 |
| D446306 | Ochi et al. | Aug 2001 | S |
| 6271021 | Burns et al. | Aug 2001 | B1 |
| 6274089 | Chow et al. | Aug 2001 | B1 |
| 6280967 | Ransom et al. | Aug 2001 | B1 |
| 6281008 | Komai et al. | Aug 2001 | B1 |
| 6284113 | Bjornson et al. | Sep 2001 | B1 |
| 6284470 | Bitner et al. | Sep 2001 | B1 |
| 6287254 | Dodds | Sep 2001 | B1 |
| 6287774 | Nikiforov | Sep 2001 | B1 |
| 6291248 | Haj-Ahmad | Sep 2001 | B1 |
| 6294063 | Becker et al. | Sep 2001 | B1 |
| 6300124 | Blumenfeld et al. | Oct 2001 | B1 |
| 6302134 | Kellogg et al. | Oct 2001 | B1 |
| 6302304 | Spencer | Oct 2001 | B1 |
| 6303343 | Kopf-Sill | Oct 2001 | B1 |
| 6306273 | Wainright et al. | Oct 2001 | B1 |
| 6306590 | Mehta et al. | Oct 2001 | B1 |
| 6310199 | Smith et al. | Oct 2001 | B1 |
| 6316774 | Giebeler et al. | Nov 2001 | B1 |
| 6319469 | Mian et al. | Nov 2001 | B1 |
| 6319474 | Krulevitch et al. | Nov 2001 | B1 |
| 6322683 | Wolk et al. | Nov 2001 | B1 |
| 6326083 | Yang et al. | Dec 2001 | B1 |
| 6326147 | Oldham et al. | Dec 2001 | B1 |
| 6326211 | Anderson et al. | Dec 2001 | B1 |
| 6334980 | Hayes et al. | Jan 2002 | B1 |
| 6337435 | Chu et al. | Jan 2002 | B1 |
| 6353475 | Jensen et al. | Mar 2002 | B1 |
| 6358387 | Kopf-Sill et al. | Mar 2002 | B1 |
| 6366924 | Parce | Apr 2002 | B1 |
| 6368561 | Rutishauser et al. | Apr 2002 | B1 |
| 6368871 | Christel et al. | Apr 2002 | B1 |
| 6370206 | Schenk | Apr 2002 | B1 |
| 6375185 | Lin | Apr 2002 | B1 |
| 6375901 | Robotti et al. | Apr 2002 | B1 |
| 6379884 | Wada et al. | Apr 2002 | B2 |
| 6379929 | Burns et al. | Apr 2002 | B1 |
| 6379974 | Parce et al. | Apr 2002 | B1 |
| 6382254 | Yang et al. | May 2002 | B1 |
| 6391541 | Petersen et al. | May 2002 | B1 |
| 6391623 | Besemer et al. | May 2002 | B1 |
| 6395161 | Schneider et al. | May 2002 | B1 |
| 6398956 | Coville et al. | Jun 2002 | B1 |
| 6399025 | Chow | Jun 2002 | B1 |
| 6399389 | Parce et al. | Jun 2002 | B1 |
| 6399952 | Maher et al. | Jun 2002 | B1 |
| 6401552 | Elkins | Jun 2002 | B1 |
| 6403338 | Knapp et al. | Jun 2002 | B1 |
| 6408878 | Unger et al. | Jun 2002 | B2 |
| 6413401 | Chow et al. | Jul 2002 | B1 |
| 6416642 | Alajoki et al. | Jul 2002 | B1 |
| 6420143 | Kopf-Sill | Jul 2002 | B1 |
| 6425972 | McReynolds | Jul 2002 | B1 |
| D461906 | Pham | Aug 2002 | S |
| 6428987 | Franzen | Aug 2002 | B2 |
| 6430512 | Gallagher | Aug 2002 | B1 |
| 6432366 | Ruediger et al. | Aug 2002 | B2 |
| 6440725 | Pourahmadi et al. | Aug 2002 | B1 |
| D463031 | Slomski et al. | Sep 2002 | S |
| 6444461 | Knapp et al. | Sep 2002 | B1 |
| 6447661 | Chow et al. | Sep 2002 | B1 |
| 6447727 | Parce et al. | Sep 2002 | B1 |
| 6448047 | Dattagupta et al. | Sep 2002 | B2 |
| 6448064 | Vo-Dinh et al. | Sep 2002 | B1 |
| 6453928 | Kaplan et al. | Sep 2002 | B1 |
| 6458259 | Parce et al. | Oct 2002 | B1 |
| 6461570 | Ishihara et al. | Oct 2002 | B2 |
| 6465257 | Parce et al. | Oct 2002 | B1 |
| 6468761 | Yang et al. | Oct 2002 | B2 |
| 6472141 | Nikiforov | Oct 2002 | B2 |
| D466219 | Wynschenk et al. | Nov 2002 | S |
| 6475364 | Dubrow et al. | Nov 2002 | B1 |
| D467348 | McMichael et al. | Dec 2002 | S |
| D467349 | Niedbala et al. | Dec 2002 | S |
| 6488897 | Dubrow et al. | Dec 2002 | B2 |
| 6495104 | Unno et al. | Dec 2002 | B1 |
| 6498497 | Chow et al. | Dec 2002 | B1 |
| 6500323 | Chow et al. | Dec 2002 | B1 |
| 6500390 | Boulton et al. | Dec 2002 | B1 |
| D468437 | McMenamy et al. | Jan 2003 | S |
| 6506609 | Wada et al. | Jan 2003 | B1 |
| 6509186 | Zou et al. | Jan 2003 | B1 |
| 6509193 | Tajima | Jan 2003 | B1 |
| 6511853 | Kopf-Sill et al. | Jan 2003 | B1 |
| D470595 | Crisanti et al. | Feb 2003 | S |
| 6515753 | Maher | Feb 2003 | B2 |
| 6517783 | Horner et al. | Feb 2003 | B2 |
| 6520197 | Deshmukh et al. | Feb 2003 | B2 |
| 6521181 | Northrup et al. | Feb 2003 | B1 |
| 6521188 | Webster | Feb 2003 | B1 |
| 6524456 | Ramsey et al. | Feb 2003 | B1 |
| 6524532 | Northrup | Feb 2003 | B1 |
| 6524790 | Kopf-Sill et al. | Feb 2003 | B1 |
| D472324 | Rumore et al. | Mar 2003 | S |
| 6534295 | Tai et al. | Mar 2003 | B2 |
| 6537432 | Schneider et al. | Mar 2003 | B1 |
| 6537771 | Farinas et al. | Mar 2003 | B1 |
| 6540896 | Manz et al. | Apr 2003 | B1 |
| 6544734 | Briscoe et al. | Apr 2003 | B1 |
| 6547942 | Parce et al. | Apr 2003 | B1 |
| 6555389 | Ullman et al. | Apr 2003 | B1 |
| 6556923 | Gallagher et al. | Apr 2003 | B2 |
| D474279 | Mayer et al. | May 2003 | S |
| D474280 | Niedbala et al. | May 2003 | S |
| 6558916 | Veerapandian et al. | May 2003 | B2 |
| 6558945 | Kao | May 2003 | B1 |
| 6565815 | Chang et al. | May 2003 | B1 |
| 6569607 | McReynolds | May 2003 | B2 |
| 6572830 | Burdon et al. | Jun 2003 | B1 |
| 6575188 | Parunak | Jun 2003 | B2 |
| 6576459 | Miles et al. | Jun 2003 | B2 |
| 6579453 | Bächler et al. | Jun 2003 | B1 |
| 6589729 | Chan et al. | Jul 2003 | B2 |
| 6592821 | Wada et al. | Jul 2003 | B1 |
| 6597450 | Andrews et al. | Jul 2003 | B1 |
| 6602474 | Tajima | Aug 2003 | B1 |
| 6605475 | Taylor et al. | Aug 2003 | B1 |
| 6613211 | Mccormick et al. | Sep 2003 | B1 |
| 6613512 | Kopf-Sill et al. | Sep 2003 | B1 |
| 6613580 | Chow et al. | Sep 2003 | B1 |
| 6613581 | Wada et al. | Sep 2003 | B1 |
| 6614030 | Maher et al. | Sep 2003 | B2 |
| 6620625 | Wolk et al. | Sep 2003 | B2 |
| 6623860 | Hu et al. | Sep 2003 | B2 |
| 6627406 | Singh et al. | Sep 2003 | B1 |
| D480814 | Lafferty et al. | Oct 2003 | S |
| 6632655 | Mehta et al. | Oct 2003 | B1 |
| 6633785 | Kasahara et al. | Oct 2003 | B1 |
| D482796 | Oyama et al. | Nov 2003 | S |
| 6640981 | Lafond et al. | Nov 2003 | B2 |
| 6649358 | Parce et al. | Nov 2003 | B1 |
| 6664104 | Pourahmadi et al. | Dec 2003 | B2 |
| 6669831 | Chow et al. | Dec 2003 | B2 |
| 6670133 | Knapp et al. | Dec 2003 | B2 |
| 6670153 | Stern | Dec 2003 | B2 |
| D484989 | Gebrian | Jan 2004 | S |
| 6672458 | Hansen et al. | Jan 2004 | B2 |
| 6681616 | Spaid et al. | Jan 2004 | B2 |
| 6681788 | Parce et al. | Jan 2004 | B2 |
| 6685813 | Williams et al. | Feb 2004 | B2 |
| 6692700 | Handique | Feb 2004 | B2 |
| 6695009 | Chien et al. | Feb 2004 | B2 |
| 6699713 | Benett et al. | Mar 2004 | B2 |
| 6706519 | Kellogg et al. | Mar 2004 | B1 |
| 6720148 | Nikiforov | Apr 2004 | B1 |
| 6730206 | Ricco et al. | May 2004 | B2 |
| 6733645 | Chow | May 2004 | B1 |
| 6734401 | Bedingham et al. | May 2004 | B2 |
| 6737026 | Bergh et al. | May 2004 | B1 |
| 6740518 | Duong et al. | May 2004 | B1 |
| D491272 | Alden et al. | Jun 2004 | S |
| D491273 | Biegler et al. | Jun 2004 | S |
| D491276 | Langille | Jun 2004 | S |
| 6750661 | Brooks et al. | Jun 2004 | B2 |
| 6752966 | Chazan | Jun 2004 | B1 |
| 6756019 | Dubrow et al. | Jun 2004 | B1 |
| 6762049 | Zou et al. | Jul 2004 | B2 |
| 6764859 | Kreuwel et al. | Jul 2004 | B1 |
| 6766817 | Dias da Silva | Jul 2004 | B2 |
| 6773567 | Wolk | Aug 2004 | B1 |
| 6777184 | Nikiforov et al. | Aug 2004 | B2 |
| 6783962 | Olander et al. | Aug 2004 | B1 |
| D495805 | Lea et al. | Sep 2004 | S |
| 6787015 | Lackritz et al. | Sep 2004 | B2 |
| 6787016 | Tan et al. | Sep 2004 | B2 |
| 6787111 | Roach et al. | Sep 2004 | B2 |
| 6790328 | Jacobson et al. | Sep 2004 | B2 |
| 6790330 | Gascoyne et al. | Sep 2004 | B2 |
| 6811668 | Berndt et al. | Nov 2004 | B1 |
| 6818113 | Williams et al. | Nov 2004 | B2 |
| 6819027 | Saraf | Nov 2004 | B2 |
| 6824663 | Boone | Nov 2004 | B1 |
| D499813 | Wu | Dec 2004 | S |
| D500142 | Crisanti et al. | Dec 2004 | S |
| D500363 | Fanning et al. | Dec 2004 | S |
| 6827831 | Chow et al. | Dec 2004 | B1 |
| 6827906 | Bjornson et al. | Dec 2004 | B1 |
| 6838156 | Neyer et al. | Jan 2005 | B1 |
| 6838680 | Maher et al. | Jan 2005 | B2 |
| 6852287 | Ganesan | Feb 2005 | B2 |
| 6858185 | Kopf-Sill et al. | Feb 2005 | B1 |
| 6859698 | Schmeisser | Feb 2005 | B2 |
| 6861035 | Pham et al. | Mar 2005 | B2 |
| 6878540 | Pourahmadi et al. | Apr 2005 | B2 |
| 6878755 | Singh et al. | Apr 2005 | B2 |
| 6884628 | Hubbell et al. | Apr 2005 | B2 |
| 6887693 | McMillan et al. | May 2005 | B2 |
| 6893879 | Petersen et al. | May 2005 | B2 |
| 6900889 | Bjornson et al. | May 2005 | B2 |
| 6905583 | Wainright et al. | Jun 2005 | B2 |
| 6905612 | Dorian et al. | Jun 2005 | B2 |
| 6906797 | Kao et al. | Jun 2005 | B1 |
| 6908594 | Schaevitz et al. | Jun 2005 | B1 |
| 6911183 | Handique et al. | Jun 2005 | B1 |
| 6914137 | Baker | Jul 2005 | B2 |
| 6915679 | Chien et al. | Jul 2005 | B2 |
| 6918404 | Dias da Silva | Jul 2005 | B2 |
| D508999 | Fanning et al. | Aug 2005 | S |
| 6939451 | Zhao et al. | Sep 2005 | B2 |
| 6940598 | Christel et al. | Sep 2005 | B2 |
| 6942771 | Kayyem | Sep 2005 | B1 |
| 6951632 | Unger et al. | Oct 2005 | B2 |
| 6958392 | Fomovskaia et al. | Oct 2005 | B2 |
| D512155 | Matsumoto | Nov 2005 | S |
| 6964747 | Banerjee et al. | Nov 2005 | B2 |
| 6977163 | Mehta | Dec 2005 | B1 |
| 6979424 | Northrup et al. | Dec 2005 | B2 |
| 6984516 | Briscoe et al. | Jan 2006 | B2 |
| D515707 | Sinohara et al. | Feb 2006 | S |
| D516221 | Wohlstadter et al. | Feb 2006 | S |
| 7001853 | Brown et al. | Feb 2006 | B1 |
| 7004184 | Handique et al. | Feb 2006 | B2 |
| D517554 | Yanagisawa et al. | Mar 2006 | S |
| 7010391 | Handique et al. | Mar 2006 | B2 |
| 7023007 | Gallagher | Apr 2006 | B2 |
| 7024281 | Unno | Apr 2006 | B1 |
| 7036667 | Greenstein et al. | May 2006 | B2 |
| 7037416 | Parce et al. | May 2006 | B2 |
| 7038472 | Chien | May 2006 | B1 |
| 7039527 | Tripathi et al. | May 2006 | B2 |
| 7040144 | Spaid et al. | May 2006 | B2 |
| 7041258 | Desmond et al. | May 2006 | B2 |
| 7049558 | Baer et al. | May 2006 | B2 |
| D523153 | Akashi et al. | Jun 2006 | S |
| 7055695 | Greenstein et al. | Jun 2006 | B2 |
| 7060171 | Nikiforov et al. | Jun 2006 | B1 |
| 7066586 | da Silva | Jun 2006 | B2 |
| 7069952 | McReynolds et al. | Jul 2006 | B1 |
| 7072036 | Jones et al. | Jul 2006 | B2 |
| 7099778 | Chien | Aug 2006 | B2 |
| D528215 | Malmsater | Sep 2006 | S |
| 7101467 | Spaid | Sep 2006 | B2 |
| 7105304 | Nikiforov et al. | Sep 2006 | B1 |
| D531321 | Godfrey et al. | Oct 2006 | S |
| 7118892 | Ammann et al. | Oct 2006 | B2 |
| 7118910 | Unger et al. | Oct 2006 | B2 |
| 7122799 | Hsieh et al. | Oct 2006 | B2 |
| 7135144 | Christel et al. | Nov 2006 | B2 |
| 7138032 | Gandhi et al. | Nov 2006 | B2 |
| D534280 | Gomm et al. | Dec 2006 | S |
| 7150814 | Parce et al. | Dec 2006 | B1 |
| 7150999 | Shuck | Dec 2006 | B1 |
| D535403 | Isozaki et al. | Jan 2007 | S |
| 7160423 | Chien et al. | Jan 2007 | B2 |
| 7161356 | Chien | Jan 2007 | B1 |
| 7169277 | Ausserer et al. | Jan 2007 | B2 |
| 7169601 | Northrup et al. | Jan 2007 | B1 |
| 7169618 | Skold | Jan 2007 | B2 |
| D537951 | Okamoto et al. | Mar 2007 | S |
| D538436 | Patadia et al. | Mar 2007 | S |
| 7188001 | Young et al. | Mar 2007 | B2 |
| 7192557 | Wu et al. | Mar 2007 | B2 |
| 7195986 | Bousse et al. | Mar 2007 | B1 |
| 7205154 | Corson | Apr 2007 | B2 |
| 7208125 | Dong | Apr 2007 | B1 |
| 7235406 | Woudenberg et al. | Jun 2007 | B1 |
| 7247274 | Chow | Jul 2007 | B1 |
| D548841 | Brownell et al. | Aug 2007 | S |
| D549827 | Maeno et al. | Aug 2007 | S |
| 7252928 | Hafeman et al. | Aug 2007 | B1 |
| 7255833 | Chang et al. | Aug 2007 | B2 |
| 7270786 | Parunak et al. | Sep 2007 | B2 |
| D554069 | Bolotin et al. | Oct 2007 | S |
| D554070 | Bolotin et al. | Oct 2007 | S |
| 7276208 | Sevigny et al. | Oct 2007 | B2 |
| 7276330 | Chow et al. | Oct 2007 | B2 |
| 7288228 | Lefebvre | Oct 2007 | B2 |
| 7297313 | Northrup et al. | Nov 2007 | B1 |
| D556914 | Okamoto et al. | Dec 2007 | S |
| 7303727 | Dubrow et al. | Dec 2007 | B1 |
| D559995 | Handique et al. | Jan 2008 | S |
| 7315376 | Bickmore et al. | Jan 2008 | B2 |
| 7323140 | Handique et al. | Jan 2008 | B2 |
| 7332130 | Handique | Feb 2008 | B2 |
| 7338760 | Gong et al. | Mar 2008 | B2 |
| D566291 | Parunak et al. | Apr 2008 | S |
| 7351377 | Chazan et al. | Apr 2008 | B2 |
| D569526 | Duffy et al. | May 2008 | S |
| 7374949 | Kuriger | May 2008 | B2 |
| 7390460 | Osawa et al. | Jun 2008 | B2 |
| 7419784 | Dubrow et al. | Sep 2008 | B2 |
| 7422669 | Jacobson et al. | Sep 2008 | B2 |
| 7440684 | Spaid et al. | Oct 2008 | B2 |
| 7476313 | Siddiqi | Jan 2009 | B2 |
| 7480042 | Phillips et al. | Jan 2009 | B1 |
| 7494577 | Williams et al. | Feb 2009 | B2 |
| 7494770 | Wilding et al. | Feb 2009 | B2 |
| 7514046 | Kechagia et al. | Apr 2009 | B2 |
| 7518726 | Rulison et al. | Apr 2009 | B2 |
| 7521186 | Burd Mehta | Apr 2009 | B2 |
| 7527769 | Bunch et al. | May 2009 | B2 |
| D595423 | Johansson et al. | Jun 2009 | S |
| 7553671 | Sinclair et al. | Jun 2009 | B2 |
| D596312 | Giraud et al. | Jul 2009 | S |
| D598566 | Allaer | Aug 2009 | S |
| 7578976 | Northrup et al. | Aug 2009 | B1 |
| D599234 | Ito | Sep 2009 | S |
| 7595197 | Brasseur | Sep 2009 | B2 |
| 7604938 | Takahashi et al. | Oct 2009 | B2 |
| 7622296 | Joseph et al. | Nov 2009 | B2 |
| 7628902 | Knowlton et al. | Dec 2009 | B2 |
| 7633606 | Northrup et al. | Dec 2009 | B2 |
| 7635588 | King et al. | Dec 2009 | B2 |
| 7645581 | Knapp et al. | Jan 2010 | B2 |
| 7670559 | Chien et al. | Mar 2010 | B2 |
| 7674431 | Ganesan | Mar 2010 | B2 |
| 7689022 | Weiner et al. | Mar 2010 | B2 |
| 7704735 | Facer et al. | Apr 2010 | B2 |
| 7705739 | Northrup et al. | Apr 2010 | B2 |
| 7723123 | Murphy et al. | May 2010 | B1 |
| D618820 | Wilson et al. | Jun 2010 | S |
| 7727371 | Kennedy et al. | Jun 2010 | B2 |
| 7727477 | Boronkay et al. | Jun 2010 | B2 |
| 7744817 | Bui | Jun 2010 | B2 |
| D621060 | Handique | Aug 2010 | S |
| 7785868 | Yuan et al. | Aug 2010 | B2 |
| D628305 | Gorrec et al. | Nov 2010 | S |
| 7829025 | Ganesan et al. | Nov 2010 | B2 |
| 7858366 | Northrup et al. | Dec 2010 | B2 |
| 7867776 | Kennedy et al. | Jan 2011 | B2 |
| 7892819 | Wilding et al. | Feb 2011 | B2 |
| D637737 | Wilson et al. | May 2011 | S |
