WO2015031848A2 - Universal breath analysis sampling device - Google Patents
Universal breath analysis sampling device Download PDFInfo
- Publication number
- WO2015031848A2 WO2015031848A2 PCT/US2014/053569 US2014053569W WO2015031848A2 WO 2015031848 A2 WO2015031848 A2 WO 2015031848A2 US 2014053569 W US2014053569 W US 2014053569W WO 2015031848 A2 WO2015031848 A2 WO 2015031848A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- breath
- expiratory
- way valve
- sample
- gas
- Prior art date
Links
- 238000005070 sampling Methods 0.000 title claims description 27
- 238000004458 analytical method Methods 0.000 title abstract description 43
- 230000029058 respiratory gaseous exchange Effects 0.000 claims description 44
- 239000012491 analyte Substances 0.000 claims description 23
- 230000003434 inspiratory effect Effects 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 10
- 230000037361 pathway Effects 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 3
- 238000011144 upstream manufacturing Methods 0.000 claims 1
- 239000007789 gas Substances 0.000 abstract description 80
- 238000002156 mixing Methods 0.000 abstract description 6
- 238000012360 testing method Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 10
- 238000005259 measurement Methods 0.000 description 9
- 238000007789 sealing Methods 0.000 description 9
- 238000011109 contamination Methods 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 230000000241 respiratory effect Effects 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 3
- 238000002405 diagnostic procedure Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 210000002345 respiratory system Anatomy 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000001595 flow curve Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/097—Devices for facilitating collection of breath or for directing breath into or through measuring devices
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/0816—Measuring devices for examining respiratory frequency
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/082—Evaluation by breath analysis, e.g. determination of the chemical composition of exhaled breath
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/08—Detecting, measuring or recording devices for evaluating the respiratory organs
- A61B5/087—Measuring breath flow
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
-
- G01N33/4975—
Definitions
- the present disclosure relates to the field of breath analysis for monitoring, diagnosing and assessing medical conditions by measuring markers in the breath.
- Some breath analysis devices acquire a breath sample using a controlled breath hold and forced exhalation maneuver by the patient.
- Other breath analysis devices acquire the breath sample from the patient by applying a vacuum sampling tube coupled to the patient's expiratory flow.
- the target analyte will typically be in a certain segment of the patient's exhaled breath, for example the beginning, middle or end of the exhaled breath. These different segments correspond to the physiologic origin of the analyte, for example alimentary, airways, deep lung, or systemic.
- end-tidal CO gas level was reported by measuring the all the sections of the exhaled gas over several breaths, then applying a transfer function to correlate the measurement to an end-tidal value. It is believed this technique had several limitations, such as potential inaccuracy because of the transfer functions not being able to accommodate the wide variety of clinical situations one will likely encounter.
- the present disclosure contemplates novel pneumatic control systems, which are intended to prevent mixing of the targeted breath section with other sections.
- present disclosure describes applying these novel control systems to both on-board analysis, off board analysis and modular analysis, as will be described in the forgoing.
- the present disclosure also describes both single breath and multiple breath analyses as opposed to only single breath analysis, and analysis of other sections of the breathing pattern besides only the deep lung or end-tidal section analysis.
- Figure 1 is a pneumatic schematic of a prior art system for collecting and measuring a breath analyte sample.
- Figure 2 is a pneumatic schematic of a system of an embodiment which measures a breath sample without suspending the movement of the sample through the system.
- Figure 3 shows a timing diagram of the system shown in Figure 2, showing the valve control during a test sequence including selecting a breath, shunting the end-tidal section of the selected breath to a sensor, and measuring the breath sample for an analyte.
- Figure 4 is a pneumatic schematic showing a removable and replaceable cartridge which receives the gas sample that is intended for analysis.
- Figure 5 is a pneumatic schematic showing a point of care breath sample collection and sample segment isolation instrument which is connectable to an off -board breath analyte sensor for analyte analysis.
- Figure 6 is a flow diagram describing a sequence of operation of the system.
- Figure 7 is a flow diagram describing operation of the system described in Figure 6 with user selectable options related to the test being conducted.
- Figure 8 is a pneumatic schematic describing an alternative to the pneumatic system described in Figure 2 in which the pump direction is reversed to divert the sample intended for measurement to the sensor.
- Figure 9 is a pneumatic schematic describing an alternative pneumatic system for obtaining a sample of a section of a breath in which the sample after collection is pushed into a removable chamber for off-board analysis.
- Figure 10 is a pneumatic schematic describing an alternative pneumatic system for obtaining a sample of a section of a breath in which the sample is drawn through a removable chamber for off -board analysis.
- Figure 11 is a pneumatic schematic describing a pneumatic system for obtaining a sample of a section of breath in which patient gas is drawn through a bypass tube until a desired section of a desired breath is identified which is then diverted into a sample isolation chamber.
- Figure 12 graphically describes breath sensor signals measuring the gas of one breath, using the example of C02 measuring in the upper graph and breathing airway pressure in the lower graph, and shows the breath cycles and gas sections related to the different breath cycles,
- Figure 13 is a pneumatic schematic describing a pneumatic system for obtaining a sample of a section of breath showing the different sections of a breaths traveling through the system and in which includes a vent port coupled with the inlet of a sample trap to purge gas prior to trapping the analyte for analysis
- Figure 14 graphically shows as a function of time a series of breaths corresponding to the breaths and breath sections of gas shown in Figure 13.
- Figure 15 shows a cross-sectional detailed side view of a removable analyte trap, such as shown in Figures 4 and 10, to facilitate offboard analysis of the analyte.
