Patent Grant
12128405
The technology described herein generally relates to microfluidic cartridges. The technology more particularly relates to microfluidic cartridges that are configured to carry out PCR on nucleotides of interest, particularly from several biological samples in parallel, within microfluidic channels in the cartridge, and permit detection of those nucleotides.
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 mix-up. 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 polymerase chain reaction (PCR) to amplify a vector of interest. Once amplified, the presence or absence of a nucleotide of interest from the sample needs to be determined unambiguously. Sample preparation is a process that is susceptible to automation but is also relatively routinely carried out in almost any location. 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.
There is therefore a need for a method and apparatus of carrying out PCR on prepared biological samples and detecting amplified nucleotides, preferably with high throughput. In particular there is a need for an easy-to-use device that can deliver a diagnostic result on several samples in a short time.
The discussion of the background to the technology herein is included to explain the context of the technology. 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 present technology includes methods and devices for detecting polynucleotides in samples, particularly from biological samples. In particular, the technology relates to microfluidic devices that carry out PCR on nucleotides of interest within microfluidic channels, and permit detection of those nucleotides.
In particular, the present technology provides for a microfluidic cartridge, comprising: a first PCR reaction chamber; a second PCR reaction chamber; a first inlet, in fluid communication with the first PCR reaction chamber; a second inlet, in fluid communication with the second PCR reaction chamber, a first set of microfluidic valves configured to control motion of a sample from the first inlet to the first PCR reaction chamber; and a second set of microfluidic valves configured to control motion of a sample from the second inlet to the second PCR reaction chamber.
The present technology includes a process for carrying out PCR on a plurality of polynucleotide-containing samples, the method comprising: introducing the plurality of samples into a microfluidic cartridge, wherein the cartridge has a plurality of PCR reaction chambers configured to permit thermal cycling of the plurality of samples independently of one another, moving the plurality of samples into the respective plurality of PCR reaction chambers; and amplifying polynucleotides contained with the plurality of samples, by application of successive heating and cooling cycles to the PCR reaction chambers.
The present technology further comprises a number of other embodiments, as set forth herein.
A microfluidic substrate, comprising: a first PCR reaction chamber; a second PCR reaction chamber; a first inlet, in fluid communication with the first PCR reaction chamber; a second inlet, in fluid communication with the second PCR reaction chamber; a first set of microfluidic valves configured to isolate the first reaction chamber from the first inlet; and a second set of microfluidic valves configured to isolate the second PCR reaction chamber from the second inlet.
A microfluidic substrate, comprising: a plurality of sample lanes, wherein each of the plurality of sample lanes comprises a microfluidic network having, in fluid communication with one another: an inlet; a first valve and a second valve; a first channel leading from the inlet, via the first valve, to a reaction chamber; and a second channel leading from the reaction chamber, via the second valve, to a vent.
A microfluidic cartridge having a plurality of microfluidic networks, wherein each of the microfluidic networks, including a PCR reaction chamber, an inlet hole, and the valves for isolating the PCR reaction chamber, is defined in a single substrate.
A method of carrying out PCR independently on a plurality of polynucleotide-containing samples, the method comprising: introducing the plurality of samples in to a microfluidic cartridge, wherein the cartridge has a plurality of PCR reaction chambers configured to permit thermal cycling of the plurality of samples independently of one another, moving the plurality of samples into the respective plurality of PCR reaction chambers; isolating the plurality of PCR reaction chambers; and amplifying polynucleotides contained with the plurality of samples, by application of successive heating and cooling cycles to the PCR reaction chambers.
A microfluidic valve, comprising: a first chamber, connected to a first load channel; a second chamber, connected to a second load channel; and a flow channel, wherein the first and second load channels are each connected to the flow channel, and wherein the first and second load channels each contain a thermally responsive substance that, upon actuation of the valve, flows into the flow channel thereby sealing it, and wherein the flow channel is constricted along a length either side of the first and second load channels.
A microfluidic valve, comprising: a chamber, connected to a load channel; and a flow channel, wherein the load channel is connected to the flow channel, and wherein the load channel contains a thermally responsive substance that, upon actuation of the valve, flows into the flow channel thereby sealing it, and wherein the flow channel is constricted along a length either side of the load channel.
A method of making a microfluidic valve, the method comprising: directing a dispensing head over an inlet hole in a microfluidic substrate; propelling a quantity of thermally responsive substance from the dispensing head into the inlet hole; and maintaining a temperature of the microfluidic substrate so that the thermally responsive substance flows by capillary action from the inlet hole into a microfluidic channel in communication with the inlet hole.
The microfluidic cartridge described herein can be configured for use with an apparatus comprising: a chamber configured to receive the microfluidic cartridge; at least one heat source thermally coupled to the cartridge and configured to apply heat and cooling cycles that carry out PCR on one or more microdroplets of polynucleotide-containing sample in the cartridge; a detector configured to detect presence of one or more polynucleotides in the one or more samples; and a processor coupled to the detector and the heat source, configured to control heating of one or more regions of the microfluidic cartridge.
The details of one or more embodiments of the technology are set forth in the accompanying drawings and further description herein. Other features, objects, and advantages of the technology will be apparent from the description and drawings, and from the claims.
Microfluidic Cartridge
The present technology comprises a microfluidic cartridge that is configured to carry out an amplification, such as by PCR, of one or more polynucleotides from one or more samples. It is to be understood that, unless specifically made clear to the contrary, where the term PCR is used herein, any variant of PCR including but not limited to real-time and quantitative, and any other form of polynucleotide amplification is intended to be encompassed. The microfluidic cartridge need not be self-contained and can be designed so that it receives thermal energy from one or more heating elements present in an external apparatus with which the cartridge is in thermal communication. An exemplary such apparatus is further described herein; additional embodiments of such a system are found in U.S. patent application Ser. No. 11/985,577, entitled “Microfluidic System for Amplifying and Detecting Polynucleotides in Parallel”, and filed Nov. 14, 2007, the specification of which is incorporated herein by reference.
By cartridge is meant a unit that may be disposable, or reusable in whole or in part, and that is configured to be used in conjunction with some other apparatus that has been suitably and complementarily configured to receive and operate on (such as deliver energy to) the cartridge.
By microfluidic, as used herein, is meant that volumes of sample, and/or reagent, and/or amplified polynucleotide are from about 0.1 μl to about 999 μl, such as from 1-100 μl, or from 2-25 μl. Similarly, as applied to a cartridge, the term microfluidic means that various components and channels of the cartridge, as further described herein, are configured to accept, and/or retain, and/or facilitate passage of microfluidic volumes of sample, reagent, or amplified polynucleotide. Certain embodiments herein can also function with nanoliter volumes (in the range of 10-500 nanoliters, such as 100 nanoliters).
One aspect of the present technology relates to a microfluidic cartridge having two or more sample lanes arranged so that analyses can be carried out in two or more of the lanes in parallel, for example simultaneously, and wherein each lane is independently associated with a given sample.
A sample lane is an independently controllable set of elements by which a sample can be analyzed, according to methods described herein as well as others known in the art. A sample lane comprises at least a sample inlet, and a microfluidic network having one or more microfluidic components, as further described herein.
In various embodiments, a sample lane can include a sample inlet port or valve, and a microfluidic network that comprises, in fluidic communication one or more components selected from the group consisting of: at least one thermally actuated valve, a bubble removal vent, at least one thermally actuated pump, a gate, mixing channel, positioning element, microreactor, a downstream thermally actuated valve, and a PCR reaction chamber. The sample inlet valve can be configured to accept a sample at a pressure differential compared to ambient pressure of between about 70 and 100 kilopascals.
The cartridge can therefore include a plurality of microfluidic networks, each network having various components, and each network configured to carry out PCR on a sample in which the presence or absence of one or more polynucleotides is to be determined.
A multi-lane cartridge is configured to accept a number of samples in series or in parallel, simultaneously or consecutively, in particular embodiments 12 samples, wherein the samples include at least a first sample and a second sample, wherein the first sample and the second sample each contain one or more polynucleotides in a form suitable for amplification. The polynucleotides in question may be the same as, or different from one another, in different samples and hence in different lanes of the cartridge. The cartridge typically processes each sample by increasing the concentration of a polynucleotide to be determined and/or by reducing the concentration of inhibitors relative to the concentration of polynucleotide to be determined.
The multi-lane cartridge comprises at least a first sample lane having a first microfluidic network and a second lane having a second microfluidic network, wherein each of the first microfluidic network and the second microfluidic network is as elsewhere described herein, and wherein the first microfluidic network is configured to amplify polynucleotides in the first sample, and wherein the second microfluidic network is configured to amplify polynucleotides in the second sample.
In various embodiments, the microfluidic network can be configured to couple heat from an external heat source to a sample mixture comprising PCR reagent and neutralized polynucleotide sample under thermal cycling conditions suitable for creating PCR amplicons from the neutralized polynucleotide sample.
At least the external heat source may operate under control of a computer processor, configured to execute computer readable instructions for operating one or more components of each sample lane, independently of one another, and for receiving signals from a detector that measures fluorescence from one or more of the PCR reaction chambers.
For example,
In various embodiments, the PCR reagent mixture can include a positive control plasmid and a plasmid fluorogenic hybridization probe selective for at least a portion of the plasmid, and the microfluidic cartridge can be configured to allow independent optical detection of the fluorogenic hybridization probe and the plasmid fluorogenic hybridization probe.
