Patent Grant
7452457
The present invention relates to a measurement method and apparatus for use in measuring concentrations of an analyte in a fluid. The invention relates more particularly, but not exclusively, to a method and apparatus which may be used for measuring the concentration of glucose in blood.
Measuring the concentration of substances, particularly in the presence of other, confounding substances, is important in many fields, and especially in medical diagnosis. For example, the measurement of glucose in body fluids, such as blood, is crucial to the effective treatment of diabetes.
Diabetic therapy typically involves two types of insulin treatment: basal, and meal-time. Basal insulin refers to continuous, e.g. time-released insulin, often taken before bed. Meal-time insulin treatment provides additional doses of faster acting insulin to regulate fluctuations in blood glucose caused by a variety of factors, including the metabolization of sugars and carbohydrates. Proper regulation of blood glucose fluctuations requires accurate measurement of the concentration of glucose in the blood. Failure to do so can produce extreme complications, including blindness and loss of circulation in the extremities, which can ultimately deprive the diabetic of use of his or her fingers, hands, feet, etc.
Multiple methods are known for measuring the concentration of analytes in a blood sample, such as, for example, glucose. Such methods typically fall into one of two categories: optical methods and electrochemical methods. Optical methods generally involve reflectance or absorbance spectroscopy to observe the spectrum shift in a reagent. Such shifts are caused by a chemical reaction that produces a color change indicative of the concentration of the analyte. Electrochemical methods generally involve, alternatively, amperometric or coulometric responses indicative of the concentration of the analyte. See, for example, U.S. Pat. No. 4,233,029 to Columbus, U.S. Pat. No. 4,225,410 to Pace, U.S. Pat. No. 4,323,536 to Columbus, U.S. Pat. No. 4,008,448 to Muggli, U.S. Pat. No. 4,654,197 to Lilja et al., U.S. Pat. No. 5,108,564 to Szuminsky et al., U.S. Pat. No. 5,120,420 to Nankai et al., U.S. Pat. No. 5,128,015 to Szuminsky et al., U.S. Pat. No. 5,243,516 to White, U.S. Pat. No. 5,437,999 to Diebold et al., U.S. Pat. No. 5,288,636 to Pollmann et al., U.S. Pat. No. 5,628,890 to Carter et al., U.S. Pat. No. 5,682,884 to Hill et al., U.S. Pat. No. 5,727,548 to Hill et al., U.S. Pat. No. 5,997,817 to Crismore et al., U.S. Pat. No. 6,004,441 to Fujiwara et al., U.S. Pat. No. 4,919,770 to Priedel, et al., and U.S. Pat. No. 6,054,039 to Shieh, which are hereby incorporated in their entireties.
An important limitation of electrochemical methods of measuring the concentration of a chemical in blood is the effect of confounding variables on the diffusion of analyte and the various active ingredients of the reagent. For example, the geometry and state of the blood sample must correspond closely to that upon which the signal-to-concentration mapping function is based.
The geometry of the blood sample is typically controlled by a sample-receiving portion of the testing apparatus. In the case of blood glucose meters, for example, the blood sample is typically placed onto a disposable test strip that plugs into the meter. The test strip may have a sample chamber (capillary fill space) to define the geometry of the sample. Alternatively, the effects of sample geometry may be limited by assuring an effectively infinite sample size. For example, the electrodes used for measuring the analyte may be spaced closely enough so that a drop of blood on the test strip extends substantially beyond the electrodes in all directions. Ensuring adequate coverage of the measurement electrodes by the sample, however, is an important factor in achieving accurate test results. This has proven to be problematic in the past, particularly with the use of capillary fill spaces.
Other examples of limitations to the accuracy of blood glucose measurements include variations in blood composition or state (other than the aspect being measured). For example, variations in hematocrit (concentration of red blood cells), or in the concentration of other chemicals in the blood, can effect the signal generation of a blood sample. Variations in the temperature of blood samples is yet another example of a confounding variable in measuring blood chemistry.
Thus, a system and method are needed that accurately measure blood glucose, even in the presence of confounding variables, including variations in temperature, hematocrit, and the concentrations of other chemicals in the blood. A system and method are also needed to ensure adequate coverage of the measurement electrodes by the sample, particularly in capillary fill devices. A system and method are likewise needed that accurately measure an analyte in a fluid. It is an object of the present invention to provide such a system and method.
In one form of the invention, a method of determining dose sufficiency in a test strip for performing a measurement on a biological fluid is disclosed, comprising: providing a biological fluid test strip, comprising: a capillary fill chamber extending a length along the test strip from an intake opening to a terminus, a reagent disposed in the capillary fill chamber between the opening and the terminus, the reagent defining a measurement zone, and at least two dose sufficiency electrodes defining a gap therebetween and in operative communication with the capillary fill chamber, the electrodes located between the measurement zone and the terminus; applying the biological fluid to the opening, whereby the fluid flows from the opening toward the terminus, the flow including a flow front selected from one of a concave, a convex and a substantially flat flow front; applying a test signal to a first one of the electrodes; determining the presence or absence of a response above a predetermined threshold at the second one of the electrodes, the response indicating that the fluid has occupied substantially all of the measurement zone regardless of whether the flow front is concave, convex or substantially flat.
In another form of the invention, a method of determining dose sufficiency in a test strip for performing a measurement on a biological fluid is disclosed, comprising: providing a biological fluid test strip, comprising: a fluid flow intake opening, a fluid flow terminus, a reagent disposed on the test strip between the opening and the terminus, the reagent defining a measurement zone, and at least two dose sufficiency electrodes defining a gap therebetween and located between the measurement zone and the terminus; applying the biological fluid to the opening, whereby the fluid flows from the opening toward the terminus, the flow including a flow front selected from one of a concave, a convex and a substantially flat flow front; applying a test signal to a first one of the electrodes; determining the presence or absence of a response above a predetermined threshold at the second one of the electrodes, the response indicating that the fluid has occupied substantially all of the measurement zone regardless of whether the flow front is concave, convex or substantially flat.
In another form of the invention, a method of determining a dose sufficiency in a test strip for performing a measurement on a biological fluid is disclosed, comprising: providing a biological fluid test strip comprising: a capillary fill chamber extending a length along the test strip, at least two measurement electrodes in operative communication with the chamber, and at least two dose sufficiency electrodes in operative communication with the chamber; applying the biological fluid to the test strip; applying a dose sufficiency test signal having an AC component to one of the dose sufficiency electrodes; and measuring a response to the dose sufficiency test signal at the other of the dose sufficiency electrodes.
In another form of the invention, a method of determining a fill sufficiency in test strip for performing a measurement on a biological fluid is disclosed, comprising: providing a biological fluid test strip including a capillary fill chamber extending a length along the test strip from an intake opening to a terminus, a measurement zone in the chamber positioned intermediate the opening and the terminus, and at least two dose sufficiency electrodes in operative communication with the chamber the electrodes positioned intermediate the measurement zone and the terminus; introducing the biological fluid to the opening effective to cause the fluid to flow toward the terminus whereby the chamber is filled; applying a test signal having an AC component to one of the dose sufficiency electrodes; and detecting a response or an absence of the response to the test signal at the other of the dose sufficiency electrodes effective to indicate the fill sufficiency of the biological fluid.
In another form of the invention, a method of determining dosage fill level in a test strip for performing a measurement on a biological fluid is disclosed, comprising: providing a biological fluid test strip including a capillary fill chamber extending a length along the test strip from an opening to a terminus, and at least two dose sufficiency electrodes in operative communication with the chamber the dose sufficiency electrodes positioned to define a gap between one another; dosing the test strip with a biological fluid effective to cause the biological fluid to begin to fill the chamber; applying a signal having an AC component to one of the dose sufficiency electrodes; measuring a response to the signal at the other of the dose sufficiency electrodes; determining the dosage fill level based upon the response.
In another form of the invention, a method of determining a fill level of a biological fluid in a test strip for performing a measurement on the fluid is disclosed, comprising: providing a test strip including a capillary fill chamber extending a length along the test strip from an opening to a terminus, and at least two dose sufficiency electrodes in operative communication with the chamber the dose sufficiency electrodes positioned to define a gap between one another; introducing the biological fluid to the opening effective to cause the fluid to flow toward the terminus whereby the chamber is filled; applying a test signal having an AC component to one of the dose sufficiency electrodes; and measuring a response to the signal at the other of the dose sufficiency electrodes; determining the fill level of the biological fluid based upon the response wherein the response varies in relation to the fill level. In another form of the invention, a method of determining dosage fill rate in a biological fluid test strip is disclosed, comprising: providing a biological fluid test strip including a capillary fill chamber extending a length along the test strip from an opening to a terminus, and at least two dose sufficiency electrodes in operative communication with the chamber the dose sufficiency electrodes positioned to define a gap between one another; dosing the test strip with a biological fluid effective to cause the biological fluid to begin to fill the chamber; applying a signal having an AC component to one of the dose sufficiency electrodes; measuring a first response to the signal at the other of the dose sufficiency electrodes at a first time; measuring a second response to the signal at the other of the dose sufficiency electrodes at a second time; and determining a rate at which the biological fluid fills the chamber based at least in part upon the first response and the second response.
In another form of the invention, a test strip for performing a measurement on a biological fluid is disclosed, comprising: a capillary fill chamber extending a length along the test strip from an opening to a terminus; at least two measurement electrodes in operative communication with the chamber; and at least two dose sufficiency electrodes in operative communication with the chamber; wherein the dose sufficiency electrodes have first edges essentially parallel to the length of the capillary chamber and second edges essentially perpendicular to the length of the capillary fill chamber with the first edges being of greater length than the second edges.
In another form of the invention, a test strip for performing a measurement on a biological fluid is disclosed, comprising: a capillary fill chamber extending a length along the test strip from an opening to a terminus; a measurement zone in the chamber positioned intermediate the opening and the terminus, and at least two dose sufficiency electrodes in operative communication with the chamber the electrodes positioned intermediate the measurement zone and the terminus; wherein the dose sufficiency electrodes have a first axis essentially parallel to the length of the capillary chamber and a second axis essentially perpendicular to the length of the capillary fill chamber with the first axis being of greater length than the second axis.
The invention will be further described, by way of example only, with reference to the accompanying drawings, in which:
For the purposes of promoting an understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the drawings, and specific language will be used to describe that embodiment. It will nevertheless be understood that no limitation of the scope of the invention is intended. Alterations and modifications in the illustrated device, and further applications of the principles of the invention as illustrated therein, as would normally occur to one skilled in the art to which the invention relates are contemplated, are desired to be protected. In particular, although the invention is discussed in terms of a blood glucose meter, it is contemplated that the invention can be used with devices for measuring other analytes and other sample types. Such alternative embodiments require certain adaptations to the embodiments discussed herein that would be obvious to those skilled in the art.
The entire disclosure of U.S. provisional applications titled DEVICES AND METHODS RELATING TO ELECTROCHEMICAL BIOSENSORS (Ser. No. 60/480,243, filed Jun. 20, 2003) and DEVICES AND METHODS RELATING TO ANALYTE SENSOR (Ser. No. 60/480,397, Filed Jun. 20, 2003) are hereby incorporated by reference in their entireties.
A system and method according to the present invention permit the accurate measurement of an analyte in a fluid. In particular, the measurement of the analyte remains accurate despite the presence of interferants, which would otherwise cause error. For example, a blood glucose meter according to the present invention measures the concentration of blood glucose without error that is typically caused by variations in the temperature and the hematocrit level of the sample. The accurate measurement of blood glucose is invaluable to the prevention of blindness, loss of circulation, and other complications of inadequate regulation of blood glucose in diabetics. An additional advantage of a system and method according to the present invention is that measurements can be made much more rapidly and with much smaller sample volumes, making it more convenient for the diabetic person to measure their blood glucose. Likewise, accurate and rapid measurement of other analytes in blood, urine, or other biological fluids provides for improved diagnosis and treatment of a wide range of medical conditions.
It will be appreciated that electrochemical blood glucose meters typically (but not always) measure the electrochemical response of a blood sample in the presence of a reagent. The reagent reacts with the glucose to produce charge carriers that are not otherwise present in blood. Consequently, the electrochemical response of the blood in the presence of a given signal is intended to be primarily dependent upon the concentration of blood glucose. Secondarily, however, the electrochemical response of the blood to a given signal is dependent upon other factors, including hematocrit and temperature. See, for example, U.S. Pat. Nos. 5,243,516; 5,288,636; 5,352,351; 5,385,846; and 5,508,171, which discuss the confounding effects of hematocrit on the measurement of blood glucose, and which are hereby incorporated by reference in their entireties. In addition, certain other chemicals can influence the transfer of charge carriers through a blood sample, including, for example, uric acid, bilirubin, and oxygen, thereby causing error in the measurement of glucose.
