Patent Grant
11614609
The above-referenced application is incorporated herein by reference.
Some applications of the presently disclosed subject matter relate generally to sample carriers that are used for optical measurements, and in particular, to sample carriers that are used for microscopic measurements that are performed upon bodily samples.
In some optics-based methods (e.g., diagnostic, and/or analytic methods), a property of a biological sample, such as a blood sample, is determined by performing an optical measurement. For example, the density of a component (e.g., a count of the component per unit volume) may be determined by counting the component within a microscopic image. Similarly, the concentration and/or density of a component may be measured by performing optical absorption, transmittance, fluorescence, and/or luminescence measurements upon the sample. Typically, the sample is placed into a sample carrier and the measurements are performed with respect to a portion of the sample that is contained within a chamber of the sample carrier. The measurements that are performed upon the portion of the sample that is contained within the chamber of the sample carrier are analyzed in order to determine a property of the sample.
For some applications, diagnostic tests are performed on a sample carrier that is filled with a bodily sample that is taken from a subject. In such cases, there is a risk that a user will try to reuse the cartridge (e.g. after washing it). This could lead to the risk of erroneous results in diagnosing a subsequent sample that is placed in the sample carrier after is has already been used, e.g. due to cross-contamination, and/or debris being left in the sample carrier from its previous use.
For some applications of the present invention, a sample carrier is configured to house the bodily sample, and at least a portion of the sample carrier is configured to fluoresce, at least under certain conditions. For some applications, the portion of the sample carrier is analyzed, in order to determine whether the portion or an area thereof has undergone photobleaching. In response to detecting that the portion or the area thereof has undergone photobleaching, it is determined that the sample carrier, or a portion thereof (e.g., a chamber thereof) has already been used, and/or the number of times the sample carrier or the portion thereof (e.g., a chamber thereof) has been used. For some applications, the above steps are performed by a computer processor. For some applications, in response to detecting that the sample carrier, or a portion thereof (e.g., a chamber thereof) has already been used, or that the usage of the sample carrier, or a portion thereof (e.g., a chamber thereof) has exceeded a given threshold, the computer processor (a) generates an output indicating that the sample carrier, or the portion thereof (e.g., the chamber thereof), should not be used, (b) generates an output indicating that the sample carrier, or the portion thereof (e.g., the chamber thereof) is contaminated, and/or (c) prevents the optical measurement device from performing optical measurements upon the sample carrier, or the portion thereof (e.g., the chamber thereof).
For some applications, a given area of the sample carrier is marked by photobleaching the area when the sample carrier is used. For example, an optical measurement device may be configured to photobleach a given area of the sample carrier, when the sample carrier is placed inside the optical measurement device, and/or when the optical measurement device performs an optical measurement on the sample carrier. For some applications, the optical measurement is configured to photobleach a given area of the sample carrier automatically, by virtue of performing optical measurements upon the sample carrier. For example, the optical measurement device may be a microscope system that performs fluorescent imaging upon the sample. For some applications, the excitation wavelength that is emitted by the microscope system, in order to cause the sample to fluoresce, also photobleaches the given area of the sample carrier. For some applications, prior to photobleaching the given area, the computer processor verifies that the sample carrier has not already been used, using the techniques described hereinabove.
For some applications, the sample carrier is configured to be reused, but only a limited number of times. For some such applications, each time the sample carrier is used, a respective different area of the sample carrier is photobleached, such that the computer processor may then determine how many times the sample carrier has been used by detecting the number and/or locations of photobleached areas upon the sample carrier.
For some applications, the above-described photobleaching effect is used by a manufacturer of sample carriers to encode manufacturing information regarding the sample carrier, in a manner that is not visible to the naked eye. For example, such information may include an authenticity mark (to reduce the likelihood of counterfeit sample carriers being utilized), sample carrier type, manufacturing date, expiry date, manufacturing location, date required for accurate performance of the test (e.g. calibration date pertaining to the sample carrier, or batch of sample carriers). For some such applications, the mark is marked using a geometric pattern that includes lines, figures, barcodes, alphanumeric characters, etc.