In various embodiments, the microfluidic cartridge can accommodate a negative control polynucleotide, wherein the microfluidic network can be configured to independently carry out PCR on each of a neutralized polynucleotide sample and a negative control polynucleotide with the PCR reagent mixture under thermal cycling conditions suitable for independently creating PCR amplicons of the neutralized polynucleotide sample and PCR amplicons of the negative control polynucleotide. Each lane of a multi-lane cartridge as described herein can perform two reactions when used in conjunction with two fluorescence detection systems per lane. A variety of combinations of reactions can be performed in the cartridge, such as two sample reactions in one lane, a positive control and a negative control in two other lanes; or a sample reaction and an internal control in one lane and a negative control in a separate lane.
In preferred embodiments, the multi-sample cartridge has a size substantially the same as that of a 96-well plate as is customarily used in the art. Advantageously, then, such a cartridge may be used with plate handlers used elsewhere in the art.
The sample inlets of adjacent lanes are reasonably spaced apart from one another to prevent any contamination of one sample inlet from another sample when a user introduces a sample into any one cartridge. In an embodiment, the sample inlets are configured so as to prevent subsequent inadvertent introduction of sample into a given lane after a sample has already been introduced into that lane. In certain embodiments, the multi-sample cartridge is designed so that a spacing between the centroids of sample inlets is 9 mm, which is an industry-recognized standard. This means that, in certain embodiments the center-to-center distance between inlet holes in the cartridge that accept samples from PCR tubes, as further described herein, is 9 mm. The inlet holes can be manufactured conical in shape with an appropriate conical angle so that industry-standard pipette tips (2 μl, 20 μl, 200 μl, volumes, etc.) fit snugly therein. The cartridge herein may be adapted to suit other, later-arising, industry standards not otherwise described herein, as would be understood by one of ordinary skill in the art.
A microfluidic cartridge as used herein may be constructed from a number of layers. Accordingly, one aspect of the present technology relates to a microfluidic cartridge that comprises a first, second, third, fourth, and fifth layers wherein one or more layers define a plurality of microfluidic networks, each network having various components configured to carry out PCR on a sample in which the presence or absence of one or more polynucleotides is to be determined. In various embodiments, one or more such layers are optional.
Microfluidic cartridge 400 can be fabricated as desired. The cartridge can include a microfluidic substrate layer 424, typically injection molded out of a plastic, such as a zeonor plastic (cyclic olefin polymer), having a PCR channel and valve channels on a first side and vent channels and various inlet holes, including wax loading holes and liquid inlet holes, on a second side (disposed toward hydrophobic vent membrane 426). It is advantageous that all the microfluidic network defining structures, such as PCR reactors, valves, inlet holes, and air vents, are defined on the same single substrate 424. This attribute facilitates manufacture and assembly of the cartridge. Additionally, the material from which this substrate is formed is rigid or non-deformable, non-venting to air and other gases, and has a low autofluorescence to facilitate detection of polynucleotides during an amplification reaction performed in the microfluidic circuitry defined therein. Rigidity is advantageous because it facilitates effective and uniform contact with a heat unit as further described herein. Use of a non-venting material is also advantageous because it reduces the likelihood that the concentration of various species in liquid form will change during analysis. Use of a material having low auto-fluorescence is also important so that background fluorescence does not detract from measurement of fluorescence from the analyte of interest.
The cartridge can further include, disposed on top of the substrate 424, an oleophobic/hydrophobic vent membrane layer 426 of a porous material, such as 0.2 to 1.0 micron pore-size membrane of modified polytetrafluorethylene, the membrane being typically between about 25 and about 100 microns thick, and configured to cover the vent channels of microfluidic substrate 424, and attached thereto using, for example, heat bonding.
Typically, the microfluidic cartridge further includes a layer 428, 430 of polypropylene or other plastic label with pressure sensitive adhesive (typically between about 50 and 150 microns thick) configured to seal the wax loading holes of the valves in substrate 424, trap air used for valve actuation, and serve as a location for operator markings. In
In various embodiments, the label is a computer-readable label. For example, the label can include a bar code, a radio frequency tag or one or more computer-readable characters. The label can be formed of a mechanically compliant material. For example, the mechanically compliant material of the label can have a thickness of between about 0.05 and about 2 millimeters and a Shore hardness of between about 25 and about 100. The label can be positioned such that it can be read by a sample identification verifier as further described herein.
The cartridge can further include a heat sealable laminate layer 422 (typically between about 100 and about 125 microns thick) attached to the bottom surface of the microfluidic substrate 424 using, for example, heat bonding. This layer serves to seal the PCR channels and vent channels in substrate 424. The cartridge can further include a thermal interface material layer 420 (typically about 125 microns thick), attached to the bottom of the heat sealable laminate layer using, for example, pressure sensitive adhesive. The layer 420 can be compressible and have a higher thermal conductivity than common plastics, thereby serving to transfer heat across the laminate more efficiently. Typically, however, layer 420 is not present.
The application of pressure to contact the cartridge to the heater of an instrument that receives the cartridge generally assists in achieving better thermal contact between the heater and the heat-receiveable parts of the cartridge, and also prevents the bottom laminate structure from expanding, as would happen if the PCR channel was only partially filled with liquid and the air entrapped therein would be thermally expanded during thermocycling.
In use, cartridge 400 is typically thermally associated with an array of heat sources configured to operate the components (e.g., valves, gates, actuators, and processing region 410) of the device. Exemplary such heater arrays are further described herein. Additional embodiments of heater arrays are described in U.S. patent application Ser. No. 11/940,315, entitled “Heater Unit for Microfluidic Diagnostic System” and filed Nov. 14, 2007, the specification of which is incorporated herein by reference in its entirety. In some embodiments, the heat sources are controlled by a computer processor and actuated according to a desired protocol. Processors configured to operate microfluidic devices are described in, e.g., U.S. application Ser. No. 09/819,105, filed Mar. 28, 2001, which application is incorporated herein by reference.
In various embodiments, during transport and storage, the microfluidic cartridge can be further surrounded by a sealed pouch. The microfluidic cartridge can be sealed in the pouch with an inert gas. The microfluidic cartridge can be disposable for example after one or more of its sample lanes have been used.
Highly Multiplexed Embodiments
Embodiments of the cartridge described herein may be constructed that have high-density microfluidic circuitry on a single cartridge that thereby permit processing of multiple samples in parallel, or in sequence, on a single cartridge. Preferred numbers of such multiple samples include 20, 24, 36, 40, 48, 50, 60, 64, 72, 80, 84, 96, and 100, but it would be understood that still other numbers are consistent with the apparatus and cartridge herein, where deemed convenient and practical.
Accordingly, different configurations of lanes, sample inlets, and associated heater networks than those explicitly depicted in the FIGS. and examples that can facilitate processing such numbers of samples on a single cartridge are within the scope of the instant disclosure. Similarly, alternative configurations of detectors and heating elements for use in conjunction with such a highly multiplexed cartridge are also within the scope of the description herein.
It is also to be understood that the microfluidic cartridges described herein are not to be limited to rectangular shapes, but can include cartridges having circular, elliptical, triangular, rhombohedral, square, and other shapes. Such shapes may also be adapted to include some irregularity, such as a cut-out, to facilitate placement in a complementary apparatus as further described herein.
In an exemplary embodiment, a highly multiplexed cartridge has 48 sample lanes, and permits independent control of each valve in each lane by suitably configured heater circuitry, with 2 banks of thermocycling protocols per lane, as shown in
The various embodiments shown in
During the design and manufacture of highly multiplexed cartridges, photolithographic processing steps such as etching, hole drilling/photo-chemical drilling/sand-blasting/ion-milling processes should be optimized to give well defined holes and microchannel pattern. Proper distances between channels should be identified and maintained to obtain good bonding between the microchannel substrate and the heat conducting substrate layer. In particular, it is desirable that minimal distances are maintained between pairs of adjacent microchannels to promote, reliable bonding of the laminate in between the channels.
The fabrication by injection molding of these complicated microfluidic structures having multiple channels and multiple inlet holes entails proper consideration of dimensional repeatability of these structures over multiple shots from the injection molding master pattern. Proper consideration is also attached to the placement of ejector pins to push out the structure from the mold without causing warp, bend or stretching of it. For example, impression of the ejector pins on the microfluidic substrate should not sink into the substrate thereby preventing planarity of the surface of the cartridge. The accurate placement of various inlet holes (such as sample inlet holes, valve inlet holes and vent holes) relative to adjacent microfluidic channels is also important because the presence of these holes can cause knit-lines to form that might cause unintended leak from a hole to a microchannel. Highly multiplexed microfluidic substrates may be fabricated in other materials such as glass, silicon.
The size of the substrate relative to the number of holes is also factor during fabrication because it is easy to make a substrate having just a simple microfluidic network with a few holes (maybe fewer than 10 holes) and a few microchannels, but making a substrate having over 24, or over 48, or over 72 holes, etc., is more difficult.
Microfluidic Networks
Particular components of exemplary microfluidic networks are further described herein.
Channels of a microfluidic network in a lane of cartridge typically have at least one sub-millimeter cross-sectional dimension. For example, channels of such a network may have a width and/or a depth of about 1 mm or less (e.g., about 750 microns or less, about 500 microns, or less, about 250 microns or less).
Both valves 204 and 206 are closed prior to thermocycling to prevent or reduce any evaporation of liquid, bubble generation, or movement of fluid from the PCR reactor. End vent 214 is configured to prevent a user from introducing an excess amount of liquid into the microfluidic cartridge, as well as playing a role of containing any sample from spilling over to unintended parts of the cartridge. A user may input sample volumes as small as an amount to fill the region from the bubble removal vent (if present) to the middle of the microreactor, or up to valve 204 or beyond valve 204. The use of microvalves prevents both loss of liquid or vapor thereby enabling even a partially filled reactor to successfully complete a PCR thermocycling reaction.