| 7955864 | Cox et al. | Jun 2011 | B2 |
| 7987022 | Handique et al. | Jul 2011 | B2 |
| 7998708 | Handique et al. | Aug 2011 | B2 |
| 8053214 | Northrup | Nov 2011 | B2 |
| 8071056 | Burns et al. | Dec 2011 | B2 |
| 8088616 | Handique | Jan 2012 | B2 |
| 8105783 | Handique | Jan 2012 | B2 |
| 8110158 | Handique | Feb 2012 | B2 |
| 8133671 | Williams et al. | Mar 2012 | B2 |
| 8182763 | Duffy et al. | May 2012 | B2 |
| 8246919 | Herchenbach et al. | Aug 2012 | B2 |
| 8273308 | Handique et al. | Sep 2012 | B2 |
| D669597 | Cavada et al. | Oct 2012 | S |
| 8287820 | Williams et al. | Oct 2012 | B2 |
| 8323584 | Ganesan | Dec 2012 | B2 |
| 8323900 | Handique et al. | Dec 2012 | B2 |
| 8324372 | Brahmasandra et al. | Dec 2012 | B2 |
| 8415103 | Handique | Apr 2013 | B2 |
| 8420015 | Ganesan et al. | Apr 2013 | B2 |
| 8440149 | Handique | May 2013 | B2 |
| 8470586 | Wu et al. | Jun 2013 | B2 |
| 8473104 | Handique et al. | Jun 2013 | B2 |
| D686749 | Trump | Jul 2013 | S |
| D687567 | Jungheim et al. | Aug 2013 | S |
| D692162 | Lentz et al. | Oct 2013 | S |
| 8592157 | Petersen et al. | Nov 2013 | B2 |
| 8679831 | Handique et al. | Mar 2014 | B2 |
| D702854 | Nakahana et al. | Apr 2014 | S |
| 8685341 | Ganesan | Apr 2014 | B2 |
| 8703069 | Handique et al. | Apr 2014 | B2 |
| 8709787 | Handique | Apr 2014 | B2 |
| 8710211 | Brahmasandra et al. | Apr 2014 | B2 |
| 8734733 | Handique | May 2014 | B2 |
| D710024 | Guo | Jul 2014 | S |
| 8765076 | Handique et al. | Jul 2014 | B2 |
| 8765454 | Zhou et al. | Jul 2014 | B2 |
| 8768517 | Handique et al. | Jul 2014 | B2 |
| 8852862 | Wu et al. | Oct 2014 | B2 |
| 8883490 | Handique et al. | Nov 2014 | B2 |
| 8894947 | Ganesan et al. | Nov 2014 | B2 |
| 8895311 | Handique et al. | Nov 2014 | B1 |
| D729404 | Teich et al. | May 2015 | S |
| 9028773 | Ganesan | May 2015 | B2 |
| 9040288 | Handique et al. | May 2015 | B2 |
| 9051604 | Handique | Jun 2015 | B2 |
| 9080207 | Handique et al. | Jul 2015 | B2 |
| D742027 | Lentz et al. | Oct 2015 | S |
| 9186677 | Williams et al. | Nov 2015 | B2 |
| 9217143 | Brahmasandra et al. | Dec 2015 | B2 |
| 9222954 | Lentz et al. | Dec 2015 | B2 |
| 9234236 | Thomas et al. | Jan 2016 | B2 |
| 9238223 | Handique | Jan 2016 | B2 |
| 9259734 | Williams et al. | Feb 2016 | B2 |
| 9259735 | Handique et al. | Feb 2016 | B2 |
| 9347586 | Williams et al. | May 2016 | B2 |
| 9480983 | Lentz et al. | Nov 2016 | B2 |
| 9528142 | Handique | Dec 2016 | B2 |
| 9618139 | Handique | Apr 2017 | B2 |
| D787087 | Duffy et al. | Jun 2017 | S |
| 9670528 | Handique et al. | Jun 2017 | B2 |
| 9677121 | Ganesan et al. | Jun 2017 | B2 |
| 9701957 | Wilson et al. | Jul 2017 | B2 |
| 9745623 | Steel | Aug 2017 | B2 |
| 9765389 | Gubatayao et al. | Sep 2017 | B2 |
| 9789481 | Petersen et al. | Oct 2017 | B2 |
| 9802199 | Handique et al. | Oct 2017 | B2 |
| 9815057 | Handique | Nov 2017 | B2 |
| 9958466 | Dalbert et al. | May 2018 | B2 |
| 10065185 | Handique | Sep 2018 | B2 |
| 10071376 | Williams et al. | Sep 2018 | B2 |
| 10076754 | Lentz et al. | Sep 2018 | B2 |
| 10100302 | Brahmasandra et al. | Oct 2018 | B2 |
| 10139012 | Handique | Nov 2018 | B2 |
| 10179910 | Duffy et al. | Jan 2019 | B2 |
| 10234474 | Williams et al. | Mar 2019 | B2 |
| 10351901 | Ganesan et al. | Jul 2019 | B2 |
| 10443088 | Wu et al. | Oct 2019 | B1 |
| 10494663 | Wu et al. | Dec 2019 | B1 |
| 10571935 | Handique et al. | Feb 2020 | B2 |
| 10590410 | Brahmasandra et al. | Mar 2020 | B2 |
| 10604788 | Wu et al. | Mar 2020 | B2 |
| 10619191 | Ganesan et al. | Apr 2020 | B2 |
| 10625261 | Williams et al. | Apr 2020 | B2 |
| 10625262 | Williams et al. | Apr 2020 | B2 |
| 10632466 | Williams et al. | Apr 2020 | B1 |
| 10695764 | Handique et al. | Jun 2020 | B2 |
| 10710069 | Handique et al. | Jul 2020 | B2 |
| 10717085 | Williams et al. | Jul 2020 | B2 |
| 10731201 | Handique et al. | Aug 2020 | B2 |
| 10781482 | Gubatayao et al. | Sep 2020 | B2 |
| 10799862 | Handique et al. | Oct 2020 | B2 |
| 10821436 | Handique et al. | Nov 2020 | B2 |
| 10821446 | Handique et al. | Nov 2020 | B1 |
| 10822644 | Steel et al. | Nov 2020 | B2 |
| 10843188 | Handique et al. | Nov 2020 | B2 |
| 10844368 | Duffy et al. | Nov 2020 | B2 |
| 10857535 | Handique et al. | Dec 2020 | B2 |
| 10865437 | Handique et al. | Dec 2020 | B2 |
| 10875022 | Williams et al. | Dec 2020 | B2 |
| 10900066 | Handique et al. | Jan 2021 | B2 |
| 10913061 | Handique et al. | Feb 2021 | B2 |
| 11060082 | Brahmasandra et al. | Jul 2021 | B2 |
| 11078523 | Handique et al. | Aug 2021 | B2 |
| 11085069 | Handique et al. | Aug 2021 | B2 |
| 11141734 | Handique et al. | Oct 2021 | B2 |
| 11142785 | Handique et al. | Oct 2021 | B2 |
| 11254927 | Brahmasandra et al. | Feb 2022 | B2 |
| 11266987 | Handique | Mar 2022 | B2 |
| 20010005489 | Roach et al. | Jun 2001 | A1 |
| 20010012492 | Acosta et al. | Aug 2001 | A1 |
| 20010016358 | Osawa et al. | Aug 2001 | A1 |
| 20010018513 | Baker | Aug 2001 | A1 |
| 20010021355 | Baugh et al. | Sep 2001 | A1 |
| 20010023848 | Gjerde et al. | Sep 2001 | A1 |
| 20010038450 | McCaffrey et al. | Nov 2001 | A1 |
| 20010045358 | Kopf-Sill et al. | Nov 2001 | A1 |
| 20010046702 | Schembri | Nov 2001 | A1 |
| 20010048899 | Marouiss et al. | Dec 2001 | A1 |
| 20010051340 | Singh et al. | Dec 2001 | A1 |
| 20010055765 | O'Keefe et al. | Dec 2001 | A1 |
| 20020001848 | Bedingham et al. | Jan 2002 | A1 |
| 20020008053 | Hansen et al. | Jan 2002 | A1 |
| 20020009015 | Laugharn, Jr. et al. | Jan 2002 | A1 |
| 20020014443 | Hansen et al. | Feb 2002 | A1 |
| 20020015667 | Chow | Feb 2002 | A1 |
| 20020021983 | Comte et al. | Feb 2002 | A1 |
| 20020022261 | Anderson et al. | Feb 2002 | A1 |
| 20020037499 | Quake et al. | Mar 2002 | A1 |
| 20020039783 | McMillan et al. | Apr 2002 | A1 |
| 20020047003 | Bedingham et al. | Apr 2002 | A1 |
| 20020053399 | Soane et al. | May 2002 | A1 |
| 20020054835 | Robotti et al. | May 2002 | A1 |
| 20020055167 | Pourahmadi et al. | May 2002 | A1 |
| 20020058332 | Quake et al. | May 2002 | A1 |
| 20020060156 | Mathies et al. | May 2002 | A1 |
| 20020068357 | Mathies et al. | Jun 2002 | A1 |
| 20020068821 | Gundling | Jun 2002 | A1 |
| 20020086443 | Bamdad | Jul 2002 | A1 |
| 20020090320 | Burow et al. | Jul 2002 | A1 |
| 20020092767 | Bjornson et al. | Jul 2002 | A1 |
| 20020094303 | Yamamoto et al. | Jul 2002 | A1 |
| 20020131903 | Ingenhoven et al. | Sep 2002 | A1 |
| 20020141903 | Parunak et al. | Oct 2002 | A1 |
| 20020143297 | Francavilla et al. | Oct 2002 | A1 |
| 20020155010 | Karp et al. | Oct 2002 | A1 |
| 20020155477 | Ito | Oct 2002 | A1 |
| 20020169518 | Luoma et al. | Nov 2002 | A1 |
| 20020173032 | Zou et al. | Nov 2002 | A1 |
| 20020176804 | Strand et al. | Nov 2002 | A1 |
| 20020187557 | Hobbs et al. | Dec 2002 | A1 |
| 20020192808 | Gambini et al. | Dec 2002 | A1 |
| 20030008308 | Enzelberger et al. | Jan 2003 | A1 |
| 20030008320 | Baker | Jan 2003 | A1 |
| 20030019522 | Parunak | Jan 2003 | A1 |
| 20030022392 | Hudak | Jan 2003 | A1 |
| 20030036067 | Schwartz | Feb 2003 | A1 |
| 20030049833 | Chen et al. | Mar 2003 | A1 |
| 20030059823 | Matsunaga et al. | Mar 2003 | A1 |
| 20030064507 | Gallagher et al. | Apr 2003 | A1 |
| 20030072683 | Stewart et al. | Apr 2003 | A1 |
| 20030073106 | Johansen et al. | Apr 2003 | A1 |
| 20030073110 | Aritomi et al. | Apr 2003 | A1 |
| 20030083686 | Freeman et al. | May 2003 | A1 |
| 20030087300 | Knapp et al. | May 2003 | A1 |
| 20030088657 | Eggers | May 2003 | A1 |
| 20030096310 | Hansen et al. | May 2003 | A1 |
| 20030099954 | Miltenyi et al. | May 2003 | A1 |
| 20030124611 | Schwartz | Jul 2003 | A1 |
| 20030127327 | Kurnik | Jul 2003 | A1 |
| 20030134333 | Dehlinger et al. | Jul 2003 | A1 |
| 20030136679 | Bohn et al. | Jul 2003 | A1 |
| 20030156991 | Halas et al. | Aug 2003 | A1 |
| 20030180192 | Seippel | Sep 2003 | A1 |
| 20030186295 | Colin et al. | Oct 2003 | A1 |
| 20030190608 | Blackburn et al. | Oct 2003 | A1 |
| 20030199081 | Wilding et al. | Oct 2003 | A1 |
| 20030211517 | Carulli et al. | Nov 2003 | A1 |
| 20040014202 | King et al. | Jan 2004 | A1 |
| 20040014238 | Krug et al. | Jan 2004 | A1 |
| 20040018116 | Desmond et al. | Jan 2004 | A1 |
| 20040018119 | Massaro | Jan 2004 | A1 |
| 20040022689 | Wulf et al. | Feb 2004 | A1 |
| 20040029258 | Heaney et al. | Feb 2004 | A1 |
| 20040029260 | Hansen et al. | Feb 2004 | A1 |
| 20040037739 | McNeely et al. | Feb 2004 | A1 |
| 20040043479 | Briscoe et al. | Mar 2004 | A1 |
| 20040053290 | Terbrueggen et al. | Mar 2004 | A1 |
| 20040063217 | Webster et al. | Apr 2004 | A1 |
| 20040065655 | Brown | Apr 2004 | A1 |
| 20040072278 | Chou et al. | Apr 2004 | A1 |
| 20040072375 | Gjerde et al. | Apr 2004 | A1 |
| 20040076996 | Kondo et al. | Apr 2004 | A1 |
| 20040086427 | Childers et al. | May 2004 | A1 |
| 20040086956 | Bachur | May 2004 | A1 |
| 20040132059 | Scurati et al. | Jul 2004 | A1 |
| 20040141887 | Mainquist et al. | Jul 2004 | A1 |
| 20040151629 | Pease et al. | Aug 2004 | A1 |
| 20040157220 | Kurnool et al. | Aug 2004 | A1 |
| 20040161788 | Chen et al. | Aug 2004 | A1 |
| 20040171515 | Hamers et al. | Sep 2004 | A1 |
| 20040189311 | Glezer et al. | Sep 2004 | A1 |
| 20040197810 | Takenaka et al. | Oct 2004 | A1 |
| 20040200909 | McMillan et al. | Oct 2004 | A1 |
| 20040209331 | Ririe | Oct 2004 | A1 |
| 20040209354 | Mathies et al. | Oct 2004 | A1 |
| 20040224317 | Kordunsky et al. | Nov 2004 | A1 |
| 20040235154 | Oh et al. | Nov 2004 | A1 |
| 20040240097 | Evans | Dec 2004 | A1 |
| 20050009174 | Nikiforov et al. | Jan 2005 | A1 |
| 20050013737 | Chow et al. | Jan 2005 | A1 |
| 20050019902 | Mathies et al. | Jan 2005 | A1 |
| 20050037471 | Liu et al. | Feb 2005 | A1 |
| 20050041525 | Pugia et al. | Feb 2005 | A1 |
| 20050042639 | Knapp et al. | Feb 2005 | A1 |
| 20050048540 | Inami et al. | Mar 2005 | A1 |
| 20050058574 | Bysouth et al. | Mar 2005 | A1 |
| 20050058577 | Micklash et al. | Mar 2005 | A1 |
| 20050064535 | Favuzzi et al. | Mar 2005 | A1 |
| 20050069898 | Moon et al. | Mar 2005 | A1 |
| 20050084424 | Ganesan et al. | Apr 2005 | A1 |
| 20050106066 | Saltsman et al. | May 2005 | A1 |
| 20050112754 | Yoon et al. | May 2005 | A1 |
| 20050121324 | Park et al. | Jun 2005 | A1 |
| 20050129580 | Swinehart et al. | Jun 2005 | A1 |
| 20050130198 | Ammann et al. | Jun 2005 | A1 |
| 20050133370 | Park et al. | Jun 2005 | A1 |
| 20050135655 | Kopf-Sill et al. | Jun 2005 | A1 |
| 20050142036 | Kim et al. | Jun 2005 | A1 |
| 20050158781 | Woudenberg et al. | Jul 2005 | A1 |
| 20050170362 | Wada et al. | Aug 2005 | A1 |
| 20050186585 | Juncosa et al. | Aug 2005 | A1 |
| 20050196321 | Huang | Sep 2005 | A1 |
| 20050202470 | Sundberg et al. | Sep 2005 | A1 |
| 20050202489 | Cho et al. | Sep 2005 | A1 |
| 20050202504 | Anderson et al. | Sep 2005 | A1 |
| 20050205788 | Itoh | Sep 2005 | A1 |
| 20050208676 | Kahatt | Sep 2005 | A1 |
| 20050214172 | Burgisser | Sep 2005 | A1 |
| 20050220675 | Reed et al. | Oct 2005 | A1 |
| 20050227269 | Lloyd et al. | Oct 2005 | A1 |
| 20050233370 | Ammann et al. | Oct 2005 | A1 |
| 20050238545 | Parce et al. | Oct 2005 | A1 |
| 20050239127 | Ammann et al. | Oct 2005 | A1 |
| 20050266489 | Ammann et al. | Dec 2005 | A1 |
| 20050276728 | Muller-Cohn et al. | Dec 2005 | A1 |
| 20060002817 | Bohm et al. | Jan 2006 | A1 |
| 20060003373 | Ammann et al. | Jan 2006 | A1 |
| 20060041058 | Yin et al. | Feb 2006 | A1 |
| 20060057039 | Morse et al. | Mar 2006 | A1 |
| 20060057629 | Kim | Mar 2006 | A1 |
| 20060058519 | Deggerdal et al. | Mar 2006 | A1 |
| 20060062696 | Chow et al. | Mar 2006 | A1 |
| 20060081539 | Safar et al. | Apr 2006 | A1 |
| 20060094004 | Nakajima et al. | May 2006 | A1 |
| 20060094108 | Yoder et al. | May 2006 | A1 |
| 20060113190 | Kurnik | Jun 2006 | A1 |
| 20060133965 | Tajima et al. | Jun 2006 | A1 |
| 20060134790 | Tanaka et al. | Jun 2006 | A1 |
| 20060148063 | Fauzzi et al. | Jul 2006 | A1 |
| 20060154341 | Chen | Jul 2006 | A1 |
| 20060165558 | Witty et al. | Jul 2006 | A1 |
| 20060165559 | Greenstein et al. | Jul 2006 | A1 |
| 20060177376 | Tomalia et al. | Aug 2006 | A1 |
| 20060177855 | Utermohlen et al. | Aug 2006 | A1 |
| 20060183216 | Handique | Aug 2006 | A1 |
| 20060201887 | Siddiqi | Sep 2006 | A1 |
| 20060205085 | Handique | Sep 2006 | A1 |
| 20060207944 | Siddiqi | Sep 2006 | A1 |
| 20060210435 | Alavie et al. | Sep 2006 | A1 |
| 20060223169 | Bedingham et al. | Oct 2006 | A1 |
| 20060228734 | Vann et al. | Oct 2006 | A1 |
| 20060246493 | Jensen et al. | Nov 2006 | A1 |
| 20060246533 | Fathollahi et al. | Nov 2006 | A1 |
| 20060269641 | Atwood et al. | Nov 2006 | A1 |
| 20060269961 | Fukushima et al. | Nov 2006 | A1 |
| 20070004028 | Lair et al. | Jan 2007 | A1 |
| 20070009386 | Padmanabhan et al. | Jan 2007 | A1 |
| 20070020699 | Carpenter et al. | Jan 2007 | A1 |
| 20070020764 | Miller | Jan 2007 | A1 |
| 20070026421 | Sundberg et al. | Feb 2007 | A1 |
| 20070042441 | Masters et al. | Feb 2007 | A1 |
| 20070048188 | Bigus | Mar 2007 | A1 |
| 20070054413 | Aviles et al. | Mar 2007 | A1 |
| 20070077643 | Nakamura et al. | Apr 2007 | A1 |
| 20070077648 | Okamoto et al. | Apr 2007 | A1 |
| 20070092901 | Ligler et al. | Apr 2007 | A1 |
| 20070098600 | Kayyem et al. | May 2007 | A1 |
| 20070099200 | Chow et al. | May 2007 | A1 |
| 20070104617 | Coulling et al. | May 2007 | A1 |
| 20070116613 | Elsener | May 2007 | A1 |
| 20070154895 | Spaid et al. | Jul 2007 | A1 |
| 20070177147 | Parce | Aug 2007 | A1 |
| 20070178603 | Takii et al. | Aug 2007 | A1 |
| 20070178607 | Prober et al. | Aug 2007 | A1 |
| 20070184463 | Molho et al. | Aug 2007 | A1 |
| 20070184547 | Handique et al. | Aug 2007 | A1 |
| 20070196237 | Neuzil et al. | Aug 2007 | A1 |
| 20070196238 | Kennedy et al. | Aug 2007 | A1 |
| 20070199821 | Chow | Aug 2007 | A1 |