There is therefore provided, in accordance with some applications of the present invention, apparatus for use with a bodily sample, the apparatus including:
a sample carrier configured to carry a portion of the bodily sample, at least a portion of the sample carrier being configured to fluoresce, at least under certain conditions; and
an optical measurement device configured to:
In some applications, the apparatus further includes an optical measurement unit that is configured to house the sample carrier while the optical measurement device performs the optical measurements upon the portion of the bodily sample, and the optical measurement device is configured to photobleach the given area of the sample carrier, in response to the sample carrier being placed inside the optical measurement unit.
In some applications, wherein the sample carrier is configured to be used for a plurality of measurements by the optical measurement device, and wherein the optical measurement device is configured to photobleach a respective different area of the sample carrier, each time the sample carrier is used for measurements by the optical measurement device.
In some applications, the apparatus further includes:
an output device; and
at least one computer processor that is operatively coupled to the optical measurement device, the computer processor being configured:
In some applications, the computer processor is configured:
to determine that at least a portion of the sample carrier has been used more than a given number of times, based upon detecting that an area within of the portion of the sample carrier has been photobleached; and
to generate the output on the output device, in response to determining that at least the portion of the sample carrier has been used more than the given number of times.
In some applications, the apparatus further includes:
an output device; and
at least one computer processor that is operatively coupled to the optical measurement device, the computer processor being configured:
In some applications, the computer processor is configured:
to determine that at least a portion of the sample carrier has been used more than a given number of times, based upon detecting that an area within of the portion of the sample carrier has been photobleached; and
to generate the output on the output device, in response to determining that at least the portion of the sample carrier has been used more than the given number of times.
In some applications, the apparatus further includes at least one computer processor that is operatively coupled to the optical measurement device, the computer processor being configured:
to detect that the area within the portion of the sample carrier has been photobleached, and
in response thereto, to prevent the optical measurement device from performing optical measurements upon at least a portion of the sample that is housed within a given portion of the sample carrier.
In some applications, wherein the computer processor is configured:
to determine that at least a portion of the sample carrier has been used more than a given number of times, based upon detecting that an area within of the portion of the sample carrier has been photobleached; and
to prevent the optical measurement device from performing the optical measurements, in response to determining that at least the portion of the sample carrier has been used more than the given number of times.
In some applications, the optical measurement device is configured to photobleach the given area of the sample carrier by virtue of performing optical measurements upon the sample.
In some applications, the optical measurement device is configured to illuminate the sample, in order to perform optical measurements on the sample, and the optical measurement device is configured to photobleach the given area of the sample carrier by virtue of illuminating the sample.
There is further provided, in accordance with some applications of the present invention, a method for use with a bodily sample, the method including:
placing a portion of the bodily sample within a sample carrier, at least a portion of the sample carrier being configured to fluoresce, at least under certain conditions; and
while the portion of the bodily sample is housed within the sample carrier, performing optical measurements upon the portion of the bodily sample that is housed within the sample carrier, using an optical measurement device; and
at least partially photobleaching an area within the portion of the sample carrier by causing the area to fluoresce.
There is further provided, in accordance with some applications of the present invention, apparatus for use with a bodily sample and an output device, the apparatus including:
a sample carrier configured to carry the bodily sample, at least a portion of the sample carrier being configured to fluoresce, at least under certain conditions;
an optical measurement device configured to perform optical measurements upon the portion of the bodily sample that is housed within the sample carrier; and
at least one computer processor that is operatively coupled to the optical measurement device, the computer processor being configured, in response to detecting that an area within the portion of the sample carrier has been photobleached, to perform an action selected from the group consisting of: generating an output upon the output device indicating that at least a portion of the sample carrier is contaminated, generating an output upon the output device indicating that optical measurements cannot be performed on at least a portion of the sample that is housed within a given portion of the sample carrier, and preventing the optical measurement device from performing optical measurements upon at least a portion of the sample that is housed within a given portion of the sample carrier.
In some applications, the computer processor is configured:
to determine that at least a portion of the sample carrier has been used more than a given number of times, based upon detecting that an area within of the portion of the sample carrier has been photobleached; and
to perform the selected action, in response to determining that at least the portion of the sample carrier has been used more than the given number of times.