- Figure 16 shows the trap shown in Figure 15 with a desired section of gas from a desired breath filling the trap, with the inlet valve closed to isolate the sample.
- Figure 17 schematically shows a sample transfer module including a syringe- type device to obtain the sample from the system shown in Figure 3.
- Figure 18 schematically shows an option to the system shown in Figure 13 in which multiple sample traps are included to broaden the utility of the system.
- Figure 19 shows a pneumatic diagram of a passive sample collection apparatus for collecting an end-tidal section of a breath, which can be coupled to a subject's respiratory cycle.
- Figure 20 shows the apparatus of Figure 19 during the inspiratory state of the subject.
- Figure 21 shows the apparatus of Figure 19 during the expiratory state of the subject.
- Figure 22 shows a means of withdrawal of the end-tidal sample shown in Figure 19, by removal of the sample through a port in the expiratory limb of the apparatus.
- Figure 23 shows an optional means of withdrawal of the end-tidal sample show in Figure 19 by removal of the expiratory limb of the apparatus.
- Figure 24 graphically shows as a function of time a subject's breathing cycle over a series of breaths.
- Figure 25 graphically shows a detailed view of one of the breaths shown in Figure 24.
- Figure 26 shows the apparatus of Figure 19 at a time that the breath from Figure 25 occupies the apparatus.
- Figure 27 shows an alternative to the apparatus of Figure 19 showing an adjustable volume expiratory limb of the apparatus so as to adjust the sample collection volume of the expiratory limb based on the subject's size and the test being performed.
- Figure 28 graphically shows the breath from Figure 25 in which the end of exhalation of the breath is segmented graphically into 4 sections, these sections optionally corresponding to the volume adjustment setting on the expiratory limb of the apparatus shown in Figure 27.
- Figure 29 shows an automated version of the apparatus shown in Figure 19 automated for identifying and collecting an end-tidal section of gas from a desired breath, shown during an expiratory cycle and shown exhausting the gas from a breath identified as a breath not suitable for analysis.
- a device can be used to verify an appropriate breath is sampled, and can prevent a subject from trying to fool the device.
- Figure 30 shows the apparatus of Figure 29 during an expiratory cycle in which a breath is identified as being suitable for analysis, showing the end-tidal section of gas passing through the expiratory limb sample collection container.
- Figure 31 graphically shows a breath parameter of a series of breaths as a function of time, showing breath 18 being identified as a breath suitable for analysis by the apparatus shown in Figures 29 and 30.
- Figure 32 is a pneumatic schematic similar to the apparatus of Figure 27 combining the features of automation shown in Figures 29 and 30 and adjustment of the sample collection compartment to match the expected sample volume, the adjustment performed manually, automatically or semi-automatically, the volume adjustment optionally based on the measured breathing pattern shown in Figure 31.
- Figure 1 depicts a prior art device which includes an inlet for attachment of a sampling cannula 1, and an instrument 2.
- the instrument includes an inlet connector for cannula attachment, an inlet value VI to switch between ambient 25 and patient gas Pt, a breathing pattern sensor SI to query the breathing pattern, a sample tube 18 to contain the sample which is to be analyzed, an inlet and outlet valve, V2 and V3,to the sample tube, a bypass tube 20 to divert other gases around the gas sample in the sample tube, a push tube 21 to push the gas in the sample tube to the gas composition sensor S2, a pump to draw the sample from the patient and to push the sample to the gas composition sensor, a valve V4 to control whether the pump is drawing from the patient or pushing the sample to the gas composition sensor.
- Figure 2 describes an embodiment.
- the pneumatic control and sampling system can be performed with as little as two 3 way valves rather than three or four, which minimizes the cost and complexity of the overall apparatus.
- positioning of the section of the breath sample may be precisely determined since the response time tolerances of the least number of valves need to be accounted for.
- the targeted sample can be analyzed by the sensor S2 without stopping it somewhere in the system. Keeping the sample in motion and minimizing the time between when the sample exits the patient and when it is analyzed, may minimize the chance of mixing of the sample with gas from other sections of the breath. In this configuration, gas is drawn from the patient through SI, V5, Tl, V6 and the pump.
- V5 and V6 are switched from ports a to ports b, and without interrupting gas flow, the targeted sample is diverted to and through the composition sensor S2 by being pulled through V6 by the pump. As it travels into and/or through the Sensor S2 the sample is analyzed for the analyte(s) in question.
- the junction Tl that bifurcates the patient flow path with the sample analysis path can be a Tee or can be a valve for further fidelity of the system. If a Tee, one way check valves can be placed before or after the Tee to prevent entrainment of unwanted gases and unwanted mixing. Calibration of the system follows the same approach using a known level of analyte.
- the system 2 includes the patient inlet Pt, a cannula 1 or collection circuit, an ambient inlet 25, an analyte sensor S2 or 14, a sensor pull through tube 15, a control system 24, a user interface 22, optionally a patient inlet sensor 16 such as a pressure transducer, a breathing pattern sensor SI, an inlet control valve V5, a flow path sensor 26 such as a pressure transducer, a tee Tl, a flow path selector valve V6, a pump P, a second flow path sensor 28 such as a pressure transducer, and an exhaust 27.
- a patient inlet sensor 16 such as a pressure transducer, a breathing pattern sensor SI
- an inlet control valve V5 such as a flow path sensor 26 such as a pressure transducer, a tee Tl, a flow path selector valve V6, a pump P, a second flow path sensor 28 such as a pressure transducer, and an exhaust 27.
