Patent Grant
11742194
The present invention relates to methods and devices for controlling the kinetic energy and/or the efficiency of desorption of neutral molecules from a surface.
The present invention relates to methods and devices for controlling the kinetic energy and/or the efficiency of desorption of neutral molecules from a surface. The present invention relates to methods and devices for controlling the kinetic energy and/or the efficiency of desorption of neutral molecules from a surface Development of devices for desorption ionization of molecules direct from solids, and liquids in open air using a direct analysis in real time (DART) source has previously been described in U.S. Pat. No. 6,949,741 “Atmospheric Pressure Ionization Source” which is expressly incorporated by reference in its entirety. DART uses a heated carrier gas to effect desorption of sample into that same carrier gas where gas phase ionization occurs. Unfortunately, the heating of the carrier gas to a sufficient temperature to enable desorption of some analytes takes considerable time. Further, the transfer of heat to the sample by that gas is not very efficient. A gas ion separator described in U.S. Pat. No. 7,700,913, “Sampling system for use with surface ionization spectroscopy” which is expressly incorporated by reference in its entirety can be used to improve the efficiency of sampling.
The present invention relates to methods and devices for controlling the kinetic energy and/or the efficiency of desorption of neutral molecules from a surface. In various embodiments of the present invention, a mesh can be placed between the source of ionizing gas, which can be at atmospheric pressure, and the inlet of a spectrometer. The mesh can be made from a conductive material and can carry an electrical current. In an embodiment of the invention a sample can be deposited directly onto the mesh. A current can be applied to the mesh in order to heat the wire. Sample related molecules can be desorbed from or in close proximity to the mesh. The desorbed molecules can interact with the ionizing gas in the region between the mesh and the atmospheric pressure ionization (API)-inlet of a spectrometer. The ions that are formed from this interaction can enter the spectrometer for analysis. In an embodiment of the present invention, the desorbed molecules can enter the high pressure region of a spectrometer by the action of an electrical field as in the case of an ion mobility spectrometer (IMS). The ions formed in the region immediately adjacent to the wire mesh which in this case has a potential equivalent to the end of the IMS enter the IMS spectrometer for analysis.
In various embodiments of the present invention, a mesh can be placed between the source of ionizing gas, which can be at atmospheric pressure, and the inlet of a spectrometer. The mesh can be made from a conductive material and can carry an electrical current. In various embodiments of the invention a sample can be deposited directly onto the mesh. A current can be applied to the mesh in order to heat the wire desorbing ions and neutrals of the sample into the atmospheric pressure region.
Sample related molecules can be desorbed from or in close proximity to the mesh. The desorbed molecules can interact with the ionizing gas in the region between the mesh and the atmospheric pressure ionization (API)-inlet of a spectrometer. The ions that are formed near to the wire mesh from this interaction can enter the spectrometer for analysis at atmospheric pressure or at a pressure that are higher than atmospheric when electrical potentials are able to draw or push those ions into the volume of the spectrometer.
In various embodiments of the present invention, two or more mesh can be placed between the source of ionizing gas, which can be at atmospheric pressure, and the inlet of a spectrometer. The two or more mesh can be made from a conductive material and can carry an electrical current. In various embodiments of the invention two or more samples can be deposited directly onto two or more of the mesh. A current can be applied to the two or more of the sample containing mesh in order to heat the wire mesh desorbing ions and neutrals into the atmospheric pressure region. The kinetic energy of ions desorbed from or in close proximity to the wire mesh can be controlled by modulating the potential applied to adjacent mesh or series of mesh. Control of the ion kinetic energy in the region between the sample laden wire mesh and the atmospheric pressure ionization (API)-inlet of a spectrometer can be used to improve the analysis of the two or more samples. Control of the ion kinetic energy in the region between the sample laden wire mesh and the atmospheric pressure ionization (API)-inlet of a spectrometer is desirable to improve the resolution of the spectrometer. The ions that are formed from this interaction can enter the spectrometer for analysis.
The kinetic energy of ions desorbed from or in close proximity to the wire mesh can be controlled by modulating the potential applied to the adjacent mesh or series of mesh. Control of the ion kinetic energy in the region between the sample laden wire mesh and the atmospheric pressure ionization (API)-inlet of a spectrometer can be used to improve the transfer of ions into the spectrometer for analysis of the one or more samples. Application of an electrical potential to the wire mesh enables limited control of the ion kinetic energy in the region between the sample laden wire mesh and the atmospheric pressure ionization (API)-inlet of a spectrometer which can have either a different electrical potential applied to its surface or be operated at the same potential as that wire mesh. Depending on the configuration of the spectrometer inlet the application of a potential can be used to improve resolution of the spectrometer. The ions that are formed near to the wire mesh can enter the spectrometer for analysis at atmospheric pressure or at a pressure that are higher than atmospheric when electrical potentials are able to draw or push those ions into the volume of the spectrometer.
In various embodiments of the invention, in order to control the ion energy of ions entering an ion mobility spectrometer the wire mesh supporting the ionization can be placed immediately in front of the wire mesh to which potential is being applied in order to control ion kinetic energy. In the case of ion mobility spectrometers it can be necessary to introduce ions at or very close to the potential of at the IMS entrance in order for the ions to enter and be retained by the spectrometer.
In traditional IMS devices ionization of neutral molecules occurs in the volume of the spectrometer. Ions are generated using radioactive particle emission from elements such as 3H (tritium), 63Ni, or other radioactive materials. Plasma-based ionization is also feasible using electrical discharge in the volume of the sampling region in order to produce ions which subsequently interact with the neutral molecules to ionize them in that volume. The production of ions inside of the volume of the IMS reduces the range of ion kinetic energies for the ionized particles since the electrical field is uniform in that region of ionization.
The position of the ionization source relative to the IMS determines a distance over which ions trajectory must follow before entering the IMS. Positioning of the IMS ionization region even a very short distance away from the entrance to the spectroscopy system results in a decline in achievable resolution of the spectroscopy system. In the case of ambient pressure ionization from a heated wire mesh, rapid vaporization of the sample into the carrier gas from the sample laden wire mesh can occur in close proximity to the entrance of the IMS between the carrier gas source, and the inlet of the IMS spectroscopy system. Thus the position of the sample laden wire mesh relative to the entrance of the IMS spectrometer influences the kinetic energy of the ions formed from those desorbed molecules. The kinetic energy distribution of ions that are formed immediately in the vicinity of the wire mesh in close proximity to the IMS can be corrected. As the majority of ions produced in the experiment are produced at or near atmospheric pressure in close proximity to the wire mesh those ions may be formed inside the volume of the ion mobility spectrometer (IMS). The kinetic energy of ions is related to the electrical fields in which they are formed. In the caser of the IMS systems the kinetic energy is thought to be uniform when all ions are formed inside the tube, however in order to effect sampling of ions for spectroscopic analysis a potential is applied to wires that form a Bradbury-Nielson gate a short distance away from the he ionizing region. The distance between the BN-gate and the position where the ions are formed effects their kinetic energy. The ability to change the energy of the ions formed in very close proximity to the IMS entrance improves the control of those ions afforded by the ion focusing of the IMS. Application of a electrical potential to the wire mesh in close proximity to the ionization region therefore will change the ion kinetic energy of those ions that are closer to the wire mesh to a greater degree than those that have been formed further away from the wire mesh. Linking the application of electrical potential applied to the wire mesh with the electrical potential used to open and close the BN-gate enables those ions that are further from the gate to catch up to the ions that are closer thus generating a collection of ions that have a more uniform kinetic energy as they are transferred from the ionization region into the ion separation region of the spectrometer.
In an embodiment of the invention application of a potential to a wire mesh located between a wire mesh from which sample molecules are being desorbed and the entrance the spectrometer to which a different potential applied is used to change the kinetic energy of ions formed in close proximity to that wire mesh.
In an alternative embodiment of the invention application of a small potential to the kinetic energy controlling mesh will result in rejection of the ions by the spectrometer. The action of rejection ions whose kinetic energy is different than those ions formed inside the atmospheric pressure region of the spectrometer can be used to further improve the resolution of the spectrometer as it reduces the kinetic energy of the ions being sampled.
In various embodiments of the invention, in order to complete a more rapid vaporization of the sample into the carrier gas the sample laden mesh can be positioned between the carrier gas source, a gas ion separator and the atmospheric pressure inlet of a spectroscopy system.
In an alternative embodiment of the invention a sample can be deposited onto a second surface that can be placed in close proximity to the mesh through which the ionizing carrier gas can flow. Sample related molecules can be desorbed from the second surface as a result of the current applied to the mesh. Sample related molecules can be desorbed from the second surface as a result of heating of the mesh by increasing the current running through the mesh. In various embodiments of the invention, by increasing the current passed through the wire, increased radiant heating can be generated. In various embodiments of the invention, increased radiant heat can effect desorption of less volatile components in a sample.
In an alternative embodiment of the invention a chemical can be deposited onto a second surface that can be placed in close proximity to the mesh through which the ionizing carrier gas can flow. Molecule of that chemical can be desorbed from the second surface as a result of the current applied to the mesh. In various embodiments of the invention, by increasing the current passed through the wire, increased radiant heating can be generated resulting in vaporization of the chemical into the ionizing region where it might be ionized creating an ion that might ionize other molecules. In various embodiments of the invention, the chemical desorbed from the second surface acts as a dopant for ionizing sample related molecules.
This invention is described with respect to specific embodiments thereof. Additional aspects can be appreciated from the Figures in which:
The transitional term “comprising” is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
The transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim, but does not exclude additional components or steps that are unrelated to the invention such as impurities ordinarily associated with a composition.