The reactor 210 is a microfluidic channel that is heated through a series of cycles to carry out amplification of nucleotides in the sample, as further described herein, and according to amplification protocols known to those of ordinary skill in the art. The inside walls of the channel in the PCR reactor are typically made very smooth and polished to a shiny finish (for example, using a polish selected from SPI A1, SPI A2, SPI A3, SPI B1, or SPI B2) during manufacture. This is in order to minimize any microscopic quantities of air trapped in the surface of the PCR channel, which would causing bubbling during the thermocycling steps. The presence of bubbles especially in the detection region of the PCR channel could also cause a false or inaccurate reading while monitoring progress of the PCR. Additionally, the PCR channel can be made shallow such that the temperature gradient across the depth of the channel is minimized.
The region of the cartridge 212 above PCR reactor 210 is a thinned down section to reduce thermal mass and autofluorscnce from plastic in the cartridge. It permits a detector to more reliably monitor progress of the reaction and also to detect fluorescence from a probe that binds to a quantity of amplified nucleotide. Exemplary probes are further described herein. The region 212 can be made of thinner material than the rest of the cartridge so as to permit the PCR channel to be more responsive to a heating cycle (for example, to rapidly heat and cool between temperatures appropriate for denaturing and annealing steps), and so as to reduce glare, autofluorescence, and undue absorption of fluorescence.
After PCR has been carried out on a sample, and presence or absence of a polynucleotide of interest has been determined, it is preferred that the amplified sample remains in the cartridge and that the cartridge is either used again (if one or more lanes remain unused), or disposed of. Should a user wish to run a post amplification analysis, such as gel electrophoresis, the user may pierce a hole through the laminate of the cartridge, and recover an amount—typically about 1.5 microliter—of PCR product. The user may also place the individual PCR lane on a special narrow heated plate, maintained at a temperature to melt the wax in the valve, and then aspirate the reacted sample from the inlet hole of that PCR lane.
In various embodiments, the microfluidic network can optionally include at least one reservoir configured to contain waste.
Table 1 outlines typical volumes, pumping pressures, and operation times associated with various components of a microfluidic cartridge described herein.
Valves
A valve (sometimes referred to herein as a microvalve) is a component in communication with a channel, such that the valve has a normally open state allowing material to pass along a channel from a position on one side of the valve (e.g., upstream of the valve) to a position on the other side of the valve (e.g., downstream of the valve). Upon actuation of the valve, the valve transitions to a closed state that prevents material from passing along the channel from one side of the valve to the other. For example, in one embodiment, a valve can include a mass of a thermally responsive substance (TRS) that is relatively immobile at a first temperature and more mobile at a second temperature. The first and second temperatures are insufficiently high to damage materials, such as polymer layers of a microfluidic cartridge in which the valve is situated. A mass of TRS can be an essentially solid mass or an agglomeration of smaller particles that cooperate to obstruct the passage when the valve is closed. Examples of TRS's include a eutectic alloy (e.g., a solder), wax (e.g., an olefin), polymers, plastics, and combinations thereof. The TRS can also be a blend of variety of materials, such as an emulsion of thermoelatic polymer blended with air microbubbles (to enable higher thermal expansion, as well as reversible expansion and contraction), polymer blended with expancel material (offering higher thermal expansion), polymer blended with heat conducting microspheres (offering faster heat conduction and hence, faster melting profiles), or a polymer blended with magnetic microspheres (to permit magnetic actuation of the melted thrmoresponsive material).
Generally, for such a valve, the second temperature is less than about 90° C. and the first temperature is less than the second temperature (e.g., about 70° C. or less). Typically, a chamber is in gaseous communication with the mass of TRS. The valve is in communication with a source of heat that can be selectively applied to the chamber of air and to the TRS. Upon heating gas (e.g., air) in the chamber and heating the mass of TRS to the second temperature, gas pressure within the chamber due to expansion of the volume of gas, forces the mass to move into the channel, thereby obstructing material from passing therealong.
An exemplary valve is shown in
In various other embodiments, a valve for use with a microfluidic network in a microfluidic cartridge herein can be a bent valve as shown in
In various other embodiments, a valve for use with a microfluidic network can include a curved valve as shown in
Gates
In various embodiments, a microfluidic network can include a narrow gate 380 as shown in
In various embodiments, the gate can be configured to minimize the effective area or footprint of the gate within the network and thus bent gate configurations, although not shown herein are consistent with the foregoing description.
Vents
In various embodiments, the microfluidic network can include at least one hydrophobic vent in addition to an end vent. A vent is a general outlet (hole) that may or may not be covered with a hydrophobic membrane. An exit hole is an example of a vent that need not be covered by a membrane.
A hydrophobic vent (e.g., a vent in
The hydrophobic vents of the present technology are preferably constructed so that the amount of air that escapes through them is maximized while minimizing the volume of the channel below the vent surface. Accordingly, it is preferable that the vent is constructed so as to have a hydrophobic membrane 1303 of large surface area and a shallow cross section of the microchannel below the vent surface.
Hydrophobic vents are useful for bubble removal and typically have a length of at least about 2.5 mm (e.g., at least about 5 mm, at least about 7.5 mm) along a channel 1305 (see
The depth of the channel within the hydrophobic vent is typically about 75% or less (e.g., about 65% or less, about 60% or less) of the depth of the channel upstream 1301 and downstream (not shown) of the hydrophobic vent. For example, in some embodiments the channel depth within the hydrophobic vent is about 150 microns and the channel depth upstream and downstream of the hydrophobic vent is about 250 microns. Other dimensions are consistent with the description herein.
A width of the channel within the hydrophobic vent is typically at least about 25% wider (e.g., at least about 50% wider) than a width of the channel upstream from the vent and downstream from the vent. For example, in an exemplary embodiment, the width of the channel within the hydrophobic vent is about 400 microns, and the width of the channel upstream and downstream from the vent is about 250 microns. Other dimensions are consistent with the description herein.
The vent in
Heater Configurations to Ensure Uniform Healing of a Region
The microfluidic cartridges described herein are configured to position in a complementary receiving bay in an apparatus that contains a heater unit. The heater unit is configured to deliver heat to specific regions of the cartridge, including but not limited to one or more microfluidic components, at specific times. For example, the heat source is configured so that particular heating elements are situated adjacent to specific components of the microfluidic network of the cartridge. In certain embodiments, the apparatus uniformly controls the heating of a region of a microfluidic network. In an exemplary embodiment, multiple heaters can be configured to simultaneously and uniformly heat a single region, such as the PCR reaction chamber, of the microfluidic cartridge. In other embodiments, portions of different sample lanes are heated simultaneously and independently of one another.
An exemplary heater array is shown in
Referring to
Generally, the heating of microfluidic components, such as a PCR reaction chamber, is controlled by passing currents through suitably configured microfabricated heaters. Under control of suitable circuitry, the lanes of a multi-lane cartridge can then be controlled independently of one another. This can lead to a greater energy efficiency of the apparatus, because not all heaters are heating at the same time, and a given heater is receiving current for only that fraction of the time when it is required to heat. Control systems and methods of controllably heating various heating elements are further described in U.S. patent application Ser. No. 11/940,315, filed Nov. 14, 2007 and entitled “Heater Unit for Microfluidic Diagnostic System”.
The configuration for uniform heating, shown in
In other embodiments, as further described in U.S. patent application Ser. No. 11/940,315, filed Nov. 14, 2007 and entitled “Heater Unit for Microfluidic Diagnostic System”, the heaters may have an associated temperature sensor, or may themselves function as sensors.
Use of Cutaways in Cartridge and Substrate to Improve Rate of Cooling During PCR Cycling
During a PCR amplification of a nucleotide sample, a number of thermal cycles are carried out. For improved efficiency, the cooling between each application of heat is preferably as rapid as possible. Improved rate of cooling can be achieved with various modifications to the heating substrate and/or the cartridge, as shown in
One way to achieve rapid cooling is to cutaway portions of the microfluidic cartridge substrate, as shown in
Another way to achieve rapid cooling is to cutaway portions of the heater substrate, and also to use ambient air cooling, as further described in U.S. patent application Ser. No. 11/940,315, filed Nov. 14, 2007 and entitled “Heater Unit for Microfluidic Diagnostic System”.
An example of thermal cycling performance in a PCR reaction chamber obtained with a configuration as described herein, is shown in
Manufacturing Process for Cartridge
At 1802, a laminate layer is applied to a microfluidic substrate that has previously been engineered, for example by injection molding, to have a microfluidic network constructed in it; edges are trimmed from the laminate where they spill over the bounds of the substrate.
At 1804, wax is dispensed and loaded into the microvalves of the microfluidic network in the microfluidic substrate. An exemplary process for carrying this out is further described herein.
At 1806, the substrate is inspected to ensure that wax from step 1804 is loaded properly and that the laminate from step 1802 adheres properly to it. If a substrate does not satisfy either or both of these tests, it is usually discarded. If substrates repeatedly fail either or both of these tests, then the wax dispensing, or laminate application steps, as applicable, are reviewed.
At 1808, a hydrophobic vent membrane is applied to, and heat bonded to, the top of the microfluidic substrate covering at least the one or more vent holes, and on the opposite face of the substrate from the laminate. Edges of the membrane that are in excess of the boundary of the substrate are trimmed.
At 1810, the assembly is inspected to ensure that the hydrophobic vent membrane is bonded well to the microfluidic substrate without heat-clogging the microfluidic channels. If any of the channels is blocked, or if the bond between the membrane and the substrate is imperfect, the assembly is discarded, and, in the case of repeated discard events, the foregoing process step 1808 is reviewed.
At 1812, optionally, a thermally conductive pad layer is applied to the bottom laminate of the cartridge.
At 1814, two label strips are applied to the top of the microfluidic substrate, one to cover the valves, and a second to protect the vent membranes. It would be understood that a single label strip may be devised to fulfill both of these roles.
