AU4600700A - Noninvasive monitoring of intracranial pressure - Google Patents
Noninvasive monitoring of intracranial pressure Download PDFInfo
- Publication number
- AU4600700A AU4600700A AU46007/00A AU4600700A AU4600700A AU 4600700 A AU4600700 A AU 4600700A AU 46007/00 A AU46007/00 A AU 46007/00A AU 4600700 A AU4600700 A AU 4600700A AU 4600700 A AU4600700 A AU 4600700A
- Authority
- AU
- Australia
- Prior art keywords
- patient
- head
- waveform
- intracranial pressure
- measuring
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
- A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/03—Detecting, measuring or recording fluid pressure within the body other than blood pressure, e.g. cerebral pressure; Measuring pressure in body tissues or organs
- A61B5/031—Intracranial pressure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/316—Modalities, i.e. specific diagnostic methods
- A61B5/318—Heart-related electrical modalities, e.g. electrocardiography [ECG]
- A61B5/346—Analysis of electrocardiograms
- A61B5/349—Detecting specific parameters of the electrocardiograph cycle
- A61B5/352—Detecting R peaks, e.g. for synchronising diagnostic apparatus; Estimating R-R interval
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
- A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
- A61B8/0808—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the brain
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Pathology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Physics & Mathematics (AREA)
- Biophysics (AREA)
- Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Radiology & Medical Imaging (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Measuring And Recording Apparatus For Diagnosis (AREA)
- Measuring Fluid Pressure (AREA)
Description
WO 00/68647 PCT/IBOO/00595 NONINVASIVE MONITORING OF INTRACRANIAL PRESSURE FIELD AND BACKGROUND OF THE INVENTION The present invention relates to noninvasive medical diagnostics and, more particularly, to a noninvasive method of monitoring intracranial pressure. Abnormal intracranial pressure (ICP) is diagnostic of brain and skull pathologies, including head injuries, abnormal growths in the brain, and hemorrhages. The normal ICP is between about 10 mm Hg and about 12 mm Hg. An ICP greater than about 20 mm Hg causes headaches. An ICP greater than about 40 mm Hg causes coma. Presently known methods of monitoring ICP are predominantly invasive. In lumbar puncture, a needle is inserted at the base of the spinal column, to monitor the pressure of the fluid in the spinal column. This pressure may not reflect accurately the ICP, because there may be a blockage between the patient's head and the base of the patient's spinal column. A second invasive method of monitoring ICP is to make a burr hole 10 mm in diameter in the patient's skull and to introduce a catheter to one of the lateral ventricles via the hole. The pressure of the cerebrospinal fluid (CSF) in the ventricle is measured directly by a transducer via the catheter. This procedure may cause a hemorrhage that blocks the penetrated ventricle. In addition, if CSF enters the catheter, the accuracy of the pressure reading is impaired. In a related invasive method, the catheter is held in place by a threaded fitting that is screwed into the patient's skull. A saline solution is introduced to the catheter and the pressure of the saline solution is measured using an appropriate transducer. If insufficient care is taken to preserve antiseptic conditions, this procedure may lead to infection of the patient's brain. 1 WO 00/68647 PCT/IBOO/00595 Furthermore, the threaded fitting may penetrate the patient's brain, causing damage to the patient's brain. In both of the latter two invasive methods, the catheter must be removed after five days. Therefore, these methods can not be used for long term (several months) monitoring of ICP of patients in comas. In a fourth invasive method, a fiber optic device, with a sensor at the tip of a fiber optic cable, is inserted in the patient's cerebral tissue, in the patient's subdural space, or in the patient's intraventricular epidural space. If a blood clot forms on the sensor, or if the fiber optic cable bends too sharply or breaks, the device may give a spuriously high pressure reading. In short, the prior art invasive methods of measuring ICP are unreliable, may lead to infection, and can not be used for more than five consecutive days. There are additional reasons why it would be advantageous to have a non-invasive method of monitoring ICP. The standard quantitative measure of the severity of coma is the Glasgow Coma Scale. See Mark S. Greenberg (ed.), Handbook ofNeurosurgery, 4' edition (1988), vol. 2 p. 553. The score value of the scale ranges from 15 for a normal individual to 3 for a patient in deep coma. The prior art protocol is to start ICP monitoring if the score is 8 or less. It would be useful to monitor ICP of patients with scores higher than 8. It also would be useful to monitor the ICP of healthy individuals under severe environmental stress, for example, astronauts, divers and submariners. Yost et al., in US Patent No. 5,617,873, purport to describe an