The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention.
A vacuum of atmospheric pressure is 1 atmosphere=760 torr. Generally, ‘approximately’ in this pressure range encompasses a range of pressures from below 101 atmosphere=7.6×103 torr to 10−1 atmosphere=7.6×101 torr. A vacuum of below 10−3 torr would constitute a high vacuum. Generally, ‘approximately’ in this pressure range encompasses a range of pressures from below 5×10−3 torr to 5×10−6 torr. A vacuum of below 10−6 torr would constitute a very high vacuum. Generally, ‘approximately’ in this pressure range encompasses a range of pressures from below 5×10−6 torr to 5×10−9 torr. In the following, the phrase ‘high vacuum’ encompasses high vacuum and very high vacuum. The prime function of the gas ion separator is to remove the carrier gas while increasing the efficiency of transfer of neutral molecules including analyte molecules into the mass spectrometer. When constructed from non conducting material, the gas ion separator can also be used to insulate or shield the high voltage applied to the inlet of the mass spectrometer.
A filament means one or more of a loop of wire, a segment of wire, a metal ribbon, a metal strand or an un-insulated wire, animal string, paper, perforated paper, fiber, cloth, silica, plastic, plastic foam, polymer, teflon, polymer impregnated teflon, cellulose and hydrophobic support material coated and impregnated filaments.
A metal comprises one or more elements consisting of lithium, beryllium, boron, carbon, nitrogen, oxygen, sodium, magnesium, aluminum, silicon, phosphorous, sulphur, potassium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, gallium, germanium, arsenic, selenium, rubidium, strontium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, indium, tin, antimony, tellurium, cesium, barium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, thallium, lead, bismuth, polonium, francium and radium.
A plastic comprises one or more of polystyrene, high impact polystyrene, polypropylene, polycarbonate, low density polyethylene, high density polyethylene, polypropylene, acrylonitrile butadiene styrene, polyphenyl ether alloyed with high impact polystyrene, expanded polystyrene, polyphenylene ether and polystyrene impregnated with pentane, a blend of polyphenylene ether and polystyrene impregnated with pentane or polyethylene and polypropylene.
A polymer comprises a material synthesized from one or more reagents selected from the group comprising of styrene, propylene, carbonate, ethylene, acrylonitrile, butadiene, vinyl chloride, vinyl fluoride, ethylene terephthalate, terephthalate, dimethyl terephthalate, bis-beta-terephthalate, naphthalene dicarboxylic acid, 4-hydroxybenzoic acid, 6-hyderoxynaphthalene-2-carboxylic acid, mono ethylene glycol (1,2 ethanediol), cyclohexylene-dimethanol, 1,4-butanediol, 1,3-butanediol, polyester, cyclohexane dimethanol, terephthalic acid, isophthalic acid, methylamine, ethylamine, ethanolamine, dimethylamine, hexamthylamine diamine (hexane-1,6-diamine), pentamethylene diamine, methylethanolamine, trimethylamine, aziridine, piperidine, N-methylpiperideine, anhydrous formaldehyde, phenol, bisphenol A, cyclohexanone, trioxane, dioxolane, ethylene oxide, adipoyl chloride, adipic, adipic acid (hexanedioic acid), sebacic acid, glycolic acid, lactide, caprolactone, aminocaproic acid and or a blend of two or more materials synthesized from the polymerization of these reagents.
A plastic foam means a polymer or plastic in which a bubble containing a gas is trapped including polyurethane, expanded polystyrene, phenolic foam, XPS foam and quantum foam.
A mesh means one or more of two or more connected filaments, two or more connected strings, foam, a grid, perforated paper, screens, paper screens, plastic screens, fiber screens, cloth screens, polymer screens, silica screens, Teflon screens, polymer impregnated Teflon screens, cellulose screens and hydrophobic support material coated or impregnated mesh. In various embodiments of the invention, a mesh includes one or more of three or more connected filaments, three or more connected strings, mesh, foam, a grid, perforated paper, screens, plastic screens, fiber screens, cloth and polymer screens.
Deployed means attached, affixed, adhered, inserted, located or otherwise associated. Thus a paper screen can be deployed on a card where the paper for the screen and the paper for the card are of a unitary construction. A card means a sample holder. A card can be made of one or more of paper, cardboard, insulating materials, conductive materials, plastic, polymers, minerals and metals. A reservoir is a vessel used to contain one or more of a liquid, a gas or a solid sample.
In the following description, various aspects of the present invention will be described. However, it will be apparent to those skilled in the art that the present invention may be practiced with only some or all aspects of the present invention. For purposes of explanation, specific numbers, materials, and configurations are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to one skilled in the art that the present invention may be practiced without the specific details. In other instances, well-known features are omitted or simplified in order not to obscure the present invention.
Parts of the description will be presented in data processing terms, such as data, selection, retrieval, generation, and so forth, consistent with the manner commonly employed by those skilled in the art to convey the substance of their work to others skilled in the art. As is well understood by those skilled in the art, these quantities (data, selection, retrieval, generation) take the form of electrical, magnetic, or optical signals capable of being stored, transferred, combined, and otherwise manipulated through electrical, optical, and/or biological components of a processor and its subsystems.
Various operations will be described as multiple discrete steps in turn, in a manner that is most helpful in understanding the present invention; however, the order of description should not be construed as to imply that these operations are necessarily order dependent.
Various embodiments will be illustrated in terms of exemplary classes and/or objects in an object-oriented programming paradigm. It will be apparent to one skilled in the art that the present invention can be practiced using any number of different classes/objects, not merely those included here for illustrative purposes.
The invention is illustrated by way of example and not by way of limitation in the figures of the accompanying drawings in which like references indicate similar elements. It should be noted that references to ‘an’ or ‘one’ embodiment in this disclosure are not necessarily to the same embodiment, and such references mean at least one.
There remain encumbrances to the employment of the DART technique for a variety of samples and various experimental conditions. Previously, in order to facilitate more comprehensive analysis of samples the DART desorption ionization method utilized heating of the carrier gas, which contains the metastable species. As the carrier gas temperature was increased molecules were vaporized where interaction with the metastable species resulted in ionization of the molecules. This transfer of energy using heated gas limits the efficiency of the analysis process. It results in consumption of large volumes of gas and more significantly adds a significant delay to the time taken for the analysis. The time required to increase the carrier gas temperature by three hundred degrees can be several minutes. In contrast, the time required for collection of the mass spectrum at the optimum temperature can be as short as a second. Enabling more efficient heating using a metal substrate often results in an increase in thermal decomposition of the material of interest. Likewise, employing more efficient heating of the carrier gas is difficult to achieve without negatively affecting the metastable species present in the carrier gas.
In various embodiments of the invention placing sample on a porous surface directly in the path of the carrier gas such that the gas flows through it, the so called “transmission-DART” configuration results in a method that does not require heating of the ionizing gas. In various embodiments of the invention, the transmission-DART configuration results in less thermal degradation of the analyte prior to gas phase ionization. In various embodiments of the invention, the transmission-DART configuration results in generation of mass spectra with fewer ions derived from thermal decomposition of the sample than observed in conventional open air ionization experiments. In various embodiments of the invention, the transmission-DART configuration uses significantly lower volumes of gas carrier during the experiment. In various embodiments of the invention, the transmission-DART configuration reduces the function of the carrier gas to providing the metastable species for ionization. In various embodiments of the invention, the transmission-DART configuration heats the porous surface by directing electrical current through a mesh in close proximity to the porous surface which transfers heat to the sample. In various embodiments of the invention, the transmission-DART configuration lowers the carrier gas temperature enabling an increase in spatial resolution of the analysis since only molecules from the heated region vaporize. In various embodiments of the invention, the transmission-DART configuration allows direct heating of specific regions of the mesh to facilitate higher throughput analysis since samples can be placed in closer proximity to each other. In various embodiments of the invention, the application of the transmission-DART configuration to heating of porous surfaces results in more rapid desorption than available by the conventional DART experiment.
In various embodiments of the invention the sample is deposited on a second surface in close proximity to the mesh in order for the heat generated from the application of current to the mesh to cause desorption of molecule from that sample into the gas phase where ionization occurs.
In an alternative embodiment of the present invention, separate aliquots of the sample are placed on separate mesh pieces and placed in close proximity to one another in the presence of the same ionizing gas in order that the temperature of the gas and the temperature of the unheated mesh simultaneously increase to effect desorption of molecules into the gas phase for analysis of the sample. In various embodiments of the invention the mesh is surrounded by a porous material to which sample has been applied for analysis. After positioning the sample in the region between the ionizing gas source and the inlet of the spectrometer a current is applied to the mesh to complete heating of the surrounding material and desorption of molecules into the gas phase for ionization.