There is further provided, in accordance with some applications of the present invention, a method for use with a bodily sample and an output device, the method including:
placing a portion of the bodily sample inside a sample carrier, at least a portion of the sample carrier being configured to fluoresce, at least under certain conditions;
performing optical measurements upon the portion of the bodily sample that is housed within the sample carrier; and
using at least one computer processor, in response to detecting that an area within the portion of the sample carrier has been photobleached, performing an action selected from the group consisting of: generating an output upon the output device indicating that at least a portion of the sample carrier is contaminated, generating an output upon the output device indicating that optical measurements cannot be performed on at least a portion of the sample that is housed within a given portion of the sample carrier, and preventing the optical measurement device from performing optical measurements upon at least a portion of the sample that is housed within a given portion of the sample carrier.
There is further provided, in accordance with some applications of the present invention, apparatus for use with a bodily sample and a microscope having an imaging module, the apparatus including:
at least one chamber configured for housing therein a portion of the bodily sample, the chamber including an upper inner surface, and a lower inner surface,
a computer processor configured to:
There is further provided, in accordance with some applications of the present invention, a method for use with a bodily sample and a microscope having an imaging module, the method including:
placing a portion of the bodily sample inside at least one chamber, the chamber including an upper inner surface, and a lower inner surface, the upper inner surface including a first mark and the lower inner surface including a second mark; and
using at least one computer processor:
The present invention will be more fully understood from the following detailed description of embodiments thereof, taken together with the drawings, in which:
Reference is now made to
A computer processor 28 typically receives and processes optical measurements that are performed by the optical measurement device. Further typically, the computer processor controls the acquisition of optical measurements that are performed by the one or more optical measurement devices. The computer processor communicates with a memory 30. A user (e.g., a laboratory technician) sends instructions to the computer processor via a user interface 32. For some applications, the user interface includes a keyboard, a mouse, a joystick, a touchscreen device (such as a smartphone or a tablet computer), a touchpad, a trackball, a voice-command interface, and/or other types of user interfaces that are known in the art. Typically, the computer processor generates an output via an output device 34. Further typically, the output device includes a display, such as a monitor, and the output includes an output that is displayed on the display. For some applications, the processor generates an output on a different type of visual, text, graphics, tactile, audio, and/or video output device, e.g., speakers, headphones, a smartphone, or a tablet computer. For some applications, user interface 32 acts as both an input interface and an output interface, i.e., it acts as an input/output interface. For some applications, the processor generates an output on a computer-readable medium (e.g., a non-transitory computer-readable medium), such as a disk, or a portable USB drive, and/or generates an output on a printer.
For some applications, optical measurement device 24 (and/or computer processor 28 and memory 30) is housed inside an optical measurement unit 31. In order to perform the optical measurements upon the sample, sample carrier 22 is placed inside the optical measurement unit.
Reference is now made to
Reference is made to
As described hereinabove, while the sample is disposed in the sample carrier, optical measurements are performed upon the sample using one or more optical measurement devices 24. Typically, the sample is viewed by the optical measurement device via the glass layer, glass being transparent at least to wavelengths that are typically used by the optical measurement device. Typically, the sample carrier is inserted into optical measurement unit 31, which houses the optical measurement device while the optical measurements are performed. Typically, the optical measurement unit houses the sample carrier such that the molded layer is disposed above the glass layer, and such that the optical measurement unit is disposed below the glass layer of the sample carrier and is able to perform optical measurements upon the sample via the glass layer. The sample carrier is formed by adhering the glass sheet to the molded component. For example, the glass sheet and the molded component may be bonded to each other during manufacture or assembly (e.g. using thermal bonding, solvent-assisted bonding, ultrasonic welding, laser welding, heat staking, adhesive, mechanical clamping and/or additional substrates). For some applications, the glass layer and the molded component are bonded to each other during manufacture or assembly using adhesive layer 46.