A preferred embodiment system and method for measuring blood glucose according to the present invention operates generally by using the signal-dependence of the contribution of various factors to the impedance (from which admittance and phase angle may be derived) of a blood sample. Because the contribution of various factors to the impedance of a blood sample is a function of the applied signal, the effects of confounding factors (that is, those other than the factors sought to be measured) can be substantially reduced by measuring the impedance of the blood sample to multiple signals. In particular, the effects of confounding factors, (primarily temperature and hematocrit, but also including chemical interferants such as oxygen), contribute primarily to the resistivity of the sample, while the glucose-dependent reaction contributes primarily to the capacitance. Thus, the effects of the confounding factors can be eliminated by measuring the impedance of the blood sample to an AC excitation, either alone or in combination with a DC excitation. The impedance (or the impedance derived admittance and phase information) of the AC signal is then used to correct the DC signal or AC derived capacitance for the effects of interferants.
It will be appreciated that measurements at sufficiently high AC frequencies are relatively insensitive to the capacitive component of the sample's impedance, while low frequency (including DC) measurements are increasingly (with decreasing frequency) sensitive to both the resistive and the capacitive components of the sample's impedance. The resistive and capacitive components of the impedance can be better isolated by measuring the impedance at a larger number of frequencies. However, the cost and complexity of the meter increases as the number of measurements increases and the number of frequencies that need to be generated increases. Thus, in the presently preferred embodiment, the impedance may be measured at greater than ten frequencies, but preferably at between two and ten frequencies, and most preferably at between two and five frequencies.
As used herein, the phrase “a signal having an AC component” refers to a signal which has some alternating potential (voltage) portions. For example, the signal may be an “AC signal” having 100% alternating potential (voltage) and no DC portions; the signal may have AC and DC portions separated in time; or the signal may be AC with a DC offset (AC and DC signals superimposed).
Sample Measurement with Successive AC and DC Signals
At time 110 a test strip is inserted into the meter and several possible responses to the insertion of the test strip into the glucose meter are shown. It will be appreciated that the test strip may also be inserted before the excitation signal 100 is initiated (i.e. before time 101); however, the test strip itself may advantageously be tested as a control for the suitability of the strip. It is therefore desirable that the excitation signal 100 be initiated prior to test strip insertion. For example, relatively large current leakage, as shown at 112, may occur if the strip is wet, either because the test strip was pre-dosed, or due to environmental moisture. If the test strip has been pre-dosed and permitted to largely or completely dry out, an intermediate current leakage may occur, as shown at 114. Ideally, insertion of the test strip will cause no or negligible leakage current due to an expected absence of charge carriers between the test electrodes, as shown at 116. Measured current leakage above a predetermined threshold level will preferably cause an error message to be displayed and prevent the test from continuing.
Once a suitable test strip has been inserted, the user doses the strip, as shown at time 120. While the blood sample is covering the electrodes the current response will rapidly increase, as the glucose reacts with the reagent and the contact area increases to maximum. The response current will reach a stable state, which indicates the impedance of the sample at this frequency. Once this measurement is made and recorded by the test meter, the excitation frequency is then stepped down to about 10 kHz in the preferred embodiment, as shown at time 130. Another measurement is made and recorded by the test meter, and the frequency is stepped down to about 2 kHz in the preferred embodiment, as shown at 140. A third measurement is made and recorded by the test meter at this frequency. A fourth measurement is made at about 1 kHz in the preferred embodiment, as shown at 150. In the preferred embodiment, measurements are taken at regular intervals (e.g. 10 points per cycle). It will be appreciated that the stable state response may be measured as current or voltage (preferably both magnitude and phase) and the impedance and/or admittance can be calculated therefrom. Although the present specification and claims may refer alternately to the AC response as impedance or admittance (magnitude and/or phase), resistance, conductivity, current or charge, and to the DC response as current, charge, resistance or conductivity, those skilled in the art will recognize that these measures are interchangeable, it only being necessary to adjust the measurement and correction mathematics to account for which measure is being employed. In the preferred embodiment, the test meter applies a voltage to one electrode and measures the current response at the other electrode to obtain both the AC and DC response.
In certain alternative embodiments measurements are made at fewer or more frequencies. Preferably measurements are made at at least two AC frequencies at least an order of magnitude apart. If more than two AC frequencies are used, then it is preferable that the highest and lowest frequencies be at least an order of magnitude apart.
It will be appreciated that various waveforms may be used in an AC signal, including, for example, sinusoidal, trapezoidal, triangle, square and filtered square. In the presently preferred embodiment the AC signal has a filtered square waveform that approximates a sine wave. This waveform can be generated more economically than a true sine wave, using a square wave generator and one or more filters.
Once all four AC measurements are made, the signal is preferably briefly reduced to zero amplitude, as shown at 160. The DC excitation is then begun, as shown at 170. The amplitude of the DC excitation is advantageously selected based on the reagent being used, in order to maximise the resulting response or response robustness. For example, if ferricyanide is being used in a biamperometry system, the DC amplitude is preferably about 300 mV. For another example, if a nitrosoaniline derivative is being used in a biamperometry system, the DC amplitude is preferably about 500-550 mV. In the alternative, if a third reference electrode is used, the DC applitude is preferably 600 mV (versus the silver/silver chloride reference electrode) for ferricyanide, and 40-100 mV (versus the silver/silver chloride reference electrode) for nitrosoaniline derivative. During DC excitation, measurements are preferably made at a rate of 100 pts/sec. The current response will follow a decay curve (known as a Cottrell curve), as the reaction is limited by the diffusion of unreacted glucose next to the working electrode. The resulting stable-state amplitude (measured or projected) is used to determine a glucose estimation of the sample, as is known in the art. A corrected estimation is then determined that corresponds more closely to the concentration of glucose in the blood, by using the impedance of the sample to the AC signal to correct for the effects of interferants, as explained in greater detail hereinbelow.
It will be appreciated that a method according to the present invention may also be used to measure the concentration of other analytes and in other fluids. For example, a method according to the present invention may be used to measure the concentration of a medically significant analyte in urine, saliva, spinal fluid, etc. Likewise, by appropriate selection of reagent a method according to the present invention may be adapted to measure the concentration of, for example, lactic acid, hydroxybutyric acid, etc.
Sample Measurement with Simultaneously Applied AC and DC Signals
It will be appreciated that at least some of the applied DC and AC components can also be applied simultaneously.
A system for measuring blood glucose according to the present invention advantageously employs a blood glucose meter and test strips generally similar to those used in prior art systems, such as those commercially available from Roche Diagnostics, and such as are described in U.S. Pat. Nos. 6,270,637; and 5,989,917, which are hereby incorporated in their entireties. These test strips provide apparati having a sample cell in which the blood sample is received for testing, and electrodes disposed within the sample cell through which the excitation signal is provided and the measurements are made. Those skilled in the art will appreciate that these test strips and meters may advantageously be used for the measurement of glucose in blood, but that other apparati may be more suitable for the measurement of other analytes or other biological fluids when practising the present invention.
A suitable glucose meter may be adapted from such known meters by the addition of electronic circuitry that generates and measures signals having AC and DC components, such as those described hereinabove, and by being programmed to correct the DC measurement using the AC measurement(s), as described in greater detail hereinbelow. It will be appreciated that the specific geometry and chemistry of the test strips can cause variations in the relationships between the concentration of glucose, hematocrit, and temperature, and the impedance of a sample. Thus, a given combination of test strip geometry and chemistry must be calibrated, and the meter programmed with the corresponding algorithm. The present invention comprehends the application of excitation signals in any order and combination. For example, the present invention comprehends the application of 1) AC only, 2) AC then DC, 3) AC then DC then AC, 4) DC then AC, and 5) AC with a DC offset, just to name a few of the possible permutations.
The use of the complex AC impedance measurement data to correct for the effects of interferants on the DC measurement is advantageously illustrated by the following series of examples. These examples illustrate how the principles of the present invention can facilitate improvements in accuracy and test speed when measuring the concentration of an analyte in a test specimen. Although the following examples deal with correcting for the interfering effects of hematocrit and temperature on blood glucose determinations, those skilled in the art will recognize that the teachings of the present invention are equally useful for correcting for the effects of other interferants in both blood glucose measurements and in the measurement of other analytes. Furthermore, the present specification and claims refer to steps such as “determine the hematocrit value” and “determine the temperature,” etc. To use the hematocrit value as an example, it is intended that such statements include not only determining the actual hematocrit value, but also a hematocrit correction factor vs. some nominal point. In other words, the process may never actually arrive at a number equal to the hematocrit value of the sample, but instead determine that the sample's hematocrit differs from a nominal value by a certain amount. Both concepts are intended to be covered by statements such as “determine the hematocrit value.”
The measurements made in Example 1 were achieved using the test strip illustrated in
In the measurements, blood samples were applied to test strip 300 and the excitation potentials illustrated in
In order to determine the minimum needed DC excitation time, a “dose response” study was performed, in which glycollyzed (glucose depleted) blood was divided into discrete aliquots and controlled levels of glucose were added to obtain five different known levels of glucose in the blood samples. The resulting DC current profile was then examined as two parameters were varied. The first parameter was the Incubation Time, or the time between the detection of the blood sample being applied to the test strip 300 and the application of the DC potential to the test strip 300. The second parameter to be varied was the Read Time, or the time period after application of the DC potential and the measurement of the resulting current. The length of time between detection of the blood sample being applied to the test strip to the taking of the last measurement used in the concentration determination calculations is the Total Test Time. In this study, therefore, the sum of the Incubation Time and the Read Time is the Total Test Time. The results of this study are illustrated in
In
The barrier to implementation of such fast test times in a consumer glucose test device, however, is the variation from blood sample to blood sample of the level of interference from the presence of blood cells in the sample. The hematocrit (the percentage of the volume of a blood sample which is comprised of cells versus plasma) varies from individual to individual. The interference effect of hematocrit on such measurements is fairly complex. In the tests of Example 1, however, all samples contained the same level of hematocrit. With no variable hematocrit influence at the different glucose levels, the hematocrit term cancels out in the correlation figures.
The measurements made in Example 2 were also achieved using the test strip illustrated in
In the measurements, capillary blood samples from various fingerstick donors were applied to test strip 300 and the excitation potentials illustrated in
In this Example 2, the AC response of the sample was derived as admittance (the inverse of impedance). The admittance response is proportionate to the hematocrit level of the sample in a temperature dependent manner. The relationship between admittance, hematocrit and testing temperature is illustrated in
Regression analysis of this data allows admittance, hematocrit and temperature to be related according to the following formula:
Hest=c0+c1Y2kHz+c2dT (Equation 1)
Using this relationship to predict the blood hematocrit is accomplished using test temperature data reported by the temperature sensor in the meter and the measured admittance. In Equation 1, c0, c1 and c2 are constants, dT is the deviation in temperature from a center defined as “nominal” (24° C. for example), and Hest is the estimated deviation in hematocrit from a similar “nominal” value. For the present purposes, the actual hematocrit value is not necessary, and it is generally preferred to produce a response which is proportionate but centers around a nominal hematocrit. Thus, for a 70% hematocrit, the deviation from a nominal value of 42% would be 28%, while conversely for a 20% hematocrit the deviation from that same nominal value would be −22%.
By using the AC admittance measurement to estimate the hematocrit level using Equation 1, the accuracy of the DC glucose response can be greatly improved by combining the estimated hematocrit, temperature and DC response to correct for the hematocrit interference in the DC response as follows:
PRED=(a0+hct1Hest+hct2Hest2+tau1dT+tau2dT2)+(a1DC)(1+hct3Hest+hct4Hest2)(1+tau3dT+tau4dT2) (Equation 2)
where DC is the measured glucose current response to the applied DC signal and PRED is the compensated (predicted) glucose response corrected for the effects of hematocrit and temperature. The constants (a0, hct1, hct2, tau1, tau2, a1, hct3, hct4, tau3 and tau4) in Equation 2 can be determined using regression analysis, as is known in the art.
The measurements made in Example 3 were also achieved using the test strip illustrated in
In the measurements, blood samples were applied to test strip 300 and the excitation potentials illustrated in
It was found that another component of the AC response, the phase angle (particularly at lower frequencies, such as 200 Hz in this Example 3), is also a function of the sample glucose level in the case of this test strip and reagent. This relationship is demonstrated in
The linearized relationship between the 200 Hz phase angle response and the blood glucose level is as follows:
Peff=(Φ200 Hz/Γ)−γ (Equation 3)
where Peff is the effective phase, which is proportional to glucose, the terms Γ and γ are constants, and Φ is the measured AC phase angle.
Using the same approach to compensate for temperature and hematocrit as used in Example 1 above (see Equations 1 and 2) produced a predictive algorithm as follows:
PRED=(a0+hct1Hest+hct2Hest2+tau1dT+tau2dT2)+(a1Peff)(1+hct3Hest+hct4Hest2)(1+tau3dT+tau4dT2) (Equation 4)
The resulting compensated (predicted) response PRED versus glucose for the 125 blood samples (each tested with eight test strips) is shown in
It was also determined that AC phase angle measurements can produce hematocrit level measurements that are almost immune to the effects of temperature variation. In another covariant study of 125 samples (five glucose concentrations, five hematocrit concentrations and five temperatures), each of the samples was tested using an excitation profile of 20 kHz, 10 kHz, 2 kHz, 1 kHz and DC. The AC phase angle at various frequencies was related to glucose, hematocrit and temperature using linear regression to determine the coefficients of the following formula at each of the four AC frequencies:
Phase=c0+c1Glu+c2HCT+c3Temp (Equation 5)
where Glu is the known glucose concentration, HCT is the known hematocrit concentration and Temp is the known temperature.