Direct Ionization in Real Time (DART) (Cody, R. B., Laramee, J. A., Durst, H. D. “Versatile New Ion Source for the Analysis of Materials in Open Air under Ambient Conditions” Anal. Chem., 2005, 77, 2297-2302 and Desorption Electrospray Surface Ionization (DESI) (Cooks, R. G., Ouyang, Z., Takats, Z., Wiseman., J. M. “Ambient Mass Spectrometry”, Science, 2006, 311, 1566-1570; both articles are herein explicitly incorporated by reference in their entireties, are recent developments enabling surface desorption ionization by producing ions in open air for detection with mass spectrometer systems. Since the invention of DART a variety of gas-based open air ionization systems have been demonstrated including but not limited to, Plasma Assisted Desorption/Ionization also known as Dielectric Barrier Discharge Ionization (PADI, DBDI or DCBI), Desorption Atmospheric Pressure Chemical Ionization (DAPCI), Desorption Sonic Spray Ionization (DeSSI), Desorption Atmospheric Pressure Photoionization (DAPPI), and Flowing Atmospheric-Pressure Afterglow (FAPA). The ability to desorb and ionize intact molecules in open air offers a number of advantages for rapid real time analysis of analyte samples. In the case of the DART ionization source, the ability to vary the carrier gas temperature has been used to permit thermal profiling of samples. This application of heat has permitted a more thorough detection of the various components of the sample. This is especially true when the components of the sample have different vapor pressure. Unfortunately due to the resistive character of heaters and the large volume of gas that these methods use to transfer heat into the sample, operation at high temperature involves a number of limitations. For example, waiting for the temperature of the gas exiting the source to increase to a desired temperature can take several minutes slowing the analysis of sample considerably.
Determination of the chemical composition of solid objects or materials present on the surface of those objects is facilitated by removing those materials to a chemical analyzer. Methods for removing chemicals from the surface include the use of heated gas, heat source capable of radiating heat to the surface, application of liquid such as water or solvents to dissolve chemicals present on or comprising the surface. In various embodiments of the invention it is desirable to desorb neutral molecules from a surface by using jets supplying steam or heated water. In various embodiments of the invention, it is desirable to apply a vacuum in the vicinity of the surface to remove the desorbed neutral molecules released from the surface. This combination combines the action of heated water vapor desorbing material from the surface while also applying suction to quickly remove the vapor from the surface area thus avoiding condensation of the liquid back onto the surface.
A problem in chemical analysis is that the use of water can damage many chemical sensors therefore generally speaking the water vapor is condensed and used in the liquid form. For reasons associated with improved analysis throughput and the determination of chemicals that might be present on surfaces that are porous, such as baggage, clothing, cardboard and inside of packaging that might be sealed for purposes of protecting the chemicals inside from analysis a directed jet of heated water vapor or steam can be used to remove molecules from surfaces or in the immediate proximity of surfaces in order to achieve a through chemical analysis.
In many cases containers carrying illicit materials such as narcotics or food are packaged in plastic so as to prevent exposure to liquid or other chemicals. Plastic packaging is not thought to be permeable, however owing to the need to keep the material flexible small molecules defined as plasticizers are an integral part of the composition of that packaging material. The use of plasticizers effectively means that there is a liquid component of the plastic that may move freely from one inside the container to outside the container. Movement of a molecule from one surface to another and back again can be driven by alternating hot and cold treatments to increase the movement of molecules. While plasticizers are generally thought of as inert molecules, they contain functional chemical subunits that are capable of binding and releasing chemicals that they come into contact with, even when the contact period is a short period of time. In various embodiments of the invention, a pulsed jet of heated water vapor can be directed at the outside surface of a plastic package to interrogate the composition of the contents of the plastic package.
In the case of a customs inspection, some chemicals are deemed to be too dangerous to open. Simple economics prevail and often high value chemicals are mislabeled for import to save on duties. The capability to essentially extract an infinitesimal volume of sample with a benign sampling protocol can aid these investigators. In various embodiments of the invention, a jet of heated water vapor can be directed at the outside surface of a plastic package to interrogate the composition of the contents of the plastic package.
Determination of Fatty Acid Content of Triacyl-Glycerides
A method for direct formation of methyl-esters in the heated injector of a gas chromatography instrument demonstrated the potential for bypassing the time consuming saponification step. The experiment incorporated mixing a chemical reagent, tetramethyl ammonium hydroxide, with the analyte followed by injection into the heated volume of the GC injector leading to a simultaneous hydrolysis of the acid and its methylation, a trans-esterification. In an embodiment of the invention alternate reactants can be used for direct formation of methyl-esters including but not limited to boron trifloride in methanol, tetramethyl ammonium chloride and similar reagents commonly used for the trans-esterification of fatty acids.
In an embodiment of the invention, a triacyl-glyceride containing sample is combined with a methylating reagent in open air on a conducting screen which can be rapidly heated by application of an electric current to the screen. Rapid heating of the screen as inert carrier gas containing metastable helium atoms flow through the screen leads to desorption of the reaction products into the vapor phase where ionization occurs. The use of inert gas results in generation of protonated molecules of the fatty acid methyl esters. The reaction products can be detected in seconds using a mass spectrometer.
In an embodiment of the invention, determination of the type and percentage of fatty acids present in the original sample can be accomplished by measuring the relative ratios of each fatty acid methyl ester. This can typically be carried out by introducing isotopically labeled fatty acids to the original reaction mixture prior to heating and desorption ionization. While the relative ionization potential of individual fatty acid methyl esters may vary, the use of these standards will serve to provide correction coefficients for use in assigning the relative ratio of the fatty acids present in the mixture.
Thermal desorption of samples in the DART carrier gas stream can be carried out using a heated filament. This technique can produce ions characteristic of the analyte molecules present in the sample. As shown in
In order to address the issue of instability caused by the electrical field in the desorption ionization region a large format mesh (216) inserted in a mesh holder (290) can be placed in the region between the DART source (201) and the API inlet of the mass spectrometer (252) and a gas ion separator used as an insulator/isolator (234). A gas ion separator is a device that can improve the signal to noise ratio of DART ionization. The gas ion separator can consist of a short length of tubing placed between the desorption ionization region at the distal end of the DART source and the API inlet of the spectrometer. The gas ion separator can be used to transport ions to the API-inlet. However as it can also act in this experiment as an electrical insulator or isolator. In various embodiments of the invention shown in
The experimental configuration where the mesh is loaded with sample and placed between the DART source and API inlet of the mass spectrometer detector is referred to as the ‘Transmission DART’ mode. In various embodiments of the invention, the heated ionizing carrier gas flows through and across the mesh surface rather than around it. In various embodiments of the invention, Transmission DART promotes desorption ionization and detection of molecules with good sensitivity. The observation that ionization was possible at lower carrier gas temperature when using the mesh compared to desorption directly from a non-conducting surface as in conventional DART, i.e., with desorption from a glass capillary tube led to the design of a rapid heating system.
In various embodiments of the invention, shown schematically in
In various embodiments of the invention, positioning a sample stage comprised of a mesh placed in-line between the exit of the DART source and the API inlet of the spectrometer enables Thermally Assisted ionization of analytes using DART, (TA-DART). In various embodiments of the invention, using the DART source with room temperature carrier gas and passing approximately 1-7 Amps of current through the mesh resulted in the desorption ionization of molecules in a few seconds. The mass spectra measured were comparable to mass spectra obtained with the carrier gas increased to high temperatures (above 300 degrees Centigrade). The mass spectra measured with heated carrier gas required several minutes before the measurement could be undertaken. In various embodiments of the invention, using the DART source with room temperature carrier gas for analysis of an aliquot of quinine deposited on the mesh was completed in less than 25 seconds by rapidly raising the current passing through the mesh from approximately 0 Amps initially to approximately 6 Amps. The resulting mass chromatogram (
Olive Oil contains predominantly triglycerides with approximate mass of 900 Dalton. The TA-DART spectra for Olive Oil revealed an unexpected result compared with the conventional DART. The spectrum shown in
In various embodiments of the invention, TA-DART generates protonated intact molecules that would normally require a DART carrier gas temperature in excess of approximately 400 degrees Centigrade. In various embodiments of the invention, TA-DART can be used to measure a spectrum of a sample in approximately 1/20 of the time required to measure a spectrum of a sample with Conventional DART using carrier gas heated to a temperature of approximately 400 degrees Centigrade. In various embodiments of the invention, TA-DART results in a significant reduction in the production of ions derived from thermal degradation. In various embodiments of the invention, TA-DART can enable a wider field of use of DART.