For some applications, diagnostic tests are performed on a sample carrier that is filled with a bodily sample that is taken from a subject. In such cases, there is a risk that a user will try to reuse the cartridge (e.g. after washing it). This could lead to the risk of erroneous results in diagnosing a subsequent sample that is placed in the sample carrier after is has already been used, e.g. due to cross-contamination, and/or debris being left in the sample carrier from its previous use. For some applications, as shown in
For some applications, a portion of sample carrier 22 is configured to fluoresce, at least under certain conditions. For example, the portion of the sample carrier may be configured to fluoresce when exposed to light emitted by optical measurement device 24 (e.g., brightfield light or fluorescent light that is emitted by a microscope system). Or the portion of the sample carrier may be configured to fluoresce when placed within optical measurement unit 31 in which optical measurement device 24 is housed. As described hereinabove, for some applications, sample carrier 22 includes adhesive layer 46. For some applications, the adhesive layer, or a portion thereof, is configured to fluoresce in the above-described manner (e.g., by an adhesive material within the adhesive layer being configured to fluoresce, by the adhesive layer containing an additional material that is configured to fluoresce, and/or by the adhesive layer being coated with such a material). For some applications, the adhesive layer is a pressure-sensitive adhesive, at least a portion of which is configured to fluoresce. For example, the pressure-sensitive adhesive may be an acrylic-based pressure-sensitive adhesive, at least a portion of which is configured to fluoresce. For some applications, the portion of the sample carrier that is configured to fluoresce is further configured to undergo photobleaching in areas that are exposed to fluorescent excitation (e.g. in the UV part of the electromagnetic spectrum). For example, such areas may be configured to undergo photobleaching when exposed to fluorescent excitation for less than one minute, less than 10 seconds, or less than 1 second. Typically, the area that is photobleached can be viewed using the optical measurement device 24 (e.g., the microscope system), and further typically, the photobleaching remains visible for at least one week, e.g., at least one month, or one year.
Reference is now made to
Reference is also made to
In accordance with the effect that is demonstrated in
For some applications, a given area of the sample carrier is marked by photobleaching the area when the sample carrier is used. For example, optical measurement device 24 may be configured to photobleach a given area of the sample carrier when the sample carrier is placed inside optical measurement unit 31 that houses the sample carrier while optical measurements are performed upon the portion of the sample. Alternatively or additionally, optical measurement device 24 may be configured to photobleach a given area of the sample carrier when the optical measurement device performs an optical measurement on the sample carrier. For some applications, the optical measurement device is configured to photobleach a given area of the sample carrier automatically, by virtue of performing optical measurements upon the sample carrier (i.e., without having to perform any activity specifically for the purpose of causing the photobleaching, which the optical measurement device would not have been performing in any event, in order to perform the optical measurements). For example, the optical measurement device may be a microscope system that performs fluorescent imaging upon the sample by exciting the sample and/or a stained portion of the sample with light that corresponds to an excitation wavelength of the sample and/or the stained portion of the sample, such that the light causes the sample and/or the stained portion of the sample to fluoresce. The light that is emitted by the microscope system, in order to cause the sample and/or the stained portion of the sample to fluoresce, may also photobleach the given area of the sample carrier. For some applications, prior to photobleaching the given area, the computer processor verifies that the sample carrier has not already been used, using the techniques described hereinabove.
As described hereinabove, for some applications, the sample carrier is configured to be reused, but only a limited number of times. For some such applications, each time the sample carrier is used, a respective different area of the sample carrier is photobleached, such that the computer processor may then determine how many times the sample carrier has been used by detecting the number and/or locations of photobleached areas upon the sample carrier.
For some applications, the above-described photobleaching effect is used by a manufacturer of sample carriers to encode manufacturing information regarding the sample carrier, in a manner which is not visible to the naked eye. For example, such information may include an authenticity mark (to reduce the likelihood of counterfeit sample carriers being utilized), sample carrier type, manufacturing date, expiry date, manufacturing location, date required for accurate performance of the test (e.g. calibration date pertaining to the sample carrier, or batch of sample carriers). For some such applications, the marking is marked using a geometric pattern that includes lines, figures, barcodes, alphanumeric characters, etc.
For some applications, a sample carrier that contains a given sample is analyzed more than once by the optical measurement devices. For example, the sample may be analyzed and then re-analyzed at certain time intervals. For some applications, respective portions of the same sample are placed in respective chambers of the sample carrier and are analyzed at respective time intervals. For some applications, in order to ensure that the same sample is being re-analyzed, the optical measurement device is configured to mark the sample carrier, via photobleaching, in a given manner. Subsequently, when the sample carrier is placed back inside the optical measurement unit, or a different optical measurement unit for the re-analysis, the computer processor verifies that it is the same sample carrier by identifying the marks on the sample carrier.