- FIG. 3 describes the breathing pattern signal measured at S 1 and the control of the valves V5 and V6, and the response of the analyte sensor S2 to the sample.
- an end- tidal sample is being targeted for analysis, however the same principle applies to other sections of the breath.
- SI end-of-exhalation of the breath being targeted
- a time counter is started.
- end-of- exhalation is identified by the breathing parameter signal crossing zero from a positive value, such as would be the case with a pressure or flow sensor.
- valve V6 is switched to divert the flow of the targeted sample to the analyte sensor S2. There may be deliberately a slight delay in the switching of V6 to assure that no gas before the sample being targeted is inadvertently rerouted to S2. The targeted sample is then pulled through S2 for an appropriate and precisely controlled duration, after which V6 is switched again and gas flow through S2 ceases.
- V6 can be controlled to switch again exactly at that time, or a time before or after that time, but always in a predetermined manner that matches the calibration procedure.
- the sensor begins to react to the analyte, and this signal response is measured in the appropriate manner, for example integration, and then correlated to a quantitative measurement of the analyte, based on the calibration factors established earlier.
- Figure 4 shows some variations of the systems shown in Figures 2 and 3.
- the tee Tl is replaced by a 3 way valve V7, to provide more precise control of the gases flowing into and out of Tl in the previous example, for example to prevent inertia related mixing of gases from different breath sections.
- Figure 4 shows a removable sample collection device 17, which can be used to bring the sample to an off- board analyzer.
- the sample is preserved typically in a tube, canister, cylinder or syringe, and protected from contamination from outside gases with a series of one-way check valves. Now that the sample is preserved in this collection device 17, it is no longer prone to mixing with patient gases from other breath sections, and the fact that it is static is of no concern.
- the sample can be then drawn out in aliquots or in its entirety and injected into the desired analyzer or instrument(s), or the sample compartment can be remove-ably designed to conveniently attach to an analyzer or instrument for convenient injection or uptake into the instrument.
- the sample can also be stored indefinitely for future analysis.
- the entire breath collection instrument itself can be modularly designed and of the correct form factor to connect to the composition analyzer via a analyzer connection 19, which may be at a central location.
- the apparatus is typically a miniature hand-held device.
- the collection can be taken in the field, or in an ambulance, at home, at a screening clinic, in a village, and later when reaching a facility, the instrument can be delivered to the laboratory and connected to the composition analyzer.
- Step 1 breath monitoring and detection, in order to identify an appropriate breath, and the appropriate section of gas within that breath, using the sampling system and tubing, and appropriate sensor(s) and algorithms
- Step 2 the appropriate sample is diverted and isolated from other breath gases, which is accomplished by special control systems, pumping, valves, tees and tubing with associated algorithms
- Step 3 On-board analysis and/or preservation and transfer to an off -board analyzer.
- Figure 7 describes the universality of the system, with a user selection to allow the user to specify the type of analysis to be performed.
- the specific analysis selected will automatically enable the appropriate control systems and algorithms to work accordingly.
- an end-tidal sample can be sampled, or multiple breaths can be sampled, or a breath of a certain breath profile can be sampled, all of which are optimized for the diagnostic test being selected by the user and performed.
- Test can be for hematology disorders such as ETCO measurements for hemolysis, alimentary disorders such as hydrogen measurements, metabolic disorders such as diabetes, respiratory disorders such as asthma, forensic applications and behavioral screening applications, etc.
- Figure 8 describes an alternative pneumatic control system in which the sample of interested is isolated in the tube 18 between V2 and V3, after which the Valve V2 changes from port a open to port b open and the pump direction is reversed and the sample is pushed to the sensor 14.
- Figure 9 describes a variation of the system in Figure 8 in which the sample is sent to a removable collection container 23 for off-board analysis.
- the sample is protected in the container 23 by check valves, self-sealing ports, or the like.
- Figure 10 describes an alternate pneumatic control system in which the unwanted gas is routed between V2 port a and V3 port a, and in which the wanted gas is routed between ports b of V2 and V3 and placed in a sample tube 18.
- the wanted gas sample can be analyzed on-board or off -board as previously described.
- Figure 11 describes an alternative pneumatic control system in which the patient gas is diverted around the tube 18 through tube 20, between V2 port c and V3 port a, until a desired section of gas is identified by the sensor S 1. When this desired section reaches V2, the appropriate valve switching takes place and routes the desired sample into the tube 18 between V2 port c and V3 port a.
- Figure 13 describes a variant of the system of Figure 11 in which there is a Valve V10 which acts as a vent to purge any unwanted gases between V2 and V10, such that the resultant sample ultimately placed in the collection device 3 is not diluted or contaminated with other gases.
- Figure 12 describes a typical breath curve based on capnometry and airway pressure, and shows the different sections of gas within a breath period that are being drawn through the apparatus shown in Figure 13.
- T(PET) is pre-end-tidal time
- T(ET) is end-tidal time
- T(I) is inspiratory time
- T(E) expiratory time
- T(PE) is post-expiratory period.
- the upper graph indicates a typical breathing curve based on a capnometry signal
- the lower graph indicates a typical breathing curve based on breathing pressure.
- the main different sections of breath gas are depicted schematically in the graphs accordingly, corresponding to the gas sections in Figure 13.
- Figure 14 describes a series of breaths on a time scale as depicted by a capnometry signal, and shows the breath, breath n, being targeted in this series of breaths for the example shown in Figure 13.