Reducing thermal decomposition of triglycerides has a practical application in the direct analysis of blood for chemicals of interest. DART analysis of blood plasma and whole blood spots for pharmacological studies have produced abundant low mass ions which limited the utility of the method, see for example Zhao Y., L. M., Wu D., Mak R., Quantification of small molecules in plasma with direct analysis in real time tandem mass spectrometry, without sample preparation and liquid chromatographic separation. Rapid Communications in Mass Spectrometry, 2008, 22(20): p. 3217-3224 and Yu, S., et al., Bioanalysis without Sample Cleanup or Chromatography: The Evaluation and Initial Implementation of Direct Analysis in Real Time Ionization Mass Spectrometry for the Quantification of Drugs in Biological Matrixes. Analytical Chemistry, 2008. Anal. Chem. 2009, 81, 193-202, both articles are herein explicitly incorporated by reference in there entireties. Yu, et al., (2008) discloses that the DART source can complete ionization of samples by the interaction of the metastable containing carrier gas vaporizing materials from a 1 to 2 μL aliquot of sample applied to the outer surface of a glass melting point capillary (ChemGlass, CG-1841-01) which has been embedded in a formed plastic piece (DIP-it Samplers, IonSense, Inc.) and can be picked up by the action of a customized autosampler (HTCPAL, LEAP technologies), the AutoDART-96, and subsequently can be presented to the ionization region of the DART for desorption. The AutoDART-96 can be programmed to execute a predetermined series of movements involving pickup of the sampler, dipping the closed end of the glass tube directly into the plasma, and subsequent sweeping of the glass tube through the ionization region, e.g., at a rate of 500 μm per second. The temperature of the DART carrier gas can be set to 425° C. to complete effective desorption of the analyte in seconds per sample. The DART source can be positioned on a flat table with the AutoDART to permit reproducible desorption ionization. Yu, et al., (2008) further discloses that utilization of helium gas for desorption ionization with the DART can present the mass spectrometer with the requirement for greater pumping efficiency; however, physical modification of the API-4000 with larger pumping capability may not be desirable. Selective removal of the helium gas from the atmospheric pressure inlet region can be completed by incorporating a new vacuum chamber assembly in front of the normal API inlet and evacuating that region with a membrane pump (Vacuubrand, Diaphragm Vacuum Pump MZ 2). The vacuum chamber can be fabricated by modifying the counter current plate with a ⅛ in. OD pump port. For the experiment, the normal counter current drying gas can be eliminated since desolvation of the sample is not necessary in the DART enabled experiment. An alumina ceramic ion transfer tube (Length 9 in., OD ¼ in., ID 4.75 mm) can be used to close the gap between the DART source and the API inlet of the mass spectrometer, leaving approximately a 2 mm gap between the API-4000 skimmer and the ceramic transfer tube inside the vacuum chamber and approximately a 1 cm sampling gap between the ceramic DART cartridge and the open end of the ceramic transfer tube. Yu, et al., (2008) further discloses sample introduction speed and placement at the DART. Specifically, the method of sample introduction at the DART can be varied to determine the most effective means of sample desorption while optimizing sample to sample signal reproducibility. Two different sampling methods can be programmed to run on the HTCPAL autosampler, AutoDart-96, using LEAP Shell software (LEAP Technologies, Version 3.0.1.106). The first sampling method can involve sweeping the DIP-it Sampler across the entire sampling region of the DART source (1 cm) at a constant rate of 500 μm per second. The second sampling method can incorporate a quick movement of the DIP-it Sampler into the center of the DART source, a short pause (5 s) with the Dip-it Sampler centered in the DART beam, and then a quick movement removing the DIP-it Sampler completely from the DART sampling region. For both sampling methods, the position of the DIP-it Sampler between the DART cartridge and the ceramic transfer tube can be varied in the y and z directions.
Since the mass of many drug candidates is in the same mass region as the products of lipid decomposition a reduction in generation of those products would be especially desirable. The potential that TA-DART might produce a simpler mass spectrum from human and animal blood which contains triglycerides with greater fatty acid diversity as well as significant concentration of phosphatidyl-ethanol amines, phosphatidyl-cholines, phosphatidyl-serines and phosphatidyl-inositols can enable lower detection limits for drug components.
A comparison of the mass spectra from whole blood by conventional DART and TA-DART confirmed the utility of the TA-DART method for detection of drugs in blood. The absence of major ions in the low mass range with TA-DART suggest that many drugs in that mass range can be more easily detected with greater signal-to-noise.
Another class of thermally sensitive molecules includes pesticides. Fruit can be sampled by rubbing the fruit on a piece of polyethylene foam material. After sample collection, the piece of foam was positioned between the conventional DART source and entry tube of the gas ion separator attached to the API-MS. Heating the DART carrier gas from approximately 150° C.-400° C. required 2 minutes during which time the pesticides collected on the foam were ionized and transferred to the mass spectrometer for detection. The pesticides were desorbed over very long periods of time making quantitation difficult. The thermal properties of the foam, unlike the mesh, increased the time needed to reach the maximum temperature. Placing a mesh in close proximity to the foam can allow a more rapid heating of the foam thus facilitating more rapid analysis.
In various embodiments of the invention, the foam sponge plastic 1010 shown attached to the wire mesh 1020 applied to a card holder in
In various embodiments of the invention, a non-conducting porous material is placed between a pair of mesh strips to hold the non-conducting material positioned immediately between the DART source and the API inlet. The current to the mesh can be gradually increased in order to both implement a source of radiant heat near the non-conducting material (foam) and increase the gas temperature as it passed through the mesh.
In various embodiments of the invention, two wire mesh 1520 and 1522 associated with a card 1530 as shown in
In various embodiments of the invention, the reservoir shown in
In various embodiments of the invention, a series of different mesh strips through which different currents can be directed permits collection of multiple mass spectra from the same sample at different temperatures. This configuration can be desirable in order to avoid heating the sample too rapidly resulting in the rapid desorption of low mass, or more volatile molecules.
In various embodiments of the invention increasing the density of the mesh positioned between the source and proximal end of the gas ion separator results in a reduction in the number of ions related to the atmosphere surrounding the sample being detected. Analysis of samples with mesh positioned between the source and API-inlet also decreases the abundance of ions from the ambient air which normally contributes significant background to the mass spectrum. The reduction in background relative to production of sample related ions improves the signal-to-noise resulting in an increase in the sensitivity of the DART technique when using the mesh as a sample containment device.
In various embodiments of the invention, a mesh includes two or more components in physical contact selected from the group consisting of two or more connected wires or two or more connected strings, foam, polymers, silica, cellulose, and hydrophobic support material. In various embodiments of the invention, a mesh includes two or more components physically bound together selected from the group consisting of two or more connected wires or two or more connected strings, foam, polymers, silica, cellulose, and hydrophobic support material.
In various embodiments of the invention, a mesh can be contacted with the analyte and can then be analyzed. In various embodiments of the invention, a mesh can be in the spatial vicinity of the analyte, the mesh can be heated and the analyte analyzed.
In various embodiments of the invention, the heating of the mesh can be effected through the use of an infra-red (IR) laser. In various embodiments of the invention, the heating of the mesh can be accomplished by directing an IR laser onto specific sites on a mesh. The IR laser frequency can be absorbed by water molecules and the energy converted into heat to effect the desorption of the analyte.
In various embodiments of the invention, the heating or cooling of the mesh can be affected through the conductive transfer of heat from a heat sink. The temperature of the heat sink can be adjusted by transfer of electric current to the heat sink. The temperature of the heat sink which is located in the vicinity of the analyte applied to the mesh can then be used to adjust the temperature of the analyte.
In various embodiments of the invention, the heating of the mesh can be affected when in proximity to a radiant heat source such as a filament with an electric current passing through the filament.
In various embodiments of the invention, heating the mesh may be used to facilitate reactions of one or more analyte, the products of which reactions can be analyzed and can be used to infer the actual identity or quantity of the one or more analytes. In various embodiments of the invention, the mesh can be mounted on a card which can be used to isolate the analyte from contaminants, facilitating handling of the sample. In various embodiments of the invention, the material of the card is capable of absorbing or otherwise retaining and releasing a chemical to be used as a dopant to assist ionization at room temperature or after application of heat to vaporize the analyte or product. In various embodiments of the invention, the mesh is in the shape of a cylinder or tube of variable diameter and size, wherein liquid or solid sample is placed into the cylinder or tube through an opening. In various embodiments of the invention, the mesh is shaped like a “bowtie,” with a thin spot in the middle and two ends that increase in width as they extend outward away from the center. In various embodiments of the invention, the mesh is in the shape of a “trough,” with mesh for the bottom and two sides and an opening in the top with which to hold loose chemicals, leaves, pulverized materials, soil, cells, or solid particles for analysis. In various embodiments of the invention, a mesh trough 2124 associated with a card 2130 can be heated by a single power supply (not shown) and used to analyze a sample (see
In various embodiments of the invention, a filament can be deployed with a card. In various embodiments of the invention, a mesh can be deployed with a card. By deploying the mesh with a card, the card can be held by the user while a sample can be applied to the mesh without the sample or the mesh being contaminated by the user.
In various embodiments of the invention, a reservoir capable of holding a gas or liquid can be deployed with a card. In various embodiments of the invention, a reservoir capable of holding a gas or liquid can be deployed in the vicinity of a mesh with a card. One or more tubes can be associated with the reservoir. One of the one or more tubes can be used for filling the reservoir with a liquid or gas sample. One or more tubes can be orientated towards a mesh. The reservoir can be filed or partially filed with a gas or solvent prior to insertion of the card into an instrument for analysis. The liquid or gas in the reservoir can be partially or fully expelled by the action of a force on the reservoir through the one or more tubes. The one or more tubes which can expel the liquid or gas can include a tube upon which an electrical potential can be applied to the tube. Applying the electrical potential to the tube can induce the liquid or gas to exit the reservoir. The tube exiting the reservoir can be orientated towards a mesh or a filament.
A device for analyzing an analyte comprising a spectrometer including an entrance for analyzing the analyte and a source including a proximal end and a distal end configured for generating ionizing species, where the distal end is proximal to the spectrometer entrance, where an atmospheric pressure region is located between the distal end of the source and the spectrometer entrance. The device further comprising a supply adapted to one or more of generate, transfer, conduct and radiate heat and one or more mesh positioned in the atmospheric pressure region, where the analyte is applied on or near the one or more mesh, where the supply can one or more of generate, transfer, conduct and radiate heat to the analyte, where analyte molecules desorbed from the one or more mesh interact with the ionizing species generated by the source to form a plurality of analyte ions which enter the spectrometer.
A device for analyzing an analyte which comprises a spectrometer including a proximal end and a distal end configured for analyzing the analyte, where an entrance for the analyte is located at the proximal end and a detector is located at the distal end, where an atmospheric pressure region is maintained through the length of the spectrometer between the proximal end and the distal end. The device further comprising a source including a proximal end and a distal end configured for generating ionizing species, where the distal end of the source is proximal to the spectrometer entrance, where an atmospheric pressure region is located between the proximal end of the source and the distal end of the source and extends to the proximal end of the spectrometer. The device further comprising a supply adapted to one or more of generate, transfer, conduct and radiate heat and one or more mesh positioned in the atmospheric pressure region, where the analyte is applied on or near the one or more mesh at the proximal end of the source, where the supply can one or more of generate, transfer, conduct and radiate heat to the analyte, where analyte molecules desorbed from the one or more mesh interact with the ionizing species generated by the source to form a plurality of analyte ions which enter the spectrometer.