At 1816, additional labels are printed or applied to show identifying characteristics, such as a barcode #, lot #and expiry date on the cartridge. Preferably one or more of these labels has a space and a writable surface that permits a user to make an identifying annotation on the label, by hand.
Optionally, at 1818, to facilitate transport and delivery to a customer, assembled and labeled cartridges are stacked, and cartridges packed into groups, such as groups of 25, or groups of 10, or groups of 20, or groups of 48 or 50. Preferably the packaging is via an inert and/or moisture-free medium.
Wax Loading in Valves
In general, a valve as shown in, e.g.,
To accomplish those steps, a heated dispenser head can be accurately positioned over the inlet hole of the microchannel in the microfluidic device, and can dispense molten wax drops in volumes as small as 75 nanoliters with an accuracy of 20%. A suitable dispenser is also one that can deposit amounts smaller than 100 nl with a precision of +/−20%. The dispenser should also be capable of heating and maintaining the dispensing temperature of the TRS to be dispensed. For example, it may have a reservoir to hold the solution of TRS. It is also desirable that the dispense head can have freedom of movement at least in a horizontal (x-y) plane so that it can easily move to various locations of a microfluidic substrate and dispense volumes of TRS into valve inlets at such locations without having to be re-set, repositioned manually, or recalibrated in between each dispense operation. Specific dimensions shown in
The inlet hole of the microfluidic cartridge, or other microchannel device, is dimensioned in such a way that the droplet of 75 nl can be accurately propelled to the bottom of the inlet hole using, for example, compressed air, or in a manner similar to an inkjet printing method. The microfluidic cartridge is maintained at a temperature above the melting point of the wax thereby permitting the wax to stay in a molten state immediately after it is dispensed. After the drop falls to the bottom of the inlet hole 1901, the molten wax is drawn into the narrow channel by capillary action, as shown in the sequence of views in
PCR Reagent Mixtures
In various embodiments, the sample for introduction into a lane of the microfluidic cartridge can include a PCR reagent mixture comprising a polymerase enzyme and a plurality of nucleotides.
In various embodiments, preparation of a PCR-ready sample for use with an apparatus and cartridge as described herein can include 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).
The PCR-ready sample can be prepared, for example, using the following steps: (1) collect sample in sample collection buffer, (2) transfer entire sample to lysis tube, mix, heat, and incubate for seven minutes, (3) place on magnetic rack, allow beads to separate, aspirate supernatant, (4) add 100 μl of Buffer 1, mix, place on magnetic rack, allow beads to separate, aspirate supernatant, (5) add 10 μl of Buffer 2, mix, place in high temperature heat block for 3 minutes, place on magnetic rack, allow beads to separate, transfer 5 μl supernatant, and (6) Add 5 μl of Buffer 3, transfer 1 to 10 μl of supernatant for PCR amplification and detection.
The PCR reagent mixture can be in the form of one or more lyophilized pellets and the steps by which the PCR-ready sample is prepared can involve reconstituting the PCR pellet by contacting it with liquid to create a PCR reagent mixture solution. In yet another embodiment, each of the PCR lanes may have dried down or lyophilized ASR reagents preloaded such that the user only needs to input prepared polynucleotide sample into the PCR. In another embodiment, the PCR lanes may have only the application-specific probes and primers pre-measured and pre-loaded, and the user inputs a sample mixed with the PCR reagents.
In various embodiments, the PCR-ready sample can include at least one probe that can be selective for a polynucleotide sequence, wherein the steps by which the PCR-ready sample is prepared involve contacting the neutralized polynucleotide sample or a PCR amplicon thereof with the probe. The probe can be a fluorogenic hybridization probe. The fluorogenic hybridization probe can include a polynucleotide sequence coupled to a fluorescent reporter dye and a fluorescence quencher dye.
In various embodiments, the PCR-ready sample further includes a sample buffer.
In various embodiments, the PCR-ready sample includes at least one probe that is selective for a polynucleotide sequence, e.g., the polynucleotide sequence that is characteristic of a pathogen selected from the group consisting of gram positive bacteria, gram negative bacteria, yeast, fungi, protozoa, and viruses.
In various embodiments, the PCR reagent mixture can further include a polymerase enzyme, a positive control plasmid and a fluorogenic hybridization probe selective for at least a portion of the plasmid.
In various embodiments, the probe can be selective for a polynucleotide sequence that is characteristic of an organism, for example any organism that employs deoxyribonucleic acid or ribonucleic acid polynucleotides. Thus, the probe can be selective for any organism. Suitable organisms include mammals (including humans), birds, reptiles, amphibians, fish, domesticated animals, wild animals, extinct organisms, bacteria, fungi, viruses, plants, and the like. The probe can also be selective for components of organisms that employ their own polynucleotides, for example mitochondria. In some embodiments, the probe is selective for microorganisms, for example, organisms used in food production (for example, yeasts employed in fermented products, molds or bacteria employed in cheeses, and the like) or pathogens (e.g., of humans, domesticated or wild mammals, domesticated or wild birds, and the like). In some embodiments, the probe is selective for organisms selected from the group consisting of gram positive bacteria, gram negative bacteria, yeast, fungi, protozoa, and viruses.
In various embodiments, the probe can be selective for a polynucleotide sequence that is characteristic of an organism selected from the group consisting of Staphylococcus spp., e.g., S. epidermidis, S. aureus, Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Staphylococcus; Streptococcus(e.g., α, β or γ-hemolytic, Group A, B, C, D or G) such as S. pyogenes, S. agalactiae; E. faecalis, E. durans, and E. faecium (formerly S. faecalis, S. durans, S. faecium); nonenterococcal group D streptococci, e.g., S. bovis and S. equines; Streptococci viridans, e.g., S. mutans, S. sanguis, S. salivarius, S. mitior, A. milleri, S. constellatus, S. intermedius, and S. anginosus; S. iniae; S. pneumoniae; Neisseria, e.g., N. meningitides, N. gonorrhoeae, saprophytic Neisseria sp; Erysipelothrix, e.g., E. rhusiopathiae; Listeria spp., e.g., L. monocytogenes, rarely L. ivanovii and L. seeligeri; Bacillus, e.g., B. anthracis, B. cereus, B. subtilis, B. subtilus niger, B. thuringiensis; Nocardia asteroids; Legionella, e.g., L. pneumonophilia, Pneumocystis, e.g., P. carinii; Enterobacteriaccae such as Salmonella, Shigella, Escherichia (e.g., E. coli, E. coliO157:H7); Klebsiella, Enterobacter, Serratia, Proteus, Morganella, Providencia, Yersinia, and the like, e.g., Salmonella, e.g., S. typhi S. paratyphi A, B (S. schottmuelleri), and C (S. hirschfeldii), S. dublin S. choleraesuis, S. enteritidis, S. typhimurium, S. heidelberg, S. newport, S. infantis, S. agona, S. montevideo, and S. saint-paul; Shigella e.g., subgroups: A. B, C, and D, such as S. flexneri, S. sonnei, S. boydii, S. dysenteriae; Proteus (P. mirabilis, P. vulgaris, and P. myxofaciens), Morganella (M. morganii); Providencia (P. rettgeri, P. alcalifaciens, and P. stuartii); Yersinia, e.g., Y. pestis, Y. enterocolitica, Haemophilus, e.g., H. influenzae, H. parainfluenzae H. aphrophilus, H. ducreyi; Brucella, e.g., B. abortus, B. melitensis, B. suis, B. canis; Francisella, e.g., F. tularensis; Pseudomonas, e.g., P. aeruginosa, P. paucimobilis, P. putida, P. fluorescens, P. acidovorans, Burkholderia (Pseudomonas) pseudomallei, Burkholderia mallei, Burkholderia cepacia and Stenotrophomonas maltophilia; Campylobacter, e.g., C. fetus fetus. C. jejuni, C. pylori (Helicobacter pylori); Vibrio, e.g., V. cholcrae, V. parahaemolyticus, V. mimicus, V. alginolyticus, V. hollisac, V. vulnificus, and the nonagglutinable vibrios; Clostridia, e.g., C. perfringens, C. tetani, C. difficile, C. botulinum; Actinomyces, e.g., A. israelii; Bacteroides, e.g., B. fragilis, B. thetaiotaomicron, B. distasonis, B. vulgatus, B. ovatus, B. caccae, and B. merdae; Prevotella, e.g., P. melaninogenica; genus Fusobacterium; Treponema, e.g. T. pallidum subspecies endemicum, T. pallidum subspecies pertenue, T. carateum, and T. pallidum subspecies pallidum; genus Borrelia, e.g., B burgdorferi; genus Leptospira; Streptobacillus, e.g., S. moniliformis; Spirillum, e.g., S. minus; Mycobacterium, e.g., M. tuberculosis, M. bovis, M. africanum, M. avium M. intracellulare, M. kansasii, M. xcnopi, M. marinum, M. ulccrans, the M. fortuitum complex (M. fortuitum and M. chelonei), M. leprae, M. asiaticum, M. chelonei subsp. abscessus, M. fallax, M. fortuitum, M. malmoense, M. shimoidei, M. simiae, M. szulgai, M. xenopi; Mycoplasma, e.g., M. hominis, M. orale, M. salivarium, M. fermentans, M. pneumoniae, M. bovis, M. tuberculosis, M. avium, M. leprae; Mycoplasma, e.g., M. genitalium; Ureaplasma, e.g., U. urealyticum; Trichomonas, e.g., T. vaginalis; Cryptococcus, e.g., C. neoformans; Histoplasma, e.g., H. capsulatum; Candida, e.g., C. albicans; Aspergillus sp; Coccidioides, e.g., C. immitis; Blastomyces, e.g. B. dermatitidis; Paracoccidioides, e.g., P. brasiliensis; Penicillium, e.g., P. marneffei; Sporothrix, e.g., S. schenckii; Rhizopus, Rhizomucor, Absidia, and Basidiobolus; diseases caused by Bipolaris, Cladophialophora, Cladosporium, Drechslera, Exophiala, Fonsecaea, Phialophora, Xylohypha, Ochroconis, Rhinocladiella, Scolecobasidium, and Wangiella; Trichosporon, e.g., T. beigelii; Blastoschizomyces, e.g., B. capitatus; Plasmodium, e.g., P. falciparum, P. vivax, P. ovale, and P. malariae; Babesia sp; protozoa of the genus Trypanosoma, e.g., T. cruzi; Leishmania, e.g., L. donovani, L. major L. tropica, L. mexicana, L. braziliensis, L. viannia braziliensis; Toxoplasma, e.g., T. gondii; Amoebas of the genera Naegleria or Acanthamoeba; Entamoeba histolytica; Giardia lamblia; genus Cryptosporidium, e.g., C. parvum; Isospora belli; Cyclospora cayetanensis; Ascaris lumbricoides; Trichuris trichiura; Ancylostoma duodenale or Necator americanus; Strongyloides stercoralis Toxocara, e.g., T. canis, T. cati; Baylisascaris, e.g., B. procyonis; Trichinella, e.g., T. spiralis; Dracunculus, e.g., D. medinensis; genus Filarioidea; Wuchereria bancrofti; Brugia, e.g., B. malayi, or B. timori; Onchocerca volvulus; Loa loa; Dirofilaria immitis; genus Schistosoma, e.g., S. japonicum, S. mansoni, S. mekongi, S. intercalatum, S. haematobium; Paragonimus, e.g., P. Westermani, P. Skriabini; Clonorchis sinensis; Fasciola hepatica; Opisthorchis sp; Fasciolopsis buski; Diphyllobothrium latum; Taenia, e.g., T. saginata, T. solium; Echinococcus, e.g., E. granulosus, E. multilocularis; Picornaviruses, rhinoviruses echoviruses, coxsackieviruses, influenza virus, paramyxoviruses, e.g., types 1, 2, 3, and 4; adnoviruses; Herpesviruses, e.g., HSV-1 and HSV-2; varicella-zoster virus; human T-lymphotrophic virus (type I and type II); Arboviruses and Arenaviruses; Togaviridae, Flaviviridae, Bunyaviridae, Reoviridae; Flavivirus; Hantavirus; Viral encephalitis (alphaviruses [e.g., Venezuelan equine encephalitis, eastern equine encephalitis, western equine encephalitis]); Viral hemorrhagic fevers (filoviruses [e.g., Ebola, Marburg] and arenaviruses [e.g., Lassa, Machupo]); Smallpox (variola); retroviruses e.g., human immunodeficiency viruses 1 and 2; human papillomavirus [HPV] types 6, 11, 16, 18, 31, 33, and 35.