It is noted that the above-described apparatus and methods, which relate to photobleaching a portion of a sample carrier that is configured to fluoresce at least under certain conditions, is not limited to any particular design of the sample carrier. Rather, any design of sample carrier may be configured to incorporate such a portion. Similarly, the above-described apparatus and methods, which relate to photobleaching a portion of a sample carrier that is configured to fluoresce at least under certain conditions, is not limited to any particular portion of a sample carrier. Rather, any portion of a sample carrier may be configured to have such characteristics. For example, any portion of the molded component, the adhesive layer, or the glass sheet of a sample carrier as described herein may be configured in this manner.
Reference is now made to
For some applications, a sample carrier as shown in
As described in WO 17/195205 to Pollack, which is incorporated herein by reference, for some applications, chambers belonging to set 54 (which is used for optical density measurements), typically define at least a first region 56 (which is typically deeper) and a second region 58 (which is typically shallower), the height of the chambers varying between the first and second regions in a predefined manner.
Typically, in order to perform optical analysis upon the sample, it is desirable to know the optical path length, the volume, and/or the thickness of the portion of the sample upon which the optical measurements were performed, as precisely as possible. Further typically, the optical measurements are performed upon a portion of the sample disposed in a sample carrier that is defined by two or more opposing surfaces. In order to provide the desired level of precision, it is desirable for the two or more opposing surfaces to be separated by a distance that is correspondingly tightly set or tightly controlled. However, in some manufacture or assembly processes, the distance between the opposing surfaces may vary substantially. For example, the upper and lower surfaces of the chambers as shown in
Typically, an optical measurement is performed on the sample. For example, the density of a component may be determined by performing a count of the component within a microscopic image. Similarly, the concentration and/or density of a component may be measured by performing optical absorption, transmittance, fluorescence, and/or luminescence measurements upon the sample. Without being bound by theory, an uncertainty of 20 percent in the distance separating the two opposing surfaces (as described in the above example), may, in turn, correspond to 20 percent uncertainty in parameters of the sample that are derived from the optical measurements that are performed upon the sample (such as, the derived concentration and/or density of a component within the sample), e.g., as described in WO 17/195205 to Pollack, which is incorporated herein by reference.
In accordance with some applications of the present invention, the above-described problems associated with uncertainty relating to the height of a sample chamber are at least partially overcome. Referring again to
As described hereinabove, the molded component is shaped to define a stepped surface such as to define the manner in which the height of the chambers belonging to set 54 varies between the first and second regions. Typically, relative manufacturing tolerances within a single substrate, and especially between nearby surfaces, are tighter than manufacturing tolerances on positioning between different substrates or even between opposing surfaces lying within the same substrate. Therefore, it is typically the case that by having a single substrate define the manner in which the height of the one or more sample chambers varies between the first and second regions, the height difference between the first and second regions is relatively precise. For example, the molded component may be manufactured with relatively tight tolerances, for example, using injection molding, embossing or machining.
As described with reference to WO 17/195205 to Pollack, which is incorporated herein by reference, for some applications, chambers belonging to set 52 (which is used for microscopy measurements) have different heights from each other, in order to facilitate different measurands being measured using microscope images of respective chambers, and/or different chambers being used for microscopic analysis of respective sample types. For example, if a blood sample, and/or a monolayer formed by the sample, has a relatively low density of red blood cells, then measurements may be performed within a chamber of the sample carrier having a relatively great height, such that there is a sufficient density of cells, and/or such that there is a sufficient density of cells within the monolayer formed by the sample, to provide statistically reliable data. Such measurements may include, for example red blood cell density measurements, measurements of other cellular attributes, (such as counts of abnormal red blood cells, red blood cells that include intracellular bodies (e.g., pathogens, Howell-Jolly bodies), etc.), and/or hemoglobin concentration. Conversely, if a blood sample, and/or a monolayer formed by the sample, has a relatively high density of red blood cells, then such measurements may be performed upon a chamber of the sample carrier having a relatively low height, for example, such that there is a sufficient sparsity of cells, and/or such that there is a sufficient sparsity of cells within the monolayer of cells formed by the sample, that the cells can be identified within microscopic images. For some applications, such methods are performed even without the variation in height between the chambers belonging to set 52 being precisely known.