indirect, noninvasive method ofmonitoring ICP. Two changes in CSF volume are induced, and the associated changes in ICP are measured. The absolute value of ICP is inferred from these measurements. Although 2 q1JRqTTI ITF H1FT (RIRF 5 ) WO 00/68647 PCT/IBOO/00595 the methods they teach for measuring the changes in ICP in fact are noninvasive, their methods of inducing changes in CSF volume are necessarily invasive, despite their claims to the contrary. Transcranial Doppler monitoring is a noninvasive technique that provides only qualitative indications of variations in ICP, not the quantitative measurements provided by the prior art invasive methods. Michaeli, in US Patent No. 5,840,018, which is incorporated by reference for all purposes as if fully set forth herein, teaches a noninvasive method for diagnosis of migraines, based on ultrasound measurements of the diameters of cranial blood vessels. Ultrasound reflection traces are integrated within a preselected gate to provide samples of an Echo Pulsogram (EPG) signal. The timing of the gate is selected to correspond to the depth within the cranium of the target blood vessel. The time lag between start systole, as indicated by an Electrocardiograph (ECG) signal, and the start of contraction of the target blood vessel, as compared to the normal time lag of 211 6 milliseconds, is diagnostic of migraines. SUMMARY OF THE INVENTION According to the present invention there is provided a method for measuring intracranial pressure in a head of a patient, the head including a forehead and a bridge of a nose, including the steps of: (a) measuring, entirely from outside the head of the patient, at least one waveform representative of a pulsation of an anatomical feature in the head of the patient; (b) identifying a plurality of diagnostic features associated with the at least one waveform; and (c) inferring the intracranial pressure from the plurality of diagnostic features. The shapes of anatomical features of a patient's skull, such as the cerebral ventricles, change in synchrony with the patient's heartbeat. The present invention is based on an empirical relationship between these shape pulsations and ICP. According to the present invention, a waveform, or a series of waveforms, representative of the pulsation of the shape of one of these anatomical features, is measured noninvasively, and the empirical relationship is used to infer 3 SUBSTITUTE SHEFT (mUl : 2R WO 00/68647 PCT/IBOO/00595 ICP. The preferred anatomical feature is the third ventricle. The preferred modality for measuring the waveform is ultrasound. The preferred waveform is obtained by integrating ultrasound reflection traces within a predetermined gate corresponding to a reflection from the anatomical feature. According to a first embodiment of the present invention, a ratio of diagnostic times that characterize the waveform is determined. An empirical quadratic relationship between this ratio and ICP as measured by a prior art invasive method is used to infer ICP quantitatively. According to a second embodiment of the present invention, several successive waveforms are received, over the course of at least one respiratory cycle. The shape of the corresponding respiratory wave, as reflected in the successive waveforms, is related qualitatively to the ICP. BRIEF DESCRIPTION OF THE DRAWINGS The invention is herein described, by way of example only, with reference to the accompanying drawings, wherein: FIG. 1A is a sketch of EPG waveforms over the course of several cardiac cycles; FIG. 1B is a sketch of an ECG trace synchronous with the waveforms of FIG 1 A; FIG. 2 shows p as a function of tIT; FIGS. 3A and 3B are sketches of waveform trains modulated by a patient's breathing. DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is of a noninvasive method of quantitative and qualitative monitoring of ICP. 4 SUBSTITUTE SHEET (RULE 2R) WO 00/68647 PCT/IBOO/00595 The principles and operation of noninvasive monitoring of ICP according to the present invention may be better understood with reference to the drawings and the accompanying description. As used herein, a waveform is said to be representative of a pulsation of an anatomic feature if the shape of the waveform, as a function of time, is isomorphic with the shape of the anatomical feature, as a function of time, up to a sign. For example, the geometric dimensions of a patient's third ventricle increase and decrease in synchrony with the change in the patient's blood pressure over the course of the patient's cardiac cycle. A waveform whose amplitude increases as a corresponding dimension of the third ventricle increases, and whose amplitude decreases as that dimension of the third ventricle decreases, is said to be representative of the pulsation of the third ventricle over the course of the cardiac cycle. This isomorphic representation is up to a sign, so a waveform whose amplitude decreases as a corresponding dimension of the third ventricle increases, and whose amplitude increases as a corresponding dimension of the third ventricle decreases, also is said to be representative of the pulsation of the third ventricle over the course of the