In various embodiments, the probe can be selective for a polynucleotide sequence that is characteristic of an organisms selected from the group consisting of Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella oxytoca, Klebsiella pneumoniae, Escherichia coli, Acinetobacter Baumannii, Serratia marcescens, Enterobacter aerogenes, Enterococcus faecium, vancomycin-resistant enterococcus (VRE), Staphylococcus aureus, methecillin-resistant Staphylococcus aureus(MRSA), Streptococcus viridans, Listeria monocytogenes, Enterococcus spp., Streptococcus Group B, Streptococcus Group C, Streptococcus Group G, Streptococcus Group F, Enterococcus faecalis, Streptococcus pneumoniae, Staphylococcus epidermidis, Gardenerella vaginalis, Micrococcus sps., Haemophilus influenzae, Neisseria gonorrhoeee, Moraxella catarrahlis, Salmonella sps., Chlamydia trachomatis, Peptostreptococcus productus, Peptostreptococcus anaerobius, Lactobacillus fermentum, Eubacterium lentum, Candida glabrata, Candida albicans, Chlamydia spp., Camplobacter spp., Salmonella spp., smallpox (Variola major). Yersina Pestis, Herpes Simplex Virus I (HSV I), and Herpes Simplex Virus II (HSV II).
In various embodiments, the probe can be selective for a polynucleotide sequence that is characteristic of Group B Streptococcus.
In various embodiments, a method of carrying out PCR on a sample can further include one or more of the following steps: heating the biological sample in the microfluidic cartridge; pressurizing the biological sample in the microfluidic cartridge at a pressure differential compared to ambient pressure of between about 20 kilopascals and 200 kilopascals, or in some embodiments, between about 70 kilopascals and 110 kilopascals.
In some embodiments, the method for sampling a polynucleotide can include the steps of: placing a microfluidic cartridge containing a PCR-ready sample in a receiving bay of a suitably configured apparatus; carrying out PCR on the sample under thermal cycling conditions suitable for creating PCR amplicons from the neutralized polynucleotide in the sample, the PCR-ready sample comprising a polymerase enzyme, a positive control plasmid, a fluorogenic hybridization probe selective for at least a portion of the plasmid, and a plurality of nucleotides; contacting the neutralized polynucleotide sample or a PCR amplicon thereof with the at least one fluorogenic probe that is selective for a polynucleotide sequence, wherein the probe is selective for a polynucleotide sequence that is characteristic of an organism selected from the group consisting of gram positive bacteria, gram negative bacteria, yeast, fungi, protozoa, and viruses; and detecting the fluorogenic probe, the presence of the organism for which the one fluorogenic probe is selective is determined.
Carrying out PCR on a PCR-ready sample can additionally include: independently contacting each of the neutralized polynucleotide sample and a negative control polynucleotide with the PCR reagent mixture under thermal cycling conditions suitable for independently creating PCR amplicons of the neutralized polynucleotide sample and PCR amplicons of the negative control polynucleotide; and/or contacting the neutralized polynucleotide sample or a PCR amplicon thereof and the negative control polynucleotide or a PCR amplicon thereof with at least one probe that is selective for a polynucleotide sequence.
In various embodiments, a method of using the apparatus and cartridge described herein can further include one or more of the following steps: determining the presence of a polynucleotide sequence in the biological sample, the polynucleotide sequence corresponding to the probe, if the probe is detected in the neutralized polynucleotide sample or a PCR amplicon thereof; determining that the sample was contaminated if the probe is detected in the negative control polynucleotide or a PCR amplicon thereof; and/or in some embodiments, wherein the PCR reagent mixture further comprises a positive control plasmid and a plasmid probe selective for at least a portion of the plasmid, the method further including determining that a PCR amplification has occurred if the plasmid probe is detected.
Kit
In various embodiments, the microfluidic cartridge as described herein can be provided in the form of a kit, wherein the kit can include a microfluidic cartridge, and a liquid transfer member (such as a syringe or a pipette). In various embodiments, the kit can further include instructions to employ the liquid transfer member to transfer a sample containing extracted nucleic acid from a sample container via a sample inlet to the microfluidic network on the microfluidic cartridge. In some embodiments, the microfluidic cartridge and the liquid transfer member can be sealed in a pouch with an inert gas.
Typically when transferring a sample from liquid dispenser, such as a pipette tip, to an inlet on the microfluidic cartridge, a volume of air is simultaneously introduced into the microfluidic network, the volume of air being between about 0.5 mL and about 5 mL. Presence of air in the microfluidic network, however, is not essential to operation of the cartridge described herein.
In various embodiments, the kit can further include at least one computer-readable label on the cartridge. The label can include, for example, a bar code, a radio frequency tag or one or more computer-readable characters. When used in conjunction with a similar computer-readable label on a sample container, such as a vial or a pouch, matching of diagnostic results with sample is thereby facilitated.
In some embodiments, a sample identifier of the apparatus described elsewhere herein is employed to read a label on the microfluidic cartridge and/or a label on the biological sample.
Overview of an Apparatus for Receiving a Microfluidic Cartridge
The present technology relates to a cartridge, complementary apparatus, and related methods for amplifying, and carrying out diagnostic analyses on, nucleotides from biological samples. The technology includes a disposable or reusable microfluidic cartridge containing multiple sample lanes capable of processing samples in parallel as described elsewhere herein, and a reusable apparatus that is configured to selectively actuate on-cartridge operations, to detect and analyze the products of the PCR amplification in each of the lanes separately, in all simultaneously, or in groups simultaneously, and, optionally, can display the progression of analyses and results thereof on a graphical user interface. Such a reusable apparatus is further described in U.S. patent application Ser. No. 11/985,577, entitled “Microfluidic System for Amplifying and Detecting Polynucleotides in Parallel” and filed on Nov. 14, 2007, and which is incorporated herein by reference in its entirety.
In some embodiments, an apparatus includes: a receiving bay configured to selectively receive a microfluidic cartridge as described herein; at least one heat source thermally coupled to the receiving bay; and a processor coupled to the heat source, wherein the heat source is configured to selectively heat individual regions of individual sample lanes in the cartridge, and the processor is configured to control application of heat to the individual sample lanes, separately, in all simultaneously, or in groups simultaneously; at least one detector configured to detect one or more polynucleotides or a probe thereof in a sample in one or more of the individual sample lanes, separately or simultaneously; and a processor coupled to the detector to control the detector and to receive signals from the detector.
The receiving bay is a portion of the apparatus that is configured to selectively receive the microfluidic cartridge. For example, the receiving bay and the microfluidic cartridge can be complementary in shape so that the microfluidic cartridge is selectively received in, e.g., a single orientation. The microfluidic cartridge can have a registration member that fits into a complementary feature of the receiving bay. The registration member can be, for example, a cut-out on an edge of the cartridge, such as a corner that is cut-off, or one or more notches or grooves that are made on one or more of the sides in a distinctive pattern that prevents a cartridge from being loaded into the bay in more than one distinct orientation. By selectively receiving the cartridge, the receiving bay can help a user to place the cartridge so that the apparatus can properly operate on the cartridge. The cartridge can be designed to be slightly smaller than the dimensions of the receiving bay, for example by approximately 200-300 microns, for easy placement and removal of the cartridge.