- Figure 15 describes a sample container of the system shown in Figures 4 and 10 in which the sample container is attached to the collection device with remove-ably attachable self-sealing connectors, so that the container can be freely removed without contamination of the sample.
- Figure 16 shows the sample container of Figure 15 filled with the desired sample, in this example, the end-tidal gas from breath n from Figure 14.
- the types of containers can be for example a tube with sealing or self-sealing inlets and outlets, a gas tight syringe with an inlet only, a tube which first is evacuated with a self- sealing inlet and which draws the sample inward optionally via its internal vacuum, a tube which is inserted in place of the sample tube 18 with a sealing or self- sealing inlet and outlet, a tube or compartment with a valve on one end.
- Figure 17 shows an alternative to Figure 13 in which the sample is drawn into a syringe or similar device such as a cuvette or pipette, for off-board analysis. In this manner, multiple syringes can be filled and labeled accordingly, for a fill work up on the patient.
- a syringe or similar device such as a cuvette or pipette
- This embodiment can be used in conjunction with the user-settable input described in Figure 7.
- Figure 18 shows a variant of the system of Figure 13 in which there are multiple valves and collection containers to collect and analyze multiple samples.
- the system described in Figures 1-18 can be useful for collecting and measuring end-tidal gas samples, as well as samples from other sections of the breath. It can be used for measuring for example CO in the breath, or other gases, such as H2, NO, and others. It can be used for measuring other non-gaseous substances in the breath as well as gaseous markers.
- the compositional analysis and breath pattern sensing can be two different sensors, or one sensor.
- the system can be used to collect and measure an analyte in the end- tidal section of a breath, or other sections of the expiratory cycle such as for example the middle airways. A host of clinical syndromes can be assess or diagnosed using this system.
- Figures 19-32 describe an optional apparatus and method in which the a breath sample is collected passively when coupled to the subject's respiration pathway, such as coupled to the mouth,
- the maneuver needs to assure that homogenous end-tidal gas is collected, and that the patient for example doesn't breath in their nose while pausing to press their lips against the collection device half way into exhalation.
- a test subject or patient may not properly follow the maneuver instructions, or there could be variability from test to test because of not strictly adhering to the instructions. Or, if performing back to back maneuvers to collect a sample, there is no way of knowing when the gas concentrations in the patient's lung reach respiratory equilibrium and are ready for a test.
- a sampling device that obviates the need for and related drawbacks of a breath hold maneuver.
- some embodiments collect a relatively large sample of end-tidal gas, and can be employed with minimal costs and maximum reliability, on both alert and non-alert patients, and on patients of all ages.
- Some embodiments further allow for flexibility in the sample collection, based on the intended use and clinical application, such as configurable sample collection volumes, sample collection from different sections of the breathing curve, and verification sampling only breaths that are representative of the breath type that should be sampled for the particular clinical application.
- the embodiments can be designed as a passive system not requiring mechanical parts only for maximum simplicity, or can include some electro-mechanical parts and a control system for added intelligence when used in more exacting clinical applications.
- FIG 19 describes an embodiment of the system.
- a novel breath pass- through apparatus is shown.
- the user applies the mouthpiece to their mouth and simply breathes normally.
- inspired air travels in through the inspiratory inlet unabated, through the one-way inspiratory check valve Vi in the inspiratory limb, and into the respiratory tract via the mouthpiece, as is shown in Figure 20.
- Exhaled air travels out of the respiratory tract, through the mouthpiece, through the one-way expiratory check valve Vel in the expiratory limb, and out of the apparatus through the one-way expiratory check valve Ve2, as is shown in Figure 21.
- the user breathes normally and naturally, and the apparatus does not inherently change the breathing mechanics.
- a nose clip can be applied to the nose to assure that all of the breathing is through the mouth.
- the apparatus can be withdrawn from the mouth, and by definition, expiratory gas must reside in the sample collection area between Vel and Ve2, as long as the user has breathed one or more breaths with the apparatus in place.
- the apparatus is typically designed so that the gas pathways are as small as possible without adding breathing resistance, so that the apparatus does not alter the breathing mechanics and respiratory equilibrium. This can be done with gas pathway diameters of about 3/8" to 3 ⁇ 4" without any noticeable breathing resistance.
- the different sections in the apparatus are designed with minimal volumes between Vi and the Tee, in the mouthpiece, and between the Tee and Vel, to avoid unnecessary dead-space and in order to place the gas from the very end of exhalation between Vel and Ve2.
- the sample can be extracted for analysis through the extraction port.
- the apparatus is versatile and can be used differently depending on the clinical application.
- the patient can breathe “normally” in order to collect a gas sample from a normal tidal volume breath.
- the patient can breathe “deeply”, to collect an expiratory reserve volume gas sample.
- other respiratory track interfaces can be used such as a nasal mask, nasal pillows, nasal cannula, face mask, tracheal tube, bronchial tube, bronchoscope, or other interfaces.
- the example is shown during spontaneous ventilation of the subject, with little or no modifications the system can be used by coupling to a mechanically ventilated subject, such as by attachment to the breathing circuit.
- Figure 22 shows an example of how the sample can be extracted from the expiratory limb for analysis, for example using a syringe type device attached to a self- sealing port, and drawing the sample into the syringe where it is preserved until the analysis is performed.
- the syringe may include a sensor media, for example a paper or plastic with the proper chemistry, which is altered for example in color when exposed to the analyte that the patient is being test for.