| 20070215554 | Kreuwel et al. | Sep 2007 | A1 |
| 20070218459 | Miller et al. | Sep 2007 | A1 |
| 20070231213 | Prabhu et al. | Oct 2007 | A1 |
| 20070243626 | Windeyer et al. | Oct 2007 | A1 |
| 20070248958 | Jovanovich et al. | Oct 2007 | A1 |
| 20070261479 | Spaid et al. | Nov 2007 | A1 |
| 20070269861 | Williams et al. | Nov 2007 | A1 |
| 20070292941 | Handique et al. | Dec 2007 | A1 |
| 20080000774 | Park et al. | Jan 2008 | A1 |
| 20080003649 | Maltezos et al. | Jan 2008 | A1 |
| 20080017306 | Liu et al. | Jan 2008 | A1 |
| 20080056948 | Dale et al. | Mar 2008 | A1 |
| 20080069729 | McNeely | Mar 2008 | A1 |
| 20080090244 | Knapp et al. | Apr 2008 | A1 |
| 20080095673 | Xu | Apr 2008 | A1 |
| 20080118987 | Eastwood et al. | May 2008 | A1 |
| 20080124723 | Dale et al. | May 2008 | A1 |
| 20080176230 | Owen et al. | Jul 2008 | A1 |
| 20080192254 | Kim et al. | Aug 2008 | A1 |
| 20080226502 | Jonsmann et al. | Sep 2008 | A1 |
| 20080240898 | Manz et al. | Oct 2008 | A1 |
| 20080247914 | Edens et al. | Oct 2008 | A1 |
| 20080257882 | Turner | Oct 2008 | A1 |
| 20080280285 | Chen et al. | Nov 2008 | A1 |
| 20080308500 | Brassard | Dec 2008 | A1 |
| 20090047180 | Kawahara | Feb 2009 | A1 |
| 20090066339 | Glezer et al. | Mar 2009 | A1 |
| 20090136385 | Handique et al. | May 2009 | A1 |
| 20090148933 | Battrell et al. | Jun 2009 | A1 |
| 20090189089 | Bedingham et al. | Jul 2009 | A1 |
| 20090223925 | Morse et al. | Sep 2009 | A1 |
| 20090325164 | Vossenaar et al. | Dec 2009 | A1 |
| 20090325276 | Battrell et al. | Dec 2009 | A1 |
| 20100009343 | Fischer et al. | Jan 2010 | A1 |
| 20100009351 | Brahmasandra et al. | Jan 2010 | A1 |
| 20100120129 | Amshey et al. | May 2010 | A1 |
| 20100233763 | Shigeura et al. | Sep 2010 | A1 |
| 20100284864 | Holenstein et al. | Nov 2010 | A1 |
| 20110008825 | Ingber et al. | Jan 2011 | A1 |
| 20110027151 | Handique et al. | Feb 2011 | A1 |
| 20110060136 | Matsunaga et al. | Mar 2011 | A1 |
| 20110097493 | Kerr et al. | Apr 2011 | A1 |
| 20110127292 | Sarofim et al. | Jun 2011 | A1 |
| 20110158865 | Miller et al. | Jun 2011 | A1 |
| 20110287447 | Norderhaug | Nov 2011 | A1 |
| 20110300033 | Battisti | Dec 2011 | A1 |
| 20120122231 | Tajima | May 2012 | A1 |
| 20120160826 | Handique | Jun 2012 | A1 |
| 20120171678 | Maltezos et al. | Jul 2012 | A1 |
| 20120258463 | Duffy et al. | Oct 2012 | A1 |
| 20130183769 | Tajima | Jul 2013 | A1 |
| 20130210127 | Williams et al. | Aug 2013 | A1 |
| 20130217013 | Steel et al. | Aug 2013 | A1 |
| 20130315800 | Yin et al. | Nov 2013 | A1 |
| 20140030798 | Wu et al. | Jan 2014 | A1 |
| 20140120544 | Brahmasandra et al. | May 2014 | A1 |
| 20140227710 | Handique et al. | Aug 2014 | A1 |
| 20140329301 | Handique et al. | Nov 2014 | A1 |
| 20150045234 | Stone et al. | Feb 2015 | A1 |
| 20150064702 | Handique et al. | Mar 2015 | A1 |
| 20150118684 | Wu et al. | Apr 2015 | A1 |
| 20150142186 | Handique et al. | May 2015 | A1 |
| 20150174579 | Iten et al. | Jun 2015 | A1 |
| 20150315631 | Handique et al. | Nov 2015 | A1 |
| 20150328638 | Handique et al. | Nov 2015 | A1 |
| 20160038942 | Roberts | Feb 2016 | A1 |
| 20170275702 | Dahiya et al. | Sep 2017 | A1 |
| 20180112252 | Handique | Apr 2018 | A1 |
| 20180119204 | Ganesan et al. | May 2018 | A1 |
| 20180135102 | Gubatayao et al. | May 2018 | A1 |
| 20180154364 | Handique et al. | Jun 2018 | A1 |
| 20180333722 | Handique | Nov 2018 | A1 |
| 20190054467 | Handique | Feb 2019 | A1 |
| 20190054471 | Williams et al. | Feb 2019 | A1 |
| 20190106692 | Brahmasandra et al. | Apr 2019 | A1 |
| 20190144849 | Duffy et al. | May 2019 | A1 |
| 20190145546 | Handique | May 2019 | A1 |
| 20190151854 | Baum et al. | May 2019 | A1 |
| 20190154719 | LaChance et al. | May 2019 | A1 |
| 20190284606 | Wu et al. | Sep 2019 | A1 |
| 20200010872 | Ganesan et al. | Jan 2020 | A1 |
| 20200139363 | Handique et al. | May 2020 | A1 |
| 20200156059 | Handique et al. | May 2020 | A1 |
| 20200156060 | Handique et al. | May 2020 | A1 |
| 20200164363 | Handique et al. | May 2020 | A1 |
| 20200216831 | Brahmasandra et al. | Jul 2020 | A1 |
| 20200291388 | Brahmasandra et al. | Sep 2020 | A1 |
| 20200324293 | Handique et al. | Oct 2020 | A1 |
| 20200325523 | Brahmasandra et al. | Oct 2020 | A1 |
| 20200325524 | Handique et al. | Oct 2020 | A1 |
| 20210001334 | Handique et al. | Jan 2021 | A1 |
| 20210010059 | Handique et al. | Jan 2021 | A1 |
| 20210047676 | Wu et al. | Feb 2021 | A1 |
| 20210060565 | Handique et al. | Mar 2021 | A1 |
| 20210071234 | Gubatayao et al. | Mar 2021 | A1 |
| 20210087609 | Handique et al. | Mar 2021 | A1 |
| 20210121887 | Handique et al. | Apr 2021 | A1 |
| 20210123090 | Handique et al. | Apr 2021 | A1 |
| 20210147923 | Steel et al. | May 2021 | A1 |
| 20210276008 | Handique et al. | Sep 2021 | A1 |
| 20210299663 | Handique | Sep 2021 | A1 |
| 20210317437 | Duffy et al. | Oct 2021 | A1 |
| 20210362155 | Williams et al. | Nov 2021 | A1 |
| 20220010364 | Handique et al. | Jan 2022 | A1 |
| 20220136034 | Handique et al. | May 2022 | A1 |
| Number | Date | Country |
|---|---|---|
| 1357102 | Mar 2002 | AU |
| 3557502 | Jul 2002 | AU |
| 4437602 | Jul 2002 | AU |
| 4437702 | Jul 2002 | AU |
| 764319 | Aug 2003 | AU |
| 2574107 | Sep 1998 | CA |
| 2294819 | Jan 1999 | CA |
| 1934451 | Mar 2007 | CN |
| 1312287 | Apr 2007 | CN |
| 1942590 | Apr 2007 | CN |
| 1968754 | May 2007 | CN |
| 101466848 | Jun 2009 | CN |
| 101522909 | Sep 2009 | CN |
| 103540518 | Jan 2014 | CN |
| 19755479 | Jun 1999 | DE |
| 19929734 | Dec 1999 | DE |
| 19833293 | Jan 2000 | DE |
| 0136126 | Apr 1985 | EP |
| 0365828 | May 1990 | EP |
| 0483620 | May 1992 | EP |
| 0402994 | Nov 1994 | EP |
| 0393744 | Jan 1995 | EP |
| 0688602 | Dec 1995 | EP |
| 0707077 | Apr 1996 | EP |
| 0698046 | Mar 1997 | EP |
| 0766256 | Apr 1997 | EP |
| 0772494 | May 1997 | EP |
| 0810030 | Dec 1997 | EP |
| 1059458 | Dec 2000 | EP |
| 1064090 | Jan 2001 | EP |
| 1077086 | Feb 2001 | EP |
| 1346772 | Sep 2003 | EP |
| 1541237 | Jun 2005 | EP |
| 1574586 | Sep 2005 | EP |
| 1621890 | Feb 2006 | EP |
| 1780290 | May 2007 | EP |
| 1792656 | Jun 2007 | EP |
| 2372367 | Oct 2011 | EP |
| 2672301 | Aug 1992 | FR |
| 2795426 | Dec 2000 | FR |
| 2453432 | Apr 2009 | GB |
| S50-100881 | Aug 1975 | JP |
| 58212921 | Dec 1983 | JP |
| S62-119460 | May 1987 | JP |
| H01-502319 | Aug 1989 | JP |
| H 03181853 | Aug 1991 | JP |
| 04-053555 | May 1992 | JP |
| 06-064156 | Sep 1994 | JP |
| 07-020010 | Jan 1995 | JP |
| H07-290706 | Nov 1995 | JP |
| H08-122336 | May 1996 | JP |
| H08-173194 | Jul 1996 | JP |
| H08-211071 | Aug 1996 | JP |
| H08-285859 | Nov 1996 | JP |
| H08-337116 | Dec 1996 | JP |
| H09-304385 | Nov 1997 | JP |
| H09-325151 | Dec 1997 | JP |
| 2001-502790 | Jan 1998 | JP |
| H01-219669 | Sep 1998 | JP |
| H10-327515 | Dec 1998 | JP |
| H11-501504 | Feb 1999 | JP |
| H11-503315 | Mar 1999 | JP |
| 2000-514928 | Apr 1999 | JP |
| H11-156231 | Jun 1999 | JP |
| H11-316226 | Nov 1999 | JP |
| H11-515106 | Dec 1999 | JP |
| 2000-180455 | Jun 2000 | JP |
| 2000-266760 | Sep 2000 | JP |
| 2000-275255 | Oct 2000 | JP |
| 2001-502319 | Feb 2001 | JP |
| 2001-204462 | Jul 2001 | JP |
| 2001-509437 | Jul 2001 | JP |
| 3191150 | Jul 2001 | JP |
| 2001-515216 | Sep 2001 | JP |
| 2001-523812 | Nov 2001 | JP |
| 2001-527220 | Dec 2001 | JP |
| 2002-503331 | Jan 2002 | JP |
| 2002-085961 | Mar 2002 | JP |
| 2002-517735 | Jun 2002 | JP |
| 2002-215241 | Jul 2002 | JP |
| 2002-540382 | Nov 2002 | JP |
| 2002-544476 | Dec 2002 | JP |
| 2003-500674 | Jan 2003 | JP |
| 2003-047839 | Feb 2003 | JP |
| 2003-047840 | Feb 2003 | JP |
| 2003-516125 | May 2003 | JP |
| 2003-164279 | Jun 2003 | JP |
| 2003-185584 | Jul 2003 | JP |
| 2003-299485 | Oct 2003 | JP |
| 2003-329693 | Nov 2003 | JP |
| 2003-329696 | Nov 2003 | JP |
| 2003-532382 | Nov 2003 | JP |
| 2004-003989 | Jan 2004 | JP |
| 2004-506179 | Feb 2004 | JP |
| 2004-150797 | May 2004 | JP |
| 2004-283728 | Oct 2004 | JP |
| 2004-531360 | Oct 2004 | JP |
| 2004-533838 | Nov 2004 | JP |
| 2004-534157 | Nov 2004 | JP |
| 2004-361421 | Dec 2004 | JP |
| 2004-536291 | Dec 2004 | JP |
| 2004-536689 | Dec 2004 | JP |
| 2005-009870 | Jan 2005 | JP |
| 2005-010179 | Jan 2005 | JP |
| 2005-511264 | Apr 2005 | JP |
| 2005-514718 | May 2005 | JP |
| 2005-518825 | Jun 2005 | JP |
| 2005-176613 | Jul 2005 | JP |
| 2005-192439 | Jul 2005 | JP |
| 2005-192554 | Jul 2005 | JP |
| 2005-519751 | Jul 2005 | JP |
| 2005-204661 | Aug 2005 | JP |
| 2005-525816 | Sep 2005 | JP |
| 2005-291954 | Oct 2005 | JP |
| 2005-532043 | Oct 2005 | JP |
| 2005-323519 | Nov 2005 | JP |
| 2005-533652 | Nov 2005 | JP |
| 2005-535904 | Nov 2005 | JP |
| 2006-021156 | Jan 2006 | JP |
| 2006-055837 | Mar 2006 | JP |
| 2006-094866 | Apr 2006 | JP |
| 2006-145458 | Jun 2006 | JP |
| 2006-167569 | Jun 2006 | JP |
| 2006-284409 | Oct 2006 | JP |
| 2007-024742 | Feb 2007 | JP |
| 2007-074960 | Mar 2007 | JP |
| 2007-097477 | Apr 2007 | JP |
| 2007-101364 | Apr 2007 | JP |
| 2007-510518 | Apr 2007 | JP |
| 2007-514405 | Jun 2007 | JP |
| 2007-178328 | Jul 2007 | JP |
| 2007-535933 | Dec 2007 | JP |
| 2009-515140 | Apr 2009 | JP |
| 2009-542207 | Dec 2009 | JP |
| 3193848 | Oct 2014 | JP |
| 1020060044489 | May 2006 | KR |
| 2418633 | May 2011 | RU |
| WO 1988006633 | Sep 1988 | WO |
| WO 1990012350 | Oct 1990 | WO |
| WO 1992005443 | Apr 1992 | WO |
| WO 1994005414 | Mar 1994 | WO |
| WO 1994011103 | May 1994 | WO |
| WO 1995033846 | Dec 1994 | WO |
| WO 1996000228 | Jan 1996 | WO |
| WO 1996004547 | Feb 1996 | WO |
| WO 1996018731 | Jun 1996 | WO |
| WO 1996039547 | Dec 1996 | WO |
| WO 1997005492 | Feb 1997 | WO |
| WO 1997016835 | May 1997 | WO |
| WO 1997021090 | Jun 1997 | WO |
| WO 1997022825 | Jun 1997 | WO |
| WO 1997027324 | Jul 1997 | WO |
| WO 1998000231 | Jan 1998 | WO |
| WO 1998007019 | Feb 1998 | WO |
| WO 1998022625 | May 1998 | WO |
| WO 199835013 | Aug 1998 | WO |
| WO 1998038487 | Sep 1998 | WO |
| WO 1998049548 | Nov 1998 | WO |
| WO 1998050147 | Nov 1998 | WO |
| WO 1998053311 | Nov 1998 | WO |
| WO 1999001688 | Jan 1999 | WO |
| WO 1999009042 | Feb 1999 | WO |
| WO 1999012016 | Mar 1999 | WO |
| WO 1999017093 | Apr 1999 | WO |
| WO 1999029703 | Jun 1999 | WO |
| WO 1999033559 | Jul 1999 | WO |
| WO 1999060397 | Nov 1999 | WO |
| WO 2000022436 | Apr 2000 | WO |
| WO 2000066783 | Nov 2000 | WO |
| WO 2000073412 | Dec 2000 | WO |
| WO 2000075623 | Dec 2000 | WO |
| WO 2000078455 | Dec 2000 | WO |
| WO 2001005510 | Jan 2001 | WO |
| WO 2001014931 | Mar 2001 | WO |
| WO 2001027614 | Apr 2001 | WO |
| WO 2001028684 | Apr 2001 | WO |
| WO 2001030995 | May 2001 | WO |
| WO 2001041931 | Jun 2001 | WO |
| WO 2001046474 | Jun 2001 | WO |
| WO 2001054813 | Aug 2001 | WO |
| WO 2001089681 | Nov 2001 | WO |
| WO 2001089705 | Nov 2001 | WO |
| WO 2001092569 | Dec 2001 | WO |
| WO 2002043864 | Jun 2002 | WO |
| WO 2002048164 | Jun 2002 | WO |
| WO 2002052002 | Jul 2002 | WO |
| WO 2002072264 | Sep 2002 | WO |
| WO 2002078845 | Oct 2002 | WO |
| WO 2002086454 | Oct 2002 | WO |
| WO 2002094185 | Nov 2002 | WO |
| WO 2003007677 | Jan 2003 | WO |
| WO 2003012325 | Feb 2003 | WO |
| WO 2003012406 | Feb 2003 | WO |
| WO 2003048295 | Jun 2003 | WO |
| WO 2003055605 | Jul 2003 | WO |
| WO 2003076661 | Sep 2003 | WO |
| WO 2003078065 | Sep 2003 | WO |
| WO 2003080868 | Oct 2003 | WO |
| WO 2003087410 | Oct 2003 | WO |
| WO 2004007081 | Jan 2004 | WO |
| WO 2004010760 | Feb 2004 | WO |
| WO 2004048545 | Jun 2004 | WO |
| WO 2004055522 | Jul 2004 | WO |
| WO 2004056485 | Jul 2004 | WO |
| WO 2004074848 | Sep 2004 | WO |
| WO 2004094986 | Nov 2004 | WO |
| WO 2005008255 | Jan 2005 | WO |
| WO 2005011867 | Feb 2005 | WO |
| WO 2005030984 | Apr 2005 | WO |
| WO 2005072353 | Aug 2005 | WO |
| WO 2005094981 | Oct 2005 | WO |
| WO 2005107947 | Nov 2005 | WO |
| WO 2005108571 | Nov 2005 | WO |
| WO 2005108620 | Nov 2005 | WO |
| WO 2005116202 | Dec 2005 | WO |
| WO 2005118867 | Dec 2005 | WO |
| WO 2005120710 | Dec 2005 | WO |
| WO 2006010584 | Feb 2006 | WO |
| WO 2006032044 | Mar 2006 | WO |
| WO 2006035800 | Apr 2006 | WO |
| WO 2006043642 | Apr 2006 | WO |
| WO 2006066001 | Jun 2006 | WO |
| WO 2006079082 | Jul 2006 | WO |
| WO 2006081995 | Aug 2006 | WO |
| WO 2006113198 | Oct 2006 | WO |
| WO 2006118420 | Nov 2006 | WO |
| WO 2006119280 | Nov 2006 | WO |
| WO 2007044917 | Apr 2007 | WO |
| WO 2007050327 | May 2007 | WO |
| WO 2007064117 | Jun 2007 | WO |
| WO 2007075919 | Jul 2007 | WO |
| WO 2007091530 | Aug 2007 | WO |
| WO 2007112114 | Oct 2007 | WO |
| WO 2007120240 | Oct 2007 | WO |
| WO 2007120241 | Oct 2007 | WO |
| WO 2008005321 | Jan 2008 | WO |
| WO 2008030914 | Mar 2008 | WO |
| WO 2008060604 | May 2008 | WO |
| WO 2008134470 | Nov 2008 | WO |
| WO 2008149282 | Dec 2008 | WO |
| WO 2009012185 | Jan 2009 | WO |
| WO 2009054870 | Apr 2009 | WO |
| WO 2010118541 | Oct 2010 | WO |
| WO 2010130310 | Nov 2010 | WO |
| WO 2010140680 | Dec 2010 | WO |
| WO 2011009073 | Jan 2011 | WO |
| WO 2011101467 | Aug 2011 | WO |
| Entry |
|---|
| BDProbeTec™ ET Neisseria gonorrhoeae Amplified DNA Assay Package Insert, Jul. 2010 (13 pages). |
| BDProbeTec™ ET System Brochure, Aug. 2010 (9 pages). |
| Gill et al., “Nucleic Acid Isothermal Amplification Technologies—A Review”, Nucleosides Nucleotides Nucleic Acids, (2008) 27(3): 224-243. |
| Rush et al., “Dispersion by Pressure-Driven Flow in Serpentine Microfluidic Channels”, Ind Eng Chem Res., (2002) 41: 4652-4662. |
| Walker et al., “Strand displacement amplification—an isothermal, in vitro DNA amplification technique”, Nucleic Acids Res. (1992) 20(7): 1691-1696. |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 14 in IPR2020-01083) dated Jan. 7, 2021 (24 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 20 in IPR2020-01133) dated Jan. 20, 2021 (67 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 19 in IPR2020-01132) dated Jan. 20, 2021 (78 pages). |