cardiac cycle. Although the scope of the present invention includes the measurement of waveforms representative of any anatomical feature of a patient's head, including, for example, the frontal cornum, the temporal cornum and the occipital cornum of the first and second ventricles, as well as the fourth ventricle, the preferred anatomical feature is the third ventricle. Again, although the scope of the present invention includes any noninvasive modality for measuring waveforms representative of pulsations of the target anatomical feature, the preferred modality is ultrasound. An ultrasound transducer is placed in contact with the patient's forehead. Pulses of ultrasound energy are introduced to the patient's head, in the saggital direction, using the transducer. These pulses are partly reflected from anatomical features, including the target anatomical feature, that lie in their propagation paths. The reflections propagate back to the transducer, where they are converted into reflection traces. The desired waveforms are obtained by integrating each of the traces within a predefined gate, as taught in US Patent No. 5,840,018. Each resulting integration value is a sample of an EPG waveform. 5 qURiRTITIITI: I:4FFT fRIIL F 9AI WO 00/68647 PCT/IBOO/00595 Referring now to the drawings, Figure 1A shows two EPG waveforms 22a and 22b and a part of a third waveform 22c thus obtained, as a function of time. Each waveform 22 includes a monotonically rising portion 24 and a falling portion 26, with falling portion 26 including a venous output notch 28. For reference, Figure 1B shows an ECG trace 30, synchronized with EPG waveforms 22, that includes several ECG pulses 32. The start of each waveform 22 is coincident with the end of the corresponding ECG pulse 32. The direction of movement is indicated by an arrow 70. The start of each EPG waveform 22 is delayed relative to the start of the corresponding ECG pulse 32 by a delay r. It has been determined empirically that the best location for the ultrasound transducer on the forehead of the patient is from 2.5 centimeters to 6 centimeters above the bridge of the patient's nose. The features of waveforms 22 that are diagnostic of ICP are two diagnostic times T and t, shown in Figure 1A with reference to waveform 22a. Diagnostic time T is the duration of waveform 22, i.e., the duration of one cardiac cycle. Diagnostic time t is the length of time from the start of waveform 22 until the time, subsequent to the time of venous output notch 28, at which the amplitude of failing portion 26 returns to the amplitude of waveform 22 at the time of venous output notch 28. Because time t is shorter than the full duration of one waveform 22, time t is referred to herein as a "subduration". By calibrating with invasive measures of ICP, it has been determined that the following equation describes ICP in terms of the ratio t/T with a 96% correlation: ICP = p(t/T) - B The constant B is 9 mm H 2 0. For t/Tless than about 0.3, p also is a constant, 373 mm HO. For t/T greater than about 0.5, p itself varies quadratically with t/T, as shown in Figure 2. Note that the units of the ordinate in Figure 2 are mm H 2 0. 6 WO 00/68647 PCT/IBOO/00595 As the patient breathes, the train of waveforms 22 shown in part by Figure 1A may be modulated by that breathing. If the ICP is less than 15 mm Hg, the overall shape of the train of waveforms 22 is flat, as in Figure IA, over many cardiac cycles. It is known from invasive studies that if the ICP is greater than about 20 mm Hg, the train of waveforms 22 is modulated by a respiratory wave (Greenberg, op. cit.,pp. 710-711). If the ICP is in the range of 20 to 40 mm Hg, the respiratory wave is in the form of a p-wave 40, as shown in Figure 3A. -wave 40 includes cycles 42 of roughly equal periodicity that tend to have sharp peaks 44 and smooth troughs 46. Diagnostic features 42, 44 and 46 of p-wave 40 define the shape of p-wave 40 as roughly sinusoidal. If the ICP is in the range of 40 to 60 mm Hg, the respiratory wave is in the form of a plateau wave 50, as shown in Figure 3B. The shape of plateau wave 50 is defined by a series of cycles 52, with each cycle 52 starting with a sharp rise 54 to a sharp peak 56, declining to a plateau 58, and then declining further to a baseline 60. Monitoring successive waveforms 22 over several respiratory cycles to observe the shape of the respiratory wave provides a qualitative indication of ICP . While the invention has been described with respect to a limited number of embodiments, it will be appreciated that many variations, modifications and other applications of the invention may be made. 7 SUBSTITUTE SHEET (RULE 261
Claims (17)
1. A method for measuring intracranial pressure in a head of a patient, the head including a forehead and a bridge of a nose, comprising the steps of: (a) measuring, entirely from outside the head of the patient, at least one waveform representative of a pulsation of a ventricle in the head of the patient; (b) identifying a plurality of diagnostic features associated with said at least one waveform; and (c) inferring the intracranial pressure from said plurality of diagnostic features.