- Figure 23 shows an alternative way to transfer the sample to an instrument for compositional analysis, by removing the sample collection area from the expiratory limb of the apparatus. Multiple samples can be taken from the same patient if required by the situation.
- FIGs 19-23 can be designed to collect a gas sample from a certain section of the expiration cycle.
- a typical breathing curve is shown as a function of time based on airway flow measurements, with an inspiratory section of the curve and an expiratory section of the curve.
- Figure 25 is a more detailed view of a curve of a typical breath from Figure 24, graphically showing that the expiratory section of the breathing curve can be broken down into multiple different sections. In the example shown it is divided into three sections, beginning, middle and end, although exhalation can be divided into more or less sections. Each section has the potential to contain a different mixture of gas concentrations.
- the end- tidal section or final third section of exhalation is desired to be collected for measurement, from a normal tidal volume breath.
- This amount of volume from the patient is represented by the area under the flow curve, or V(E3) in Figure 25.
- V(E3) the area under the flow curve
- exhalation may be 500ml, and the final third of exhalation may be 150ml, and V(l) may be 15ml, V(2) may be 20ml, V(3) may be 5ml, and V(4) may be 75ml, giving the apparatus a 30% safety factor in assurance that the collected sample will be a pure sample from the targeted section.
- V(E3)'s ranging from 5ml to 750ml.
- the test may require obtaining more or less precise sections of gas from the expiratory cycle. In some cases this is handled by different sized collection apparatus. In other cases this requirement in collection volume ranges can be handled by an adjustable apparatus, to adjust to the volume of V(E3). As shown in Figure 27, the sample collection area volume in the expiratory limb can be adjusted and increased or decreased depending on the expected V(E3) volume.
- the adjustment can be accomplished by a replaceable section, or by a moveable section, for example with threads or a sealing slide, or by a module expiratory limb that can be switched with different sized modules.
- the apparatus may be provided as part of a kit, with different sized expiratory limbs indicated for different test requirements.
- the sample collection area can include graduated markings to indicate to the user the volume to which the apparatus is adjusted or set.
- the apparatus can be adjustable for the purpose of collecting a gas sample from a different percentage of the end-of exhalation.
- the second half of exhalation can be divided into four or five segments, and the adjustment scale on the apparatus shown in Figure 27 can correspond to each of these segments. The finer the setting of the volume of the expiratory limb in Figure 27, the more precise the collection of gas from the expiratory cycle shown in Figure 28 can be.
- the one-way expiratory valve Vel of Figure 19 is replaced with an electronically controlled 3 way solenoid valve.
- breaths that are not desired to be sampled are expired out through port b of the 3 way valve as shown in Figure 29, and a breath that is desired to be sampled is expired out through port a of the 3 way valve as shown in Figure 30.
- a breathing sensor is placed in the breathing gas flow path to measure the breathing pattern so that breaths can be classified as appropriate or inappropriate, based on thresholds, criteria, and algorithms.
- the breathing sensor can be for example a flow sensor, temperature sensor, pressure sensor, or gas composition sensor. Since the apparatus is of some complexity and cost, the mouthpiece can be disposable and the balance reusable, in which case the mouthpiece includes a two way bacterial filter to prevent cross
- the breathing parameter signal from the breathing sensor of Figures 29 and 30 is plotted as a function of time for a series of breaths. Algorithms in the apparatus' control system determine which breaths are rejected for sampling, and which breath is targeted, in this case breath 18.
- the 3 way valve can be switched to port a after breath 17 is expelled out of port b for example, then breath 18 is expelled through port a and into the sample collection area, then the valve is switched again to port b, preserving the end- tidal sample from breath 18 in the sample collection area, and preventing contamination from other breaths.
- the control system by using the information from the sensor, confirms that breath 18 was still an appropriate breath to sample. If this is confirmed affirmatively, then the sample collection is completed and the user can remove the apparatus at any time, otherwise if it is decided that the sample was in- appropriate after all, then the process of finding an appropriate breath is repeated and eventually the sample from breath 18 in the sample collection area is displaced with a sample from the next targeted breath.
- the control system in conjunction with the breath sensor and 3 way valve can be used to collect the end-tidal section of multiple breaths in the sample collection area, by the proper switching and timing of the 3 way valve.
- a sample from a certain type of breath For example, after a sigh breath, or a breath after some other type of breath or during or after a certain type of breathing pattern chosen for the diagnostic test at hand.
- the control system and the appropriate algorithms are used to capture the appropriate sample.
- a user interface may be included which allows the user to enter a certain sampling protocol, and the system then automatically makes the necessary adjustment and algorithm changes in order to conduct the desired test.
- the system can also be adaptive and automatically or semi-automatically adapt to the prevailing clinical situation and conditions. The specific analysis selected will automatically enable the appropriate control systems and algorithms to work accordingly.
- an end-tidal sample can be sampled, or multiple breaths can be sampled, or a breath of a certain breath profile can be sampled, all of which are optimized for the diagnostic test being performed.
- Adjustments to the expiratory limb can allow the sample collection area to collect different portions of gas from the expiratory cycle, for example a section of gas from the middle airways rather than an end- tidal section as described in previous embodiments.
- the position of valves in the expiratory limb, together with the breath rate and breathing volumes being measured by the breath sensor, can dictate what area of the expiratory gas is isolated between the valves for analysis.
- FIG 32 and alternative embodiment is shown in which the volume V(3) shown in Figure 26 is adjustable, in order to set the apparatus to collect a certain section of breath from the exhaled gas.