The determined coefficients revealed that the temperature coefficient (c3) was essentially zero at 20 kHz and 10 kHz, cancelling temperature from the equation at these frequencies. Furthermore, the glucose coefficient (c1) is essentially zero at all of the AC frequencies because, as explained hereinabove, the higher frequency AC impedance measurements are largely unaffected by glucose levels and are therefore useful for measuring the levels of interfering substances. It was therefore found that the hematocrit level could be determined independent of temperature and glucose level using only the AC phase angle measurements. In a preferred embodiment, the hematocrit may be measured using the phase angle data from all four measured frequencies:
Hest=c0+c1Φ20 kHz+c2Φ10kHz+c3Φ2kHz+c4Φ1kHz (Equation 6)
Those skilled in the art will recognise that that the coefficients can be empirically determined for any particular test strip architecture and reagent chemistry. The present invention therefore may be used to estimate hematocrit using only AC phase angle measurements preferably made at at least one AC frequency, more preferably made at at least two AC frequencies, and most preferably made at at least four AC frequencies.
The measurements made in Example 4 were also achieved using the test strip illustrated in
The method for the manufacture of the glucose biosensor for this Example 4 is the same in all respects as disclosed in U.S. Pat. No. 5,997,817 except for the manufacture of the reagent. A protocol for the preparation of the preferred embodiment nitrosoaniline reagent is as follows:
Spiked venous blood samples were used. Five levels of glucose, four temperatures (19, 23, 32 and 38° C.) and five levels of hematocrit (20, 30, 45, 60 and 70%) were independently varied, producing a covariance study with 100 samples. 16 test strips 300 were tested for each unique combination of glucose, temperature and hematocrit. The blood samples were applied to test strip 300 and the excitation potentials illustrated in
In this Example 4, the AC response of the sample was derived as admittance (the inverse of impedance). The admittance response is proportionate to the hematocrit level of the sample in a temperature dependent manner. The relationship between admittance, hematocrit and testing temperature is illustrated in
Regression analysis of this data allows admittance, hematocrit and temperature to be related according to the following formula:
Hest=(Y3.2kHz+c0+c1dT)/(c2dT+c3) (Equation 7)
It was determined that the admittance measurement made at 3.2 kHz was best correlated with hematocrit for this test system. Using this relationship to predict the blood hematocrit is accomplished using test temperature data reported by the temperature sensor in the meter and the measured admittance. In Equation 7, c0, c1, c2 and c3 are constants, dT is the deviation in temperature from a center defined as “nominal” (24° C. for example), and Hest is the estimated deviation in hematocrit from a similar “nominal” value. For the present purposes, the actual hematocrit value is not necessary, and it is generally preferred to produce a response which is proportionate but centers around a nominal hematocrit. Thus, for a 70% hematocrit, the deviation from a nominal value of 42% would be 28%, while conversely for a 20% hematocrit the deviation from the same nominal value would be −22%.
By using the AC admittance measurement to estimate the hematocrit level using Equation 7, the accuracy of the DC glucose response can be greatly improved by combining the estimated hematocrit, temperature and DC response to correct for the hematocrit interference in the DC response as follows (same as Equation 2 above):
PRED=(a0+hct1Hest+hct2Hest2+tau1dT+tau2dT2)+(a1DC)(1+hct3Hest+hct4Hest2)(1+tau3dT+tau4dT2) (Equation 8)
The constants in Equation 8 can be determined using regression analysis, as is known in the art.
The measurement methods of the present invention have been found to be useful with other test strip designs as well. Example 5 was conducted using the test strip design illustrated in
Examples of the use of laser ablation techniques in preparing electrodes for biosensors are described in U.S. patent application Ser. No. 09/866,030, “Biosensors with Laser Ablation Electrodes with a Continuous Coverlay Channel” filed May 25, 2001, and in U.S. patent application Ser. No. 09/411,940, entitled “Laser Defined Features for Patterned Laminates and Electrode,” filed Oct. 4, 1999, both disclosures incorporated herein by reference.
The bottom foil layer 1702 is then coated in the area extending over the electrodes with a reagent layer 1704 in the form of an extremely thin reagent film. This procedure places a stripe of approximately 7.2 millimeters width across the bottom foil 1702 in the region labelled “Reagent Layer” on
The materials are processed in continuous reels such that the electrode pattern is orthogonal to the length of the reel, in the case of the bottom foil 1702. Once the bottom foil 1702 has been coated with reagent, the spacer is slit and placed in a reel-to-reel process onto the bottom foil 1702. Two spacers 1706 formed from 100 μm polyester (in the preferred embodiment this is Melinex 329 available from DuPont) coated with 25 μm PSA (hydrophobic adhesive) on both the dorsal and ventral surfaces are applied to the bottom foil layer 1702, such that the spacers 1706 are separated by 1.5 mm and the working, counter and dose sufficiency electrodes are centered in this gap. A top foil layer 1708 formed from 100 μm polyester coated with a hydrophilic film on its ventral surface (using the process described in U.S. Pat. No. 5,997,817) is placed over the spacers 1706. In the preferred embodiment, the hydrophilic film is coated with a mixture of Vitel and Rhodapex surfactant at a nominal thickness of 10 microns. The top foil layer 1708 is laminated using a reel-to-reel process. The sensors can then be produced from the resulting reels of material by means of slitting and cutting.
The 1.5 mm gap in the spacers 1706 therefore forms a capillary fill space between the bottom foil layer 1702 and the top foil layer 1708. The hydrophobic adhesive on the spacers 1706 prevents the test sample from flowing into the reagent under the spacers 1706, thereby defining the test chamber volume. Because the test strip 1700 is 5 mm wide and the combined height of the spacer 1706 and conductive layer is 0.15 mm, the sample receiving chamber volume is
5mm×1.5mm×0.15mm=1.125μl (Equation 9)
As shown in
1.5mm×1.765mm×0.15mm=0.397μl (Equation 10)
The reagent composition for the test strip 1700 is given in Tables V and VI.
A protocol for the preparation of the preferred embodiment nitrosoaniline reagent is as follows:
The measurement results illustrated in
Based upon the encouraging results obtained in
A covariance study using spiked venous blood samples representing five glucose levels (40, 120, 200, 400 and 600), five hematocrit levels (20, 30, 45, 60 and 70%) and five temperatures (12, 18, 24, 32 and 44° C.) was designed, resulting in 125 separate combinations. As in the previous examples, the relationship between admittance, temperature and hematocrit was examined and plotted (
Hest=c0+c1(Φ10kHz−Φ20kHz)+c2(Φ2kHz−Φ1kHz) (Equation 11)
For the test strip used in this Example 5, the correlation between phase angle and hematocrit was better at higher frequencies. Because of this, the c2 constant approaches zero and Hest can reliably be estimated using only the 10 kHz and 20 kHz data. Use of lower frequencies, however, allows for slight improvements in the strip-to-strip variability of the Hest function. The present invention therefore may be used to estimate hematocrit using only AC phase angle measurements preferably made at at least one AC frequency, more preferably made at at least two AC frequencies, and most preferably made at at least four AC frequencies.
Because the hematocrit can be determined using only the AC response data, and we know from
Test=b0+b1(Y10kHZ−Y20kHz)+b2(Y2kHz−Y1kHz)+b3Hest (Equation 12)
where b0, b1, b2 and b3 are constants. It will be appreciated that the estimation of hematocrit and temperature from the AC response data may be made with more or fewer frequency measurements, and at different frequencies than those chosen for this example. The particular frequencies that produce the most robust results will be determined by test strip geometries and dimensions. The present invention therefore may be used to estimate test sample temperature using only AC response measurements preferably made at at least one AC frequency, more preferably made at at least two AC frequencies, and most preferably made at at least four AC frequencies.
Those skilled in the art will recognise that the direct measurement of the temperature of the sample under test (by means of the AC response) is a great improvement over prior art methods for estimating the temperature of the sample. Typically, a thermistor is placed in the test meter near where the test strip is inserted into the meter. Because the thermistor is measuring a temperature remote from the actual sample, it is at best only a rough approximation of the true sample temperature. Furthermore, if the sample temperature is changing (for example due to evaporation), then the thermal inertia of the test meter and even the thermistor itself will prevent the meter-mounted thermistor from accurately reflecting the true temperature of the sample under test. By contrast, the temperature estimation of the present invention is derived from measurements made within the sample under test (i.e. within the reaction zone in which the sample under test reacts with the reagent), thereby eliminating any error introduced by the sample being remote from the measuring location. Additionally, the temperature estimation of the present invention is made using data that was collected very close in time to the glucose measurement data that will be corrected using the temperature estimation, thereby further improving accuracy. This represents a significant improvement over the prior art methods.
As a demonstration of the effectiveness of the method of this Example 5 for correcting for the effects of interferants on the blood glucose measurement, the uncompensated DC current response versus known glucose concentration is plotted in
As previously discussed, the accuracy of the DC glucose response can be greatly improved by combining the estimated hematocrit, temperature and DC response to correct for the hematocrit and temperature interference in the DC response as follows:
PRED=(a0+hct1Hest+hct2Hest2+tau1Test+tau2Test)+(a1DC)(1+hct3Hest+hct4Hest2)(1+tau3Test+tau4Test) (Equation 13)
The constants in Equation 13 can be determined using regression analysis, as is known in the art. The present invention therefore allows one to estimate hematocrit by using the AC phase angle response (Equation 11). The estimated hematocrit and the measured AC admittance can be used to determine the estimated temperature (Equation 12). Finally, the estimated hematocrit and estimated temperature can be used with the measured DC response to obtain the predicted glucose concentration (Equation 13).
Applying the above methodology to the test data plotted in
Using the same test strip 1700 and reagent described above for Example 5, the excitation profile illustrated in
For this Example 6, 49 spiked venous blood samples representing seven glucose levels and seven hematocrit levels were tested. The correlation coefficient r2 between the DC current and the blood hematocrit was then examined at three DC measurement times: 1.1 seconds, 1.5 seconds and 1.9 seconds after sample application. These correlations are plotted versus hematocrit level in
Hest=c0+c1Φ20kHz (Equation 14)
As discussed hereinabove, the accuracy of the DC glucose response can be greatly improved by compensating for the interference caused by hematocrit as follows:
PRED=(a0+hct1Hest+hct2Hest2)+(a1DC)(1+hct3Hest+hct4Hest2) (Equation 15)
Note that Equation 15 does not include temperature compensation terms since temperature variation was not included in the experiment of this Example 6, it can be reasonably inferred from previous examples that a Test term could be included using the 10 kHz and 20 kHz admittance values in combination with the Hest term. Because the hematocrit can be reliably estimated using only the 20 kHz phase angle measurement data, the hematocrit compensated predicted glucose response can be determined using only this phase angle information and the measured DC response. The compensated DC response versus glucose level for only the DC read at 1.1 seconds (representing a 1.1 second Total Test Time) is illustrated in
The same data for the 1.5 second DC read is illustrated in
In order to provide an extra measure of quality control to the analyte measurement process, particularly when the test system is to be used by a non-professional end user, it is desirable to detect sensors (test strips) that have been mis-dosed (double dosed, etc.), that have been previously used, or that have degraded enzymes (from being stored in too humid an environment, being too old, etc.). These conditions are collectively referred to as “abused sensors.” It is desired to devise a test that will abort the analyte measurement process (or at least warn the user that the test results may not be accurate) if an abused sensor is inserted into the test meter.
When performing a blood glucose analysis, the test meter will typically make several successive current measurements as the blood sample continues to react with the reagent chemistry. As is well known in the art, this response current is known as the Cottrell current and it follows a pattern of decay as the reaction progresses. We may define a Cottrell Failsafe Ratio (CFR) as follows:
The Cottrell response of the biosensor in the Confidence system can be given by:
As the time terms in this equation are known and constant for a sensor measurement, the ratio always yields a constant for Cottrell curves with identical sample times and intervals. Therefore, the sum of sensor currents divided by the last sensor current should yield a constant independent of glucose concentration. This relationship is used in the preferred embodiment to detect potentially faulty biosensor responses.
A Current Sum Failsafe can be devised that places a check on the Cottrell response of the sensor by summing all of the acquired currents during sensor measurement. When the final current is acquired, it is multiplied by two constants (which may be loaded into the meter at the time of manufacture or, more preferably, supplied to the meter with each lot of sensors, such as by a separate code key or by information coded onto the sensor itself). These constants represent the upper and lower threshold for allowable NCFR values.