For some applications, based upon the measurand that is being measured, the chamber within the sample carrier upon which to perform optical measurements is selected. For example, a chamber of the sample carrier having a relatively great height may be used to perform a white blood cell count (e.g., to reduce statistical errors which may result from a low count in a shallower region), white blood cell differentiation, and/or to detect more rare forms of white blood cells. Conversely, in order to determine mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), red blood cell distribution width (RDW), red blood cell morphologic features, and/or red blood cell abnormalities, microscopic images may be obtained from a chamber of the sample chamber having a relatively low height, since in such chambers the cells are relatively sparsely distributed across the area of the region, and/or form a monolayer in which the cells are relatively sparsely distributed. Similarly, in order to count platelets, classify platelets, and/or extract any other attributes (such as volume) of platelets, microscopic images may be obtained from a chamber of the sample chamber having a relatively low height, since within such chambers there are fewer red blood cells which overlap (fully or partially) with the platelets in microscopic images, and/or in a monolayer.
In accordance with the above-described examples, it is preferable to use a chamber of the sample carrier having a lower height for performing optical measurements for measuring some measurands within a sample (such as a blood sample), whereas it is preferable to use a chamber of the sample carrier having a greater height for performing optical measurements for measuring other measurands within such a sample. Therefore, for some applications, a first measurand within a sample is measured, by performing a first optical measurement upon (e.g., by acquiring microscopic images of) a portion of the sample that is disposed within a first chamber belonging to set 52 of the sample carrier, and a second measurand of the same sample measured, by performing a second optical measurement upon (e.g., by acquiring microscopic images of) a portion of the sample that is disposed within a second chamber of set 52 of the sample carrier. For some applications, the first and second measurands are normalized with respect to each other, for example, using techniques as described in WO 17/195208 to Zait, which is incorporated herein by reference.
Reference is now made to
Sample carrier as shown in
For some applications, a cover 60 (shown in
For some applications, sample carrier 22 is shaped to define a reservoir 39 that is adjacent to inlet hole 38. Typically, the reservoir is configured to allow the user to fill the chambers of the sample carrier with the bodily sample, such that, on the one hand, the user is not required to insert a precise volume of the bodily sample into the inlet hole, and yet, on the other hand, the inlet hole is left substantially free of liquids.
Reference is now made to
Typically, a sample fills a volume having a height that is defined by the upper and lower surfaces. For example, the volume of a portion of the sample in one of the chambers is defined by the area of the chamber multiplied by the height of the chamber. However, in some cases, the exact height of the chamber is not known, for example, for the reasons provided hereinabove. For some applications, the computer processor determines the height of the chamber by focusing an imaging module of the optical measurement device on first marking 62 and registering an indication of the focusing distance F1 associated with the first marking. The computer processor also focuses the imaging module of the optical measurement device on second marking 64 and registers an indication of the focusing distance F2 associated with the second marking. The computer processor then determines the height of the chamber, based upon the difference between F1 and F2. For some applications, the computer processor determines the volume of the chamber, or a portion thereof, based upon the determined height of the chamber. Typically, the computer processor determines a property of the sample at least partially based upon the determined height of the chamber, for example, using techniques as described hereinabove.
There is typically a degree of variation in the positioning of the sample carrier with respect to an imaging module of optical measurement device 24. For example, placement of the sample carrier on a microscope stage can vary significantly in view of the required imaging resolution (due for example to limitations of the microscope, variation in the sample carrier, variations in placement by an operator of the device, etc.). Therefore, in accordance with some applications, the positioning of the sample carrier with respect to an imaging module of optical measurement device 24 is determined, in accordance with the techniques described herein.