- the apparatus can be set to obtain the last 50ml of expiratory gas except for the last 35ml inherently left in the mouthpiece and Tee.
- the apparatus can be set to obtain 50ml of gas with 100ml of expiratory gas still behind it.
- the apparatus can be set to obtain a 50ml sample from the beginning of exhalation, by increasing V(3) to 415ml. This adjustment can be made manually, automatically or semi-automatically, or alternatively different apparatuses can be made available for each situation.
- the adjustment shown in Figure 32 can optionally be performed by integrating this adjustment feature with the embodiments shown in Figures 29- 31, in which breathing signal measurements can be used to adjust the volume.
- a simple motor or slide mechanism is built into the expiratory limb of the apparatus, which can be battery powered.
- the system described in Figures 19-32 can be useful for collecting and measuring end-tidal gas samples, as well as samples from other sections of the breath. It can be used for measuring for example CO in the breath, or other gases, such as H2, NO, and others. It can be used for measuring other non-gaseous substances in the breath as well as gaseous markers, and used for collecting for measurement gas sections from different portions of the expiratory cycle.
- the system can be applied to any type of breathing and patient interface and applied to forced breathing maneuvers or spontaneous breathing, depending on the desired test.
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14838958.8A EP3038529A4 (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device |
CA2922349A CA2922349A1 (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device |
AU2014312042A AU2014312042A1 (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device |
SG11201601440QA SG11201601440QA (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device |
RU2016111651A RU2016111651A (en) | 2013-08-30 | 2014-08-29 | UNIVERSAL RESPIRATORY AND EXHAUSED AIR SAMPLING DEVICE FOR ANALYSIS |
JP2016537920A JP2016532117A (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device |
MX2016002628A MX2016002628A (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device. |
CN201480054249.9A CN105592791A (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device |
KR1020167008190A KR20160047565A (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device |
IL244304A IL244304A0 (en) | 2013-08-30 | 2016-02-26 | Universal breath analysis sampling device |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361872514P | 2013-08-30 | 2013-08-30 | |
US201361872450P | 2013-08-30 | 2013-08-30 | |
US61/872,450 | 2013-08-30 | ||
US61/872,514 | 2013-08-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2015031848A2 true WO2015031848A2 (en) | 2015-03-05 |
WO2015031848A3 WO2015031848A3 (en) | 2015-10-29 |
Family
ID=52584195
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2014/053569 WO2015031848A2 (en) | 2013-08-30 | 2014-08-29 | Universal breath analysis sampling device |
Country Status (12)
Country | Link |
---|---|
US (1) | US20150065901A1 (en) |
EP (1) | EP3038529A4 (en) |
JP (1) | JP2016532117A (en) |
KR (1) | KR20160047565A (en) |
CN (1) | CN105592791A (en) |
AU (1) | AU2014312042A1 (en) |
CA (1) | CA2922349A1 (en) |
IL (1) | IL244304A0 (en) |
MX (1) | MX2016002628A (en) |
RU (1) | RU2016111651A (en) |
SG (2) | SG10201703241UA (en) |
WO (1) | WO2015031848A2 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105388274A (en) * | 2015-12-04 | 2016-03-09 | 无锡市尚沃医疗电子股份有限公司 | Measuring apparatus for concentrations of nitric oxide and carbon monoxide in expired air |
WO2017187120A1 (en) * | 2016-04-25 | 2017-11-02 | Owlstone Medical Limited | Systems and device for capturing breath samples |
US9936897B2 (en) | 2003-06-19 | 2018-04-10 | Capnia, Inc. | Breath end-tidal gas monitor |
US10034621B2 (en) | 2011-12-21 | 2018-07-31 | Capnia, Inc. | Collection and analysis of a volume of exhaled gas with compensation for the frequency of a breathing parameter |
US10499819B2 (en) | 2013-01-08 | 2019-12-10 | Capnia, Inc. | Breath selection for analysis |
US11191449B2 (en) | 2013-08-30 | 2021-12-07 | Capnia, Inc. | Neonatal carbon dioxide measurement system |
US11331004B2 (en) | 2013-02-12 | 2022-05-17 | Capnia, Inc. | Sampling and storage registry device for breath gas analysis |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9970950B1 (en) | 2014-03-09 | 2018-05-15 | Hound Labs, Inc. | Method and apparatus for detecting acute use of target substance(s) |
US10067108B2 (en) | 2015-05-13 | 2018-09-04 | Elemental Sensor Llc | Device for detecting volatile organic compounds |
CN204988804U (en) * | 2015-05-29 | 2016-01-20 | 彭万旺 | Gaseous rapid sampling device of high pressure synthesis |
US10463275B2 (en) * | 2015-08-09 | 2019-11-05 | Elemental Sensor Llc | Device for capturing and concentrating volatile organic compounds |
US9933445B1 (en) | 2016-05-16 | 2018-04-03 | Hound Labs, Inc. | System and method for target substance identification |