The two products of the constants multiplied by the final current are compared to the sum of the biosensor currents. The sum of the currents should fall between the two products, thereby indicating that the ratio above was fulfilled, plus or minus a tolerance.
Therefore, the preferred embodiment performs the following check when there is a single DC block:
Because some embodiments may contain two DC blocks in the measurement sequence, a Modified Cottrell Failsafe Ratio (MCFR) can be formulated as:
The NCFR (and MCFR) is correlated with hematocrit. As demonstrated hereinabove in Example 3, the AC phase angle is also correlated with hematocrit. It follows then, that the AC phase angle and the NCFR are correlated with one another. This relationship holds only if the sensor is unabused. The correlation degrades for an abused sensor.
It is therefore possible to design an equation to analyze the measured phase angle data to produce a failsafe calculation that will indicate if an abused sensor is being used. In the preferred embodiment, it was chosen to use the difference between the phase angles measured at two separate frequencies in order to make the test more robust to errors caused by parasitic resistance, etc. Applying the arctangent function to drive the two populations to different asymptotes yields the following failsafe equation:
FAILSAFE=1000×arc tan [NCFR/(fs0+fs1(Φ10kHz−Φ20kHz))] (Equation 21)
where 1000=scaling factor
NCFR=Cottrell Failsafe Ratio
Using Equation 21, the intercept term fs0 can be chosen such that a FAILSAFE value below zero indicates an abused sensor, while a FAILSAFE value above zero indicates a non-abused sensor. Those skilled in the art will recognise that the opposite result could be obtained by choosing a different intercept.
Use of Dose Sufficiency Electrodes
As described hereinabove, it has been recognised that accurate sample measurement requires adequate coverage of the measurement electrodes by the sample. Various methods have been used to detect the insufficiency of the sample volume in the prior art. For example, the Accu-Chek® Advantage® glucose test meter sold by Roche Diagnostics Corporation of Indianapolis, Ind. warned the user of the possible inadequacy of the sample volume if non-Cotrellian current decay was detected by the single pair of measurement electrodes. Users were prompted to re-dose the test strip within a specified time allotment.
The possibility of insufficient sample size has been heightened in recent years due to the use of capillary fill devices used in conjunction with blood lancing devices designed to minimize pain through the requirement of only extremely small sample volumes. If an inadequate amount of sample is drawn into the capillary fill space, then there is a possibility that the measurement electrodes will not be adequately covered and the measurement accuracy will be compromised. In order to overcome the problems associated with insufficient samples, various prior art solutions have been proposed, such as placing an additional electrode downstream from the measurement electrodes; or a single counter electrode having a sub-element downstream and major element upstream of a working electrode; or an indicator electrode arranged both upstream and downstream from a measurement electrode (allowing one to follow the flow progression of the sample across the working and counter electrodes or the arrival of the sample at a distance downstream). The problem associated with each of these solutions is that they each incorporate one or the other electrode of the measurement pair in communication with either the upstream or the downstream indicator electrodes to assess the presence of a sufficient volume of sample to avoid biased test results.
Despite these prior art design solutions, failure modes persist wherein the devices remain prone to misinterpretation of sample sufficiency. The present inventors have determined that such erroneous conclusions are related primarily to the distances between a downstream member of a measurement electrode pair (co-planar or opposing geometries) and the dose detection electrode, in combination with the diversity of non-uniform flow fronts. A sample traversing the capillary fill space having an aberrant (uneven) flow front can close the circuit between a measurement electrode and an indicator electrode and erroneously advise the system that sufficient sample is present to avoid a biased measurement result.
Many factors employed in the composition and/or fabrication of the test strip capillary fill spaces influence such irregular flow front behavior. These factors include:
Another problem with prior art dose sufficiency methodologies determined by the present inventors relates to the use of one or the other of the available measurement electrodes in electrical communication with an upstream or downstream dose detection electrode. In such arrangements, the stoichiometry of the measurement zone (the area above or between the measurement electrodes) is perturbed during the dose detect/dose sufficiency test cycle prior to making a measurement of the analyte of interest residing in the measurement zone. As sample matrices vary radically in make-up, the fill properties of these samples also vary, resulting in timing differences between sample types. Such erratic timing routines act as an additional source of imprecision and expanded total system error metrics.
Trying to solve one or more of these obstacles typically can lead to 1) more complex manufacturing processes (additional process steps each bringing an additional propensity for contamination); 2) additional raw material quality control procedures; 3) more costly raw materials such as laminate composites having mixtures of hydrophobic and hydrophyllic resins and negatively impacting manufacturing costs; and 4) labor-intensive surfactant coatings of meshes and or capillary walls.
In order to design an electrode system that will adequately indicate dose sufficiency in a test strip employing a capillary fill space, an experiment was performed to examine the flow front shape at the leading edge of the sample as it progresses through the capillary fill space. Test fixtures comprising two sheets of clear polycarbonate sheets joined together with double-sided adhesive tape were used, where the capillary fill space was formed by cutting a channel in the double-sided tape. Use of the polycarbonate upper and lower sheets allowed the flow fronts of the sample to be videotaped as it flowed through the capillary fill space.
Specifically, the test devices were laminated using laser cut 1 mm thick Lexan® polycarbonate sheets (obtained from Cadillac Plastics Ltd., Westlea, Swindon SN5 7EX, United Kingdom). The top and bottom polycarbonate sheets were coupled together using double-sided adhesive tapes (#200MP High Performance acrylic adhesive obtained from 3M Corporation, St. Paul, Minn.). The capillary channels were defined by laser cutting the required width openings into the double-sided tape. Tape thicknesses of 0.05 μm, 0.125 μm, and 0.225 μm were used to give the required channel heights. The dimensions of the capillary spaces of the test devices are tabulated in
The top and bottom polycarbonate parts were laminated together with the laser cut adhesive tapes using a custom-built jig to ensure reproducible fabrication. For each test device, a fluid receptor region defineing the entrance to the capillary channel was formed by an opening pre-cut into the upper polycarbonate sheet and adhesive tape components. For each of the three channel heights, channel widths of 0.5 mm, 1.00 mm, 1.5 mm, 2.00 mm, 3.00 mm, and 4.00 mm were fabricated. The capillary channel length for all devices was 50 mm. Twenty-eight (28) of each of the eighteen (18) device types were constructed. The assembled devices were plasma treated by Weidman Plastics Technology of Dortmund, Germany. The following plasma treatment conditions were used:
Each of the test devices was dosed with a fixed volume of venous blood having a hematocrit value of 45%. Flow and flow front behavior was captured on videotape for later analysis. It was determined that the relative dimensions of the capillary fill channel determined the flow front behavior. Devices to the left of the dashed line in
Use of Dose Sufficiency Electrodes Cont'd
The problems associated with a concave flow front in a capillary fill space are illustrated in
Similarly,
The present invention solves the stoichiometric problems associated with the prior art designs pairing the dose sufficiency electrode with one of the measurement electrodes when making the dose sufficiency determination. As shown in
When the test strip 3300 is inserted into the test meter, the test meter will continuously check for a conduction path between the dose sufficiency electrodes 3308 and 3310 in order to determine when the sample has migrated to this region of the capillary fill space. Once the sample has reached this level, the test meter may be programmed to conclude that the measurement electrodes are covered with sample and the sample measurement sequence may be begun. It will be appreciated that, unlike as required with prior art designs, no voltage or current need be applied to either of the measurement electrodes 3302 and 3304 during the dose sufficiency test using the test strip design of
The test strip 3300 is also desirable for judging dose sufficiency when the capillary fill space is designed to produce samples that exhibit a convex flow front while filling the capillary fill space 3306, as illustrated in
It will be appreciated that the dose sufficiency electrodes 3308,3310 have their longest axis within the capillary fill space 3306 oriented perpendicular to the longitudinal axis of the capillary fill space 3306. Such electrodes are referred to herein as “perpendicular dose sufficiency electrodes.” An alternative dose sufficiency electrode arrangement is illustrated in
When the test strip 3500 is inserted into the test meter, the test meter will continuously check for a conduction path between the dose sufficiency electrodes 3508 and 3510 in order to determine when the sample has migrated to this region of the capillary fill space. Once the sample has reached this level, the test meter may be programmed to conclude that the measurement electrodes are covered with sample and the sample measurement sequence may be begun. It will be appreciated that, as with the test strip 3300 (and unlike as required with prior art designs), no voltage or current need be applied to either of the measurement electrodes 3502 and 3504 during the dose sufficiency test using the test strip design of
A further improved operation is realized with the parallel dose sufficiency electrodes of the test strip 3500 when the dose sufficiency electrodes are energized with a relatively high frequency AC excitation signal. When a relatively high frequency AC signal is used as the dose sufficiency excitation signal, the dose sufficiency electrodes 3508,3510 display significant edge effects, wherein the excitation signal traverses the gap between the electrodes only when the electrode edges along the gap are covered with the sample fluid. The test strip 3500 is illustrated in enlarged size in
Higher AC frequencies produce the best edge-only sensitivity from the dose sufficiency electrodes. In the preferred embodiment, a 9 mVrms (+/−12.7 mV peak-to-peak) excitation signal of 10 kHz is used to excite one of the dose sufficiency electrodes. The gap width GW between the edges of the dose sufficiency electrodes 3508,3510 is preferably 100-300 μm, more preferably 150-260 μm, and most preferably 255 μm. A smaller gap width GW increases the amount of signal transmitted between dose sufficiency electrodes whose edges are at least partially covered by sample; however, the capacitance of the signal transmission path increases with decreasing gap width GW.
An advantage of the parallel dose sufficiency electrode design of
Another advantage to the parallel dose sufficiency electrodes illustrated in
While the electrode geometry itself demonstrates an advantage over previous embodiments in terms of detecting an adequate sample, particularly in the case of a convex flow front, it was found that further improvement is achieved in the use of AC responses over DC responses for sample detection. DC responses have the problems of being sensitive to variations in, for example, temperature, hematocrit and the analyte (glucose for example). AC responses at sufficiently high frequency can be made robust to the variation in the analyte concentration. Further, the AC response generated at sufficiently high frequencies in such capillary fill devices is primarily limited by the amount of the parallel gap between the electrode edges which is filled by the sample. Thus, for a convex flow front, little or no AC response (in this case admittance) is perceived until the trough of the flow front actually intrudes within the parallel edges of the sample sufficiency electrodes. Further, by means of threshold calibration, the sensor can be made more or less sensitive as is deemed advantageous, with a higher threshold for admittance requiring more of the parallel gap to be filled before test initiation.
A further limitation of existing devices is the inability of the electrode geometry to discern the amount of time needed to fill the capillary space of the sensor. This limitation is caused by having interdependence of the dose sufficiency electrode and the measurement electrodes. This is a further advantage of independent dose sufficiency electrodes. In the preferred embodiment a signal is first applied across the measurement electrodes prior to dosing. When a response is observed, the potential is immediately switched off and a second signal is applied across the dose sufficiency electrodes during which time the system both looks for a response to the signal (indicating electrode coverage) and marks the duration between the first event (when a response is observed at the measurement electrodes) and the second event (when a response is observed at the dose sufficiency electrodes). In cases where very long intervals may lead to erroneous results, it is possible to establish a threshold within which acceptable results may be obtained and outside of which a failsafe is triggered, preventing a response or at a minimum warning the user of potential inaccuracy. The amount of time lag between dosing and detection of a sufficient sample that is considered allowable is dependent upon the particular sensor design and chemistry. Alternatively, an independent pair of dose detection electrodes (not shown) may be added upstream from the measurement electrodes in order to detect when the sample is first applied to the sensor.
While a DC signal could be used for detection in either or both of the above events, the preferred embodiment uses an AC signal at sufficiently high frequency to avoid unnecessarily perturbing the electrochemical response at the measurement electrodes and to provide robust detection with respect to flow front irregularities.
All publications, prior applications, and other documents cited herein are hereby incorporated by reference in their entirety as if each had been individually incorporated by reference and fully set forth.
While the invention has been illustrated and described in detail in the drawings and foregoing description, the description is to be considered as illustrative and not restrictive in character. Only the preferred embodiment, and certain other embodiments deemed helpful in further explaining how to make or use the preferred embodiment, have been shown. All changes and modifications that come within the spirit of the invention are desired to be protected.