In various embodiments of the invention, the source operates by a technique selected from the group consisting of electro spray ionization, nano-electro spray ionization, atmospheric pressure matrix-assisted laser desorption ionization, atmospheric pressure chemical ionization, desorption electrospray ionization, atmospheric pressure dielectric barrier discharge ionization, atmospheric pressure low temperature plasma desorption ionization, and electrospray-assisted laser desorption ionization, a direct analysis real time, plasma assisted desorption/ionization, dielectric barrier discharge ionization source, desorption atmospheric pressure chemical ionization, desorption sonic spray ionization, desorption atmospheric pressure photoionization, and flowing atmospheric-pressure afterglow, an atmospheric laser desorption ionization, a Corona discharge, an inductively coupled plasma and a glow discharge source.
In various embodiments of the invention, the spectrometer is selected from the group consisting of a mass spectrometer, a handheld mass spectrometer, an ion mobility spectrometer (IMS) and a handheld IMS. In various embodiments of the invention, the spectrometer is selected from the group consisting of a quadrupole ion trap, a rectilinear ion trap, a cylindrical ion trap, a ion cyclotron resonance trap, an orbitrap, a sector, and a time of flight mass spectrometer.
In an embodiment of the invention, a device for analyzing an analyte comprises a spectrometer configured for analyzing the analyte, with an entrance for accepting analyte ions, a detector for detecting analyzed analyte ions and an atmospheric pressure source configured for generating ionizing species. The device further comprises a flow of the analyte molecules or clusters of analyte and solvent molecules from a solution where the analyte molecules or clusters of analyte and solvent molecules interact with the ionizing species generated by the source to form a plurality of analyte ions which enter the spectrometer and are analyzed. The flow of the analyte molecules or clusters of analyte and solvent molecules can be generated by one or more techniques including matrix assisted laser desorption, secondary ion impact techniques, electrospray, thermospray and electro-hydrodynamic desorption. Prior to forming the flow of analyte molecules or clusters of analyte and solvent molecules, the analyte can be chromatographically separated by interacting with a solid support.
A device for analyzing an analyte comprises an ion mobility spectrometer including an entrance and a detector with a first potential applied to the ion mobility spectrometer entrance, a source configured for generating ionizing species, a supply adapted to one or more of generate heat, transfer heat, conduct heat, radiate heat and apply an electric potential, and two or more mesh positioned between the source and the spectrometer. The analyte is applied on or near a first mesh, where the supply can one or more of generate heat, transfer heat, conduct heat and radiate heat to the analyte to desorb molecules of the analyte, where molecules desorbed from the first mesh interact with the ionizing species generated by the source to form analyte ions. The device where the mesh on which the analyte is applied is grounded. The device where the mesh on which the analyte is applied does not have the first potential. The device where the mesh on which the analyte is applied has a potential that is approximately 100 volts different than the first potential. The device where the mesh on which the analyte is applied has a potential that is approximately 1000 volts different than the first potential. The two or more mesh have two or more potentials, where the two or more potential are approximately 100 volts different than the first potential. The two or more mesh have two or more potentials, where the two or more potential are approximately 1000 volts different than the first potential.
In various embodiments of the invention, the analyte is of at least one state selected from the group consisting of solid phase, liquid phase, and gas phase. In various embodiments of the invention, the analyte is of biological origin. In various embodiments of the invention, the analyte is of non-biological origin. In various embodiments of the invention, the analyte is selected from the group consisting of an industrial work piece, a pharmaceutical product, a pharmaceutical ingredient, a food, a food ingredient, a toxin, a drug, an explosive, a bacterium, and a biological tissue.
While the systems, methods, and devices have been illustrated by describing examples, and while the examples have been described in considerable detail, it is not the intention of the applicants to restrict or in any way limit the scope of the appended claims to such detail. It is, of course, not possible to describe every conceivable combination of components or methodologies for purposes of describing the systems, methods, and devices provided herein. Additional advantages and modifications will readily be apparent to those skilled in the art. Therefore, the invention, in its broader aspects, is not limited to the specific details, the representative system, method or device, and illustrative examples shown and described. Accordingly, departures may be made from such details without departing from the spirit or scope of the applicant's general inventive concept. Thus, this application is intended to embrace alterations, modifications, and variations that fall within the scope of the appended claims. Furthermore, the preceding description is not meant to limit the scope of the invention. Rather, the scope of the invention is to be determined by the appended claims and their equivalents.
This application is a continuation of (1) U.S. patent application Ser. No. 16/850,443 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Apr. 16, 2020 which is a continuation of (2) U.S. patent application Ser. No. 16/186,413 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Nov. 9, 2018, which is a continuation of (3) U.S. patent application Ser. No. 15/942,162 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Mar. 30, 2018, which issued as U.S. Pat. No. 10,134,575 on Nov. 20, 2018 which is a continuation of (4) U.S. patent application Ser. No. 15/368,490 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Dec. 2, 2016, which issued as U.S. Pat. No. 9,960,029 on May 1, 2018, which is a continuation of (5) U.S. patent application Ser. No. 14/876,677 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Oct. 6, 2015 which issued as U.S. Pat. No. 9,514,923 on Dec. 6, 2016, which is a continuation of (6) U.S. patent application Ser. No. 14/589,687 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Jan. 5, 2015 which issued as U.S. Pat. No. 9,224,587 on Dec. 29, 2015, which is a continuation of (7) U.S. patent application Ser. No. 14/455,611 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Aug. 8, 2014 which issued as U.S. Pat. No. 8,963,101 on Feb. 24, 2015 and which is a continuation of and claims priority to (8) U.S. patent application Ser. No. 13/364,322 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Feb. 2, 2012 which issued as U.S. Pat. No. 8,822,949 on Sep. 2, 2014, and which claims priority to (9) U.S. Provisional Patent Application No. 61/439,866 entitled “APPARATUS FOR THERMAL ASSISTED DESORPTION IONIZATION”, inventors Jordan Krechmer and Brian D. Musselman, filed Feb. 5, 2011; (10) U.S. Provisional Patent Application No. 61/582,204 and entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS” by, inventors Jordan Krechmer and Brian D. Musselman, filed Dec. 30, 2011, and (11) U.S. Provisional Patent Application No. 61/587,218 and entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors Jordan Krechmer and Brian D. Musselman, filed Jan. 17, 2012. The present application is related to (12) U.S. patent application Ser. No. 13/797,409 entitled “APPARATUS AND METHOD FOR THERMAL ASSISTED DESORPTION IONIZATION SYSTEMS”, inventors: Jordan Krechmer and Brian D. Musselman, filed Mar. 12, 2013 which issued as U.S. Pat. No. 8,754,365 on Jun. 17, 2014. The contents of each of (1)-(12) are herein expressly incorporated by reference in their entireties.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3633027 | Rhyage | Jan 1972 | A |