PT109617A (en) | 2016-09-12 | 2018-03-12 | Faculdade De Ciencias E Tecnologia Da Univ Nova De Lisboa | SYSTEM FOR CONTROLLED AND SELECTED AIR COLLECTION EXHAUSTED AND OPERATING METHOD |
GB201704367D0 (en) * | 2017-03-20 | 2017-05-03 | Exhalation Tech Ltd | A breath condensate analyser |
US11187711B1 (en) | 2017-09-11 | 2021-11-30 | Hound Labs, Inc. | Analyte detection from breath samples |
KR20190088662A (en) | 2018-01-19 | 2019-07-29 | 충남대학교산학협력단 | Standard Sample and Method for Analysis of Exhaled Breath Gas |
WO2019164925A1 (en) * | 2018-02-20 | 2019-08-29 | Regents Of The University Of Minnesota | Breath sampling mask and system |
CN112930142A (en) * | 2018-07-14 | 2021-06-08 | 阿瑞特医疗技术有限公司 | Respiratory diagnostic tool and method |
US11426097B1 (en) * | 2018-10-17 | 2022-08-30 | Hound Labs, Inc. | Rotary valve assemblies and methods of use for breath sample cartridge systems |
CN109602420A (en) * | 2018-11-23 | 2019-04-12 | 深圳市美好创亿医疗科技有限公司 | Exhaled gas detection device and detection method |
US20200245899A1 (en) | 2019-01-31 | 2020-08-06 | Hound Labs, Inc. | Mechanical Breath Collection Device |
US11977086B2 (en) | 2019-03-21 | 2024-05-07 | Hound Labs, Inc. | Biomarker detection from breath samples |
AU2020255671A1 (en) | 2019-03-31 | 2021-12-02 | Agscent Pty Ltd | Biological sample capturing device |
CN110596310B (en) * | 2019-08-05 | 2023-03-10 | 苏州迈优医疗科技有限公司 | Exhaled gas analyzer and operation method |
US11933731B1 (en) | 2020-05-13 | 2024-03-19 | Hound Labs, Inc. | Systems and methods using Surface-Enhanced Raman Spectroscopy for detecting tetrahydrocannabinol |
FR3111266A1 (en) * | 2020-06-12 | 2021-12-17 | Institut Mines Telecom | Device for sampling gases exhaled by a patient |
US11806711B1 (en) | 2021-01-12 | 2023-11-07 | Hound Labs, Inc. | Systems, devices, and methods for fluidic processing of biological or chemical samples using flexible fluidic circuits |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3306283A (en) * | 1964-02-27 | 1967-02-28 | Univ Iowa State Res Found Inc | Oxygen utilization analyzer |
US3343529A (en) * | 1965-03-31 | 1967-09-26 | Ronald A Miller | Spirometer |
US3858573A (en) * | 1973-07-09 | 1975-01-07 | Said Ryan By Said Williams | Alveolar gas trap and method of use |
US3910261A (en) * | 1974-06-11 | 1975-10-07 | Bourns Inc | End-tidal gas analysis apparatus for respirators |
US4671298A (en) * | 1984-11-26 | 1987-06-09 | Meridian Medical Corporation | Isothermal rebreathing apparatus and method |
US5069220A (en) * | 1989-05-26 | 1991-12-03 | Bear Medical Systems, Inc. | Measurement of gas concentration in exhaled breath |
US5361772A (en) * | 1993-07-07 | 1994-11-08 | Diagnostics & Devices, Inc. | Breath collection devices |
US5787885A (en) * | 1994-10-13 | 1998-08-04 | Lemelson; Jerome H. | Body fluid analysis system |
DE19619763A1 (en) * | 1996-05-17 | 1997-11-20 | Univ Ludwigs Albert | Device for taking inspiratory and / or expiratory gas samples |
SE9703545D0 (en) * | 1997-09-30 | 1997-09-30 | Siemens Elema Ab | A method for determining the concentration of NO in a respiratory gas and an analyzer for carrying out the process |
IL148468A (en) * | 2002-03-03 | 2012-12-31 | Exalenz Bioscience Ltd | Breath collection system |
US8088333B2 (en) * | 2003-04-28 | 2012-01-03 | Invoy Technology, LLC | Thermoelectric sensor for analytes in a gas |
US7353825B2 (en) * | 2003-05-01 | 2008-04-08 | Axon Medical, Inc. | Apparatus and techniques for reducing the effects of general anesthetics |
AU2003238288A1 (en) * | 2003-06-19 | 2005-02-04 | Everest Biomedical Instruments | Breath end-tidal gas monitor |
GB0403612D0 (en) * | 2004-02-18 | 2004-03-24 | Univ Glasgow | Method, apparatus and kit for breath diagnosis |
US20060178592A1 (en) * | 2005-02-07 | 2006-08-10 | Aperson Biosystems Corp. | System and method for controlling the flow of exhaled breath during analysis |
US7600439B1 (en) * | 2005-04-29 | 2009-10-13 | Griffin Analytical Technologies, Inc. | Apparatus and method for storage of atmospheric sample for eventual chemical analysis |
EP2066236B1 (en) * | 2006-08-16 | 2015-09-16 | Aerocrine AB | Device for fractionating expiration volume |
KR100983827B1 (en) * | 2007-08-20 | 2010-09-27 | 동양물산기업 주식회사 | Apparatus and method of analyzing constituents of gas in oral cavity and alveolar gas |
US8313440B2 (en) * | 2008-01-22 | 2012-11-20 | Mitchell Friedman | Infant breath collector |
CN201692453U (en) * | 2010-06-18 | 2011-01-05 | 虞慧华 | Oxygen therapy and breathed air collection integrated end expiration CO2 monitoring conduit |
EP2725974A1 (en) * | 2011-06-28 | 2014-05-07 | Fred Hutchinson Cancer Research Center | End-tidal gas monitoring apparatus |
BR112014015145B1 (en) * | 2011-12-21 | 2022-08-16 | Capnia, Inc. | APPARATUS FOR ANALYZING A GAS CONCENTRATION IN A BREATH OF A PATIENT AND A METHOD FOR DETERMINING A CONCENTRATION OF A GAS IN A BREATH OF A PATIENT |
-
2014
- 2014-08-29 SG SG10201703241UA patent/SG10201703241UA/en unknown
- 2014-08-29 US US14/473,878 patent/US20150065901A1/en not_active Abandoned