| Declaration of M. Allen Northrup, Ph.D. in support of Patent Owner Preliminary Responses in IPR2020-01132 and IPR2020-01133 (Exhibit H2016) dated Jan. 20, 2021 (154 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 19 in IPR2020-01136) dated Jan. 20, 2021 (77 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 19 in IPR2020-01137) dated Jan. 20, 2021 (69 pages). |
| Declaration of M. Allen Northrup, Ph.D. in support of Patent Owner Preliminary Responses in IPR2020-01136 and IPR2020-01137 (Exhibit H2016) dated Jan. 20, 2021 (111 pages). |
| Opening Brief [Corrected] of Appellants Qiagen North American Holdings, Inc. and NeuMoDx Molecular Inc. in Appeals to IPR2019-00488, IPR2019-00490, IPR2019-01493 and IPR2019-01494 filed Jan. 22, 2021 in U.S. Court of Appeals for the Federal Circuit Case Nos. 20-2249, 20-2250, 20-2273 and 20-2276 (82 pages). |
| Decision Granting Institution of Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 20 in IPR2020-01132) dated Apr. 19, 2021 (33 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 21 in IPR2020-01133) dated Apr. 19, 2021 (24 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 20 in IPR2020-01136) dated Apr. 19, 2021 (19 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 20 in IPR2020-01137) dated Apr. 19, 2021 (14 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 10,625,262 (Paper 6 in IPR2021-00250) dated Apr. 19, 2021 (71 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 10,625,261 (Paper 6 in IPR2021-00251) dated Apr. 19, 2021 (82 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 10,632,466 (Paper 6 in IPR2021-00253) dated Apr. 19, 2021 (66 pages). |
| Declaration of James P. Landers, Ph.D. in support of Patent Owner Preliminary Responses in IPR2021-00250, IPR2021-00251, and IPR2021-00253 (Exhibit H2003) dated Apr. 19, 2021 (189 pages). |
| Second Amended and Supplemental Complaint filed by Becton, Dickinson and Company et al. on Feb. 25, 2021 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (75 pages). |
| Defendant NeuMoDx's First Supplemental Invalidity Contentions filed Mar. 17, 2021 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (55 pages). |
| Defendant NeuModx's Answer, Affirmative Defenses, and Counterclaims to Plaintiffs' Second and Supplemental Complaint filed Mar. 18, 2021 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (67 pages). |
| Plaintiffs' Answer and/or Reply to Defendants' Counterclaims and Counterclaims-In-Reply filed Apr. 22, 2021 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (127 pages). |
| Claim Construction (Markman) Order dated May 10, 2021 in in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (30 pages). |
| Northrup et al., “A MEMS-based Miniature DNA Analysis System.” Transducers '95—Eurosensors in Proc. 1995 (8th) IEEE Int. Conf. Solid-State Sens. Actuators, pp. 764-767. |
| Petition for Inter Partes Review of U.S. Pat. No. 10,625,262 (Paper 2 in IPR2021-00250) dated Nov. 25, 2020 (107 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 10,625,261 (Paper 2 in IPR2021 -00251) dated Nov. 25, 2020 (117 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 10,632,466 (Paper 2 in IPR2021-00253) dated Nov. 25, 2020 (121 pages). |
| Declaration of Mark A. Burns, Ph.D. (Exhibit N1001 in IPR2021-00250, IPR2021-00251 and IPR2021-00253) dated Nov. 24, 2020 (311 pages). |
| Declaration of James L. Mullins, Ph.D. (Exhibit N1029 in IPR2021-00250, IPR2021-00251, and IPR2021-00253) dated Nov. 18, 2020 (54 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 14 in IPR2020-01091) dated Dec. 4, 2020 (21 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,703,069 (Paper 14 in IPR2020-01095) dated Dec. 4, 2020 (22 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 8,703,069 (Paper 15 in IPR2020-01100) dated Dec. 4, 2020 (19 pages). |
| Defendant NeuModx's Joint Claim Construction Chart [Exhibit N1023] filed Oct. 21, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (25 pages). |
| Defendant NeuModx's Initial Amended Answer, Affirmative Defenses, and Counterclaims to Plaintiffs' First Amended and Supplemental Complaint filed Nov. 23, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (97 pages). |
| Altet et al., [Eds.] “Thermal Transfer and Thermal Coupling in IC's”, Thermal Testing of Integrated Circuits; Chapter 2 (2002) Springer Science pp. 23-51. |
| Ateya et al., “The good, the bad, and the tiny: a review of microflow cytometry”, Anal Bioanal Chem. (2008) 391(5):1485-1498. |
| Auroux et al., “Miniaturised nucleic acid analysis”, Lab Chip. (2004) 4(6):534-546. |
| Baechi et al., “High-density microvalve arrays for sample processing in PCR chips”, Biomed Microdevices. (2001) 3(3):183-190. |
| Baker M., “Clever PCR: more genotyping, smaller volumes.” Nature Methods (May 2010) 70(5):351-356. |
| Becker H. “Fabrication of Polymer Microfluidic Devices”, in Biochip Technology (2001), Chapter 4, pp. 63-96. |
| Becker H., “Microfluidic Devices Fabricated by Polymer Hot Embossing,” in Integrated Microfabricated Biodevices: Advanced Technologies for Genomics, Drug Discovery, Bioanalysis, and Clinical Diagnostics (2002), Chapter 13, 32 pages. |
| Becker H., “Microfluidics: A Technology Coming of Age”, Med Device Technol. (2008) 19(3):21-24. |
| Becker et al., “Portable CE system with contactless conductivity detection in an injection molded polymer chip for on-site food analysis”, SPIE Proceedings MOEMS-MEMS 2008 Micro and Nanofabrication (2008) vol. 6886 in 8 pages. |
| Belgrader et al., “Rapid PCR for Identity Testing Using a Battery-Powered Miniature Thermal Cycler”, J Forensic Sci. (1998) 43(2):315-319. |
| Belgrader et al., “A minisonicator to rapidly disrupt bacterial spores for DNA analysis.”, Anal Chem. (1999) 71 (19):4232-4236. |
| Belgrader et al., “Real-time PCR Analysis on Nucleic Acids Purified from Plasma Using a Silicon Chip”, Micro Total Analysis Systems 2000 (pp. 525-528). Springer, Dordrecht. |
| Belgrader et al., “A microfluidic cartridge to prepare spores for PCR analysis”, Biosens Bioelectron. (2000) 14(10-11):849-852. |
| Belgrader et al., “A Battery-Powered Notebook Thermal Cycler for Rapid Multiplex Real-Time PCR Analysis”, Anal Chem. (2001) 73(2):286-289. |
| Belgrader et al., “Rapid and Automated Cartridge-based Extraction of Leukocytes from Whole Blood for Microsatellite DNA Analysis by Capillary Electrophoresis”, Clin Chem. (2001) 47(10):1917-1933. |
| Belgrader et al., “A Rapid, Flow-through, DNA Extraction Module for Integration into Microfluidic Systems”, Micro Total Analysis Systems (2002) pp. 697-699). Springer, Dordrecht. |
| Belgrader et al., “Development of a Battery-Powered Portable Instrumentation for Rapid PCR Analysis”, in Integrated Microfabricated Devices, (2002) Ch. 8, pp. 183-206, CRC Press. |
| Bell M., “Integrated Microsystems in Clinical Chemistry”, in Integrated Microfabricated Devices, (2002) Ch. 16, pp. 415-435, CRC Press. |
| Berthier et al., “Managing evaporation for more robust microscale assays Part 1. Volume loss in high throughput assays”, Lab Chip (2008) 8(6):852-859. |
| Berthier et al., “Managing evaporation for more robust microscale assays Part 2. Characterization of convection and diffusion for cell biology”, Lab Chip (2008) 8(6):860-864. |
| Berthier et al., “Microdrops,” in Microfluidics for Biotechnology (2006), Chapter 2, pp. 51-88. |
| BIOMERIEUX Press Release: “bioMerieux - 2018 Financial Results,” dated Feb. 27, 2019, accessed atwww.biomerieux.com, pp. 13. |
| Blanchard et al., “Micro structure mechanical failure characterization using rotating Couette flow in a small gap”, J Micromech Microengin. (2005) 15(4):792-801. |
| Blanchard et al., “Single-disk and double-disk viscous micropumps”, Sensors and Actuators A (2005) 122:149-158. |
| Blanchard et al., “Performance and Development of a Miniature Rotary Shaft Pump”, J Fluids Eng. (2005) 127(4):752-760. |
| Blanchard et al., “Single-disk and double-disk viscous micropump”, ASME 2004 Inter'l Mechanical Engineering Congress & Exposition, Nov. 13-20, 2004, Anaheim, CA, IMECE2004-61705:411-417. |
| Blanchard et al., “Miniature Single-Disk Viscous Pump (Single-DVP), Performance Characterization”, J Fluids Eng. (2006) 128(3):602-610. |
| Brahmasandra et al., “Microfabricated Devices for Integrated DNA Analysis”, in Biochip Technology by Cheng et al., [Eds.] (2001) pp. 229-250. |
| Bu et al., “Design and theoretical evaluation of a novel microfluidic device to be used for PCR”, J Micromech Microengin. (2003) 13(4):S125-S130. |
| Cady et al., “Real-time PCR detection of Listeria monocytogenes using an integrated microfluidics platform”, Sensors Actuat B. (2005) 107:332-341. |
| Carlen et al., “Paraffin Actuated Surface Micromachined Valve,” in IEEE MEMS 2000 Conference, Miyazaki, Japan, (Jan. 2000) pp. 381-385. |
| Carles et al., “Polymerase Chain Reaction on Microchips” in Methods in Molecular Biology- Microfluidic Techniques, Reviews & Protocols by Minteer S.D. [Ed.] Humana Press (2006), vol. 321; Chapter 11, pp. 131-140. |
| Chang-Yen et al., “A novel integrated optical dissolved oxygen sensor for cell culture and micro total analysis systems”, IEEE Technical Digest MEMS International Conference Jan. 24, 2002, 4 pages. |
| Chang-Yen et al., “A PDMS microfluidic spotter for fabrication of lipid microarrays”, IEEE 3rd EMBS Special Topic Conference May 12-15, 2005; 2 pages. |
| Chang-Yen et al., “Design and fabrication of a multianalyte-capable optical biosensor using a multiphysics approach”, IEEE 3rd EMBS Special Topic Conference May 12-15, 2005; 2 pages. |
| Chang-Yen et al., “A Novel PDMS Microfluidic Spotter for Fabrication of Protein Chips and Microarrays”, IEEE J of Microelectromech Sys. (2006) 15(5): 1145-1151. |
| Chang-Yen et al., “Spin-assembled nanofilms for gaseous oxygen sensing.” Sens Actuators B: Chemical (2007), 120(2):426-433. |
| Chen P-C., “Accelerating micro-scale PCR (polymerase chain reactor) for modular lab-on-a-chip system”, LSU Master's Theses—Digital Commons, (2006) 111 pages. |
| Cheng et al., “Biochip-Based Portable Laboratory”, Biochip Tech. (2001):296-289. |
| Cho et al., “A facility for characterizing the steady-state and dynamic thermal performance of microelectromechanical system thermal switches”, Rev Sci Instrum. (2008) 79(3):034901-1 to 034901-8. |
| Chong et al., “Disposable Polydimethylsioxane Package for ‘Bio-Microfluidic System’”, IEEE Proceedings Electronic Components and Technology (2005); 5 pages. |
| Chou et al., “A miniaturized cyclic PCR device—modeling and experiments”, Microelec Eng. (2002) 61-62:921-925. |
| Christel et al., “Nucleic Acid Concentration and PCR for Diagnostic Applications”, in Micro Total Analysis Systems. (1998) D.J. Harrison et al. [Eds.] pp. 277-280. |
| Christel et al., “Rapid, Automated Nucleic Acid Probe Assays Using Silicon Microstructures for Nucleic Acid Concentration”, J Biomech Eng. (1999) 121(1):22-27. |
| Christensen et al., “Characterization of interconnects used in PDMS microfluidic systems”, J Micromech Microeng. (2005) 15:928 in 8 pages. |
| Crews et al., “Rapid Prototyping of a Continuous-Flow PCR Microchip”, Proceedings of the AiChE Annual Meeting(Nov. 15, 2006) (335a) 3 pages. |
| Crews et al., Thermal gradient PCR in a continuous-flow microchip. In Microfluidics, BioMEMS, and Medical Microsystems V; Jan. 2007; vol. 6465, p. 646504; 12 pages. |
| Crews et al., “Continuous-flow thermal gradient PCR”, Biomed Microdevices. (2008) 10(2):187-195. |
| Cui et al., “Electrothermal modeling of silicon PCR chips”, In MEMS Design, Fabrication, Characterization, and Packaging, (Apr. 2001) (vol. 4407, pp. 275-280. |
| DANAHER Press Release: “Danaher to Acquire Cepheid for $53.00 per share, or approximately $4 Billion,” dated Sep. 6, 2016, accessed atwww.danaher.com, pp. 3. |
| Demchenko A.P., “The problem of self-calibration of fluorescence signal in microscale sensor systems”, Lab Chip. (2005) 5(11):1210-1223. |
| Dineva et al., “Sample preparation: a challenge in the development of point-of-care nucleic acid-based assays for resource-limited settings”, Analyst. (2007) 132(12):1193-1199. |
| Dishinger et al., “Multiplexed Detection and Applications for Separations on Parallel Microchips”, Electophoresis. (2008) 29(16):3296-3305. |
| Dittrich et al., “Single-molecule fluorescence detection in microfluidic channels—the Holy Grail in muTAS?”, Anal Bioanal Chem. (2005) 382(8):1771-1782. |
| Dittrich et al., “Lab-on-a-chip: microfluidics in drug discovery”, Nat Rev Drug Discov. (2006) 5(3):210-208. |
| Dunnington et al., “Approaches to Miniaturized High-Throughput Screening of Chemical Libraries”, in Integrated Microfabicated Devices, (2002) Ch. 15, pp. 371-414, CRC Press. |
| Eddings et al., “A PDMS-based gas permeation pump for on-chip fluid handling in microfluidic devices”, J Micromech Microengin. (2006) 16(11):2396-2402. |
| Edwards et al., “Micro Scale Purification Systems for Biological Sample Preparation”, Biomed Microdevices (2001) 3(3):211-218. |
| Edwards et al., “A microfabricated thermal field-flow fractionation system”, Anal Chem. (2002) 74(6):1211-1216. |
| Ehrlich et al., “Microfluidic devices for DNA analysis”, Trends Biotechnol. (1999) 17(8):315-319. |
| El-Ali et al., “Simulation and experimental validation of a SU-8 based PCR thermocycler chip with integrated heaters and temperature sensor”, Sens Actuators A: Physical (2004) 110(1-3):3-10. |
| Erickson et al., “Joule heating and heat transfer in poly(dimethylsiloxane) microfluidic systems”, Lab Chip (2003) 3(3):141-149. |
| Erickson et al., “Integrated Microfluidic Devices”, Analytica Chim Acta. (2004) 507:11-26. |