The receiving bay can also be configured so that various components of the apparatus that operate on the microfluidic cartridge (heat sources, detectors, force members, and the like) are positioned to properly operate thereon. For example, a contact heat source can be positioned in the receiving bay such that it can be thermally coupled to one or more distinct locations on a microfluidic cartridge that is selectively received in the bay. Microheaters in the heater module as further described elsewhere herein were aligned with corresponding heat-requiring microcomponents (such as valves, pumps, gates, reaction chambers, etc). The microheaters can be designed to be slightly bigger than the heat requiring microfluidic components so that even though the cartridge may be off-centered from the heater, the individual components can still function effectively.
As further described elsewhere herein, the lower surface of the cartridge can have a layer of mechanically compliant heat transfer laminate that can enable thermal contact between the microfluidic substrate and the microheater substrate of the heater module. A minimal pressure of 1 psi can be employed for reliable operation of the thermal valves, gates and pumps present in the microfluidic cartridge.
In various embodiments of the apparatus, the apparatus can further include a sensor coupled to the processor, the sensor configured to sense whether the microfluidic cartridge is selectively received.
The heat source can be, for example, a heat source such as a resistive heater or network of resistive heaters. In preferred embodiments, the at least one heat source can be a contact heat source selected from a resistive heater (or network thereof), a radiator, a fluidic heat exchanger and a Peltier device. The contact heat source can be configured at the receiving bay to be thermally coupled to one or more distinct locations of a microfluidic cartridge received in the receiving bay, whereby the distinct locations are selectively heated. The contact heat source typically includes a plurality of contact heat sources, each configured at the receiving bay to be independently thermally coupled to a different distinct location in a microfluidic cartridge received therein, whereby the distinct locations are independently heated. The contact heat sources can be configured to be in direct physical contact with one or more distinct locations of a microfluidic cartridge received in the bay. In various embodiments, each contact source heater can be configured to heat a distinct location having an average diameter in 2 dimensions from about 1 millimeter (mm) to about 15 mm (typically about 1 mm to about 10 mm), or a distinct location having a surface area of between about 1 mm2 about 225 mm2 (typically between about 1 mm2 and about 100 mm2, or in some embodiments between about 5 mm2 and about 50 mm2). Various configurations of heat sources are further described in U.S. patent application Ser. No. 11/940,315, entitled “Heater Unit for Microfluidic Diagnostic System” and filed Nov. 14, 2007.
In various embodiments, the heat source is disposed in a heating module that is configured to be removable from the apparatus.
In various embodiments, the apparatus can include a compliant layer at the contact heat source configured to thermally couple the contact heat source with at least a portion of a microfluidic cartridge received in the receiving bay. The compliant layer can have a thickness of between about 0.05 and about 2 millimeters and a Shore hardness of between about 25 and about 100. Such a compliant layer may not be required if the instrument is able to reliably press the cartridge over the heater surface with a minimum contact pressure of say 1 psi over the entirety of the cartridge.
The detector can be, for example, an optical detector. For example, the detector can include a light source that selectively emits light in an absorption band of a fluorescent dye, and a light detector that selectively detects light in an emission band of the fluorescent dye, wherein the fluorescent dye corresponds to a fluorescent polynucleotide probe or a fragment thereof. Alternatively, for example, the optical detector can include a bandpass-filtered diode that selectively emits light in the absorption band of the fluorescent dye and a bandpass filtered photodiode that selectively detects light in the emission band of the fluorescent dye; or for example, the optical detector can be configured to independently detect a plurality of fluorescent dyes having different fluorescent emission spectra, wherein each fluorescent dye corresponds to a fluorescent polynucleotide probe or a fragment thereof; or for example, the optical detector can be configured to independently detect a plurality of fluorescent dyes at a plurality of different locations on a microfluidic cartridge, wherein each fluorescent dye corresponds to a fluorescent polynucleotide probe or a fragment thereof in a different sample. The detector can also be configured to detect the presence or absence of sample in a PCR reaction chamber in a given sample lane, and to condition initiation of thermocycling upon affirmative detection of presence of the sample. Further description of suitably configured detectors are described in U.S. patent application Ser. No. 11/940,321, filed on Nov. 14, 2007 and entitled “Fluorescence Detector for Microfluidic Diagnostic System”, incorporated herein by reference.
Although the various depictions therein show a heater substrate disposed underneath a microfluidic substrate, and a detector disposed on top of it, it would be understood that an inverted arrangement would work equally as well. In such an embodiment, the heater would be forced down onto the microfluidic substrate, making contact therewith, and the detector would be mounted underneath the substrate, disposed to collect light directed downwards towards it.
In another preferred embodiment (not shown in the FIGS. herein), a cartridge and apparatus are configured so that the read-head does not cover the sample inlets, thereby permitting loading of separate samples while other samples are undergoing PCR thermocycling.
In various embodiments, the apparatus can further include an analysis port. The analysis port can be configured to allow an external sample analyzer to analyze a sample in the microfluidic cartridge. For example, the analysis port can be a hole or window in the apparatus which can accept an optical detection probe that can analyze a sample or progress of PCR in situ in the microfluidic cartridge. In some embodiments, the analysis port can be configured to direct a sample from the microfluidic cartridge to an external sample analyzer; for example, the analysis port can include a conduit in fluid communication with the microfluidic cartridge that directs a liquid sample containing an amplified polynucleotide to a chromatography apparatus, an optical spectrometer, a mass spectrometer, or the like.
In various embodiments, the apparatus can further include one or more force members configured to apply force to at least a portion of a microfluidic cartridge received in the receiving bay. The one or more force members are configured to apply force to thermally couple the at least one heat source to at least a portion of the microfluidic cartridge. The application of force is important to ensure consistent thermal contact between the heater wafer and the PCR reactor and microvalves in the microfluidic cartridge.
The apparatus preferably also includes a processor, comprising microprocessor circuitry, in communication with, for example, the input device and a display, that accepts a user's instructions and controls analysis of samples.
In various embodiments, the apparatus can further include a lid at the receiving bay, the lid being operable to at least partially exclude ambient light from the receiving bay.
In various embodiments, the apparatus can further include at least one input device coupled to the processor, the input device being selected from the group consisting of a keyboard, a touch-sensitive surface, a microphone, and a mouse.
In various embodiments, the apparatus can further include at least one sample identifier coupled to the processor, the sample identifier being selected from an optical scanner such as an optical character reader, a bar code reader, or a radio frequency tag reader. For example, the sample identifier can be a handheld bar code reader.
In various embodiments, the apparatus can further include at least one data storage medium coupled to the processor, the medium selected from: a hard disk drive, an optical disk drive, or one or more removable storage media such as a CD-R, CD-RW, USB-drive, or flash memory card.
In various embodiments, the apparatus can further include at least one output coupled to the processor, the output being selected from a display, a printer, and a speaker, the coupling being either directly through a directly dedicated printer cable, or wirelessly, or via a network connection.
The apparatus further optionally comprises a display that communicates information to a user of the system. Such information includes but is not limited to: the current status of the system; progress of PCR thermocycling; and a warning message in case of malfunction of either system or cartridge. The display is preferably used in conjunction with an external input device as elsewhere described herein, through which a user may communicate instructions to apparatus 100. A suitable input device may further comprise a reader of formatted electronic media, such as, but not limited to, a flash memory card, memory stick, USB-stick, CD, or floppy diskette. An input device may further comprise a security feature such as a fingerprint reader, retinal scanner, magnetic strip reader, or bar-code reader, for ensuring that a user of the system is in fact authorized to do so, according to pre-loaded identifying characteristics of authorized users. An input device may additionally—and simultaneously—function as an output device for writing data in connection with sample analysis. For example, if an input device is a reader of formatted electronic media, it may also be a writer of such media. Data that may be written to such media by such a device includes, but is not limited to, environmental information, such as temperature or humidity, pertaining to an analysis, as well as a diagnostic result, and identifying data for the sample in question.
The apparatus may further include a computer network connection that permits extraction of data to a remote location, such as a personal computer, personal digital assistant, or network storage device such as computer server or disk farm. The network connection can be a communications interface selected from the group consisting of: a serial connection, a parallel connection, a wireless network connection, and a wired network connection such as an ethernet or cable connection, wherein the communications interface is in communication with at least the processor. The computer network connection may utilize, e.g., ethernet, firewire, or USB connectivity. The apparatus may further be configured to permit a user to e-mail results of an analysis directly to some other party, such as a healthcare provider, or a diagnostic facility, or a patient.
In various embodiments, there is an associated computer program product includes computer readable instructions thereon for operating the apparatus and for accepting instructions from a user.
In various embodiments, the computer program product can include one or more instructions to cause the system to: output an indicator of the placement of the microfluidic cartridge in the receiving bay; read a sample label or a microfluidic cartridge label; output directions for a user to input a sample identifier; output directions for a user to load a sample transfer member with the PCR-ready sample; output directions for a user to introduce the PCR-ready sample into the microfluidic cartridge; output directions for a user to place the microfluidic cartridge in the receiving bay; output directions for a user to close the lid to operate the force member; output directions for a user to pressurize the PCR-ready sample in the microfluidic cartridge by injecting the PCR-ready sample with a volume of air between about 0.5 mL and about 5 mL; and output status information for sample progress from one or more lanes of the cartridge.