| 3957470 | Dawes | May 1976 | A |
| 4016421 | Hull | Apr 1977 | A |
| 4144451 | Kambara | Mar 1979 | A |
| 4213326 | Brodasky | Jul 1980 | A |
| 4542293 | Fenn | Sep 1985 | A |
| 4546253 | Tsuchiya | Oct 1985 | A |
| 4654052 | Sharp | Mar 1987 | A |
| 4662914 | Hansen | May 1987 | A |
| 4861988 | Henion | Aug 1989 | A |
| 4941618 | Hildebrand | Jul 1990 | A |
| 5012052 | Hayes | Apr 1991 | A |
| 5055677 | Amirav | Oct 1991 | A |
| 5137553 | Dawes | Aug 1992 | A |
| 5192865 | Zhu | Mar 1993 | A |
| 5306412 | Whitehouse | Apr 1994 | A |
| 5352892 | Mordehai | Oct 1994 | A |
| 5367163 | Otsuka | Nov 1994 | A |
| 5381008 | Tanner | Jan 1995 | A |
| 5412208 | Covey | May 1995 | A |
| 5448062 | Cooks | Sep 1995 | A |
| 5552599 | Giessmann | Sep 1996 | A |
| 5559326 | Goodley | Sep 1996 | A |
| 5614711 | Li | Mar 1997 | A |
| 5624537 | Turner | Apr 1997 | A |
| 5629518 | Grotheer | May 1997 | A |
| 5684300 | Taylor | Nov 1997 | A |
| 5716825 | Hancock | Feb 1998 | A |
| 5736741 | Bertsch | Apr 1998 | A |
| 5788166 | Valaskovic | Aug 1998 | A |
| 5859433 | Franzen | Jan 1999 | A |
| 5868322 | Loucks, Jr. | Feb 1999 | A |
| 5877495 | Takada | Mar 1999 | A |
| 5889404 | Abdel-Rahman | Mar 1999 | A |
| 5959297 | Weinberg | Sep 1999 | A |
| 5997746 | Valaskovic | Dec 1999 | A |
| 6085601 | Linker | Jul 2000 | A |
| 6107628 | Smith | Aug 2000 | A |
| 6124675 | Betrand | Sep 2000 | A |
| 6188065 | Takada | Feb 2001 | B1 |
| 6190559 | Valaskovic | Feb 2001 | B1 |
| 6225623 | Turner | May 2001 | B1 |
| 6297499 | Fenn | Oct 2001 | B1 |
| 6335525 | Takada | Jan 2002 | B1 |
| 6359275 | Bertsch | Mar 2002 | B1 |
| 6395183 | Valaskovic | May 2002 | B1 |
| 6562211 | Kunnecke | May 2003 | B1 |
| 6583408 | Smith | Jun 2003 | B2 |
| 6600155 | Andrien, Jr. | Jul 2003 | B1 |
| 6646256 | Gourley | Nov 2003 | B2 |
| 6649907 | Ebeling | Nov 2003 | B2 |
| 6670608 | Taylor | Dec 2003 | B1 |
| 6690006 | Valaskovic | Feb 2004 | B2 |
| 6713757 | Tanner | Mar 2004 | B2 |
| 6717139 | Taniguchi | Apr 2004 | B2 |
| 6723985 | Schultz | Apr 2004 | B2 |
| 6744041 | Sheehan | Jun 2004 | B2 |
| 6744046 | Valaskovic | Jun 2004 | B2 |
| 6753523 | Whitehouse | Jun 2004 | B1 |
| 6784424 | Willoughby | Aug 2004 | B1 |
| 6794642 | Bateman | Sep 2004 | B2 |
| 6803565 | Smith | Oct 2004 | B2 |
| 6806468 | Laiko | Oct 2004 | B2 |
| 6818889 | Sheehan | Nov 2004 | B1 |
| 6861647 | Reilly | Mar 2005 | B2 |
| 6875980 | Bateman | Apr 2005 | B2 |
| 6878930 | Willoughby | Apr 2005 | B1 |
| 6888132 | Sheehan | May 2005 | B1 |
| 6914243 | Sheehan | Jul 2005 | B2 |
| 6943347 | Willoughby | Sep 2005 | B1 |
| 6949739 | Franzen | Sep 2005 | B2 |
| 6949740 | Sheehan | Sep 2005 | B1 |
| 6949741 | Cody | Sep 2005 | B2 |
| 6956205 | Park | Oct 2005 | B2 |
| 6977372 | Valaskovic | Dec 2005 | B2 |
| 6979816 | Tang | Dec 2005 | B2 |
| 6987264 | Whitehouse | Jan 2006 | B1 |
| 6992299 | Lee | Jan 2006 | B2 |
| 7015466 | Takats | Mar 2006 | B2 |
| 7019289 | Wang | Mar 2006 | B2 |
| 7034292 | Whitehouse | Apr 2006 | B1 |
| 7041972 | Bajic | May 2006 | B2 |
| 7049584 | Whitehouse | May 2006 | B1 |
| 7053368 | Thakur | May 2006 | B2 |
| 7064317 | McLuckey | Jun 2006 | B2 |
| 7071464 | Reinhold | Jul 2006 | B2 |
| 7081618 | Laprade | Jul 2006 | B2 |
| 7081621 | Willoughby | Jul 2006 | B1 |
| 7095019 | Sheehan | Aug 2006 | B1 |
| 7098452 | Schneider | Aug 2006 | B2 |
| 7112785 | Laramee | Sep 2006 | B2 |
| 7138626 | Karpetsky | Nov 2006 | B1 |
| 7157698 | Makarov | Jan 2007 | B2 |
| 7161145 | Oser | Jan 2007 | B2 |
| 7196525 | Sparkman | Mar 2007 | B2 |
| 7247495 | Amirav | Jul 2007 | B2 |
| 7253406 | Sheehan | Aug 2007 | B1 |
| 7332345 | Darrach | Feb 2008 | B2 |
| 7423261 | Truche | Sep 2008 | B2 |
| 7429731 | Karpetsky | Sep 2008 | B1 |
| 7462826 | Schneider | Dec 2008 | B2 |
| 7544933 | Cooks | Jun 2009 | B2 |
| 7569812 | Karpetsky | Aug 2009 | B1 |
| 7582864 | Verentchikov | Sep 2009 | B2 |
| 7700913 | Musselman | Apr 2010 | B2 |
| 7705297 | Musselman | Apr 2010 | B2 |
| 7714281 | Musselman | May 2010 | B2 |
| 7772546 | Jackson | Aug 2010 | B2 |
| 7777181 | Musselman | Aug 2010 | B2 |
| 7815484 | Kriman | Oct 2010 | B2 |
| 7858926 | Whitehouse | Dec 2010 | B1 |
| 7893408 | Hieftje | Feb 2011 | B2 |
| 7915579 | Chen | Mar 2011 | B2 |
| 7923681 | Collings | Apr 2011 | B2 |
| 7928364 | Musselman | Apr 2011 | B2 |
| 7929138 | Webb | Apr 2011 | B1 |
| 7982183 | Marakov | Jul 2011 | B2 |
| 7982185 | Whitehouse | Jul 2011 | B2 |
| 8003935 | Robinson | Aug 2011 | B2 |
| 8026477 | Musselman | Sep 2011 | B2 |
| 8044346 | Kostiainen | Oct 2011 | B2 |
| RE43078 | Cody | Jan 2012 | E |
| 8101910 | Loboda | Jan 2012 | B2 |
| 8207497 | Musselman | Jun 2012 | B2 |
| 8217341 | Musselman | Jul 2012 | B2 |
| 8242459 | Sun | Aug 2012 | B2 |
| 8278619 | Makarov | Oct 2012 | B2 |
| 8304718 | Ouyang | Nov 2012 | B2 |
| 8308339 | Karpetsky | Nov 2012 | B2 |
| 8334507 | Whitehouse | Dec 2012 | B1 |
| 8362418 | Xu | Jan 2013 | B2 |
| 8410431 | Ouyang | Apr 2013 | B2 |
| 8410452 | Koenig | Apr 2013 | B2 |
| 8421005 | Musselman | Apr 2013 | B2 |
| 8440965 | Musselman | May 2013 | B2 |
| 8481922 | Musselman | Jul 2013 | B2 |
| 8497474 | Musselman | Jul 2013 | B2 |
| 8519354 | Charipar | Aug 2013 | B2 |
| 8525109 | Musselman | Sep 2013 | B2 |
| 8558170 | Musselman | Oct 2013 | B1 |
| 8563945 | Musselman | Oct 2013 | B2 |
| RE44603 | Cody | Nov 2013 | E |
| 8592756 | Ouyang | Nov 2013 | B2 |
| 8592758 | Nilles | Nov 2013 | B1 |
| 8604423 | Enke | Dec 2013 | B2 |
| 8648295 | Enke | Feb 2014 | B2 |
| 8664000 | Yang | Mar 2014 | B2 |
| 8686351 | Ouyang | Apr 2014 | B2 |
| 8704167 | Cooks | Apr 2014 | B2 |
| 8710437 | Cooks | Apr 2014 | B2 |
| 8729496 | Musselman | May 2014 | B2 |
| 8754365 | Krechmer | Jun 2014 | B2 |
| 8766178 | Ouyang | Jul 2014 | B2 |
| 8803085 | Ouyang | Aug 2014 | B2 |
| 8816275 | Ouyang | Aug 2014 | B2 |
| 8822949 | Krechmer | Sep 2014 | B2 |
| 8853627 | Ouyang | Oct 2014 | B2 |
| 8859956 | Ouyang | Oct 2014 | B2 |
| 8859957 | Ouyang | Oct 2014 | B2 |
| 8859958 | Ouyang | Oct 2014 | B2 |
| 8859959 | Ouyang | Oct 2014 | B2 |
| 8859986 | Cooks | Oct 2014 | B2 |
| 8890063 | Ouyang | Nov 2014 | B2 |
| 8895916 | Musselman | Nov 2014 | B2 |
| 8895918 | Cooks | Nov 2014 | B2 |
| 8901488 | Musselman | Dec 2014 | B1 |
| 8927926 | Shimada | Jan 2015 | B2 |
| 8932875 | Cooks | Jan 2015 | B2 |
| 8933398 | Ouyang | Jan 2015 | B2 |
| 8937288 | Cooks | Jan 2015 | B1 |
| 8963079 | Ouyang | Feb 2015 | B2 |
| 8963101 | Krechmer | Feb 2015 | B2 |
| 9024254 | Cooks | May 2015 | B2 |