2. The method of claim 1, wherein said ventricle is a third ventricle.
3. The method of claim 1, wherein said measuring of said waveform is effected by steps including repeatedly receiving ultrasound echoes from said anatomical feature, said echoes defining said waveform.
4. The method of claim 3, wherein said receiving of said ultrasound echoes is effected by steps including: (i) placing an ultrasound transducer in contact with the head of the patient; (ii) repeatedly introducing pulses of ultrasound energy into the head of the patient, using said transducer; and (iii) for each of said pulses, receiving a reflection trace of said pulse.
5. The method of claim 4, wherein said waveform is obtained from said reflection traces by integrating each of said reflection traces within a predetermined gate, said integration of said each reflection trace providing a sample of said waveform.
6. The method of claim 4, wherein said receiving of said reflection traces is effected using said transducer. 8 C tDCTrT ITE C UET II Imm - WO 00/68647 PCT/IBOO/00595
7. The method of claim 6, wherein said ultrasound transducer is placed in contact with the forehead of the patient, between about 2.5 centimeters and about 6 centimeters above the bridge of the nose.
8. The method of claim 1, wherein said plurality of diagnostic features includes a plurality of diagnostic times.
9. The method of claim 8, wherein said plurality of diagnostic times includes a duration and a subduration.
10. The method of claim 9, wherein the intracranial pressure is inferred from a ratio of said subduration to said duration.
11. The method of claim 10, wherein the intracranial pressure is inferred from a linear function of said ratio.
12. The method of claim 1, wherein said measuring of said at least one waveform is effected for a sufficiently long time to include at least one respiratory wave.
13. The method of claim 12, wherein said plurality of diagnostic features defines a shape of said at least one respiratory wave.
14. A method for measuring intracranial pressure in a head of a patient, the head including a forehead and a bridge of a nose, comprising the steps of: (a) measuring, entirely from outside the head of the patient, at least one waveform representative of a pulsation of an anatomical feature in the head of the patient by: (i) placing an ultrasound transducer in contact with the forehead of the patient, between about 2.5 centimeters and about 6 centimeters above the bridge of the nose, 9 URETITUTF SHEET IRULE 9R WO 00/68647 PCT/IBOO/00595 (ii) repeatedly introducing pulses of ultrasound energy into the head of the patient, using said transducer, and (iii) for each of said pulses, receiving a reflection trace of said pulse, using said transducer, said reflection traces defining said waveform; (b) identifying a plurality of diagnostic features associated with said at least one waveform; and (c) inferring the intracranial pressure from said plurality of diagnostic features.
15. A method for measuring intracranial pressure in a head of a patient, comprising the steps of: (a) measuring, entirely from outside the head of the patient, at least one waveform representative of a pulsation of an anatomical feature in the head of the patient; (b) identifying a duration and a subduration associated with said at least one waveform; and (c) inferring the intracranial pressure from said duration and said subduration.
16. A method for measuring intracranial pressure in a head of a patient, comprising the steps of: (a) measuring, entirely from outside the head of the patient, for a sufficiently long time to include at least one respiratory wave, at least one EPG waveform representative of a pulsation of an anatomical feature in the head of the patient; (b) identifying a plurality of diagnostic features, associated with said at least one waveform, that define a shape of said respiratory wave; and (c) inferring the intracranial pressure from said plurality of diagnostic features.