This application claims the benefit of U.S. Provisional Application No. 60/480,298, filed Jun. 20, 2003. The contents of this application are hereby incorporated by reference herein.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3526480 | Findl et al. | Sep 1970 | A |
| 3551295 | Dyer | Dec 1970 | A |
| 3621381 | Eckfeldt | Nov 1971 | A |
| 3715192 | Wenz et al. | Feb 1973 | A |
| 3720093 | Gill | Mar 1973 | A |
| 3763422 | MacPhee et al. | Oct 1973 | A |
| 3770607 | Williams | Nov 1973 | A |
| 3776832 | Oswin et al. | Dec 1973 | A |
| 3838033 | Mindt et al. | Sep 1974 | A |
| 3902970 | Levin | Sep 1975 | A |
| 3919627 | Allen | Nov 1975 | A |
| 3925183 | Oswin et al. | Dec 1975 | A |
| 3937615 | Clack et al. | Feb 1976 | A |
| 3980437 | Kishimoto et al. | Sep 1976 | A |
| 4005002 | Racine et al. | Jan 1977 | A |
| 4008448 | Muggli | Feb 1977 | A |
| 4040908 | Clark, Jr. | Aug 1977 | A |
| 4053381 | Hamblen et al. | Oct 1977 | A |
| 4065263 | Woodbridge, III | Dec 1977 | A |
| 4086631 | Vick | Apr 1978 | A |
| 4123701 | Josefsen et al. | Oct 1978 | A |
| 4127448 | Schick et al. | Nov 1978 | A |
| 4184936 | Paul et al. | Jan 1980 | A |
| 4214968 | Battaglia et al. | Jul 1980 | A |
| 4217196 | Huch | Aug 1980 | A |
| 4224125 | Nakamura et al. | Sep 1980 | A |
| 4225410 | Pace | Sep 1980 | A |
| 4230537 | Delente et al. | Oct 1980 | A |
| 4233029 | Columbus | Nov 1980 | A |
| 4260680 | Muramatsu et al. | Apr 1981 | A |
| 4263343 | Kim | Apr 1981 | A |
| 4265250 | Parker | May 1981 | A |
| 4273134 | Ricciardelli | Jun 1981 | A |
| 4273639 | Gottermeier | Jun 1981 | A |
| 4297569 | Flies | Oct 1981 | A |
| 4301412 | Hill et al. | Nov 1981 | A |
| 4303887 | Hill et al. | Dec 1981 | A |
| 4323536 | Columbus | Apr 1982 | A |
| 4329642 | Luthi et al. | May 1982 | A |
| 4366033 | Richter et al. | Dec 1982 | A |
| 4407290 | Wilber | Oct 1983 | A |
| 4407959 | Tsuji et al. | Oct 1983 | A |
| 4413407 | Columbus | Nov 1983 | A |
| 4413628 | Tamulis | Nov 1983 | A |
| 4420564 | Tsuji et al. | Dec 1983 | A |
| 4431004 | Bessman et al. | Feb 1984 | A |
| 4436094 | Cerami | Mar 1984 | A |
| 4440175 | Wilkins | Apr 1984 | A |
| 4476149 | Poppe et al. | Oct 1984 | A |
| 4477314 | Richter et al. | Oct 1984 | A |
| 4477575 | Vogel et al. | Oct 1984 | A |
| 4499423 | Matthiessen | Feb 1985 | A |
| 4510383 | Ruppender | Apr 1985 | A |
| 4517291 | Seago | May 1985 | A |
| 4545382 | Higgins et al. | Oct 1985 | A |
| 4547735 | Kiesewetter et al. | Oct 1985 | A |
| 4552458 | Lowne | Nov 1985 | A |
| 4571292 | Liu et al. | Feb 1986 | A |
| 4578716 | van Rijckevorsel et al. | Mar 1986 | A |
| 4592893 | Poppe et al. | Jun 1986 | A |
| 4628193 | Blum | Dec 1986 | A |
| 4642295 | Baker | Feb 1987 | A |
| 4648665 | Davis et al. | Mar 1987 | A |
| 4652830 | Brown | Mar 1987 | A |
| 4654197 | Lilja et al. | Mar 1987 | A |
| 4671288 | Gough | Jun 1987 | A |
| 4676653 | Strohmeier et al. | Jun 1987 | A |
| 4679562 | Luksha | Jul 1987 | A |
| 4682602 | Prohaska | Jul 1987 | A |
| 4686479 | Young et al. | Aug 1987 | A |
| 4703017 | Campbell et al. | Oct 1987 | A |
| 4703756 | Gough et al. | Nov 1987 | A |
| 4711245 | Higgins et al. | Dec 1987 | A |
| 4713347 | Mitchell et al. | Dec 1987 | A |
| 4714874 | Morris et al. | Dec 1987 | A |
| 4731726 | Allen, III | Mar 1988 | A |
| 4734184 | Burleigh et al. | Mar 1988 | A |
| 4750496 | Reinhart et al. | Jun 1988 | A |
| 4759828 | Young et al. | Jul 1988 | A |
| 4789804 | Karube et al. | Dec 1988 | A |
| 4795542 | Ross et al. | Jan 1989 | A |
| 4797256 | Watlington, IV | Jan 1989 | A |
| 4805624 | Yao et al. | Feb 1989 | A |
| 4806311 | Greenquist | Feb 1989 | A |
| 4806312 | Greenquist | Feb 1989 | A |
| 4810203 | Komatsu | Mar 1989 | A |
| 4816224 | Vogel et al. | Mar 1989 | A |
| 4820399 | Senda et al. | Apr 1989 | A |
| 4820636 | Hill et al. | Apr 1989 | A |
| 4832814 | Root | May 1989 | A |
| 4834234 | Sacherer et al. | May 1989 | A |
| 4849330 | Humphries et al. | Jul 1989 | A |
| 4865873 | Cole, Jr. et al. | Sep 1989 | A |
| 4877580 | Aronowitz et al. | Oct 1989 | A |
| 4897162 | Lewandowski et al. | Jan 1990 | A |
| 4897173 | Nankai et al. | Jan 1990 | A |
| 4919770 | Preidel et al. | Apr 1990 | A |
| 4927516 | Yamaguchi et al. | May 1990 | A |
| 4929426 | Bodai et al. | May 1990 | A |
| 4935105 | Churchouse | Jun 1990 | A |
| 4935106 | Liston et al. | Jun 1990 | A |
| 4935346 | Phillips et al. | Jun 1990 | A |
| 4938860 | Wogoman | Jul 1990 | A |
| 4940945 | Littlejohn et al. | Jul 1990 | A |
| 4954087 | Lauks et al. | Sep 1990 | A |
| 4956275 | Zuk et al. | Sep 1990 | A |
| 4963814 | Parks | Oct 1990 | A |
| 4970145 | Bennetto et al. | Nov 1990 | A |
| 4975647 | Downer et al. | Dec 1990 | A |
| 4976724 | Nieto et al. | Dec 1990 | A |
| 4999582 | Parks et al. | Mar 1991 | A |
| 4999632 | Parks | Mar 1991 | A |
| 5018164 | Brewer et al. | May 1991 | A |
| 5019974 | Beckers | May 1991 | A |
| 5035862 | Dietze et al. | Jul 1991 | A |
| 5039618 | Stone | Aug 1991 | A |
| 5049487 | Phillips et al. | Sep 1991 | A |
| 5053199 | Keiser et al. | Oct 1991 | A |
| 5059394 | Phillips et al. | Oct 1991 | A |
| 5066372 | Weetall | Nov 1991 | A |
| 5075077 | Durley, III et al. | Dec 1991 | A |
| 5096669 | Lauks et al. | Mar 1992 | A |
| 5108564 | Szuminsky et al. | Apr 1992 | A |
| 5112455 | Cozzette et al. | May 1992 | A |
| 5112758 | Fellman et al. | May 1992 | A |
| 5118183 | Cargill et al. | Jun 1992 | A |
| 5120420 | Nankai et al. | Jun 1992 | A |
| 5122244 | Hoenes et al. | Jun 1992 | A |
| 5126952 | Kildal-Brandt et al. | Jun 1992 | A |
| 5128015 | Szuminsky et al. | Jul 1992 | A |
| 5141850 | Cole et al. | Aug 1992 | A |
| 5141868 | Shanks et al. | Aug 1992 | A |
| 5143694 | Schafer et al. | Sep 1992 | A |
| 5179005 | Phillips et al. | Jan 1993 | A |
| 5179288 | Miffitt et al. | Jan 1993 | A |
| 5182707 | Cooper et al. | Jan 1993 | A |
| 5187100 | Matzinger et al. | Feb 1993 | A |
| 5192415 | Yoshioka et al. | Mar 1993 | A |
| 5220920 | Gharib | Jun 1993 | A |
| 5232516 | Hed | Aug 1993 | A |
| 5232667 | Hieb et al. | Aug 1993 | A |
| 5232668 | Grant et al. | Aug 1993 | A |
| 5234813 | McGeehan et al. | Aug 1993 | A |
| 5243516 | White | Sep 1993 | A |
| 5246858 | Arbuckle et al. | Sep 1993 | A |
| 5250439 | Musho et al. | Oct 1993 | A |
| 5261411 | Hughes | Nov 1993 | A |
| 5264103 | Yoshioka et al. | Nov 1993 | A |
| 5266179 | Nankai et al. | Nov 1993 | A |
| 5269891 | Colin | Dec 1993 | A |
| 5279294 | Anderson et al. | Jan 1994 | A |
| 5281395 | Markart et al. | Jan 1994 | A |
| 5284770 | Adrian et al. | Feb 1994 | A |
| 5286362 | Hoenes et al. | Feb 1994 | A |
| 5288636 | Pollmann et al. | Feb 1994 | A |
| 5296192 | Carroll et al. | Mar 1994 | A |
| 5304468 | Phillips et al. | Apr 1994 | A |
| 5306623 | Kiser et al. | Apr 1994 | A |
| 5311426 | Donohue et al. | May 1994 | A |
| 5312762 | Guiseppi-Elie | May 1994 | A |
| 5344754 | Zweig | Sep 1994 | A |
| 5352351 | White et al. | Oct 1994 | A |
| 5353351 | Bartoli et al. | Oct 1994 | A |
| 5366609 | White et al. | Nov 1994 | A |
| 5371687 | Holmes, II et al. | Dec 1994 | A |
| 5376254 | Fisher | Dec 1994 | A |
| 5379214 | Arbuckle et al. | Jan 1995 | A |
| 5385846 | Kuhn et al. | Jan 1995 | A |
| 5389215 | Horiuchi et al. | Feb 1995 | A |
| 5395504 | Saurer et al. | Mar 1995 | A |
| 5405511 | Brown et al. | Apr 1995 | A |
| 5411647 | Johnson et al. | May 1995 | A |
| 5413690 | Kost et al. | May 1995 | A |
| 5413764 | Haar | May 1995 | A |
| 5418142 | Kiser et al. | May 1995 | A |
| 5421189 | Dussault | Jun 1995 | A |
| 5424035 | Hones et al. | Jun 1995 | A |
| 5426032 | Phillips et al. | Jun 1995 | A |
| 5437772 | De Castro et al. | Aug 1995 | A |
| 5437999 | Diebold et al. | Aug 1995 | A |
| 5438271 | White et al. | Aug 1995 | A |
| 5439826 | Kontorovich | Aug 1995 | A |
| 5445967 | Deuter | Aug 1995 | A |
| 5447837 | Urnovitz | Sep 1995 | A |
| 5453360 | Yu | Sep 1995 | A |
| 5469846 | Khan | Nov 1995 | A |
| 5470533 | Shindo et al. | Nov 1995 | A |
| 5477326 | Dosmann | Dec 1995 | A |
| 5489414 | Schreiber et al. | Feb 1996 | A |
| 5494638 | Gullick | Feb 1996 | A |
| 5500350 | Baker et al. | Mar 1996 | A |
| 5504011 | Gavin et al. | Apr 1996 | A |
| 5508171 | Walling et al. | Apr 1996 | A |
| 5508200 | Tiffany et al. | Apr 1996 | A |
| 5508203 | Fuller et al. | Apr 1996 | A |
| 5509410 | Hill et al. | Apr 1996 | A |
| 5515170 | Matzinger | May 1996 | A |
| 5515847 | Braig et al. | May 1996 | A |
| 5526111 | Collins et al. | Jun 1996 | A |
| 5526120 | Jina et al. | Jun 1996 | A |
| 5526808 | Kaminsky | Jun 1996 | A |
| 5532128 | Eggers et al. | Jul 1996 | A |
| 5552116 | Yokota et al. | Sep 1996 | A |