For some applications, the imaging module of the optical measurement device and a stage upon which the sample carrier is placed are initially positioned such that a visible mark on the sample carrier appears within the observation field of the imaging module. This is followed by scanning a portion of the sample carrier surface until sufficient information is available to define the sample carrier's position and/or orientation at least with respect to the X-Y plane. (In the present application, the term Z-axis is used to refer to the optical axis of the optical system, and the X-Y plane is used to denote the plane that is perpendicular to the optical axis, as is common in the art.)
Reference is now made to
It may be observed that the spacing between the vertical lines 72 is irregular, i.e. the distance between each two neighboring vertical lines 72 is different than any of two other neighboring vertical lines 72. The same design is applied to the horizontal lines. By way of example, the irregular pattern may measure about 2.7×2.7 mm2, while the observation field may measure about 0.6×0.8 mm2.
It is noted that while irregular pattern 70 and the observation field are shown as being essentially rectangular or square, any other shape may be used. For example, a round or other shape observation field may be selected, for example based on optical limitations which may provide a better image in a portion of a diagnostic field.
As described hereinabove, the optical measurement device is typically used to capture images of the sample using an observation field O.F. (also referred herein as an orientation field), which has a predetermined size and shape, and through which (when properly place above the sample carrier) a portion of the sample carrier can be viewed. The irregular pattern is designed with a resolution that is complementary to the observation field size so that in any lateral X-Y position of the observation field over the irregular pattern, the portion of the irregular pattern observed through the observation field is unique to that specific position and detectable at the set resolution of the device. Optionally, an observation field may be a diagnostic field or a portion thereof. In some embodiments, an observation field is assembled using a plurality of adjacent diagnostic fields, such that the combined information from two or more diagnostic fields is used as an observation field.
Reference is now made to
It is also noted that, typically, the resolution of the irregular pattern is designed to be complementary to the size and shape of the observation field, such that it is typically not the case that the observation field is smaller than the distance between two neighboring lines of the pattern (either horizontal or vertical), so that an observation field never includes a single line, an empty space or the sole thickness of a single line. Typically, the only exception to this configuration is an irregular pattern designed specifically so that such a single line, empty space and/or sole thickness can occur in a single position of the observation field across the entire irregular pattern.
Since each position of the observation field corresponds to its own unique pattern, the computer processor typically determines the position of the irregular pattern with respect to the observation field. Since the irregular pattern is fixedly associated with the sample carrier, the computer processor thereby determines the location, and optionally orientation, of the sample carrier that is imaged within the observation field.
Reference is now made to
In accordance with some applications, the irregular pattern is imprinted on the sample carrier, drawn on the sample carrier, etched on the sample carrier, engraved on the sample carrier, glued on the sample carrier, embedded within the sample carrier, constitutes protrusions and/or indentations within the sample carrier, and/or other visible features of the sample carrier, and/or is attached to the sample carrier. Typically, the irregular pattern (e.g., a 2D pattern as described with reference to
Reference is now made to
The examples that are shown are as follows:
Each of the patterns shown in
In principle, it should be appreciated that while a single irregular pattern may be sufficient for determining both location and orientation of the sample carrier, the subject matter of the present disclosure does not exclude the use of two or more such patterns in a single carrier/chamber, potentially allowing for more accurate results.
For some applications, the irregular pattern is a 3D pattern having elements thereof located at different heights along the Z-axis. Optionally, the maximum height of the 3D pattern relative to the minimum height measures about 10 μm. For some applications, the 3D pattern is marked on a surface having the same position along the optical axis of the imaging module of the optical measurement device as the surface upon which the sample is to be imaged. For example, the 3D pattern may be located on the surface and/or be embedded within the material.
It should be noted that according to some applications, a 3D pattern is used such that even a single image, or no more than 10 images, are needed to provide sufficient information to determine the position, and optionally also orientation of the sample carrier, with respect to an imaging module of an optical measurement device, both with respect to an XY plane of the observation field and along the optical axis of the imaging module.
For some applications, the 3D pattern is associated with a 2D pattern or mark as described above (either juxtaposed therewith or being a part thereof), so that once information is gathered from the 2D mark or pattern (regarding the position, and optionally orientation, of the sample carrier with respect to an X-Y plane of the visual examination zone), a single image of the 3D pattern is enough to determine the location of the sample carrier along the optical axis of an imaging module.