| Erill et al., “Development of a CMOS-compatible PCR chip: comparison of design and system strategies”, J Micromech Microengin. (2004) 14(11):1-11. |
| Fair R.B., Digital microfluidics: is a true lab-on-a-chip possible? Microfluidics Nanofluid. (2007)3:245-281. |
| Fan et al., “Integrated Plastic Microfluidic Devices for Bacterial Detection”, in Integrated Biochips for DNA Analysis by Liu et al. [Eds], (2007) Chapter 6, pp. 78-89. |
| Fiorini et al., “Disposable microfluidic devices: fabrication, function, and application”, Biotechniques (2005) 38(3):429-446. |
| Frazier et al., “Integrated micromachined components for biological analysis systems”, J Micromech. (2000) 1(1):67-83. |
| Gale et al., “Micromachined electrical field-flow fractionation (mu-EFFF) system”, IEEE Trans Biomed Eng. (1998) 45(12):1459-1469. |
| Gale et al., “Geometric scaling effects in electrical field flow fractionation. 1. Theoretical analysis”, Anal Chem. (2001) 73(10):2345-2352. |
| Gale et al., “BioMEMS Education at Louisiana Tech University”, Biomed Microdevices, (2002) 4:223-230. |
| Gale et al., “Geometric scaling effects in electrical field flow fractionation. 2. Experimental results”, Anal Chern. (2002) 74(5):1024-1030. |
| Gale et al., “Cyclical electrical field flow fractionation”, Electrophoresis. (2005) 26(9):1623-1632. |
| Gale et al., “Low-Cost MEMS Technologies”, Elsevier B.V. (2008), Chapter 1.12; pp. 342-372. |
| Garst et al., “Fabrication of Multilayered Microfluidic 3D Polymer Packages”, IEEE Proceedings Electronic Components & Tech, Conference May/Jun. 2005, pp. 603-610. |
| Gärtner et al., “Methods and instruments for continuous-flow PCR on a chip”, Proc. SPIE 6465, Microfluidics, BioMEMS, and Medical Microsystems V, (2007) 646502; 8 pages. |
| Giordano et al., “Toward an Integrated Electrophoretic Microdevice for Clinical Diagnostics”, in Integrated Microfabricated Biodevices: Advanced Technologies for Genomics, Drug Discovery, Bioanalysis, and Clinical Diagnostics (2002) Chapter 1; pp. 1-34. |
| Graff et al., “Nanoparticle Separations Using Miniaturized Field-flow Fractionation Systems”, Proc. Nanotechnology Conference and Trade Show (NSTI) (2005); pp. 8-12. |
| Greer et al., “Comparison of glass etching to xurography prototyping of microfluidic channels for DNA melting analysis”, J Micromech Microengin. (2007) 17(12):2407-2413. |
| Guijt et al., “Chemical and physical processes for integrated temperature control in microfluidic devices”, Lab Chip. (2003) 3(1):1-4. |
| Gulliksen A., “Microchips for Isothermal Amplification of RNA”, Doctoral Thesis (2007); Department of Mol. Biosciences—University of Oslo; 94 pages. |
| Guttenberg et al., “Planar chip device for PCR and hybridization with surface acoustic wave pump”, Lab Chip. (2005) 5(3):308-317. |
| Haeberle et al., “Microfluidic platforms for lab-on-a-chip applications”, Lab Chip. (2007) 7(9):1094-1110. |
| Hansen et al., “Microfluidics in structural biology: smaller, faster . . . better”, Curr Opin Struct Biol. (2003)13(5):538-544. |
| Heid et al., “Genome Methods—Real Time Quantitative PCR”, Genome Res. (1996) 6(10):986-994. |
| Henry C.S. [Ed], “Microchip Capillary electrophoresis”, Methods in Molecular Biology, Humana Press 339 (2006) Parts 1-IV in 250 pages. |
| Herr et al., “Investigation of a miniaturized capillary isoelectric focusing (cIEF) system using a full-field detection approach”, Solid State Sensor and Actuator Workshop, Hilton Head Island (2000), pp. 4-8. |
| Herr et al., “Miniaturized Isoelectric Focusing (μIEF) as a Component of a Multi-Dimensional Microfluidic System”, Micro Total Analysis Systems (2001) pp. 51-53. |
| Herr et al., Miniaturized Capillary Isoelectric Focusing (cIEF): Towards a Portable High-Speed Separation Method. In Micro Total Analysis Systems (2000) Springer, Dordrecht; pp. 367-370. |
| Holland et al., “Point-of-care molecular diagnostic systems—past, present and future”, Curr Opin Microbiol. (2005) 8(5):504-509. |
| Hong et al., “Integrated nanoliter systems”, Nat Biotechnol. (2003) 21(10):1179-1183. |
| Hong et al., “Molecular biology on a microfluidic chip”, J Phys.: Condens Matter (2006) 18(18):S691-S701. |
| Hong et al., “Integrated Nucleic Acid Analysis in Parallel Matrix Architecture”, in Integrated Biochips for DNA Analysis by Liu et al. [Eds], (2007) Chapter 8, pp. 107-116. |
| Horsman et al., “Forensic DNA Analysis on Microfluidic Devices: A Review”, J Forensic Sci. (2007) 52(4):784-799. |
| Hsieh et al., “Enhancement of thermal uniformity for a microthermal cycler and its application for polymerase chain reaction”, Sens Actuators B: Chemical. (2008) 130(2):848-856. |
| Huang et al., “Temperature Uniformity and DNA Amplification Efficiency in Micromachined Glass PCR Chip”, TechConnect Briefs; Tech Proc. of the 2005 NSTI Nanotechnology Conference and Trade Show. (2005) vol. 1:452-455. |
| Huebner et al., “Microdroplets: A sea of applications?”, Lab Chip. (2008) 8(8):1244-1254. |
| Iordanov et al., “PCR Array on Chip—Thermal Characterization”, IEEE Sensors (2003) Conference Oct. 22-24, 2003; pp. 1045-1048. |
| Ji et al., “DNA Purification Silicon Chip”, Sensors and Actuators A: Physical (2007) 139(1-2):139-144. |
| Jia et al., “A low-cost, disposable card for rapid polymerase chain reaction”, Colloids Surfaces B: Biointerfaces (2007) 58:52-60. |
| Kaigala et al., “An inexpensive and portable microchip-based platform for integrated RT-PCR and capillary electrophoresis”, The Analyst (2008) 133(3):331-338. |
| Kajiyama et al., “Genotyping on a Thermal Gradient DNA Chip”, Genome Res. (2003) 13(3):467-475. |
| Kang et al., “Simulation and Optimization of a Flow-Through Micro PCR Chip”, NSTI-Nanotech (2006) vol. 2, pp. 585-588. |
| Kantak et al., “Microfluidic platelet function analyzer for shear-induced platelet activation studies”, 2nd Annual International IEEE-EMBS Special Topic Conference on Microtechnologies in Med and Biol. (May 2002) 5 pages. |
| Kantak et al., “Microfabricated cyclical electrical field flow fractionation”, 7th International Conference on Miniaturized Chomical and Biochem Analysis Sys. (2003) pp. 1199-1202. |
| Kantak et al., “Platelet function analyzer: Shear activation of platelets in microchannels”, Biomedical Microdevices (2003) 5(3):207-215. |
| Kantak et al., “Characterization of a microscale cyclical electrical field flow fractionation system”, Lab Chip. (2006) 6(5):645-654. |
| Kantak et al., “Effect of carrier ionic strength in microscale cyclical electrical field-flow fractionation”, Anal Chern. (2006) 78(8):2557-2564. |
| Kantak et al., “Improved theory of cyclical electrical field flow fractions”, Electrophoresis (2006) 27(14):2833-2843. |
| Karunasiri et al.,“Extraction of thermal parameters of microbolometer infrared detectors using electrical measurement”, SPIE's Inter'l Symposium on Optical Science, Engineering, and Instrumentation; Proceedings (1998) vol. 3436, Infrared Technology and Applications XXIV; (1998) 8 pages. |
| Kelly et al., “Microfluidic Systems for Integrated, High-Throughput DNA Analysis,” Analytical Chemistry, (2005), 97A-102A, Mar. 1, 2005, in 7 pages. |
| Kim et al., “Reduction of Microfluidic End Effects In Micro-Field Flow Fractionation Channels”, Proc. MicroTAS 2003, pp. 5-9. |
| Kim et al., “Multi-DNA extraction chip based on an aluminum oxide membrane integrated into a PDMS microfluidic structure”, 3rd IEEE/EMBS Special Topic Conference on Microtechnology in Med and Biol. (May 2005). |
| Kim et al., “Geometric optimization of a thin film ITO heater to generate a uniform temperature distribution”, (2006), Tokyo, Japan; pp. 293-295; Abstract. |
| Kim et al., “Micro-Raman thermometry for measuring the temperature distribution inside the microchannel of a polymerase chain reaction chip”, J Micromech Microeng. (2006) 16(3):526-530. |
| Kim et al., “Patterning of a Nanoporous Membrane for Multi-sample DNA Extraction”, J Micromech Microeng. (2006) 16:33-39. |
| Kim et al., “Performance evaluation of thermal cyclers for PCR in a rapid cycling condition”, Biotechniques. (2008) 44(4):495-505. |
| Kim et al., “Quantitative and qualitative analysis of a microfluidic DNA extraction system using a nanoporous AIO(x) membrane”, Lab Chip. (2008) 8(9):1516-1523. |
| Kogi et al., “Microinjection-microspectroscopy of single oil droplets in water: an application to liquid/liquid extraction under solution-flow conditions”, Anal Chim Acta. (2000) 418(2):129-135. |
| Kopf-Sill et al., “Creating a Lab-on-a-Chip with Microfluidic Technologies”, in Integrated Microfabricated Biodevices: Advanced Technologies for Genomics, Drug Discovery, Bioanalysis, and Clinical Diagnostics (2002) Chapter 2; pp. 35-54. |
| Kricka L.J., “Microchips, Bioelectronic Chips, and Gene Chips—Microanalyzers for the Next Century”, in Biochip Technology by Cheng et al. [Eds]; (2006) Chapter 1, pp. 1-16. |
| Krishnan et al., “Polymerase chain reaction in high surface-to-vol. ratio SiO2 microstructures”, Anal Chem. (2004) 76(22):6588-6593. |
| Kuswandi et al., “Optical sensing systems for microfluidic devices: a review”, Anal Chim Acta. (2007) 601(2):141-155. |
| Lagally et al., “Genetic Analysis Using Portable PCR-CE Microsystem”, Proceedings 7th International Conference on Miniaturized Chemical and Biochemical Analysis Systems (2003) pp. 1283-1286. |
| Lagally et al., “Integrated portable genetic analysis microsystem for pathogen/infectious disease detection”, Anal Chem. (2004) 76(11):3152-3170. |
| Lauerman L.H., “Advances in PCR technology”, Anim Health Res Rev. (2004) 5(2):247-248. |
| Lawyer et al., “High-level Expression, Purification, and Enzymatic Characterization of Full-length Thermus aquaticus DNA Polymerase and a Truncated Form Deficient in 5′to 3′Exonuclease Activity.” Genome research (1993) 2(4):275-287. |
| Lee et al., “Submicroliter-volume PCR chip with fast thermal response and very power consumption”, 7th International Conference on Miniaturized Chemical and Biochemical Analysis Systems, (2003) pp. 187-190. |
| Lee et al., “Bulk-micromachined submicroliter-volume PCR chip with very rapid thermal response and low power consumption”, Lab Chip. (2004) 4(4):401-407. |
| Lewin et al., “Use of Real-Time PCR and Molecular Beacons to Detect Virus Replication in Human Immunodeficiency Virus Type 1-infected Individuals on Prolonged Effective Antiretroviral Therapy”. J Virol. (1999) 73(7), 6099-6103. |
| Li et al., “Effect of high-aspect-ratio microstructures on cell growth and attachment”, 1st Annual Inter'l IEEE-EMBS Special Topic Conference on Microtechnologies in Med and Biol. Proceedings Cat. No. 00EX451; (Oct. 2000) Poster 66, pp. 531-536. |
| Li PCh., “Micromachining Methods et al.” in Microfluidic Lab-on-a-Chip for Chemical and Biological Analysis and Discovery, CRC Press (2005), Chapter 2-3 to 2-5; pp. 10-49. |
| Li PCH., “Microfluidic Flow” in Microfluidic Lab-on-a-Chip for Chemical and Biological Analysis and Discovery, CRC Press (2005), Chapter 3, pp. 55-99. |
| Li PCH., “Detection Methods” in Microfluidic Lab-on-a-Chip for Chemical and Biological Analysis and Discovery, CRC Press (2005), Chapter 7, pp. 187-249. |
| Li PCH., “Applications to Nucleic Acids Analysis” in Microfluidic Lab-on-a-Chip for Chemical and Biological Analysis and Discovery, CRC Press (2005), Chapter 9; pp. 293-325. |
| Li et al., “A Continuous-Flow Polymerase Chain Reaction Microchip With Regional Velocity Control”, J Microelectromech Syst. (2006) 15(1):223-236. |
| Lien et al., “Integrated reverse transcription polymerase chain reaction systems for virus detection”, Biosens Bioelectron. (2007) 22(8):1739-1748. |
| Lien et al., “Microfluidic Systems Integrated with a Sample Pretreatment Device for Fast Nucleic-Acid Amplification”, J Microelectro Sys. (2008) 17(2):288-301. |
| Lifesciences et al., “Microfluidics in commercial applications; an industry perspective.” Lab Chip (2006) 6:1118-1121. |
| Lin et al., “Simulation and experimental validation of micro polymerase chain reaction chips”, Sens Actuators B: Chemical. (2000) 71(1-2):127-133. |
| Linder et al., “Microfluidics at the Crossroad with Point-of-care Diagnostics”, Analyst (2007) 132:1186-1192. |
| Liu et al., “Integrated portable polymerase chain reaction-capillary electrophoresis microsystem for rapid forensic short tandem repeat typing”, Anal Chem. (2007) 79(5):1881-1889. |
| Liu et al. [Eds], Integrated Biochips for DNA Analysis—Biotechnology Intelligence Unit; Springer/Landes Bioscience (2007) ISBN:978-0-387-76758-1; 216 pages. |
| Locascio et al., “ANYL 67 Award Address—Microfluidics as a tool to enable research and discovery in the life sciences”, Abstract; The 236th ACS National Meeting (Aug. 2008); 2 pages. |
| Mahjoob et al., “Rapid microfluidic thermal cycler for polymerase chain reaction nucleic acid amplification”, Inter'l J Heat Mass Transfer. (2008) 51(9-10):2109-2122. |
| Marcus et al., “Parallel picoliter rt-PCR assays using microfluidics”, Anal Chem. (2006) 78(3):956-958. |
| Mariella R.P. Jr., “Microtechnology”, Thrust Area Report FY 96 UCRL-ID-125472; Lawrence Livermore National Lab., CA (Feb. 1997) Chapter 3 in 44 pages. |
| Mariella R., “Sample preparation: the weak link in microfluidics-based biodetection”, Biomed Microdevices. (2008) 10(6):777-784. |
| McMillan et al., “Application of advanced microfluidics and rapid PCR to analysis of microbial targets”, In Proceedings of the 8th international symposium on microbial ecology (1999), in 13 pages. |
| Melin et al., “Microfluidic large-scale integration: the evolution of design rules for biological automation”, Annu Rev Biophys Biomol Struct. (2007) 36:213-231. |
| Merugu et al., “High Throughput Separations Using a Microfabricated Serial Electric Split Ssystem” (2003), Proceedings of μTAS 2003, 7th International Conference on Miniaturized Chemical and Biochemical Analysis Systems, Oct. 5-9, 2003, Squaw Valley, California; 1191-1194, in 3 pages. |