| 5554531 | Zweig | Sep 1996 | A |
| 5556789 | Goerlach-Graw et al. | Sep 1996 | A |
| 5563031 | Yu | Oct 1996 | A |
| 5563042 | Phillips et al. | Oct 1996 | A |
| 5569591 | Kell et al. | Oct 1996 | A |
| 5569608 | Sommer | Oct 1996 | A |
| 5572159 | McFarland | Nov 1996 | A |
| 5575895 | Ikeda et al. | Nov 1996 | A |
| 5576073 | Kickelhain | Nov 1996 | A |
| 5580794 | Allen | Dec 1996 | A |
| 5582697 | Ikeda et al. | Dec 1996 | A |
| 5593390 | Castellano et al. | Jan 1997 | A |
| 5593739 | Kickelhain | Jan 1997 | A |
| 5594906 | Holmes, II et al. | Jan 1997 | A |
| 5597532 | Connolly | Jan 1997 | A |
| 5604110 | Baker et al. | Feb 1997 | A |
| 5605662 | Heller et al. | Feb 1997 | A |
| 5605837 | Karimi et al. | Feb 1997 | A |
| 5611900 | Worden et al. | Mar 1997 | A |
| 5620579 | Genshaw et al. | Apr 1997 | A |
| 5620863 | Tomasco et al. | Apr 1997 | A |
| 5628890 | Carter et al. | May 1997 | A |
| 5630986 | Charlton et al. | May 1997 | A |
| 5635362 | Levine et al. | Jun 1997 | A |
| 5635364 | Clark et al. | Jun 1997 | A |
| 5639671 | Bogart et al. | Jun 1997 | A |
| 5642734 | Ruben et al. | Jul 1997 | A |
| 5645798 | Schreiber et al. | Jul 1997 | A |
| 5650061 | Kuhr et al. | Jul 1997 | A |
| 5650062 | Ikeda et al. | Jul 1997 | A |
| 5653863 | Genshaw et al. | Aug 1997 | A |
| 5654178 | Fitzpatrick et al. | Aug 1997 | A |
| 5656502 | MacKay et al. | Aug 1997 | A |
| 5658443 | Yamamoto et al. | Aug 1997 | A |
| 5658802 | Hayes et al. | Aug 1997 | A |
| 5665215 | Bussmann et al. | Sep 1997 | A |
| 5670031 | Hintsche et al. | Sep 1997 | A |
| 5682884 | Hill et al. | Nov 1997 | A |
| 5686659 | Neel et al. | Nov 1997 | A |
| 5691486 | Behringer et al. | Nov 1997 | A |
| 5691633 | Liu et al. | Nov 1997 | A |
| 5695623 | Michel et al. | Dec 1997 | A |
| 5698083 | Glass | Dec 1997 | A |
| 5700695 | Yassinzadeh et al. | Dec 1997 | A |
| 5708247 | McAleer et al. | Jan 1998 | A |
| 5710622 | Neel et al. | Jan 1998 | A |
| 5719667 | Miers | Feb 1998 | A |
| 5720862 | Hamamoto et al. | Feb 1998 | A |
| 5723284 | Ye | Mar 1998 | A |
| 5727548 | Hill et al. | Mar 1998 | A |
| 5728074 | Castellano et al. | Mar 1998 | A |
| 5745308 | Spangenberg | Apr 1998 | A |
| 5748002 | Scott et al. | May 1998 | A |
| 5757666 | Schreiber et al. | May 1998 | A |
| 5759794 | Levine et al. | Jun 1998 | A |
| 5762770 | Pritchard et al. | Jun 1998 | A |
| 5776710 | Levine et al. | Jul 1998 | A |
| 5780304 | Matzinger et al. | Jul 1998 | A |
| 5786584 | Button et al. | Jul 1998 | A |
| 5788833 | Lewis et al. | Aug 1998 | A |
| 5789255 | Yu | Aug 1998 | A |
| 5792668 | Deamer et al. | Aug 1998 | A |
| 5798031 | Charlton et al. | Aug 1998 | A |
| 5801057 | Smart et al. | Sep 1998 | A |
| 5820551 | Hill et al. | Oct 1998 | A |
| 5820622 | Gross et al. | Oct 1998 | A |
| 5832921 | Lennert et al. | Nov 1998 | A |
| 5834217 | Levine et al. | Nov 1998 | A |
| 5837546 | Allen et al. | Nov 1998 | A |
| 5843691 | Douglas et al. | Dec 1998 | A |
| 5843692 | Phillips et al. | Dec 1998 | A |
| 5846744 | Athey et al. | Dec 1998 | A |
| 5849174 | Sanghera et al. | Dec 1998 | A |
| 5856195 | Charlton et al. | Jan 1999 | A |
| 5873990 | Wojciechowski et al. | Feb 1999 | A |
| 5883378 | Irish et al. | Mar 1999 | A |
| 5885839 | Lingane et al. | Mar 1999 | A |
| 5890489 | Elden | Apr 1999 | A |
| 5904898 | Markart | May 1999 | A |
| 5911872 | Lewis et al. | Jun 1999 | A |
| 5916156 | Hildenbrand et al. | Jun 1999 | A |
| 5921925 | Cartmell et al. | Jul 1999 | A |
| 5922530 | Yu | Jul 1999 | A |
| 5922591 | Anderson et al. | Jul 1999 | A |
| 5925021 | Castellano et al. | Jul 1999 | A |
| 5945341 | Howard, III | Aug 1999 | A |
| 5948289 | Noda et al. | Sep 1999 | A |
| 5951836 | McAleer et al. | Sep 1999 | A |
| 5965380 | Heller | Oct 1999 | A |
| 5968760 | Phillips et al. | Oct 1999 | A |
| 5971923 | Finger | Oct 1999 | A |
| 5989917 | McAleer et al. | Nov 1999 | A |
| 5997817 | Crismore et al. | Dec 1999 | A |
| 6004441 | Fujiwara et al. | Dec 1999 | A |
| 6004442 | Choulga et al. | Dec 1999 | A |
| 6013170 | Meade | Jan 2000 | A |
| 6042714 | Lin et al. | Mar 2000 | A |
| 6044285 | Chaiken et al. | Mar 2000 | A |
| 6045567 | Taylor et al. | Apr 2000 | A |
| 6061128 | Zweig et al. | May 2000 | A |
| 6071391 | Gotoh et al. | Jun 2000 | A |
| 6087182 | Jeng et al. | Jul 2000 | A |
| 6091975 | Daddona et al. | Jul 2000 | A |
| 6102872 | Doneen et al. | Aug 2000 | A |
| 6103033 | Say et al. | Aug 2000 | A |
| 6120676 | Heller et al. | Sep 2000 | A |
| 6121009 | Heller et al. | Sep 2000 | A |
| 6121050 | Han | Sep 2000 | A |
| 6126609 | Keith et al. | Oct 2000 | A |
| 6128519 | Say | Oct 2000 | A |
| 6129823 | Hughes et al. | Oct 2000 | A |
| 6134461 | Say et al. | Oct 2000 | A |
| 6136549 | Feistel | Oct 2000 | A |
| 6136610 | Polito et al. | Oct 2000 | A |
| 6143164 | Heller et al. | Nov 2000 | A |
| 6143247 | Sheppard, Jr. et al. | Nov 2000 | A |
| 6144869 | Berner et al. | Nov 2000 | A |
| 6150124 | Riedel | Nov 2000 | A |
| 6153069 | Pottgen et al. | Nov 2000 | A |
| RE36991 | Yamamoto et al. | Dec 2000 | E |
| 6156051 | Schraga | Dec 2000 | A |
| 6156173 | Gotoh et al. | Dec 2000 | A |
| 6159745 | Roberts et al. | Dec 2000 | A |
| 6162611 | Heller et al. | Dec 2000 | A |
| 6162639 | Douglas | Dec 2000 | A |
| 6168563 | Brown | Jan 2001 | B1 |
| 6168957 | Matzinger et al. | Jan 2001 | B1 |
| 6170318 | Lewis | Jan 2001 | B1 |
| 6174420 | Hodges et al. | Jan 2001 | B1 |
| 6175752 | Say et al. | Jan 2001 | B1 |
| 6176988 | Kessler | Jan 2001 | B1 |
| 6179979 | Hodges et al. | Jan 2001 | B1 |
| 6180062 | Naka et al. | Jan 2001 | B1 |
| 6180416 | Kurnik et al. | Jan 2001 | B1 |
| 6193873 | Ohara et al. | Feb 2001 | B1 |
| 6197040 | LeVaughn et al. | Mar 2001 | B1 |
| 6200773 | Ouyang et al. | Mar 2001 | B1 |
| 6201607 | Roth et al. | Mar 2001 | B1 |
| 6203952 | O'Brien et al. | Mar 2001 | B1 |
| 6206282 | Hayes, Sr. et al. | Mar 2001 | B1 |
| 6206292 | Robertz et al. | Mar 2001 | B1 |
| 6218571 | Zheng et al. | Apr 2001 | B1 |
| 6225078 | Ikeda et al. | May 2001 | B1 |
| 6226081 | Fantone et al. | May 2001 | B1 |
| 6241862 | McAleer et al. | Jun 2001 | B1 |
| 6246330 | Nielsen | Jun 2001 | B1 |
| 6246966 | Perry | Jun 2001 | B1 |
| 6251260 | Heller et al. | Jun 2001 | B1 |
| 6258229 | Winarta et al. | Jul 2001 | B1 |
| 6258254 | Miyamoto et al. | Jul 2001 | B1 |
| 6259937 | Schulman et al. | Jul 2001 | B1 |
| 6261519 | Harding et al. | Jul 2001 | B1 |
| 6262749 | Finger et al. | Jul 2001 | B1 |
| 6268162 | Phillips et al. | Jul 2001 | B1 |
| 6270637 | Crismore et al. | Aug 2001 | B1 |
| 6271044 | Ballerstadt et al. | Aug 2001 | B1 |
| 6272364 | Kurnik | Aug 2001 | B1 |
| 6277641 | Yager | Aug 2001 | B1 |
| 6281006 | Heller et al. | Aug 2001 | B1 |
| 6284125 | Hodges et al. | Sep 2001 | B1 |
| 6284550 | Carroll et al. | Sep 2001 | B1 |
| 6287451 | Winarta et al. | Sep 2001 | B1 |
| 6287595 | Loewy et al. | Sep 2001 | B1 |
| 6287875 | Geisberg | Sep 2001 | B1 |
| 6294281 | Heller | Sep 2001 | B1 |
| 6295506 | Heinonen et al. | Sep 2001 | B1 |
| 6299757 | Feldman et al. | Oct 2001 | B1 |
| 6300123 | Vadgama et al. | Oct 2001 | B1 |
| 6300142 | Andrews et al. | Oct 2001 | B1 |
| 6300961 | Finger et al. | Oct 2001 | B1 |
| 6309526 | Fujiwara et al. | Oct 2001 | B1 |
| 6315951 | Markart | Nov 2001 | B1 |
| 6316264 | Corey et al. | Nov 2001 | B1 |
| 6325917 | Maxwell et al. | Dec 2001 | B1 |
| 6326160 | Dunn et al. | Dec 2001 | B1 |
| 6329161 | Heller et al. | Dec 2001 | B1 |
| 6330464 | Colvin, Jr. et al. | Dec 2001 | B1 |
| 6335203 | Patel et al. | Jan 2002 | B1 |
| 6338790 | Feldman et al. | Jan 2002 | B1 |
| 6340428 | Ikeda et al. | Jan 2002 | B1 |
| 6342364 | Watanabe et al. | Jan 2002 | B1 |
| 6349230 | Kawanaka | Feb 2002 | B1 |
| 6358752 | Durst et al. | Mar 2002 | B1 |
| 6377894 | Deweese et al. | Apr 2002 | B1 |
| 6377896 | Sato et al. | Apr 2002 | B1 |
| 6379513 | Huang et al. | Apr 2002 | B1 |
| 6389891 | D'Angelico et al. | May 2002 | B1 |
| 6391558 | Henkens et al. | May 2002 | B1 |
| 6391645 | Huang et al. | May 2002 | B1 |
| 6394952 | Anderson et al. | May 2002 | B1 |
| 6395227 | Kiser et al. | May 2002 | B1 |
| 6399258 | O'Brien et al. | Jun 2002 | B2 |
| 6401532 | Lubbers | Jun 2002 | B2 |
| 6413213 | Essenpreis et al. | Jul 2002 | B1 |
| 6413395 | Bhullar et al. | Jul 2002 | B1 |
| 6413410 | Hodges et al. | Jul 2002 | B1 |
| 6420128 | Ouyang et al. | Jul 2002 | B1 |
| 6444115 | Hodges et al. | Sep 2002 | B1 |
| 6447657 | Bhullar et al. | Sep 2002 | B1 |
| 6454921 | Hodges et al. | Sep 2002 | B1 |
| 6461496 | Feldman et al. | Oct 2002 | B1 |
| 6475360 | Hodges et al. | Nov 2002 | B1 |