| 9064674 | Ouyang | Jun 2015 | B2 |
| 9105435 | Musselman | Aug 2015 | B1 |
| 9116154 | Ouyang | Aug 2015 | B2 |
| 9159540 | Ouyang | Oct 2015 | B2 |
| 9165752 | Cooks | Oct 2015 | B2 |
| 9224587 | Krechmer | Dec 2015 | B2 |
| 9230792 | Cooks | Feb 2016 | B2 |
| 9337007 | Musselman | May 2016 | B2 |
| 9390899 | Musselman | Jul 2016 | B2 |
| 9484195 | Ouyang | Nov 2016 | B2 |
| 9500630 | Cooks | Nov 2016 | B2 |
| 9514923 | Krechmer | Dec 2016 | B2 |
| 9538945 | Cooks | Jan 2017 | B2 |
| 9546979 | Cooks | Jan 2017 | B2 |
| 9548192 | Cooks | Jan 2017 | B2 |
| 9551079 | Cooks | Jan 2017 | B2 |
| 9558926 | Musselman | Jan 2017 | B2 |
| 9607306 | Hieftje | Mar 2017 | B2 |
| RE46366 | Cody | Apr 2017 | E |
| 9620344 | Cooks | Apr 2017 | B2 |
| 9633827 | Musselman | Apr 2017 | B2 |
| 9700251 | Cooks | Jul 2017 | B2 |
| 9704700 | Cooks | Jul 2017 | B2 |
| 9719181 | Cooks | Aug 2017 | B2 |
| 9733228 | Cooks | Aug 2017 | B2 |
| 9824875 | Musselman | Nov 2017 | B2 |
| 9941105 | Cooks | Apr 2018 | B2 |
| 9960029 | Krechmer | May 2018 | B2 |
| 10004440 | Cooks | Jun 2018 | B2 |
| 10008374 | Ouyang | Jun 2018 | B2 |
| 10014169 | Cooks | Jul 2018 | B2 |
| 10056243 | Musselman | Aug 2018 | B2 |
| 10079140 | Cooks | Sep 2018 | B2 |
| 10088461 | Cooks | Oct 2018 | B2 |
| 10090142 | Musselman | Oct 2018 | B2 |
| 10113242 | Cooks | Oct 2018 | B2 |
| 10134575 | Krechmer | Nov 2018 | B2 |
| 10283340 | Musselman | May 2019 | B2 |
| 10395911 | Cooks | Aug 2019 | B2 |
| 10395913 | Cooks | Aug 2019 | B2 |
| 10553417 | Musselman | Feb 2020 | B2 |
| 10636640 | Musselman | Apr 2020 | B2 |
| 10643833 | Krechmer | May 2020 | B2 |
| 10643834 | Musselman | May 2020 | B2 |
| 10679839 | Musselman | Jun 2020 | B2 |
| 11049707 | Krechmer | Jun 2021 | B2 |
| 20020121596 | Laiko | Sep 2002 | A1 |
| 20020121598 | Park | Sep 2002 | A1 |
| 20020162967 | Atkinson | Nov 2002 | A1 |
| 20020185593 | Doring | Dec 2002 | A1 |
| 20020185595 | Smith | Dec 2002 | A1 |
| 20020185606 | Smith | Dec 2002 | A1 |
| 20030052268 | Doroshenko | Mar 2003 | A1 |
| 20030070913 | Miller | Apr 2003 | A1 |
| 20040094706 | Covey | May 2004 | A1 |
| 20040129876 | Franzen | Jul 2004 | A1 |
| 20040159784 | Doroshenko | Aug 2004 | A1 |
| 20050230635 | Takats | Oct 2005 | A1 |
| 20050236374 | Blankenship | Oct 2005 | A1 |
| 20060266941 | Vestal | Nov 2006 | A1 |
| 20070114389 | Karpetsky | May 2007 | A1 |
| 20070228271 | Truche | Oct 2007 | A1 |
| 20070272849 | Kirihara | Nov 2007 | A1 |
| 20080156985 | Venter | Jul 2008 | A1 |
| 20080202915 | Hieftje | Aug 2008 | A1 |
| 20080217254 | Anders | Sep 2008 | A1 |
| 20090090197 | Finlay | Apr 2009 | A1 |
| 20090090858 | Musselman | Apr 2009 | A1 |
| 20100078550 | Wiseman | Apr 2010 | A1 |
| 20100140468 | Musselman | Jun 2010 | A1 |
| 20110215798 | Beer | Sep 2011 | A1 |
| 20120006983 | Cody | Jan 2012 | A1 |
| 20120068063 | Fernandez | Mar 2012 | A1 |
| 20120145890 | Goodlett | Jun 2012 | A1 |
| 20120208004 | Wolcott | Aug 2012 | A1 |
| 20120223226 | Rafferty | Sep 2012 | A1 |
| 20120312980 | Whitehouse | Dec 2012 | A1 |
| 20120322683 | Liu | Dec 2012 | A1 |
| 20130020482 | Enke | Jan 2013 | A1 |
| 20130037710 | Wu | Feb 2013 | A1 |
| 20130092832 | Enke | Apr 2013 | A1 |
| 20130273552 | Ohashi | Oct 2013 | A1 |
| 20130280812 | Krechmer | Oct 2013 | A1 |
| 20130284915 | Shimada | Oct 2013 | A1 |
| 20130299688 | Balogh | Nov 2013 | A1 |
| 20140024822 | Connolly | Jan 2014 | A1 |
| 20150206730 | Krechmer | Jul 2015 | A1 |
| 20150364310 | Musselman | Dec 2015 | A1 |
| 20160042931 | Krechmer | Feb 2016 | A1 |
| 20160314956 | Cooks | Oct 2016 | A1 |
| 20170082604 | Ouyang | Mar 2017 | A1 |
| 20170084438 | Cooks | Mar 2017 | A1 |
| 20170103879 | Cooks | Apr 2017 | A1 |
| 20170130352 | Cooks | May 2017 | A1 |
| 20170135613 | Cooks | May 2017 | A1 |
| 20170148622 | Musselman | May 2017 | A1 |
| 20170154761 | Ouyang | Jun 2017 | A1 |
| 20170168032 | Cooks | Jun 2017 | A1 |
| 20170221695 | Cooks | Aug 2017 | A1 |
| 20170229299 | Musselman | Aug 2017 | A1 |
| 20170248547 | Campbell | Aug 2017 | A1 |
| 20170248607 | Cooks | Aug 2017 | A1 |
| 20170273605 | Cooks | Sep 2017 | A1 |
| 20170287690 | Cooks | Oct 2017 | A1 |
| 20170309462 | Cooks | Oct 2017 | A1 |
| 20170335477 | Cooks | Nov 2017 | A1 |
| 20170343526 | Cooks | Nov 2017 | A1 |
| 20170349547 | Cooks | Dec 2017 | A1 |
| 20180017535 | Cooks | Jan 2018 | A1 |
| 20180024108 | Cooks | Jan 2018 | A1 |
| 20180033603 | Cooks | Feb 2018 | A1 |
| 20180040464 | Cooks | Feb 2018 | A1 |
| 20180043327 | Cooks | Feb 2018 | A1 |
| 20180047552 | Cooks | Feb 2018 | A1 |
| 20180061620 | Cooks | Mar 2018 | A1 |
| 20180076015 | Musselman | Mar 2018 | A1 |
| 20180188273 | Cooks | Jul 2018 | A1 |
| 20180204712 | Cooks | Jul 2018 | A1 |
| 20180247804 | Shelley | Aug 2018 | A1 |
| 20180275118 | Cooks | Sep 2018 | A1 |
| 20180279927 | Cooks | Oct 2018 | A1 |
| 20180286651 | Ouyang | Oct 2018 | A1 |
| 20180330934 | Cooks | Nov 2018 | A1 |
| 20190206668 | Cooks | Jul 2019 | A1 |
| 20190219555 | Cooks | Jul 2019 | A1 |
| 20190237315 | Cooks | Aug 2019 | A1 |
| 20190371592 | Musselman | Dec 2019 | A1 |
| 20200020516 | Cooks | Jan 2020 | A1 |
| 20200110010 | Pawliszyn | Apr 2020 | A1 |
| 20200121229 | Cooks | Apr 2020 | A1 |
| 20200219711 | Cooks | Jul 2020 | A1 |
| 20200321208 | Cooks | Oct 2020 | A1 |
| 20200340962 | Cooks | Oct 2020 | A1 |
| 20200355587 | Pawliszyn | Nov 2020 | A1 |
| 20200357620 | Cooks | Nov 2020 | A1 |
| 20200357671 | Ouyang | Nov 2020 | A1 |
| 20200381237 | Cooks | Dec 2020 | A1 |
| 20200381238 | Cooks | Dec 2020 | A1 |
| 20200381239 | Ouyang | Dec 2020 | A1 |
| 20200402786 | Cooks | Dec 2020 | A1 |
| 20210098245 | Shelley | Apr 2021 | A1 |
| 20210166927 | Ouyang | Jun 2021 | A1 |
| 20210265155 | Cooks | Aug 2021 | A1 |
| Number | Date | Country |
|---|---|---|
| 102007015542 | Oct 2007 | DE |
| 1434050 | Jun 2004 | EP |
| 2263578 | Jul 1993 | GB |
| 50-106694 | Aug 1975 | JP |
| 51-120288 | Oct 1976 | JP |
| 52-91494 | Aug 1977 | JP |
| 60-41748 | Mar 1985 | JP |
| 2003185635 | Jul 2003 | JP |
| 2003222574 | Aug 2003 | JP |
| 2005-150027 | Jun 2005 | JP |
| 2007525677 | Jun 2007 | JP |
| 2009539114 | Nov 2009 | JP |
| WO03025973 | Mar 2003 | WO |
| WO03081205 | Oct 2003 | WO |
| WO2004068131 | Aug 2004 | WO |
| WO2005094389 | Oct 2005 | WO |
| WO2008054393 | May 2008 | WO |
| WO2008082603 | Jul 2008 | WO |
| WO2015195599 | Dec 2015 | WO |
| WO2016145041 | Sep 2016 | WO |
| WO2017040359 | Mar 2017 | WO |
| WO2017053911 | Mar 2017 | WO |
| WO2017070478 | Apr 2017 | WO |
| WO2017079193 | May 2017 | WO |
| WO2017127670 | Jul 2017 | WO |
| WO2017132444 | Aug 2017 | WO |
| WO2017180871 | Oct 2017 | WO |
| WO2018175713 | Sep 2018 | WO |
| Entry |
|---|
| The AccuTOF-DART Mass Spectrometer, Jan. 1, 2006, pp. 1-6; www.jeolusa.com/SERVICESUPPORT/ApplicationsResources/AnalyticalInstruments/Docum ents/Downloads/tabid/337/DMXModule/693/CommandCore_Download/Default.aspx?EntryId =171. |
| Cody, R.B. et al., “Versatile New Ion Source for the Analysis of Materials in Open Air under Ambient Conditions” Anal. Chem., 2005, 77, 2297-2302. |
| Cooks, R.G. et al., “Ambient Mass Spectrometry”, Science, 2006, 311, 1566-1570. |
| Dalton, C.N. et al., “Electrospray-Atmospheric Sampling Glow Discharge Ionization Source for the Direct Analysis of Liquid Samples”, Analytical Chemistry, Apr. 1, 2003, vol. 75, No. 7, pp. 1620-1627. |
| Garimella, S. et al., “Gas-flow assisted ion transfer for mass spectrometry”, J. Mass Spectrom. 2012, 17, 201-207. |