| Miao et al., “Low cost micro-PCR array and micro-fluidic integration on single silicon chip”, Int'l J Comput Eng Science (2003) 4(2):231-234. |
| Miao et al., “Flip-Chip packaged micro-plate for low cost thermal multiplexing”, Int'l J Comput Eng Science. (2003) 4(2):235-238. |
| Micheletti et al., “Microscale Bioprocess Optimisation”, Curr Opin Biotech. (2006) 17:611-618. |
| MicroTAS 2005., “Micro Total Analysis Systems”, Proceedings 9th Int. Conference on Miniaturized Systems for Chemistry and Life Sciences; Presentations/Posters/Articles for Conference; Boston, MA in Oct. 10-12, 2005 in 1667 pages. |
| MicroTAS 2007., “Micro Total Analysis Systems”, Proceedings 11th Int. Conference on Miniaturized Systems for Chemistry and Life Sciences; Presentations/Posters/Articles for Conference; Paris, France in Oct. 7-11, 2007 in 1948 pages. |
| MicroTAS 2007., “Micro Total Analysis Systems”, Advance Program for the Proceedings 11th Int. Conference on Miniaturized Systems for Chemistry and Life Sciences; Presentations/Posters/Articles for Conference; Paris, France in Oct. 7-11, 2007 in 42 pages. |
| Mitchell et al., “Modeling and validation of a molded polycarbonate continuous-flow polymerase chain reaction device,” Microfluidics, BioMEMS, and Medical Microsystems, Proc. SPIE (2003) 4982:83-98. |
| Myers et al., “Innovations in optical microfluidic technologies for point-of-care diagnostics”, Lab Chip (2008) 8:2015-2031. |
| Namasivayam et al., “Advances in on-chip photodetection for applications in miniaturized genetic analysis systems”, J Micromech Microeng. (2004) 14:81-90. |
| Narayanan et al., “A microfabricated electrical SPLITT system,” Lab Chip, (2006) 6:105-114. |
| Neuzil et al., “Disposable real-time microPCR device: lab-on-a-chip at a low cost,” Mol. Biosyst., (2006)2:292-298. |
| Neuzil et al., “Ultra fast miniaturized real-time PCR: 40 cycles in less than six minutes,” Nucleic Acids Research, (2006) 34(11 )e77, in 9 pages. |
| Nguyen et al. [Eds], “Microfluidics for Internal Flow Control: Microfluidics” in Fundamentals and Applications of Microfluidics; 2nd Edition (2006) Introduction Chapter 1, pp. 1-9. |
| Nguyen et al. [Eds], “Microfluidics for Internal Flow Control: Microvalves” in Fundamentals and Applications of Microfluidics; (2006) 2nd Edition, Chapter 6, pp. 211-254. |
| Nguyen et al. [Eds], “Microfluidics for Internal Flow Control: Micropumps” in Fundamentals and Applications of Microfluidics; (2006) 2nd Edition, Chapter 7, pp. 255-309. |
| Nguyen et al. [Eds], “Microfluidics for Life Sciences and Chemistry: Microdispensers” in Fundamentals and Applications of Microfluidics; (2006) , Chapter 11, pp. 395-418. |
| Nguyen et al. [Eds], “Microfluidics for Life Sciences and Chemistry: Microreactors” in Fundamentals and Applications of Microfluidics; (2006) 2nd Edition, Chapter 13, pp. 443-477. |
| Ning et al., “Microfabrication Processes for Silicon and Glass Chips”, in Biochip Technology, CRC-Press (2006) Chapter 2, pp. 17-38. |
| Northrup et al., “A MEMs-based Miniature DNA Analysis System,” Lawrence Livermore National Laboratory, (1995), submitted to Transducers '95, Stockholm, Sweden, Jun. 25-29, 1995, in 7 pages. |
| Northrup et al., “Advantages Afforded by Miniaturization and Integration of DNA Analysis Instrumentation,” Microreaction Technology, (1998) 278-288. |
| Northrup et al., “A New Generation of PCR Instruments and Nucleic Acid Concentration Systems,” in PCR Applications: Protocols for Functional Genomics, (1999), Chapter 8, pp. 105-125. |
| Northrup, “Microfluidics, A few good tricks,” Nature materials (2004), 3:282-283. |
| Northrup et al.,“Microfluidics-based integrated airborne pathogen detection systems,” Abstract, Proceedings of the SPIE, (2006), vol. 6398, Abstract in 2 pages. |
| Oh et al., “World-to-chip microfluidic interface with built-in valves for multichamber chip-based PCR assays,” Lab Chip, (2005), 5:845-850. |
| Ohno et al., “Microfluidics: Applications for analytical purposes in chemistry and biochemistry,” Electrophoresis (2008), 29:4443-4453. |
| Pal et al., “Phase Change Microvalve for Integrated Devices,” Anal. Chem. (2004), 76(13):3740-3748, Jul. 1, 2004, in 9 pages. |
| Pal et al., “An integrated microfluidic for influenza and other genetic analyses,” Lab Chip, (2005), 5:1024-1032, in 9 pages. |
| Pamme, “Continuous flow separations in microfluidic devices,” Lab Chip, (2007), 7:1644-1659. |
| Pang et al., “A novel single-chip fabrication technique for three-dimensional MEMS structures,” Institute of Microelectronics, Tsinghua University, Beijing, P.R. China, (1998), IEEE, 936-938. |
| Pang et al., “The Study of Single-Chip Integrated Microfluidic System,” Tsinghua University, Beijing, P.R. China, (1998), IEEE, 895-898. |
| Papautsky et al., “Effects of rectangular microchannel aspect ratio on laminar friction constant”, in Microfluidic Devices and Systems II (1999) 3877:147-158. |
| Petersen, Kurt E., “Silicon as a Mechanical Material.” Proceedings of the IEEE, (May 1982) 70(5):420-457. |
| Petersen et al., “Toward Next Generation Clinical Diagnostic Instruments: Scaling and New Processing Paradigms,” Biomedical Microdevices (1998) 1(1):71-79. |
| Poser et al., “Chip elements for fast thermocycling,” Sensors and Actuators A, (1997), 62:672-675. |
| Pourahmadi et al., “Toward a Rapid, Integrated, and Fully Automated DNA Diagnostic Assay for Chlamydia trachomatis and Neisseria gonorrhea,” Clinical Chemistry, (2000), 46(9):1511-1513. |
| Pourahmadi et al., “Versatile, Adaptable and Programmable Microfluidic Platforms for DNA Diagnostics and Drug Discovery Assays,” Micro Total Analysis Systems, (2000), 243-248. |
| Raisi et al., “Microchip isoelectric focusing using a miniature scanning detection system,” Electrophoresis, (2001), 22:2291-2295. |
| Raja et al., “Technology for Automated, Rapid, and Quantitative PCR or Reverse Transcriptin-PCR Clinical Testing,” Clinical Chemistry, (2005), 51(5):882-890. |
| Reyes et al., “Micro Total Analysis Systems. 1. Introduction, Theory, and Technology”, Anal Chem (2002) 74:2623-2636. |
| Rodriguez et al., “Practical integration of polymerase chain reaction amplification and electrophoretic analysis in microfluidic devices for genetic analysis,” Electrophoresis, (2003), 24:172-178. |
| Roper et al., “Advances in Polymer Chain Reaction on Microfluidic Chips,” Anal. Chem., (2005), 77:3887-3894. |
| Ross et al., “Scanning Temperature Gradient Focusing for Simultaneous Concentration and Separation of Complex Samples,” Micro Total Analysis Systems 2005, vol. 2, (2005), Proceedings of μTAS 2005, Ninth International Conference on Miniaturized Systems for Chemistry and Life Sciences, Oct. 9-13, 2005, Boston, Massachusetts; 1022-1024. |
| Ross et al., “Simple Device for Multiplexed Electrophoretic Separations Using Gradient Elution Moving Boundary Electrophoresis with Channel Current Detection,” Anal. Chem., (2008), 80(24):9467-9474. |
| Sadler et al., “Thermal Management of BioMEMS: Temperature Control for Ceramic-Based PCR and DNA Detection Devices,” IEEE Transactions on Components and Packaging Technologies, (2003) 26(2):309-316. |
| Sant et al., “An Integrated Optical Detector for Microfabricated Electrical Field Flow Fractionation System,” Proceedings of μTAS 2003, 7th International Conference on Miniaturized Chemical and Biochemical Analysis Systems, Oct. 5-9, 2003, Squaw Valley, California; pp. 1259-1262. |
| Sant et al., “Geometric scaling effects on instrumental plate height in field flow fractionation”, J Chromatography A (2006) 1104:282-290. |
| Sant H.J., “Reduction of End Effect-Induced Zone Broadening in Field-Flow Fractionation Channels”, Anl Chem. (2006) 78:7978-7985. |
| Sant et al., “Microscale Field-Flow Fractionation: Theory and Practice”, in Microfluidic Technologies for Miniaturized Analysis Systems. (2007) Chapter 12, pp. 4710521. |
| Schäferling et al., “Optical technologies for the read out and quality control of DNA and protein microarrays,” Anal Bioanal Chem, (2006), 385: 500-517. |
| Serpengüzel et al., “Microdroplet identification and size measurement in sprays with lasing images”, Optics express (2002) 10(20):1118-1132. |
| Shackman et al., “Gradient Elution Moving Boundary Electrophoresis for High-Throughput Multiplexed Microfluidic Devices,” Anal. Chem. (2007), 79(2), 565-571. |
| Shackman et al., “Temperature gradient focusing for microchannel separations,” Anal Bioanal Chem, (2007), 387:155-158. |
| Shadpour et al., “Multichannel Microchip Electrophoresis Device Fabricated in Polycarbonate with an Integrated Contact Conductivity Sensor Array,” Anal Chem., (2007), 79(3), 870-878. |
| Sia et al., “Microfluidic devices fabricated in poly(dimethylsiloxane) for biological studies,” Electrophoresis, (2003), 24:3563-3576. |
| Sigurdson M., “AC Electrokinetic Enhancement for Assay Enhancement”, ProQuest LLC (2008) Doctoral Thesis UMI Microform 3319791 in 24 pages. |
| Singh et al., “PCR thermal management in an integrated Lab on Chip,” Journal of Physics: Conference Series, (2006), 34:222-227. |
| Situma et al., “Merging microfluidics with microarray-based bioassays”, Biomol Engin. (2006) 23:213-231. |
| Smith et al., “(576d) Micropatterned fluid lipid bilayers created using a continuous flow microspotter for multi-analyte assays,” (2007), Biosensors II, 2007 AiChE Annual Meeting, Nov. 8, 2007, Abstract in 2 pages. |
| Sommer et al., “Introduction to Microfluidics”, in Microfluidics for Biological Applications by Tian et al. [Eds] (2008) Chapter 1, pp. 1-34. |
| Squires et al., “Microfluidics: Fluid physics at the nanoliter scale,” Reviews of Modern Physics, (2005), 77(3):977-1026. |
| Sundberg et al., “Solution-phase DNA mutation scanning and SNP genotyping by nanoliter melting analysis,” Biomed Microdevices, (2007), 9:159-166, in 8 pages. |
| Tabeling, P. [Ed.], “Physics at the micrometric scale,” in Introduction to Microfluidics (2005) Chapter 1, pp. 24-69. |
| Tabeling, P. [Ed.], “Hydrodynamics of Microfluidic Systems”, in Introduction to Microfluidics; (2005) Chapter 2, pp. 70-129. |
| Tabeling, P. [Ed.], Introduction to Microfluidics; (2005) Chapters 5-7, pp. 216-297. |
| Taylor et al., Fully Automated Sample Preparation for Pathogen Detection Performed in a Microfluidic Cassette, in Micro Total Analysis Systems, Springer (2001), pp. 670-672. |
| Taylor et al., “Lysing Bacterial Spores by Sonication through a Flexible Interface in a Microfluidic System,” Anal. Chem., (2001), 73(3):492-496. |
| Taylor et al., “Microfluidic Bioanalysis Cartridge with Interchangeable Microchannel Separation Components,” (2001), The 11th International Conference on Solid-State Sensors and Actuators, Jun. 10-14, 2001, Munich, Germany; 1214-1247. |
| Taylor et al., “Disrupting Bacterial Spores and Cells using Ultrasound Applied through a Solid Interface,” (2002), 2nd Annual International IEEE-EMBS Special Topic Conference on Microtechnologies in Medicine & Biology, May 2-4, 2002, Madison, Wisconsin; 551-555. |
| Thorsen et al., “Microfluidic Large-scale integration,” Science, (2002), 298:580-584. |
| Toriello et al., “Multichannel Reverse Transcription-Polymerase Chain Reaction Microdevice for Rapid Gene Expression and Biomarker Analysis,” Anal. Chem., (2006) 78(23):7997-8003. |
| Ugaz et al., “Microfabricated electrophoresis systems for DNA sequencing and genotyping applications,” Phil. Trans. R. Soc. Lond. A, (2004), 362:1105-1129. |
| Ugaz et al., “PCR in Integrated Microfluidic Systems”, in Integrated Biochips for DNA Analysis by Liu et al. [Eds]; (2007) Chapter 7, pp. 90-106. |
| Ullman et al., “Luminescent oxygen channeling assay (LOCI™): sensitive, broadly applicable homogeneous immunoassay method”. Clin Chem. (1996) 42(9), 1518-1526. |
| Vinet et al., “Microarrays and microfluidic devices: miniaturized systems for biological analysis,” Microelectronic Engineering, (2002), 61-62:41-47. |
| Wang et al., “From biochips to laboratory-on-a-chip system”, in Genomic Signal Processing and Statistics by Dougherty et al. [Eds]; (2005) Chapter 5, pp. 163-200. |
| Wang et al., “A disposable microfluidic cassette for DNA amplification and detection”, Lab on a Chip (2006) 6(1):46-53. |
| Wang et al., “Micromachined Flow-through Polimerase Chain Reaction Chip Utilizing Multiple Membrane-activated Micropumps,” (2006), MEMS 2006, Jan. 22-26, 2006, Istanbul, Turkey; 374-377. |
| Woolley A.T., “Integrating Sample Processing and Detection with Microchip Capillary Electrophoresis of DNA”, in Integrated Biochips for DNA Analysis by Liu et al. [Eds]; (2007) Chapter 5, pp. 68-77. |
| Xiang et al., “Real Time PCR on Disposable PDMS Chip with a Miniaturized Thermal Cycler,” Biomedical Microdevices, (2005), 7(4):273-279. |
| Xuan, “Joule heating in electrokinetic flow,” Electrophoresis, (2008), 298:33-43. |
| Yang et al., “High sensitivity PCR assay in plastic micro reactors,” Lab Chip, (2002), 2:179-187. |
| Yang et al., “An independent, temperature controllable-microelectrode array,” Anal. Chem., (2004), 76(5):1537-1543. |
| Yang et al., “Cost-effective thermal isolation techniques for use on microfabricated DNA amplification and analysis devices,” J Micromech Microeng, (2005), 15:221-230. |
| Yobas et al., Microfluidic Chips for Viral RNA Extraction & Detection, (2005), 2005 IEEE, 49-52. |
| Yobas et al., “Nucleic Acid Extraction, Amplification, and Detection on Si-Based Microfluidic Platforms,” IEEE Journal of Solid-State Circuits, (2007), 42(8):1803-1813. |
| Yoon et al., “Precise temperature control and rapid thermal cycling in a micromachined DNA polymer chain reaction chip,” J. Micromech. Microeng., (2002), 12:813-823. |
| Zhang et al., “Temperature analysis of continuous-flow micro-PCR based on FEA,” Sensors and Actuators B, (2002), 82:75-81. |