| 6475372 | Ohara et al. | Nov 2002 | B1 |
| 6484046 | Say et al. | Nov 2002 | B1 |
| 6485923 | Yani et al. | Nov 2002 | B1 |
| 6488827 | Shartle | Dec 2002 | B1 |
| 6489133 | Phillips et al. | Dec 2002 | B2 |
| 6491803 | Shen et al. | Dec 2002 | B1 |
| 6491870 | Patel et al. | Dec 2002 | B2 |
| 6501976 | Sohrab | Dec 2002 | B1 |
| 6503381 | Gotoh et al. | Jan 2003 | B1 |
| 6512986 | Harmon | Jan 2003 | B1 |
| 6514718 | Heller et al. | Feb 2003 | B2 |
| 6514769 | Lee | Feb 2003 | B2 |
| 6521110 | Hodges et al. | Feb 2003 | B1 |
| 6521182 | Shartle et al. | Feb 2003 | B1 |
| 6525330 | Paolini et al. | Feb 2003 | B2 |
| 6525549 | Pollmann | Feb 2003 | B1 |
| 6526298 | Khalil et al. | Feb 2003 | B1 |
| 6531239 | Heller | Mar 2003 | B2 |
| 6531322 | Jurik et al. | Mar 2003 | B1 |
| 6538735 | Duebendorfer et al. | Mar 2003 | B1 |
| 6540890 | Bhullar et al. | Apr 2003 | B1 |
| 6540891 | Stewart et al. | Apr 2003 | B1 |
| 6541266 | Modzelewski et al. | Apr 2003 | B2 |
| 6544474 | Douglas | Apr 2003 | B2 |
| 6549796 | Sohrab | Apr 2003 | B2 |
| 6551494 | Heller et al. | Apr 2003 | B1 |
| 6555061 | Leong et al. | Apr 2003 | B1 |
| 6557427 | Weigl et al. | May 2003 | B2 |
| 6558528 | Matzinger | May 2003 | B1 |
| 6560471 | Heller et al. | May 2003 | B1 |
| 6562625 | Modzelewski et al. | May 2003 | B2 |
| 6565509 | Say et al. | May 2003 | B1 |
| 6565738 | Henning et al. | May 2003 | B1 |
| 6570390 | Hirayama et al. | May 2003 | B2 |
| 6571651 | Hodges | Jun 2003 | B1 |
| 6572822 | Jurik et al. | Jun 2003 | B2 |
| 6574425 | Weiss et al. | Jun 2003 | B1 |
| 6576101 | Heller et al. | Jun 2003 | B1 |
| 6576117 | Iketaki et al. | Jun 2003 | B1 |
| 6576416 | Haviland et al. | Jun 2003 | B2 |
| 6576461 | Heller et al. | Jun 2003 | B2 |
| 6579690 | Bonnecaze et al. | Jun 2003 | B1 |
| 6591125 | Buse et al. | Jul 2003 | B1 |
| 6592744 | Hodges et al. | Jul 2003 | B1 |
| 6592745 | Feldman et al. | Jul 2003 | B1 |
| 6594514 | Berner et al. | Jul 2003 | B2 |
| 6599406 | Kawanaka et al. | Jul 2003 | B1 |
| 6600997 | Deweese et al. | Jul 2003 | B2 |
| 6605200 | Mao et al. | Aug 2003 | B1 |
| 6605201 | Mao et al. | Aug 2003 | B1 |
| 6607658 | Heller et al. | Aug 2003 | B1 |
| 6616819 | Liamos et al. | Sep 2003 | B1 |
| 6618934 | Feldman et al. | Sep 2003 | B1 |
| 6623501 | Heller et al. | Sep 2003 | B2 |
| 6627057 | Bhullar et al. | Sep 2003 | B1 |
| 6632349 | Hodges et al. | Oct 2003 | B1 |
| 6638415 | Hodges et al. | Oct 2003 | B1 |
| 6638716 | Heller et al. | Oct 2003 | B2 |
| 6645359 | Bhullar et al. | Nov 2003 | B1 |
| 6645368 | Beaty et al. | Nov 2003 | B1 |
| 6654625 | Say et al. | Nov 2003 | B1 |
| 6656702 | Yugawa et al. | Dec 2003 | B1 |
| 6660141 | Minter et al. | Dec 2003 | B1 |
| 6676995 | Dick et al. | Jan 2004 | B2 |
| 6689411 | Dick et al. | Feb 2004 | B2 |
| 6743635 | Neel et al. | Jun 2004 | B2 |
| 7018843 | Heller | Mar 2006 | B2 |
| 20010006149 | Taniike et al. | Jul 2001 | A1 |
| 20010006150 | Taniike et al. | Jul 2001 | A1 |
| 20010017269 | Heller et al. | Aug 2001 | A1 |
| 20010019831 | Phillips et al. | Sep 2001 | A1 |
| 20010034068 | Spivey et al. | Oct 2001 | A1 |
| 20010039057 | Douglas et al. | Nov 2001 | A1 |
| 20010041830 | Varalli et al. | Nov 2001 | A1 |
| 20010042683 | Musho et al. | Nov 2001 | A1 |
| 20010052470 | Hodges et al. | Dec 2001 | A1 |
| 20010053535 | Ladisch et al. | Dec 2001 | A1 |
| 20010054319 | Heller et al. | Dec 2001 | A1 |
| 20010055784 | Heller et al. | Dec 2001 | A1 |
| 20020003087 | Chih-hui | Jan 2002 | A1 |
| 20020004196 | Whitson | Jan 2002 | A1 |
| 20020008038 | Heller et al. | Jan 2002 | A1 |
| 20020019707 | Cohen et al. | Feb 2002 | A1 |
| 20020023489 | Reimelt et al. | Feb 2002 | A1 |
| 20020025469 | Heller | Feb 2002 | A1 |
| 20020029058 | LeVaughn et al. | Mar 2002 | A1 |
| 20020033345 | Meade | Mar 2002 | A1 |
| 20020040850 | Liu et al. | Apr 2002 | A1 |
| 20020042090 | Heller et al. | Apr 2002 | A1 |
| 20020043471 | Ikeda et al. | Apr 2002 | A1 |
| 20020044890 | Black | Apr 2002 | A1 |
| 20020053523 | Liamos et al. | May 2002 | A1 |
| 20020081588 | De Lumley-woodyear et al. | Jun 2002 | A1 |
| 20020082797 | Deweese et al. | Jun 2002 | A1 |
| 20020084184 | Chambers et al. | Jul 2002 | A1 |
| 20020084196 | Liamos et al. | Jul 2002 | A1 |
| 20020092612 | Davies et al. | Jul 2002 | A1 |
| 20020100685 | Huang et al. | Aug 2002 | A1 |
| 20020102739 | Nomura et al. | Aug 2002 | A1 |
| 20020112969 | Hodges et al. | Aug 2002 | A1 |
| 20020117404 | Maxwell et al. | Aug 2002 | A1 |
| 20020117639 | Paolini et al. | Aug 2002 | A1 |
| 20020125145 | Ohara et al. | Sep 2002 | A1 |
| 20020130042 | Moerman et al. | Sep 2002 | A1 |
| 20020130043 | Hodges et al. | Sep 2002 | A1 |
| 20020133064 | Ueno et al. | Sep 2002 | A1 |
| 20020137200 | Takahashi et al. | Sep 2002 | A1 |
| 20020137230 | Nadaoka et al. | Sep 2002 | A1 |
| 20020138275 | Amano et al. | Sep 2002 | A1 |
| 20020138356 | Dutta et al. | Sep 2002 | A1 |
| 20020139692 | Tokunaga et al. | Oct 2002 | A1 |
| 20020146835 | Modzelewski et al. | Oct 2002 | A1 |
| 20020148726 | Yamamoto et al. | Oct 2002 | A1 |
| 20020148739 | Liamos et al. | Oct 2002 | A2 |
| 20020150930 | Nadaoka et al. | Oct 2002 | A1 |
| 20020152793 | Sato et al. | Oct 2002 | A1 |
| 20020155030 | Matsuda et al. | Oct 2002 | A1 |
| 20020155615 | Novikov et al. | Oct 2002 | A1 |
| 20020157948 | Liamos et al. | Oct 2002 | A2 |
| 20020160517 | Modzelewski et al. | Oct 2002 | A1 |
| 20020164822 | Takahashi et al. | Nov 2002 | A1 |
| 20020168290 | Yuzhakov et al. | Nov 2002 | A1 |
| 20020168298 | Huhn et al. | Nov 2002 | A1 |
| 20020175075 | Deng et al. | Nov 2002 | A1 |
| 20020175087 | Hodges et al. | Nov 2002 | A1 |
| 20020177788 | Hodges et al. | Nov 2002 | A1 |
| 20020179440 | Tokunaga et al. | Dec 2002 | A1 |
| 20020179441 | Yamanishi et al. | Dec 2002 | A1 |
| 20020179442 | Miyazaki et al. | Dec 2002 | A1 |
| 20020185385 | Charlton | Dec 2002 | A1 |
| 20020189941 | Katsuki et al. | Dec 2002 | A1 |
| 20030000834 | Yoshioka et al. | Jan 2003 | A1 |
| 20030024811 | Davies et al. | Feb 2003 | A1 |
| 20030032875 | Taniike et al. | Feb 2003 | A1 |
| 20030036202 | Teodorcyzk et al. | Feb 2003 | A1 |
| 20030042137 | Mao et al. | Mar 2003 | A1 |
| 20030042150 | Ryu et al. | Mar 2003 | A1 |
| 20030054427 | Phillips et al. | Mar 2003 | A1 |
| 20030064525 | Liess | Apr 2003 | A1 |
| 20030073151 | Phillips et al. | Apr 2003 | A1 |
| 20030073152 | Phillips et al. | Apr 2003 | A1 |
| 20030073153 | Phillips et al. | Apr 2003 | A1 |
| 20030079987 | Hodges et al. | May 2003 | A1 |
| 20030080001 | Hodges et al. | May 2003 | A1 |
| 20030088166 | Say et al. | May 2003 | A1 |
| 20030094383 | Kermani | May 2003 | A1 |
| 20030098233 | Kermani et al. | May 2003 | A1 |
| 20030098234 | Hasegawa et al. | May 2003 | A1 |
| 20030100030 | Nadaoka et al. | May 2003 | A1 |
| 20030100040 | Bonnecaze et al. | May 2003 | A1 |
| 20030100821 | Heller et al. | May 2003 | A1 |
| 20030102213 | Gotoh et al. | Jun 2003 | A1 |
| 20030106809 | Kermani et al. | Jun 2003 | A1 |
| 20030108976 | Braig et al. | Jun 2003 | A1 |
| 20030109798 | Kermani | Jun 2003 | A1 |
| 20030132110 | Hasegawa et al. | Jul 2003 | A1 |
| 20030134347 | Heller et al. | Jul 2003 | A1 |
| 20030143113 | Yuzhakov et al. | Jul 2003 | A2 |
| 20030143116 | Zheng et al. | Jul 2003 | A1 |
| 20030146110 | Karinka et al. | Aug 2003 | A1 |
| 20030150724 | Kawanaka et al. | Aug 2003 | A1 |
| 20030152823 | Heller | Aug 2003 | A1 |
| 20030155237 | Surridge et al. | Aug 2003 | A1 |
| 20030155538 | Siepmann | Aug 2003 | A1 |
| 20030159944 | Pottgen et al. | Aug 2003 | A1 |
| 20030159945 | Miyazaki et al. | Aug 2003 | A1 |
| 20030164293 | Hodges et al. | Sep 2003 | A1 |
| 20030167862 | Hodges | Sep 2003 | A1 |
| 20030168338 | Gao et al. | Sep 2003 | A1 |
| 20030175841 | Watanabe et al. | Sep 2003 | A1 |
| 20030175946 | Tokunaga et al. | Sep 2003 | A1 |
| 20030176183 | Druker et al. | Sep 2003 | A1 |
| 20030178322 | Iyengar et al. | Sep 2003 | A1 |
| 20030179440 | Tokunaga et al. | Sep 2003 | A1 |
| 20030180183 | Fukuoka et al. | Sep 2003 | A1 |
| 20030187338 | Say et al. | Oct 2003 | A1 |
| 20030188427 | Say et al. | Oct 2003 | A1 |
| 20030190069 | Nikitin et al. | Oct 2003 | A1 |
| 20030199744 | Buse et al. | Oct 2003 | A1 |
| 20030199893 | Boecker et al. | Oct 2003 | A1 |
| 20030201194 | Heller et al. | Oct 2003 | A1 |
| 20030203498 | Neel et al. | Oct 2003 | A1 |
| 20030203503 | Fukuoka et al. | Oct 2003 | A1 |
| 20030217918 | Davies et al. | Nov 2003 | A1 |
| 20040005721 | Tanike et al. | Jan 2004 | A1 |
| 20040016642 | Miyazaki et al. | Jan 2004 | A1 |
| 20040020777 | Miyamoto et al. | Feb 2004 | A1 |