17. A method for measuring intracranial pressure in a head of a patient, comprising the steps of: (a) measuring, entirely from outside the head of the patient, at least one EPG waveform representative of a pulsation of an anatomical feature in the head of the patient; 10 WO 00/68647 PCT/IBOO/00595 (b) identifying a plurality of diagnostic features associated with said at least one waveform; and (c) inferring the intracranial pressure from said plurality of diagnostic features. 11 SUjRTITilTF RHFFT (RuLE R
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US30756899A | 1999-05-10 | 1999-05-10 | |
US09307568 | 1999-05-10 | ||
PCT/IB2000/000595 WO2000068647A2 (en) | 1999-05-10 | 2000-05-09 | Noninvasive monitoring of intracranial pressure |
Publications (1)
Publication Number | Publication Date |
---|---|
AU4600700A true AU4600700A (en) | 2000-11-21 |
Family
ID=23190310
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU46007/00A Abandoned AU4600700A (en) | 1999-05-10 | 2000-05-09 | Noninvasive monitoring of intracranial pressure |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1182969A2 (en) |
JP (1) | JP2003521284A (en) |
AU (1) | AU4600700A (en) |
CA (1) | CA2373200A1 (en) |
MX (1) | MXPA01011471A (en) |
WO (1) | WO2000068647A2 (en) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7547283B2 (en) | 2000-11-28 | 2009-06-16 | Physiosonics, Inc. | Methods for determining intracranial pressure non-invasively |
EP1345527A4 (en) * | 2000-11-28 | 2007-09-19 | Allez Physionix Ltd | Systems and methods for making non-invasive physiological assessments |
FR2827495B1 (en) | 2001-07-23 | 2004-05-14 | Univ Clermont Auvergne | METHODS AND EQUIPMENT FOR THE ANALYSIS OF BIOLOGICAL SIGNALS REPRESENTATIVE OF VARIATIONS IN INTRACRANIAL PRESSURE AND BLOOD PRESSURE |
FR2827496B1 (en) | 2001-11-09 | 2004-06-04 | Univ Clermont Auvergne | METHODS AND EQUIPMENT FOR THE ANALYSIS OF BIOLOGICAL SIGNALS REPRESENTATIVE OF VARIATIONS IN INTRACRANIAL PRESSURE AND BLOOD PRESSURE |
US8211031B2 (en) | 2002-01-15 | 2012-07-03 | Orsan Medical Technologies Ltd. | Non-invasive intracranial monitor |
US6761695B2 (en) | 2002-03-07 | 2004-07-13 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Method and apparatus for non-invasive measurement of changes in intracranial pressure |
US6746410B2 (en) | 2002-04-04 | 2004-06-08 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Method and apparatus for determining changes in intracranial pressure utilizing measurement of the circumferential expansion or contraction of a patient's skull |
US6740048B2 (en) | 2002-04-08 | 2004-05-25 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Non-invasive method of determining diastolic intracranial pressure |
US7147605B2 (en) | 2002-07-08 | 2006-12-12 | Uab Vittamed | Method and apparatus for noninvasive determination of the absolute value of intracranial pressure |
EP1633234A4 (en) * | 2003-06-03 | 2009-05-13 | Physiosonics Inc | Systems and methods for determining intracranial pressure non-invasively and acoustic transducer assemblies for use in such systems |
WO2010014815A1 (en) * | 2008-07-30 | 2010-02-04 | Rappaport, Arthur | Method for measuring intracranial elasticity |
US8277385B2 (en) | 2009-02-04 | 2012-10-02 | Advanced Brain Monitoring, Inc. | Method and apparatus for non-invasive assessment of hemodynamic and functional state of the brain |
US9345411B2 (en) | 2011-02-09 | 2016-05-24 | Orsan Medical Technologies, Ltd. | Devices and methods for monitoring cerebral hemodynamic conditions |
WO2015191902A1 (en) | 2014-06-11 | 2015-12-17 | Nihon Kohden Corporation | Apparatus and methods for detecting increase in intracranial pressure |
US10709345B1 (en) | 2019-11-26 | 2020-07-14 | David Michaeli | Method and apparatus for noninvasive absolute (mean) intracranial pressure (A-ICP) measurement and/or monitoring |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5117835A (en) * | 1990-07-31 | 1992-06-02 | Mick Edwin C | Method and apparatus for the measurement of intracranial pressure |
US5919144A (en) * | 1997-05-06 | 1999-07-06 | Active Signal Technologies, Inc. | Apparatus and method for measurement of intracranial pressure with lower frequencies of acoustic signal |
US5873840A (en) * | 1997-08-21 | 1999-02-23 | Neff; Samuel R. | Intracranial pressure monitoring system |
-
2000
- 2000-05-09 AU AU46007/00A patent/AU4600700A/en not_active Abandoned
- 2000-05-09 WO PCT/IB2000/000595 patent/WO2000068647A2/en active Search and Examination
- 2000-05-09 JP JP2000617389A patent/JP2003521284A/en active Pending
- 2000-05-09 CA CA002373200A patent/CA2373200A1/en not_active Abandoned
- 2000-05-09 EP EP00927617A patent/EP1182969A2/en not_active Withdrawn
- 2000-05-09 MX MXPA01011471A patent/MXPA01011471A/en unknown
Also Published As
Publication number | Publication date |
---|---|
EP1182969A2 (en) | 2002-03-06 |
WO2000068647A3 (en) | 2001-06-28 |
WO2000068647A2 (en) | 2000-11-16 |
JP2003521284A (en) | 2003-07-15 |
MXPA01011471A (en) | 2004-08-12 |
CA2373200A1 (en) | 2000-11-16 |
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Legal Events
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MK6 | Application lapsed section 142(2)(f)/reg. 8.3(3) - pct applic. not entering national phase | ||
TH | Corrigenda |
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