| Zhang et al., “Continuous-Flow PCR Microfluidics for Rapid DNA Amplification Using Thin Film Heater with Low Thermal Mass,” Analytical Letters, (2007), 40:1672-1685, in 15 pages. |
| Zhang et al., “Direct Adsorption and Detection of Proteins, Including Ferritin, onto Microlens Array Patterned Bioarrays,” J Am Chem Soc., (2007), 129:9252-9253. |
| Zhang et al., “Micropumps, microvalves, and micromixers within PCR microfluidic chips: Advances and trens,” Biotechnology Advances, (2007), 25:483-514. |
| Zhao et al., “Heat properties of an integrated micro PCR vessel,” Proceedings of SPIE, (2001), International Conference on Sensor Technology, 4414:31-34. |
| Zou et al., “Micro-assembled multi-chamber thermal cycler for low-cost reaction chip thermal multiplexing,” Sensors and Actuators A, (2002), 102:114-121. |
| Zou et al., “Miniaturized Independently Controllable Multichamber Thermal Cycler,” IEEE Sensors Journal, (2003), 3(6):774-780. |
| Petitioner's Reply to Patent Owner's Response to Petition in Inter Partes Review of U.S. Pat. No. 7,998,708 and Exhibit List (Paper 32 in IPR 2019-00488) dated Jan. 31, 2020 (34 pages). |
| Petitioner's Reply to Patent Owner's Response to Petition in Inter Partes Review of U.S. Pat. No. 8,323,900 and Exhibit List (Paper 32 in IPR 2019-00490) dated Jan. 31, 2020 (35 pages). |
| Second Declaration of Bruce K. Gale, Ph.D. (Exhibit 1026 in IPR2019-00488 and IPR2019-00490) dated Jan. 31, 2020 (91 pages). |
| Transcript of Deposition of M. Allen Northrup, Ph.D., (Exhibit 1027 in IPR2019-00488 and IPR2019-00490), taken Dec. 19, 2019 (109 pages). |
| Patent Owner's Sur-Reply in Inter Partes Review of U.S. Pat. No. 8,323,900 (Paper 42 in IPR2019-00490) dated Mar. 12, 2020 (39 pages). |
| Patent Owner's Sur-Reply in Inter Partes Review of U.S. Pat. No. 7,998,708 (Paper 43 in IPR 2019-00488) dated Mar. 12, 2020 (41 pages). |
| Transcript of Second Deposition of Bruce K. Gale, Ph.D., (Exhibit 2068 in IPR2019-00488 and IPR2019-00490), taken Feb. 19, 2020 (352 pages). |
| Allemand et al., “pH-Dependent Specific Binding and Combing of DNA”, Biophys J. (1997) 73(4): 2064-2070. |
| Bollet, C. et al., “A simple method for the isolation of chromosomal DNA from Gram positive or acid-fast bacteria”, Nucleic Acids Research, vol. 19, No. 8 (1991), p. 1955. |
| Brahmasandra et al., On-chip DNA detection in microfabricated separation systems, SPIE Conference on Microfluidic Devices and Systems, 1998, vol. 3515, pp. 242-251, Santa Clara, CA. |
| Breadmore, M.C. et al., “Microchip-Based Purification of DNA from Biological Samples”, Anal. Chem., vol. 75 (2003), pp. 1880-1886. |
| Brody, et al., Diffusion-Based Extraction in a Microfabricated Device, Sensors and Actuators Elsevier, 1997, vol. A58, No. 1, pp. 13-18. |
| Broyles et al., “Sample Filtration, Concentration, and Separation Integrated on Microfluidic Devices” Analytical Chemistry (American Chemical Society), (2003) 75(11): 2761-2767. |
| Burns et al., “An Integrated Nanoliter DNA Analysis Device”, Science 282:484-487 (1998). |
| Chung, Y. et al., “Microfluidic chip for high efficiency DNA extraction”, Miniaturisation for Chemistry, Biology & Bioengineering, vol. 4, No. 2 (Apr. 2004), pp. 141-147. |
| Cooley et al., “Applications of Ink-Jet Printing Technology to BioMEMS and Microfluidic Systems”, Proceedings, SPIE Conference on Microfluids and BioMEMS, (Oct. 2001), 12 pages. |
| Goldmeyer et al., “Identification of Staphylococcus aureus and Determination of Methicillin Resistance Directly from Positive Blood Cultures by Isothermal Amplification and a Disposable Detection Device”, J Clin Microbiol. (Apr. 2008) 46(4): 1534-1536. |
| Handique et al., “Microfluidic flow control using selective hydrophobic patterning”, SPIE, (1997) 3224: 185-194. |
| Handique et al., “On-Chip Thermopneumatic Pressure for Discrete Drop Pumping”, Anal. Chem., (2001) 73(8):1831-1838. |
| Handique et al., “Nanoliter-vol. discrete drop injection and pumping in microfabricated chemical analysis systems”, Solid-State Sensor and Actuator Workshop (Hilton Head, South Carolina, Jun. 8-11, 1998) pp. 346-349. |
| Handique et al., “Mathematical Modeling of Drop Mixing in a Slit-Type Microchannel”, J. Micromech. Microeng., 11:548-554 (2001). |
| Handique et al., “Nanoliter Liquid Metering in Microchannels Using Hydrophobic Patterns”, Anal. Chem., 72(17):4100-4109 (2000). |
| Harding et al., “DNA isolation using Methidium-Spermine-Sepharose”, Meth Enzymol. (1992) 216:29-39. |
| Harding et al., “Rapid isolation of DNA from complex biological samples using a novel capture reagent—methidium-spermine-sepharose”, Nucl Acids Res. (1989) 17(17): 6947-6958. |
| He, et al., Microfabricated Filters for Microfluidic Analytical Systems, Analytical Chemistry, American Chemical Society, 1999, vol. 71, No. 7, pp. 1464-1468. |
| Ibrahim, et al., Real-Time Microchip PCR for Detecting Single-Base Differences in Viral and Human DNA, Analytical Chemistry, American Chemical Society, 1998, 70(9): 2013-2017. |
| International Search Report and Written Opinion dated Apr. 4, 2008 for PCT/US2007/007513, filed Mar. 26, 2007. |
| International Search Report and Written Opinion dated Jan. 5, 2009 for PCT/US2007/024022, filed Nov. 14, 2007. |
| International Search Report dated Jun. 17, 2009 for Application No. PCT/US2008/008640, filed Jul. 14, 2008. |
| Khandurina et al., Microfabricated Porous Membrane Structure for Sample Concentration and Electrophoretic Analysis, Analytical Chemistry American Chemical Society, 1999, 71(9): 1815-1819. |
| Kim et al., “Electrohydrodynamic Generation and Delivery of Monodisperse Picoliter Droplets Using a Poly(dimethylsiloxane) Microchip”, Anal Chem. (2006) 78: 8011-8019. |
| Kopp et al., Chemical Amplification: Continuous-Flow PCR on a Chip, www.sciencemag.org, 1998, vol. 280, pp. 1046-1048. |
| Kuo et al., “Remnant cationic dendrimers block RNA migration in electrophoresis after monophasic lysis”, J Biotech. (2007) 129: 383-390. |
| Kutter et al., Solid Phase Extraction on Microfluidic Devices, J. Microcolumn Separations, John Wiley & Sons, Inc., 2000, 12(2): 93-97. |
| Labchem; Sodium Hydroxide, 0,5N (0.5M); Safety Data Sheet, 2015; 8 pages. |
| Lagally et al., Single-Molecule DNA Amplification and Analysis in an Integrated Microfluidic Device, Analytical Chemistry, American Chemical Society, 2001,73(3): 565-570. |
| Livache et al., “Polypyrrole DNA chip on a Silicon Device: Example of Hepatitis C Virus Genotyping”, Analytical Biochemistry, (1998) 255: 188-194. |
| Mascini et al., “DNA electrochemical biosensors”, Fresenius J. Anal. Chem., 369: 15-22, (2001). |
| Meyers, R.A., Molecular Biology and Biotechnology: A Comprehensive Desk Reference; VCH Publishers, Inc. New York, NY; (1995) pp. 418-419. |
| Nakagawa et al., Fabrication of amino silane-coated microchip for DNA extraction from whole blood, J of Biotechnology, Mar. 2, 2005, 116:105-111. |
| Northrup et al., A Miniature Analytical Instrument for Nucleic Acids Based on Micromachined Silicon Reaction Chambers, Analytical Chemistry, American Chemical Society, 1998, 70(5): 918-922. |
| Oh K.W et al., “A Review of Microvalves”, J Micromech Microeng. (2006) 16:R13-R39. |
| Oleschuk et al., Trapping of Bead-Based Reagents within Microfluidic Systems: On-Chip Solid-Phase Extraction and Electrochromatography, Analytical Chemistry, American Chemical Society, 2000, 72(3): 585-590. |
| Pal et al., “Phase Change Microvalve for Integrated Devices”, Anal Chem. (2004) 76: 3740-3748. |
| Plambeck et al., “Electrochemical Studies of Antitumor Antibiotics”, J. Electrochem Soc.: Electrochemical Science and Technology (1984), 131(11): 2556-2563. |
| Roche et al. “Ectodermal commitment of insulin-producing cells derived from mouse embryonic stem cells” Faseb J (2005) 19: 1341-1343. |
| Ross et al., Analysis of DNA Fragments from Conventional and Microfabricated PCR Devices Using Delayed Extraction MALDI-TOF Mass Spectrometry, Analytical Chemistry, American Chemical Society, 1998, 70(10): 2067-2073. |
| Sanchez et al., “Linear-After-The-Exponential (LATE)-PCR: An advanced method of asymmetric PCR and its uses in quantitative real-time analysis”, PNAS (2004) 101(7): 1933-1938. |
| Shoffner et al., Chip PCR.I. Surface Passivation of Microfabricated Silicon-Glass Chips for PCR, Nucleic Acids Research, Oxford University Press, (1996) 24(2): 375-379. |
| Smith, K. et al., “Comparison of Commercial DNA Extraction Kits for Extraction of Bacterial Genomic DNA from Whole-Blood Samples”, Journal of Clinical Microbiology, vol. 41, No. 6 (Jun. 2003), pp. 2440-2443. |
| Wang, “Survey and Summary, from DNA Biosensors to Gene Chips”, Nucleic Acids Research, 28(16):3011 -3016, (2000). |
| Waters et al., Microchip Device for Cell Lysis, Multiplex PCR Amplification, and Electrophoretic Sizing, Analytical Chemistry, American Chemical Society, 1998, 70(1): 158-162. |
| Weigl, et al., Microfluidic Diffusion-Based Separation and Detection, www.sciencemag.org, 1999, vol. 283, pp. 346-347. |
| Wu et al., “Polycationic dendrimers interact with RNA molecules: polyamine dendrimers inhibit the catalytic activity of Candida ribozymes”, Chem Common. (2005) 3: 313-315. |
| Yoza et al., “Fully Automated DNA Extraction from Blood Using Magnetic Particles Modified with a Hyperbranched Polyamidoamine Dendrimer”, J Biosci Bioeng, 2003, 95(1): 21-26. |
| Yoza et al., DNA extraction using bacterial magnetic particles modified with hyperbranched polyamidoamine dendrimer, J Biotechnol., Mar. 20, 2003, 101(3): 219-228. |
| Zhou et al., “Cooperative binding and self-assembling behavior of cationic low molecular-weight dendrons with RNA molecules”, Org Biomol Chem. (2006) 4(3): 581-585. |
| Zhou et al., “PAMAM dendrimers for efficient siRNA delivery and potent gene silencing”, Chem Comm.(Camb.) (2006) 22: 2362-2364. |
| Edwards, “Silicon (Si),” in “Handbook of Optical Constants of Solids” (Ghosh & Palik eds., 1997) in 24 pages. |
| Hale et al., “Optical constants of Water in the 200-nm to 200-pm Wavelength Region”, Applied Optics, 12(3): 555-563 (1973). |
| Malitson, “Interspecimen Comparison of the Refractive Index of Fused Silica,” J Optical Society of America, 55:1205-1209 (1965). |
| Mastrangelo et al., Microfabricated Devices for Genetic Diagnostics. Proceedings of the IEEE (1998) 86(8):1769-1787. |
| Palina et al., “Laser Assisted Boron Doping of Silicon Wafer Solar Cells Using Nanosecond and Picosecond Laser Pulses,” 2011 37th IEEE Photovoltaic Specialists Conference, pp. 002193-002197, IEEE (2011). |
| Paulson et al., “Optical dispersion control in surfactant-free DNA thin films by vitamin B2 doping,” Nature, Scientific Reports 8:9358 (2018) published at www.nature.com/scientificreports, Jun. 19, 2018. |
| Tanaka et al., “Improved Method of DNA Extraction from Seeds Using Amine-Dendrimer Modified Magnetic Particles”, Proceedings of the 74th Annual Meeting of the Electrochemical Society of Japan; Abstract #2E09 on p. 149, Mar. 29, 2007; Faculty of Engineering, Science University of Tokyo; 4 pages. |
| Zhang et al., “PCR Microfluidic Devices for DNA Amplification,” Biotechnology Advances, 24:243-284 (2006). |
| Zou et al., “A Micromachined Integratable Thermal Reactor,” technical digest from International Electron Devices Meeting, IEEE, Washington, D.C., Dec. 2-5, 2001 (6 pages). |
| European Extended Search Report dated Feb. 16, 2017 for Application No. EP 16191793.5, filed Sep. 30, 2016. |
| International Preliminary Report on Patentability and Written Opinion dated Jan. 19, 2010 for Application No. PCT/US2008/008640, filed Jul. 14, 2008. |
| Petition for Inter Partes Review of U.S. Pat. No. 7,998,708 (Paper 1 in IPR2019-00488) dated Dec. 20, 2018 (94 pages). |
| Declaration of Bruce K. Gale, Ph.D. (Exhibit 1001 in IPR2019-00488 and IPR2019-00490) dated Dec. 20, 2018 (235 pages). |
| Patent Owner Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 7,998,708 and Exhibit List (Papers 5 and 6 in IPR2019-00488) dated Apr. 18, 2019 (79 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,323,900 (Paper 1 in IPR2019-00490) dated Dec. 20, 2018 (85 pages). |
| Patent Owner Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,323,900 and Exhibit List (Papers 5 and 6 in IPR2019-00490) dated Apr. 18, 2019 (73 pages). |
| Declaration of Michael G. Mauk, Ph.D. in Support of Patent Owner Preliminary Responses in IPR2019-00488 and IPR2019-00490 dated Apr. 18, 2019 (43 pages). |
| Decision instituting Inter Partes Review of U.S. Pat. No. 7,998,708 (Paper 8 in IPR2019-00488) dated Jul. 16, 2019 (20 pages). |
| Decision instituting Inter Partes Review of U.S. Pat. No. 8,323,900 (Paper 8 in IPR2019-00490) dated Jul. 16, 2019 (23 pages). |
| Anderson et al., “Microfluidic biochemical analysis system” Proc. 1997 IEEE Int. Conf. Solid-State Sens. Actuat. (1997) pp. 477-480. |
| Anderson et al., “Advances in Integrated Genetic Analysis” Micro Total Analysis Systems '98 Conference Proceedings, D. Kluwer Academic Publishers (1998) in 6 pages. |
| Anderson et al., “A Miniature Integrated Device for Automated Multistep Genetic Assays” Nucleic Acids Research (2000) 28(12), i-vi. |
| Burns et al., “Microfabricated Structures for Integrated DNA Analysis” Proc. Natl. Acad. Sci. USA (May 1996) 93: 5556-5561. |
| Harrison et al., “Capillary Electrophoresis and Sample Injection Systems Integrated on a Planar Glass Chip”, Anal. Chem., (1992) 64: 1926-1932. |
| Hsueh et al., “A microfabricated, electrochemiluminescence cell for the detection of amplified DNA” Proc. 1995 IEEE Int. Conf. Solid-State Sens. Actuators (1995) pp. 768-771. |
| Hsueh et al., “DNA quantification with an electrochemiluminescence microcell” Proc. 1997 IEEE Int. Conf. Solid-State Sens. Actuators (1997) pp. 175-178. |