- 2014-08-29 KR KR1020167008190A patent/KR20160047565A/en not_active Application Discontinuation
- 2014-08-29 CA CA2922349A patent/CA2922349A1/en not_active Abandoned
- 2014-08-29 EP EP14838958.8A patent/EP3038529A4/en not_active Withdrawn
- 2014-08-29 WO PCT/US2014/053569 patent/WO2015031848A2/en active Application Filing
- 2014-08-29 RU RU2016111651A patent/RU2016111651A/en unknown
- 2014-08-29 SG SG11201601440QA patent/SG11201601440QA/en unknown
- 2014-08-29 AU AU2014312042A patent/AU2014312042A1/en not_active Abandoned
- 2014-08-29 CN CN201480054249.9A patent/CN105592791A/en active Pending
- 2014-08-29 MX MX2016002628A patent/MX2016002628A/en unknown
- 2014-08-29 JP JP2016537920A patent/JP2016532117A/en active Pending
-
2016
- 2016-02-26 IL IL244304A patent/IL244304A0/en unknown
Non-Patent Citations (1)
Title |
---|
See references of EP3038529A4 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9936897B2 (en) | 2003-06-19 | 2018-04-10 | Capnia, Inc. | Breath end-tidal gas monitor |
US10034621B2 (en) | 2011-12-21 | 2018-07-31 | Capnia, Inc. | Collection and analysis of a volume of exhaled gas with compensation for the frequency of a breathing parameter |
US10499819B2 (en) | 2013-01-08 | 2019-12-10 | Capnia, Inc. | Breath selection for analysis |
US11331004B2 (en) | 2013-02-12 | 2022-05-17 | Capnia, Inc. | Sampling and storage registry device for breath gas analysis |
US11191449B2 (en) | 2013-08-30 | 2021-12-07 | Capnia, Inc. | Neonatal carbon dioxide measurement system |
CN105388274A (en) * | 2015-12-04 | 2016-03-09 | 无锡市尚沃医疗电子股份有限公司 | Measuring apparatus for concentrations of nitric oxide and carbon monoxide in expired air |
CN105388274B (en) * | 2015-12-04 | 2017-09-15 | 无锡市尚沃医疗电子股份有限公司 | A kind of measurement apparatus of expiration nitric oxide and carbonomonoxide concentration |
WO2017187120A1 (en) * | 2016-04-25 | 2017-11-02 | Owlstone Medical Limited | Systems and device for capturing breath samples |
US11033203B2 (en) | 2016-04-25 | 2021-06-15 | Owlstone Medical Limited | Systems and device for capturing breath samples |
Also Published As
Publication number | Publication date |
---|---|
JP2016532117A (en) | 2016-10-13 |
EP3038529A4 (en) | 2017-08-09 |
MX2016002628A (en) | 2016-06-06 |
CA2922349A1 (en) | 2015-03-05 |
SG11201601440QA (en) | 2016-03-30 |
RU2016111651A (en) | 2017-10-06 |
EP3038529A2 (en) | 2016-07-06 |
IL244304A0 (en) | 2016-04-21 |
AU2014312042A1 (en) | 2016-03-17 |
SG10201703241UA (en) | 2017-06-29 |
US20150065901A1 (en) | 2015-03-05 |
WO2015031848A3 (en) | 2015-10-29 |
CN105592791A (en) | 2016-05-18 |
KR20160047565A (en) | 2016-05-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20150065901A1 (en) | Universal breath sampling and analysis device | |
US20210085213A1 (en) | Cannabis drug detection device | |
US20190021632A1 (en) | Sampling and storage registry device for breath gas analysis | |
AU2019204455B2 (en) | Neonatal carbon dioxide measurement system | |
US7377901B2 (en) | Apparatus for collection of airway gases | |
JP3838671B2 (en) | Breath collection device | |
CN105388274B (en) | A kind of measurement apparatus of expiration nitric oxide and carbonomonoxide concentration | |
KR20210071994A (en) | breath sampler | |
US20190307396A1 (en) | Device and method for detection of cannabis and other controlled substances using faims | |
TWI642936B (en) | Apparatus and method for analyzing breath gas mixture for halitosis detection | |
US20150065902A1 (en) | Columnar flow gas sampling and measurement system | |
EP2641537A1 (en) | Auxiliary device for collection and sampling of exhaled air | |
JPH08313408A (en) | Breath sampling and analyzing apparatus | |
CN110664408A (en) | Alveolar gas collection system, cleaning system and alveolar gas collection method | |
US11320419B2 (en) | Sampling of breath gas | |
WO2016166623A1 (en) | Cannabis drug detection device |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14838958 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase |
Ref document number: 2922349 Country of ref document: CA Ref document number: 2016537920 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 244304 Country of ref document: IL |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2016/002628 Country of ref document: MX |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112016004096 Country of ref document: BR |
|
ENP | Entry into the national phase |
Ref document number: 2014312042 Country of ref document: AU Date of ref document: 20140829 Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2014838958 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2014838958 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20167008190 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2016111651 Country of ref document: RU Kind code of ref document: A |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14838958 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase |
Ref document number: 112016004096 Country of ref document: BR Kind code of ref document: A2 Effective date: 20160225 |