| 20040106941 | Roe et al. | Jun 2004 | A1 |
| Number | Date | Country |
|---|---|---|
| 737 787 | Aug 2001 | AU |
| 36 43 263 | Jul 1988 | DE |
| 40 11 428 | Nov 1990 | DE |
| 298 14 997 | Aug 1993 | DE |
| 199 36 693 | Feb 2001 | DE |
| 0 010 456 | Apr 1980 | EP |
| 0 034 049 | Aug 1981 | EP |
| 0 057 110 | Aug 1982 | EP |
| 0 073 056 | Mar 1983 | EP |
| 0 084 874 | Aug 1983 | EP |
| 0 101 880 | Mar 1984 | EP |
| 0 132 790 | Feb 1985 | EP |
| 0 164 180 | Dec 1985 | EP |
| 0 171 148 | Feb 1986 | EP |
| 0 171 239 | Feb 1986 | EP |
| 0 186 286 | Jul 1986 | EP |
| 0 241 309 | Oct 1987 | EP |
| 0 287 883 | Oct 1988 | EP |
| 0 359 831 | Mar 1990 | EP |
| 0 206 218 | Jun 1991 | EP |
| 0 471 986 | Feb 1992 | EP |
| 0 471 986 | Apr 1992 | EP |
| 0 255 291 | Jun 1992 | EP |
| 0 546 536 | Jun 1993 | EP |
| 0 244 326 | Aug 1993 | EP |
| 0 537 761 | Feb 1994 | EP |
| 0 417 796 | Nov 1994 | EP |
| 0 213 343 | Feb 1995 | EP |
| 0 636 880 | Feb 1995 | EP |
| 0 640 832 | Mar 1995 | EP |
| 0 651 250 | May 1995 | EP |
| 0 471 986 | Oct 1995 | EP |
| 0 127 958 | Apr 1996 | EP |
| 0 732 406 | Sep 1996 | EP |
| 0 732 590 | Sep 1996 | EP |
| 0 383 322 | Feb 1997 | EP |
| 0 537 761 | Aug 1997 | EP |
| 0 840 122 | May 1998 | EP |
| 0 851 224 | Jul 1998 | EP |
| 0 859 230 | Aug 1998 | EP |
| 0 878 713 | Nov 1998 | EP |
| 0 837 320 | Dec 1998 | EP |
| 0 887 421 | Dec 1998 | EP |
| 0 894 509 | Feb 1999 | EP |
| 0 470 649 | Jun 1999 | EP |
| 0 942 278 | Sep 1999 | EP |
| 0 964 059 | Dec 1999 | EP |
| 0 987 544 | Mar 2000 | EP |
| 1 024 358 | Aug 2000 | EP |
| 1 035 216 | Sep 2000 | EP |
| 0 230 472 | Dec 2000 | EP |
| 1 067 384 | Jan 2001 | EP |
| 1 074 832 | Feb 2001 | EP |
| 1 081 490 | Mar 2001 | EP |
| 1 130 390 | Sep 2001 | EP |
| 0 741 186 | Oct 2001 | EP |
| 1 143 245 | Oct 2001 | EP |
| 1 147 739 | Oct 2001 | EP |
| 1 152 239 | Nov 2001 | EP |
| 1 156 324 | Nov 2001 | EP |
| 1 225 448 | Jul 2002 | EP |
| 1 235 069 | Aug 2002 | EP |
| 0 958 495 | Nov 2002 | EP |
| 1 102 991 | Nov 2002 | EP |
| 1 256 798 | Nov 2002 | EP |
| 1 275 732 | Jan 2003 | EP |
| 1 281 955 | Feb 2003 | EP |
| 1 009 850 | Mar 2003 | EP |
| 1 288 653 | Mar 2003 | EP |
| 1 312 919 | May 2003 | EP |
| 1 316 367 | Jun 2003 | EP |
| 1 318 396 | Jun 2003 | EP |
| 0 876 506 | Jul 2003 | EP |
| 1 129 211 | Jul 2003 | EP |
| 1 308 720 | Jul 2003 | EP |
| 1 324 025 | Jul 2003 | EP |
| 1 324 038 | Jul 2003 | EP |
| 1 327 881 | Jul 2003 | EP |
| 1 352 611 | Oct 2003 | EP |
| 1 352 969 | Oct 2003 | EP |
| 1 369 684 | Dec 2003 | EP |
| 1 369 687 | Dec 2003 | EP |
| 1 119 637 | Mar 2004 | EP |
| 1 394 535 | Mar 2004 | EP |
| 1 413 879 | Apr 2004 | EP |
| 1 431 758 | Jun 2004 | EP |
| 2 295 676 | Jun 1996 | GB |
| 2 365 123 | Feb 2002 | GB |
| 63-111453 | May 1988 | JP |
| 63-128252 | May 1988 | JP |
| 01-291153 | Nov 1989 | JP |
| 03-099254 | Apr 1991 | JP |
| 04-121652 | Apr 1992 | JP |
| 93-31261 | Nov 1993 | JP |
| 08-262026 | Oct 1996 | JP |
| 09-043242 | Feb 1997 | JP |
| 91-59644 | Jun 1997 | JP |
| 10 332626 | Dec 1998 | JP |
| 2000-19146 | Jan 2000 | JP |
| 2000 019147 | Jan 2000 | JP |
| 2180514 | Mar 2002 | RU |
| WO 8101794 | Jul 1981 | WO |
| WO 8300926 | Mar 1983 | WO |
| WO 8607632 | Dec 1986 | WO |
| WO 8908713 | Sep 1989 | WO |
| WO 8909397 | Oct 1989 | WO |
| WO 9005293 | May 1990 | WO |
| WO 9201928 | Feb 1992 | WO |
| WO 9207655 | May 1992 | WO |
| WO 9215859 | Sep 1992 | WO |
| WO 9215861 | Sep 1992 | WO |
| WO 9215950 | Sep 1992 | WO |
| WO 9222669 | Dec 1992 | WO |
| WO 9309433 | May 1993 | WO |
| WO 9412950 | Jun 1994 | WO |
| WO 9416095 | Jul 1994 | WO |
| WO 9423295 | Oct 1994 | WO |
| WO 9428414 | Dec 1994 | WO |
| WO 9429705 | Dec 1994 | WO |
| WO 9503542 | Feb 1995 | WO |
| WO 9506919 | Mar 1995 | WO |
| WO 9507050 | Mar 1995 | WO |
| WO 9522597 | Aug 1995 | WO |
| WO 9604398 | Feb 1996 | WO |
| WO 9607908 | Mar 1996 | WO |
| WO 9613707 | May 1996 | WO |
| WO 9615454 | May 1996 | WO |
| WO 9633403 | Oct 1996 | WO |
| WO 9700441 | Jan 1997 | WO |
| WO 9702487 | Jan 1997 | WO |
| WO 9708544 | Mar 1997 | WO |
| WO 9716726 | May 1997 | WO |
| WO 9718465 | May 1997 | WO |
| WO 9729366 | Aug 1997 | WO |
| WO 9729847 | Aug 1997 | WO |
| WO 9730344 | Aug 1997 | WO |
| WO 9739341 | Oct 1997 | WO |
| WO 9739343 | Oct 1997 | WO |
| WO 9742882 | Nov 1997 | WO |
| WO 9742888 | Nov 1997 | WO |
| WO 9745719 | Dec 1997 | WO |
| WO 9805424 | Feb 1998 | WO |
| WO 9819153 | May 1998 | WO |
| WO 9819159 | May 1998 | WO |
| WO 9829740 | Jul 1998 | WO |
| WO 9835225 | Aug 1998 | WO |
| WO 9855853 | Dec 1998 | WO |
| WO 9857159 | Dec 1998 | WO |
| WO 9905966 | Feb 1999 | WO |
| WO 9909404 | Feb 1999 | WO |
| WO 9912008 | Mar 1999 | WO |
| WO 9912021 | Mar 1999 | WO |
| WO 9913099 | Mar 1999 | WO |
| WO 9913100 | Mar 1999 | WO |
| WO 9905516 | Apr 1999 | WO |
| WO 9922236 | May 1999 | WO |
| WO 9923479 | May 1999 | WO |
| WO 9929230 | Jun 1999 | WO |
| WO 9930152 | Jun 1999 | WO |
| WO 9932881 | Jul 1999 | WO |
| WO 9939627 | Aug 1999 | WO |
| WO 9941596 | Aug 1999 | WO |
| WO 9951974 | Oct 1999 | WO |
| WO 9957317 | Nov 1999 | WO |
| WO 9958709 | Nov 1999 | WO |
| WO 9959464 | Nov 1999 | WO |
| WO 9960383 | Nov 1999 | WO |
| WO 9964620 | Dec 1999 | WO |
| WO 0009996 | Feb 2000 | WO |
| WO 0010007 | Feb 2000 | WO |
| WO 0020626 | Apr 2000 | WO |
| WO 0026638 | May 2000 | WO |
| WO 0028068 | May 2000 | WO |
| WO 0033072 | Jun 2000 | WO |
| WO 0033074 | Jun 2000 | WO |
| WO 0042422 | Jul 2000 | WO |
| WO 0045160 | Aug 2000 | WO |
| WO 0054047 | Sep 2000 | WO |
| WO 0057177 | Sep 2000 | WO |
| WO 0060340 | Oct 2000 | WO |
| WO 0062047 | Oct 2000 | WO |
| WO 0073778 | Dec 2000 | WO |
| WO 0073785 | Dec 2000 | WO |
| WO 0078917 | Dec 2000 | WO |
| WO 00078992 | Dec 2000 | WO |
| WO 0102093 | Jan 2001 | WO |
| WO 0113115 | Feb 2001 | WO |
| WO 0113115 | Feb 2001 | WO |
| WO 0125775 | Apr 2001 | WO |
| WO 0125776 | Apr 2001 | WO |
| WO 0128423 | Apr 2001 | WO |
| WO 0173420 | Apr 2001 | WO |
| WO 0130915 | May 2001 | WO |
| WO 0133216 | May 2001 | WO |
| WO 0136430 | May 2001 | WO |
| WO 0136660 | May 2001 | WO |
| WO 0136953 | May 2001 | WO |
| WO 0146457 | Jun 2001 | WO |
| WO 0140788 | Jul 2001 | WO |
| WO 0157238 | Aug 2001 | WO |
| WO 0157239 | Aug 2001 | WO |
| WO 0157510 | Aug 2001 | WO |
| WO 0164105 | Sep 2001 | WO |
| WO 0167099 | Sep 2001 | WO |
| WO 0171328 | Sep 2001 | WO |
| WO 0171329 | Sep 2001 | WO |
| WO 0172220 | Oct 2001 | WO |
| WO 0173109 | Oct 2001 | WO |
| WO 0173114 | Oct 2001 | WO |
| WO 0173124 | Oct 2001 | WO |
| WO 0173395 | Oct 2001 | WO |
| WO 0174242 | Oct 2001 | WO |
| WO 0175433 | Oct 2001 | WO |
| WO 0175438 | Oct 2001 | WO |
| WO 0184133 | Nov 2001 | WO |
| WO 0184142 | Nov 2001 | WO |
| WO 0188524 | Nov 2001 | WO |
| WO 0192857 | Dec 2001 | WO |
| WO 0195806 | Dec 2001 | WO |
| WO 0196596 | Dec 2001 | WO |
| WO 0200112 | Jan 2002 | WO |
| WO 0206822 | Jan 2002 | WO |
| WO 0208750 | Jan 2002 | WO |
| WO 0208753 | Jan 2002 | WO |
| WO 0210728 | Feb 2002 | WO |
| WO 0213966 | Feb 2002 | WO |
| WO 0213970 | Feb 2002 | WO |
| WO 0214535 | Feb 2002 | WO |
| WO 0218053 | Mar 2002 | WO |
| WO 0222855 | Mar 2002 | WO |
| WO 0232559 | Apr 2002 | WO |
| WO 0248707 | Jun 2002 | WO |
| WO 0249507 | Jun 2002 | WO |
| WO 0250609 | Jun 2002 | WO |
| WO 02054055 | Jul 2002 | WO |
| WO 02057767 | Jul 2002 | WO |
| WO 02057768 | Jul 2002 | WO |
| WO 02057781 | Jul 2002 | WO |
| WO 02058537 | Aug 2002 | WO |
| WO 02062212 | Aug 2002 | WO |
| WO 02067768 | Sep 2002 | WO |
| WO 02070734 | Sep 2002 | WO |
| WO 02071044 | Sep 2002 | WO |
| WO 02078512 | Oct 2002 | WO |
| WO 02078533 | Oct 2002 | WO |
| WO 02086483 | Oct 2002 | WO |
| WO 02093152 | Nov 2002 | WO |
| WO 02095355 | Nov 2002 | WO |
| WO 02097418 | Dec 2002 | WO |
| WO 02103343 | Dec 2002 | WO |
| WO 03005015 | Jan 2003 | WO |
| WO 03012422 | Feb 2003 | WO |
| WO 03014740 | Feb 2003 | WO |
| WO 03014741 | Feb 2003 | WO |
| WO 03015627 | Feb 2003 | WO |
| WO 03015629 | Feb 2003 | WO |
| WO 03021706 | Mar 2003 | WO |
| WO 03025257 | Mar 2003 | WO |
| WO 03029804 | Apr 2003 | WO |
| WO 03032411 | Apr 2003 | WO |
| WO 03039483 | May 2003 | WO |
| WO 03042679 | May 2003 | WO |
| WO 03042680 | May 2003 | WO |
| WO 03044513 | May 2003 | WO |
| WO 03048756 | Jun 2003 | WO |
| WO 03060154 | Jul 2003 | WO |
| WO 03067252 | Aug 2003 | WO |
| WO 03069304 | Aug 2003 | WO |
| WO 03083469 | Oct 2003 | WO |
| WO 03085372 | Oct 2003 | WO |
| WO 03091717 | Nov 2003 | WO |
| WO 2004005908 | Jan 2004 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20040256248 A1 | Dec 2004 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60480298 | Jun 2003 | US |