| Jiang et al., “Directing cell migration with asymmetric micropatterns” Proc. Natl. Acad. Sci. USA (2005) 102, 975-978. |
| Lagally et al., “Monolithic integrated microfluidic DNA amplification and capillary electrophoresis analysis system” Sensors and Actuators B (2000) 63:138-146. |
| Manz et al., “Design of an open-tubular col. liquid chromatograph using silicon chip technology” Sensors and Actuators B (1990) 1:249-255. |
| Manz et al., “Planar chips technology for miniaturization and integration of separation techniques into monitoring systems: Capillary electrophoresis on a chip” Journal of Chromatography A (1992) 593:253-258. |
| Rhee et al., “Drop Mixing in a Microchannel for Lab-on-a-Chip Applications” Langmuir (2008) 24 (2): 590-601. |
| Sammarco et al., “Thermocapillary Pumping of Discrete Drops in Microfabricated Analysis Devices” AIChE Journal (1999) 45(2): 350-366. |
| Taylor et al., “Optimization of the performance of the polymerase chain reaction in silicon-based microstructures” Nucleic Acids Res. (1997) vol. 25, pp. 3164-3168. |
| Terry et al., “A Gas Chromatographic Air Analyzer Fabricated on a Silicon Wafer” IEEE T Electron Dev (1979) 26:1880-1886. |
| Whitesides G.M., “The origins and the future of microfluidics” Nature (2006) 442(7101):368-373. |
| Woias P., “Micropumps - past, progress and future prospects” Sensors and Actuators B (2005) 105, 28-38. |
| Woolley et al., “Functional integration of PCR amplification and capillary electrophoresis in a microfabricated DNA analysis device” Anal. Chem. (1996) vol. 68, pp. 4081-4086. |
| Wu et al., “Fabrication of Complex Three-dimensional Microchannel Systems in Pdms” J. Am. Chem. Soc. (2003) 125, 554-559. |
| Record of Oral Hearing in IPR2019-00488 and IPR2019-00490 held Apr. 21, 2020 in 80 pages; Petitioner's Demonstratives for Oral Hearing in IPR2019-00488 and IPR2019-00490 held Apr. 21, 2020 in 72 pages; Patent Owner's Demonstratives for Oral Hearing in IPR2019-00488 and IPR2019-00490 held Apr. 21, 2020 in 88 pages; Patent Owner's Objections to Petitioner's Oral Hearing Demonstratives in IPR2019-00488 and IPR2019-00490 dated Apr. 16, 2020 (4 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 2 in IPR2020-01083) dated Jun. 12, 2020 (104 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 2 in IPR2020-01091) dated Jun. 12, 2020 (105 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,803,069 (Paper 2 in IPR2020-01095) dated Jun. 12, 2020 (84 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,803,069 (Paper 3 in IPR2020-01100) dated Jun. 12, 2020 (83 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 2 in IPR2020-01132) dated Jun. 18, 2020 (96 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 2 in IPR2020-01133) dated Jun. 18, 2020 (96 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 2 in IPR2020-01137) dated Jun. 19, 2020 (86 pages). |
| Petition for Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 2 in IPR2020-01136) dated Jun. 19, 2020 (85 pages). |
| Declaration of Mark A. Burns, Ph.D. (Exhibit N1001 in IPR2020-01083, IPR2020-01091, IPR2020-01095 and IPR2020-01100) dated Jun. 12, 2020 (378 pages). |
| Declaration of Mark A. Burns, Ph.D. (Exhibit N1101 in IPR2020-01132 and IPR2020-01133) dated Jun. 17, 2020 (253 pages). |
| Declaration of Mark A. Burns, Ph.D. (Exhibit N1201 in IPR2020-01136 and IPR2020-01137) dated Jun. 19, 2020 (205 pages). |
| Becker H., “Hype, hope and hubris: the quest for the killer application in microfluidics”, Lab on a Chip, The Royal Society of Chemistry (2009) 9:2119-2122. |
| Becker H., “Collective Wisdom”, Lab on a Chip, The Royal Society of Chemistry (2010) 10:1351-1354. |
| Chaudhari et al., “Transient Liquid Crystal Thermometry of Microfabricated PCR Vessel Arrays”, J Microelectro Sys., (1998) 7(4):345-355. |
| Chang-Yen et al., “Design, fabrication, and packaging of a practical multianalyte-capable optical biosensor,” J Microlith Microfab Microsyst. (2006) 5(2):021105 in 8 pages. |
| Chen et al., “Total nucleic acid analysis integrated on microfluidic devices,” Lab on a Chip. (2007)7:1413-1423. |
| Cui et al., “Design and Experiment of Silicon PCR Chips,” Proc. SPIE 4755, Design, Test, Integration, and Packaging of MEMS/MOEMS 2002, (Apr. 19, 2002) pp. 71-76. |
| Grunenwald H., “Optimization of Polymerase Chain Reactions,” in Methods in Molecular Biology, PCR Protocols., Second Edition by Bartlett et al. [Eds.] Humana Press (2003) vol. 226, pp. 89-99. |
| Handal et al., “DNA mutation detection and analysis using miniaturized microfluidic systems”, Expert Rev Mol Diagn. (2006) 6(1):29-38. |
| Irawan et al., “Cross-Talk Problem on a Fluorescence Multi-Channel Microfluidic Chip System,” Biomed Micro. (2005) 7(3):205-211. |
| Khandurina et al., “Bioanalysis in microfluidic devices,” J Chromatography A, (2002) 943:159-183. |
| Liao et al., “Miniature RT-PCR system for diagnosis of RNA-based viruses,” Nucl Acids Res. (2005) 33(18):e156 in 7 pages. |
| Lin et al., “Thermal Uniformity of 12-in Silicon Wafer During Rapid Thermal Processing by Inverse Heat Transfer Method,” IEEE Transactions on Semiconductor Manufacturing, (2000) 13(4):448-456. |
| Manz et al., “Miniaturized Total Chemical Analysis Systems: a Novel Concept for Chemical Sensing,” Sensors and Actuators B1, (1990) 244-248. |
| Minco, “Conductive Heating Technologies for Medical Diagnostic Equipment,” (2006) in 13 pages. |
| Picard et al., Laboratory Detection of Group B Streptococcus for Prevention of Perinatal Disease, Eur. J. Clin. Microbiol. Infect. Dis., Jul. 16, 2004, 23: 665-671. |
| Rohsenow et al. [Eds.], Handbook of Heat Transfer, 3rd Edition McGraw-Hill Publishers (1998) Chapters 1 & 3; p. 108. |
| Shen et al., “A microchip-based PCR device using flexible printed circuit technology,” Sensors and Actuators B (2005), 105:251-258. |
| Spitzack et al., “Polymerase Chain Reaction in Miniaturized Systems: Big Progress in Little Devices”, in Methods in Molecular Biology—Microfluidic Techniques, Minteer S.D. [Ed.] Humana Press (2006), pp. 97-129. |
| Squires et al., “Microfluidics: Fluid physics at the nanoliter scale”, Rev Modern Phys. (2005) 77:977-1026. |
| Velten et al., “Packaging of Bio-MEMS: Strategies, Technologies, and Applications,” IEEE Transactions on Advanced Packaging, (2005) 28(4):533-546. |
| Zhang et al., “Miniaturized PCR chips for nucleic acid amplification and analysis: latest advances and future trends,” Nucl Acids Res., (2007) 35(13):4223-4237. |
| Patent Owner's Response in Inter Partes Review of U.S. Pat. No. 8,323,900 and Exhibit List (Paper 25 in IPR2019-00490) dated Oct. 16, 2019 (80 pages). |
| Patent Owner's Response in Inter Partes Review of U.S. Pat. No. 7,998,708 and Exhibit List (Paper 25 in IPR 2019-00488) dated Oct. 16, 2019 (93 pages). |
| Transcript of Deposition of Bruce K. Gale, Ph.D., in Support of Patent Owner's Responses (Exhibit 2012 in IPR2019-00488 and IPR2019-00490), taken Sep. 24, 2019 (124 pages). |
| Declaration of M. Allen Northrup, Ph.D. in Support of Patent Owner's Responses (Exhibit 2036 in IPR2019-00488 and IPR2019-00490) dated Oct. 16, 2019 (365 pages). |
| Complaint filed by Becton, Dickinson and Company et al., v. NeuModx Molecular, Inc. on Jun. 18, 2019 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS, Infringement Action involving U.S. Pat. Nos. 7,998,708; 8,273,308; 8,323,900; 8,415,103; 8,703,069; and 8,709,787 (29 pages). |
| Answer to Complaint filed by NeuModx Molecular, Inc. on Aug. 9, 2019 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (24 pages). |
| Amended Answer to Complaint filed by NeuModx Molecular, Inc. on Oct. 4, 2019 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (31 pages). |
| U.S. File History of U.S. Appl. No. 60/491,264, filed Jul. 31, 2003 (50 pages). |
| U.S. File History of U.S. Appl. No. 60/491,269, filed Jul. 31, 2003 (59 pages). |
| U.S. File History of U.S. Appl. No. 60/491,539, filed Aug. 1, 2003 (55 pages). |
| U.S. File History of U.S. Appl. No. 60/553,553, filed Mar. 17, 2004 (59 pages). |
| U.S. File History of U.S. Appl. No. 60/726,066, filed Oct. 11, 2005 (68 pages). |
| U.S. File History of U.S. Appl. No. 60/786,007, filed Mar. 24, 2006 (247 pages). |
| U.S. File History of U.S. Appl. No. 60/859,284, filed Nov. 14, 2006 (121 pages). |
| Zhang et al., “Parallel DNA amplification by convective polymerase chain reaction with various annealing temperatures on a thermal gradient device,” Analytical Biochemistry, (2009) 387:102-112. |
| Judgment/Final Written Decision Determining No. Challenged Claims Unpatentable in Inter Partes Review of U.S. Pat. No. 7,998,708 (Paper No. 52 in IPR2019-00488) dated Jul. 14, 2020 (43 pages). |
| Judgment/Final Written Decision Determining No. Challenged Claims Unpatentable in Inter Partes Review of U.S. Pat. No. 8,323,900 (Paper No. 51 in IPR2019-00490) dated Jul. 14, 2020 (43 pages). |
| Petitioner's Notice of Appeal in Inter Partes Review of U.S. Pat. No. 7,998,708 (Paper No. 54 in IPR2019-00488) dated Sep. 9, 2020 (48 pages). |
| Petitioner's Notice of Appeal in Inter Partes Review of U.S. Pat. No. 8,323,900 (Paper No. 53 in IPR2019-00490) dated Sep. 9, 2020 (48 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,703,069 (Paper 13 in IPR2020-01095) dated Sep. 17, 2020 (77 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 13 in IPR2020-01091) dated Sep. 17, 2020 (70 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,703,069 (Paper 14 in IPR2020-01100) dated Sep. 17, 2020 (59 pages). |
| Declaration of M. Allen Northrup, Ph.D. in Support of Patent Owner Preliminary Responses in IPR2020-01091, IPR2020-01095 and IPR2020-01100 (Exhibit H2003) dated Sep. 16, 2020 (137 pages). |
| Patent Owner's Preliminary Response to Petition for Inter Partes Review of U.S. Pat. No. 8,273,308 (Paper 13 in IPR2020-01083) dated Oct. 22, 2020 (88 pages). |
| Declaration of M. Allen Northrup, Ph.D. in support of Patent Owner Preliminary Responses in IPR2020-01083, IPR2020-01091, IPR2020-01095 and IPR2020-01100 (Exhibit H2003) dated Oct. 21, 2020 (171 pages). |
| First Amended and Supplemental Complaint filed by Becton, Dickinson and Company et al. on Jun. 25, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS, Infringement Action involving U.S. Pat. Nos. 7,998,708; 8,273,308; 8,323,900; 8,415,103; 8,703,069; 8,709,787; 10,494,663; 10,364,456; 10,443,088; 10,604,788; 10,625,261; 10,625,262; and 10,632,466 (55 pages). |
| Answer to Amended and Supplemental Complaint filed by NeuModx Molecular, Inc. on Jul. 16, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (42 pages). |
| Defendant NeuModx's Initial Invalidity Contentions filed Sep. 30, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (47 pages). |
| Benters et al., “Dendrimer-Activated Solid Supports for Nucleic Acid and Protein Microarrays”, ChemBioChem (2001) 2(9): 686-694. |
| Devarakonda et al., “The effect of PAMAM dendrimer generation size and surface functional group on the aqueous solubility of nifedipine”, Int J Pharma. 284(1-2): 133-140. |
| Brief for Appellee HandyLab, Inc. in Appeals from the USPTO, Ptab, in Nos. IPR2019-00488, IPR2019-00490, IPR2019-01493 and IPR2019-01494 filed May 24, 2021 in U.S. Court of Appeals for the Federal Circuit Case Nos. 20-2249, 20-2250, 20-2273 and 20-2276 (74 pages). |
| Reply Brief of Appellants Qiagen North American Holdings, Inc. and NeuMoDx Molecular, Inc. in Appeals from the USPTO, Ptab, in Nos. IPR2019-00488, IPR2019-00490, IPR2019-01493 and IPR2019-01494 filed Jun. 21, 2021 in U.S. Court of Appeals for the Federal Circuit Case Nos. 20-2249, 20-2250, 20-2273 and 20-2276 (44 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 10,625,262 (Paper 7 in IPR2021 -00250) dated Jul. 15, 2021 (15 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 10,632,466 (Paper 7 in IPR2021-00253) dated Jul. 15, 2021 (22 pages). |
| Decision Denying Institution of Inter Partes Review of U.S. Pat. No. 10,625,261 (Paper 7 in IPR2021-00251) dated Jul. 15, 2021 (24 pages). |
| Patent Owner's Response in Inter Partes Review of U.S. Pat. No. 8,709,787 and Exhibit List (Paper 29 in IPR 2020-01132) dated Jul. 15, 2021 (87 pages). |
| Decision Granting Institution of Inter Partes Review of U.S. Pat. No. 8,415,103 on Rehearing (Paper 23 in IPR2020-01133) dated Aug. 6, 2021 (20 pages). |
| Decision of U.S. Court of Appeal for the Federal Circuit Affirming Inter Partes Review Final Written Decisions Determining No Challenged Claims of U.S. Pat. Nos. 7,998,708 and 8,323,900 are Unpatentable (IPR2019-00488, IPR2019-00490, IPR2019-01493, and IPR2019-01494) dated Oct. 29, 2021 (12 pages). |
| Joint Motion to Terminate Inter Partes Review of U.S. Pat. No. 8,709,787 (Paper 37 in IPR 2020-01132) dated Nov. 15, 2021 (8 pages). |
| Joint Motion to Terminate Inter Partes Review of U.S. Pat. No. 8,415,103 (Paper 35 in IPR 2020-01133) dated Nov. 15, 2021 (8 pages). |
| Stipulation of Dismissal filed by Plaintiffs Becton, Dickinson and Company, Geneohm Sciences Canada, Inc. and HandyLab, Inc. and Defendants NeuMoDx Molecular, Inc., Qiagen GmbH, and Qiagen North American Holdings, Inc. on Nov. 12, 2021 in U.S. District Court, Delaware, Case # 1:19-cv-01226-LPS (3 pages). |
| Number | Date | Country | |
|---|---|---|---|
| 20190324050 A1 | Oct 2019 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60959437 | Jul 2007 | US | |
| 60959437 | Jul 2007 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15160186 | May 2016 | US |
| Child | 16354746 | US | |
| Parent | 13652368 | Oct 2012 | US |
| Child | 15160186 | US | |
| Parent | 12212403 | Sep 2008 | US |
| Child | 13652368 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12173023 | Jul 2008 | US |
| Child | 12212403 | US | |
| Parent | 12218498 | Jul 2008 | US |
| Child | 12173023 | US |