In various embodiments, the computer program product can include one or more instructions to cause the system to: heat the PCR ready-sample under thermal cycling conditions suitable for creating PCR amplicons from the neutralized polynucleotide; contact the neutralized polynucleotide sample or a PCR amplicon thereof with at least one probe that is selective for a polynucleotide sequence; independently contact each of the neutralized polynucleotide sample and a negative control polynucleotide with the PCR reagent mixture under thermal cycling conditions suitable for independently creating PCR amplicons of the neutralized polynucleotide sample and PCR amplicons of the negative control polynucleotide; contact the neutralized polynucleotide sample or a PCR amplicon thereof and the negative control polynucleotide or a PCR amplicon thereof with at least one probe that is selective for a polynucleotide sequence; output a determination of the presence of a polynucleotide sequence in the biological sample, the polynucleotide sequence corresponding to the probe, if the probe is detected in the neutralized polynucleotide sample or a PCR amplicon thereof; and/or output a determination of a contaminated result if the probe is detected in the negative control polynucleotide or a PCR amplicon thereof.
Apparatus 100 may optionally comprise one or more stabilizing feet that cause the body of the device to be elevated above a surface on which system 100 is disposed, thereby permitting ventilation underneath system 100, and also providing a user with an improved ability to lift system 100.
Many applications such as genotyping, sequencing, multiple analyte detection (microarray, electrochemical sensing) require post-PCR sample retrieval and subsequent analysis of the retrieved sample in a different instrument. The cartridge of this example, of which a 24 lane embodiment is shown in
Sample DNA mixed with PCR enzymes is input into a sample lane 2501 through the inlet hole 2502 in the microfluidic network described below. The valves 2506, 2504 (valves 1 and 2) are initially open while the gates 2522, 2520 (gates 1 and 2) are closed, enabling the reaction mix to fill up the PCR reactor 2510 with the excess air venting out through vent hole 1 (label 2514). The valves 1 and 2 are then closed to scal off the reaction mixture. Thermocycling is initiated to conduct the PCR reaction within the PCR reactor. After the reaction is completed, a pipette is mechanically interfaced with the inlet hole 2502 and suction force applied to the pipette. Gates 1 and 2 are opened to enable the reacted sample to exit the PCR reactor and enter the pipette. This controlled opening of the PCR device will also prevent post-PCR contamination of the apparatus in which the cartridge resides as there is minimal exposure of the PCR product with the atmosphere.
It will be understood that reactions other than PCR can easily be performed in the cartridge of this example.
The 12 channel cartridge of this example is the same basic design that is described and shown in
This 24-lane cartridge has two rows of 12 sample lanes. Each lane has: a liquid inlet port, that interfaces with a disposable pipette; a 4 microliter PCR reaction chamber (1.5 mm wide, 300 microns deep and approximately 10 mm long), and two microvalves on either side of the PCR reactor and outlet vent. Microvalves are normally open, and close the channel on actuation. The outlet holes enable extra liquid (˜1 μl) to be contained in the fluidic channel in case more than 6 μl of fluid is dispensed into the cartridge. Thus, the cartridge of this example does not require a bubble vent as it will be used in an automated PCR machine having a reliable, precision liquid dispenser.
The inlet holes of the cartridge of this example are made conical in shape and have a diameter of 3-6 mm at the top to ensure that pipette tips can be easily landed by an automated fluid dispensing head into the conical hole, with some tolerance. There is also an optional raised annulus around the top of the holes. Once the pipette tip lands within the cone, the conical shape guides the pipette and mechanically seals to provide error free dispensing into, or withdrawal of fluid from, the cartridge. The bigger the holes, the better it is to align with the pipette, however, given the opposing need to maximize the number of inlet ports within the width of the cartridge as well as to maintain the pitch between holes compatible with the inter-pipette distance, the holes cannot be too big. In this design, the inter-pipette tip distance is 18 mm and the distance between the loading holes in the cartridge is 6 mm. So lanes 1, 4, 7, 11 are pipetted into during one dispensing operation that utilizes four pipette tips; lanes 2, 5, 8 and 12 in the next, and so on and so forth.
The height of the conical holes is kept lower than the height of the ledges on the edges of the cartridge to ensure the cartridges can be stacked on the ledges. The ledges on the two long edges of the cartridge enable stacking of the cartridges with minimal surface contact between two stacked cartridges and also help guide the cartridge into the reader from a spring-loader, where used.
This 12-lane cartridge has 12 sample lanes in parallel, as shown in
The barcode labels of both cartridge and sample container can be read with a bar code reader prior to use.
Exemplary Wax-Deposition Process
Deposition of wax in valves of the microfluidic network, as at step 1804 of
A DJ-9000 is manufactured under quality control standards that aim to provide precise and reliable performance. Representative specifications of the apparatus are as follows.
An exploded view of this apparatus is shown in
Theory of Operation of DJ-9000
The DJ-9000 has a normally closed, air-actuated, spring-return mechanism, which uses momentum transfer principles to expel precise volumes of material. Pressurized air is regulated by a high-speed solenoid to retract a needle assembly from the seat. Fluid, fed into the fluid chamber, flows over the seat. When the air is exhausted, the needle travels rapidly to the closed position, displacing fluid through the seat and nozzle in the form of a droplet. Multiple droplets fired in succession can be used to form larger dispense volumes and lines when combined with the motion of a dispenser robot.
The equipment has various adjustable features: The following features affect performance of the DJ-9000 and are typically adjusted to fit specific process conditions.
Fluid Pressure should be set so that fluid fills to the seat, but should not be influential in pushing the fluid through the seat and nozzle. In general, higher fluid pressure results in a larger volume of material jetted.
The Stroke Adjustment controls the travel distance of the Needle Assembly. The control is turned counterclockwise to increase needle assembly travel, or turned clockwise to decrease travel. An increase of travel distance will often result in a larger volume of material jetted.
The Solenoid Valve controls the valve operation. When energized, it allows air in the jet air chamber to compress a spring and thereby raise the Needle Assembly. When de-energized, the air is released and the spring forces the piston down so that the needle tip contacts the seat.
The seat and nozzle geometry are typically the main factors controlling dispensed material volume. The seat and nozzle size are determined based on the application and fluid properties. Other parameters are adjusted in accordance with seat and nozzle choices. Available seat and nozzle sizes are listed in the table hereinbelow.
Thermal Control Assembly: Fluid temperature often influences fluid viscosity and flow characteristics. The DJ-9000 is equipped with a Thermal Control Assembly that assures a constant fluid temperature.
Dot and Line Parameters: In addition to the DJ-9000 hardware configuration and settings, Dot and Line Parameters are set in a software program (referred to as FmNT) to control the size and quality of dots and lines dispensed.
Such an arrangement lends itself to whole area imaging (e.g., by a CCD) for detection instead of optical based methods using diodes and lenses.
The foregoing description is intended to illustrate various aspects of the present technology. It is not intended that the examples presented herein limit the scope of the present technology. 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. 14/318,160, filed Jun. 27, 2014 and scheduled to issue on Jul. 14, 2020 as U.S. Pat. No. 10,710,069, which is a continuation of U.S. patent application Ser. No. 12/515,003, filed Mar. 17, 2010 and issued on Jul. 1, 2014 as U.S. Pat. No. 8,765,076, which is a national phase application of International Application No. PCT/US07/084730, filed Nov. 14, 2007, which claims the benefit of U.S. Provisional Patent Application No. 60/859,284, filed Nov. 14, 2006, and U.S. Provisional Patent Application No. 60/959,437, filed Jul. 13, 2007. The disclosures of all 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 |
| 3444742 | Ellis et al. | May 1969 | 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 | Killat 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 |
| 5098663 | Berthold 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 | 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 | Scalice 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 |
| 5700429 | Bühler et al. | Dec 1997 | A |
| 5700637 | Southern | Dec 1997 | A |
| 5705610 | Zuckermann et al. | Jan 1998 | 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 |
| 5851492 | Blattner | 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 |
| 5922289 | Wong | 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 | 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 | 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 |
| 6066300 | Carey 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, Jr. | 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 et al. | 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 |
| 6352673 | Rainin et al. | Mar 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 |
| 6679279 | Liu | Jan 2004 | B1 |
| 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 | 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 | 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 |
| 6969835 | Rushbrooke et al. | Nov 2005 | B1 |
| 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 |
| 8232900 | Takeda | Jul 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 |
| 10364456 | Wu 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 |
| 11441171 | Wu et al. | Sep 2022 | B2 |
| 11453906 | Handique | Sep 2022 | B2 |
| 11466263 | Duffy et al. | Sep 2022 | B2 |
| 11549959 | Williams et al. | Jan 2023 | 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 |
| 20030129094 | Schubert et al. | 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 |
| 20040203173 | Peck 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 |
| 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 |
| 20060228268 | Heimberg 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 |
| 20070134808 | Sullivan | Jun 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 |
| 20070238161 | Cerrone 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 |
| 20080149840 | Handique et al. | Jun 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 |
| 20090130719 | Handique | May 2009 | A1 |
| 20090130745 | Williams et al. | May 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 |
| 20150174579 | Iten et al. | Jun 2015 | A1 |
| 20150315631 | Handique et al. | Nov 2015 | A1 |
| 20160038942 | Roberts | Feb 2016 | A1 |
| 20170275702 | Dahiya et al. | Sep 2017 | A1 |
| 20180135102 | Gubatayao et al. | May 2018 | A1 |
| 20180333722 | Handique | Nov 2018 | A1 |
| 20190054467 | Handique | Feb 2019 | A1 |
| 20190054471 | Williams et al. | Feb 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 |
| 20190324050 | Williams et al. | Oct 2019 | 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 |
| 20200215536 | Handique et al. | Jul 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 |
| 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 |
| 20220170008 | Brahmasandra et al. | Jun 2022 | A1 |
| 20220203371 | Handique et al. | Jun 2022 | A1 |
| 20220241782 | Handique et al. | Aug 2022 | A1 |
| 20230023741 | Handique | Jan 2023 | A1 |
| 20230041595 | Wu et al. | Feb 2023 | 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 |
| 1745153 | Jan 2007 | 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 |
| H03181853 | 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 |
| H11-009258 | Jan 1999 | 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 |