| Guzowski, J.P. Jr. et al., “Development of a Direct Current Gas Sampling Glow Discharge Ionization Source for the Time-of-Flight Mass Spectrometer”, J. Anal. At. Spectrom., 14, 1999, pp. 1121-1127. |
| Haddad, R., et al., “Easy Ambient Sonic-Spray Ionization Mass Spectrometry Combined with Thin-Layer Chromatography,” Analytical Chemistry, vol. 80, No. 8, Apr. 15, 2008, pp. 2744-2750. |
| Harris, Glenn A. et al., Ambient Sampling/Ionization Mass Spectrometry: Applications and Current Trends, Apr. 15, 2011, Anal. Chem. 2011, 83, pp. 4508-4538. |
| Harris, Glenn A. et al., Simulations and Experimental Investigation of Atmospheric Transport in an Ambient Metastable-Induced Chemical Ionization Source, Anal. Chem. 2009, 81, pp. 322-329. |
| Hill, C.A. et al., “A pulsed corona discharge switchable high resolution ion mobility spectrometer-mass spectrometer”, Analyst, 2003, 128, pp. 55-60. |
| Hiraoka, K. et al., “Atmospheric-Pressure Penning Ionization Mass Spectrometry”, Rapid Commun. Mass Spectrom., 18, 2004, pp. 2323-2330. |
| McLuckey, S.A. et al., “Atmospheric Sampling Glow Discharge Ionization Source for the Determination of Trace Organic Compounds in Ambient Air”, Anal. Chem., 60, 1988, pp. 2220-2227. |
| Otsuka, K. et al., “An Interface for Liquid Chromatograph/Liquid Ionization Mass Spectrometer”, Analytical Sciences, Oct. 1988, vol. 4, pp. 467-472. |
| Takáts et al., “Mass Spectrometry Sampling Under Ambient Conditions with Desorption Electrospray Ionization,” Science, vol. 306, No. 5695, Oct. 15, 2004, pp. 471-473. |
| Tembreull, R., et al., “Pulsed Laser Desorption with Resonant Two-Photon Ionization Detection in Supersonic Beam Mass Spectrometry,” Anal. Chem., vol. 58, 1986, pp. 1299-1303, pp. 1299-1303, p. 1299. |
| Ifa et al., Ambient Ionization Mass Spectrometry for Cancer Diagnosis and Surgical Margin Evaluation, Clinical Chem., (2016) 62, 111-123. |
| Voelker, S.E. et al., “Evaluation of four field portable devices for the rapid detection of mitragynine in suspected kratom products” 201 (2021) 114104. |
| Yang et al., Argon Direct Analysis in Real Time Mass Spectrometry in Conjunction with Makeup Solvents: A Method for Analysis of Labile Compounds, Anal Chem., (2013) 83, 1305-1309. |
| Yu et al., Bioanalysis without Sample Cleanup or Chromatography: The Evaluation and Initial Implementation of Direct Analysis in Real Time Ionization Mass Spectrometry for the Quantification of Drugs in Biological Matrixes, Anal Chem., (2009) 81, 193-202. |
| Zang et al., Comparison of Ambient and Atmospheric Pressure Ion Sources for Cystic Fibrosis Exhaled Breath Condensate Ion Mobility-Mass Spectrometry Metabolomics, J. Am. Soc. Mass Spectrom., (2017) 28, 1489-1496. |
| Zhang et al., Will Ambient Ionization Mass Spectrometry Become an Integral Technology in the Operating Room of the Future?, Clinical Chem., (2016) 62, 1172-1174. |
| Zhao, J. et al., Liquid Sample Injection Using an Atmospheric Pressure Direct Current Glow Discharge Ionization Source, Analytical Chemistry, Jul. 1, 1992, vol. 64, No. 13, pp. 1426-1433. |
| International Search Report, Application No. PCT/US2007/63006, dated Feb. 5, 2008, 8 pages. |
| Extended European Search Report, Application No. 07757665.0 PCT/US2007/063006 dated Jan. 7, 2010, 8 pages. |
| Article 94(3) European Communication, Application No. 07757665.0 PCT/US2007/063006, dated Mar. 14, 2012, 9 pages. |
| International Search Report, Application No. PCT/US2007/69823, dated Feb. 15, 2008, 8 pages. |
| Extended European Search Report, Application No. 07797812.0 PCT/US2007/069823, dated Apr. 4, 2010, 9 pages. |
| Article 94(3) European Communication, Application No. 07797812.0 PCT/US2007/069823, dated Jul. 27, 2012, 9 pages. |
| International Search Report, Application No. PCT/US2007/69821, dated Feb. 7, 2008. |
| Extended European Search Report, Application No. 07797811.2 PCT/US2007/069821, dated Mar. 25, 2010, 9 pages. |
| European Summons, Application No. 07797811.2 PCT/US2007/069821, Feb. 18, 2013, 8 pages. |
| International Search Report, Application No. PCT/US2007/81439, dated Mar. 20, 2008, 9 pages. |
| Extended European Search Report, Application No. 07844307.4 PCT/US2007/081439, dated Apr. 14, 2010, 12 pages. |
| Japanese Office Action, Application No. 2008-558459 PCT/US2007/063006, dated Jan. 19, 2012, 4 pages. |
| Unofficial Translation of Japanese Office Action, Application No. 2008-558459 PCT/US2007/063006, dated Jan. 19, 2012, 5 pages. |
| Chinese Office Action, Application No. 200780015974.5 PCT/US2007/063006, Feb. 2, 2012, 5 pages. |
| Chinese Office Action, Application No. 200780015974.5 PCT/US2007/063006, dated Sep. 25, 2012, 8 pages. |
| Chinese Office Action, Application No. 200780015974.5 PCT/US2007/063006, dated Dec. 26, 2012, 7 pages. |
| International Search Report, Application No. PCT/US2012/000061, dated Aug. 6, 2013, 8 pages. |
| Oral Proceedings European Communication, Application No. 07757665.0 PCT/US2007/063006, Sep. 3, 2013, 5 pages. |
| Korean Patent Application 7024130/2008 Office Action, dated Jun. 29, 2013, 3 pages. |
| Korean Patent Application 7024130/2008 Office Action, translation, dated Jun. 29, 2013, 3 pages. |
| Article 94(3) European Communication, Application No. 07797811.2 PCT/US2007/069821, dated Feb. 2, 2012, 8 pages. |
| Summons Application No. 07797811.2 PCT/US2007/069821, Feb. 18, 2013, 10 pages. |
| Chinese Office Action, Application No. 201280003101.3, PCT/US12/00061, Jan. 22, 2016, 3 pages. |
| Translation of Chinese Office Action, Application No. 201280003101.3, PCT/US12/00061, dated Jan. 22, 2016, 18 pages. |
| Japanese Office Action, Application No. 2013552527 , PCT/US12/00061, dated Jan. 22, 2016, 3 pages. |
| Translation of Japanese Office Action, Application No. 2013552527 , PCT/US12/00061, dated Jan. 22, 2016, 4 pages. |
| Extended European Search Report, Application No. 12742544.5, PCT/US20012/0000061, Sep. 12, 2017, 9 pages. |
| Form 1224, Preliminary amendment, EP Application No. 12742544.5, PCT/US20012/0000061, dated Mar. 22, 2018, 7 pages. |
| Amended Claims, EP Application No. 12742544.5, PCT/US20012/0000061, Mar. 22, 2018, 3 pages. |
| Gibbins, J.R., ‘Variable Heating Rate Wire Mesh Pyrolysis Apparatus’ Rev. Sci. Instr. 60 (1989) pp. 1129-1139. |
| Korean Patent Application, Application No. 10-2013-7008108, Notice of Final Rejection, dated Jun. 7, 2018, 2 pages. |
| Korean Patent Application, Application No. 10-2013-7008108, Notice of Final Rejection, dated Sep. 5, 2018, 6 pages. |
| Translation of Korean Patent Application, Application No. 10-2013-7008108, Notice of Final Rejection, dated Sep. 5, 2018, 5 pages. |
| Korean Patent Application, Application No. 10-2013-7008108, Response to Notice of Final Rejection, Amendment dated Oct. 31, 2018, 3 pages. |
| Machine Translation of Amendment, Response to Notice of Final Rejection in Korean Patent Application, Application No. 10-2013-7008108, dated Oct. 31, 2018, 2 pages. |
| Korean Patent Application, Application No. 10-2013-7008108, Response to Notice of Final Rejection, Argument dated Oct. 31, 2018, 12 pages. |
| Machine Translation of Argument, Response to Notice of Final Rejection in Korean Patent Application, Application No. 10-2013-7008108, dated Oct. 31, 2018, 27 pages. |
| International Search Report, Application No. PCT/US 19/34041, dated Nov. 1, 2019, 4 pages. |
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