| 2003-500169 | Jan 2003 | 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 1998022625 | May 1998 | WO |
| WO 1998035013 | 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 1999016549 | Apr 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 2005100538 | 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 |
|---|
| “ASI Adhesives and Sealants industry”, published Nov. 17, 2003 https:// https://www.adhesivesmag.com/articles/84986-asymtek-high-speed-dispensejet-dj-9000-jet (Year: 2003). |
| Cooley et.al. Proceedings, SPIE Conference on Microfluidics and BioMEMS, Oct. 2001, pp. 1-12. |
| 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. |
| 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. |
| 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. |
| 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). |
| 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). |
| 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 Amended Answer, Affirmative Defenses, and Counterclaims to Plaintiffs' First Amended and Supplemental Complaint filed Dec. 11, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (43 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). |
| 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). |
| 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). |
| 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). |
| Defendant NeuModx's Initial Invalidity Contentions filed Sep. 30, 2020 in U.S. District Court, Delaware, Case #1:19-cv-01126-LPS (47 pages). |
| Davis et al., “Surface vibrational sum frequency and Raman studies of PAMAM G0, G1 and acylated PAMAM G0 dendrimers”. Anal Chimica Acta. Oct. 31, 2003;496(1-2): 117-131. |
| Allemand et al., “pH-Dependent Specific Binding and Combing of DNA”, Biophys J. (1997) 73(4): 2064-2070. |
| 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. |
| 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). |
| 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. |
| 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. |
| Edwards, “Silicon (Si),” in “Handbook of Optical Constants of Solids” (Ghosh & Palik eds., 1997) in 24 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. |
| Hale et al., “Optical constants of Water in the 200-nm to 200-μm Wavelength Region”, Applied Optics, 12(3): 555-563 (1973). |
| 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-volume 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. |
| Hsueh et al., “DNA quantification with an electrochemiluminescence microcell” Proc. 1997 IEEE Int. Conf. Solid-State Sens. Actuators (1997) pp. 175-178. |
| 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 Sep. 11, 2008 for International Patent Application No. PCT/US2007/084730, filed Nov. 14, 2007. |
| Khandurina et al., Microfabricated Porous Membrane Structure for Sample Concentration and Electrophoretic Analysis, Analytical Chemistry American Chemical Society, 1999, 71(9): 1815-1819. |
| 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. |
| 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. |
| 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 et al., “World-to-chip microfluidic interface with built-in valves for multichamber chip-based PCR assays,” Lab Chip, (2005), 5:845-850. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 Commun. (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. |
| Zhang et al., “PCR Microfluidic Devices for DNA Amplification,” Biotechnology Advances, 24:243-284 (2006). |
| 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. |
| 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. |
| 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). |
| 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). |
| Decision instituting Inter Partes Review of U.S. Pat. No. 7,998,708 (Paper 8 in IPR2019-00488) dated Jul. 16, 2019 (20 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). |
| 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). |
| 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). |
| Decision instituting Inter Partes Review of U.S. Pat. No. 8,323,900 (Paper 8 in IPR2019-00490) dated Jul. 16, 2019 (23 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. |
| 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. |
| 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. |
| 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. |
| 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., “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: “bioMérieux—2018 Financial Results,” dated Feb. 27, 2019, accessed at www.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. |
| Burns et al., “Microfabricated Structures for Integrated DNA Analysis” Proc. Natl. Acad. Sci. USA (May 1996) 93: 5556-5561. |
| 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., “Design, fabrication, and packaging of a practical multianalyte-capable optical biosensor,” J Microlith Microfab Microsyst. (2006) 5(2):021105 in 8 pages. |
| Chang-Yen et al., “Spin-assembled nanofilms for gaseous oxygen sensing.” Sens Actuators B: Chemical (2007), 120(2):426-433. |
| Chaudhari et al., “Transient Liquid Crystal Thermometry of Microfabricated PCR Vessel Arrays”, J Microelectro Sys., (1998) 7(4):345-355. |
| 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. |
| Chen et al., “Total nucleic acid analysis integrated on microfluidic devices,” Lab on a Chip. (2007) 7:1413-1423. |
| Cheng et al., “Biochip-Based Portable Laboratory”, Biochip Tech. (2001):269-289. |
| 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 -8. |
| Chong et al., “Disposable Polydimethylsiloxane 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. |
| 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. |
| Danaher Press Release: “Danaher to Acquire Cepheid for $53.00 per share, or approximately $4 Billion,” dated Sep. 6, 2016, accessed at www.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”, Electrophoresis. (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):210-218. |
| Dunnington et al., “Approaches to Miniaturized High-Throughput Screening of Chemical Libraries”, in Integrated Microfabricated 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 Chem. (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. |
| 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. |
| 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. |
| Handal et al., “DNA mutation detection and analysis using miniaturized microfluidic systems”, Expert Rev Mol Diagn. (2006) 6(1):29-38. |
| Hansen et al., “Microfluidics in structural biology: smaller, faster . . . better”, Curr Opin Struct Biol. (2003) 13(5):538-544. |
| Harrison et al., “Capillary Electrophoresis and Sample Injection Systems Integrated on a Planar Glass Chip”, Anal. Chem., (1992) 64: 1926-1932. |
| 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 I-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. |
| 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. |
| 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. |
| Irawan et al., “Cross-Talk Problem on a Fluorescence Multi-Channel Microfluidic Chip System,” Biomed Micro. (2005) 7(3):205-211. |
| 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. |
| Jiang et al., “Directing cell migration with asymmetric micropatterns” Proc. Natl. Acad. Sci. USA (2005) 102, 975-978. |
| 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 Chem. (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. |
| Khandurina et al., “Bioanalysis in microfluidic devices,” J Chromatography A, (2002) 943:159-183. |
| 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-volume 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., “Monolithic integrated microfluidic DNA amplification and capillary electrophoresis analysis system” Sensors and Actuators B (2000) 63:138-146. |
| 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'I 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. |
| Liao et al., “Miniature RT-PCR system for diagnosis of RNA-based viruses,” Nucl Acids Res. (2005) 33(18):e156 in 7 pages. |
| 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., “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. |
| 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. |
| Manz et al., “Miniaturized Total Chemical Analysis Systems: a Novel Concept for Chemical Sensing,” Sensors and Actuators B1, (1990) 244-248. |
| Manz et al., “Design of an open-tubular column 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. |
| 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 System” (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. |
| Minco, “Conductive Heating Technologies for Medical Diagnostic Equipment,” (2006) in 13 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. |
| Ohno et al., “Microfluidics: Applications for analytical purposes in chemistry and biochemistry,” Electrophoresis (2008), 29:4443-4453. |
| Pal et al., “An integrated microfluidic for influenza and other genetic analyses,” Lab Chip, (2005), 5:1024-1032. |
| 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. |
| 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. |
| 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 Transcription-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. |
| Rhee et al., “Drop Mixing in a Microchannel for Lab-on-a-Chip Applications” Langmuir (2008) 24 (2): 590-601. |
| Rodriguez et al., “Practical integration of polymerase chain reaction amplification and electrophoretic analysis in microfluidic devices for genetic analysis,” Electrophoresis, (2003), 24:172-178. |
| Rohsenow et al. [Eds.], Handbook of Heat Transfer, 3rd Edition McGraw-Hill Publishers (1998) Chapters 1 & 3; pp. 108. |
| 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. |
| Sammarco et al., “Thermocapillary Pumping of Discrete Drops in Microfabricated Analysis Devices” AlChE Journal (1999) 45(2): 350-366. |
| 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”, Anal 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. |
| Shen et al., “A microchip-based PCR device using flexible printed circuit technology,” Sensors and Actuators B (2005), 105:251-258. |
| 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 AlChE 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. |
| 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), Chapter 10, pp. 97-129. |
| Squires et al., “Microfluidics: Fluid physics at the nanoliter scale”, Rev Modern Phys. (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., “Optimization of the performance of the polymerase chain reaction in silicon-based microstructures” Nucleic Acids Res. (1997) vol. 25, pp. 3164-3168. |
| 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. |
| Terry et al., “A Gas Chromatographic Air Analyzer Fabricated on a Silicon Wafer” IEEE T Electron Dev (1979) 26:1880-1886. |
| 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. |
| Velten et al., “Packaging of Bio-MEMS: Strategies, Technologies, and Applications,” IEEE Transactions on Advanced Packaging, (2005) 28(4):533-546. |
| 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 Polymerase Chain Reaction Chip Utilizing Multiple Membrane-activated Micropumps,” (2006), MEMS 2006, Jan. 22-26, 2006, Istanbul, Turkey; 374-377. |
| 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. |
| 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. |
| Wu et al., “Fabrication of Complex Three-dimensional Microchannel Systems in PDMS” J. Am. Chem. Soc. (2003) 125, 554-559. |
| 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 trends,” Biotechnology Advances, (2007), 25:483-514. |
| 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. |
| 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. |
| 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). |
| 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). |
| 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). |
| 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). |
| 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). |
| Complaint filed by Becton, Dickinson 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). |
| 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 (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). |
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| 20210001334 A1 | Jan 2021 | US |
| Number | Date | Country | |
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| 60959437 | Jul 2007 | US | |
| 60859284 | Nov 2006 | US |
| Number | Date | Country | |
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| Parent | 14318160 | Jun 2014 | US |
| Child | 16925762 | US | |
| Parent | 12515003 | US | |
| Child | 14318160 | US |