Reference is now made to
Reference is also made to
Reference is also made to
Thus, for some applications, the 3D feature of the irregular pattern is used by computer processor 28 to provide an additional degree of accuracy for determining the position of the sample carrier with respect to the imaging module of the optical measurement device. Alternatively or additionally, the 3D feature of the irregular pattern is used by computer processor 28 to provide an indication as to the focal length of the imaging module of the optical measurement device. A single image taken of the 3D pattern may provide sufficient information regarding the position of the grid in the X-Y plane as well as along the optical axis of the imaging module of the optical measurement device. Optionally, once the X-Y position is known, an image (e.g., a single image) of the 3D pattern is taken at the known X-Y position, and the computer processor derives the location of the 3D pattern along the optical axis of the imaging module of the optical measurement device using the image.
It should be appreciated that the depths D0 to D3 are not necessarily equally spaced, and the height differences between respective pairs of consecutive height levels can be different from each other.
Reference is now made to
For some applications, the sample as described herein is a sample that includes blood or components thereof (e.g., a diluted or non-diluted whole blood sample, a sample including predominantly red blood cells, or a diluted sample including predominantly red blood cells), and parameters are determined relating to components in the blood such as platelets, white blood cells, anomalous white blood cells, circulating tumor cells, red blood cells, reticulocytes, Howell-Jolly bodies, etc.
In general, it is noted that although some applications of the present invention have been described with respect to a blood sample, the scope of the present invention includes applying the apparatus and methods described herein to a variety of samples. For some applications, the sample is a biological sample, such as, blood, saliva, semen, sweat, sputum, vaginal fluid, stool, breast milk, bronchoalveolar lavage, gastric lavage, tears and/or nasal discharge. The biological sample may be from any living creature, and is typically from warm blooded animals. For some applications, the biological sample is a sample from a mammal, e.g., from a human body. For some applications, the sample is taken from any domestic animal, zoo animals and farm animals, including but not limited to dogs, cats, horses, cows and sheep. Alternatively or additionally, the biological sample is taken from animals that act as disease vectors including deer or rats.
For some applications, similar techniques to those described hereinabove are applied to a non-bodily sample. For some applications, the sample is an environmental sample, such as, a water (e.g. groundwater) sample, surface swab, soil sample, air sample, or any combination thereof. In some embodiments, the sample is a food sample, such as, a meat sample, dairy sample, water sample, wash-liquid sample, beverage sample, and/or any combination thereof.
Applications of the invention described herein can take the form of a computer program product accessible from a computer-usable or computer-readable medium (e.g., a non-transitory computer-readable medium) providing program code for use by or in connection with a computer or any instruction execution system, such as computer processor 28. For the purposes of this description, a computer-usable or computer readable medium can be any apparatus that can comprise, store, communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device. The medium can be an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system (or apparatus or device) or a propagation medium. Typically, the computer-usable or computer readable medium is a non-transitory computer-usable or computer readable medium.
Examples of a computer-readable medium include a semiconductor or solid state memory, magnetic tape, a removable computer diskette, a random-access memory (RAM), a read-only memory (ROM), a rigid magnetic disk and an optical disk. Current examples of optical disks include compact disk-read only memory (CD-ROM), compact disk-read/write (CD-R/W) and DVD.
A data processing system suitable for storing and/or executing program code will include at least one processor (e.g., computer processor 28) coupled directly or indirectly to memory elements (e.g., memory 30) through a system bus. The memory elements can include local memory employed during actual execution of the program code, bulk storage, and cache memories which provide temporary storage of at least some program code in order to reduce the number of times code must be retrieved from bulk storage during execution. The system can read the inventive instructions on the program storage devices and follow these instructions to execute the methodology of the embodiments of the invention.
Network adapters may be coupled to the processor to enable the processor to become coupled to other processors or remote printers or storage devices through intervening private or public networks. Modems, cable modem and Ethernet cards are just a few of the currently available types of network adapters.
Computer program code for carrying out operations of the present invention may be written in any combination of one or more programming languages, including an object-oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the C programming language or similar programming languages.
It will be understood that algorithms described herein, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general-purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer (e.g., computer processor 28) or other programmable data processing apparatus, create means for implementing the functions/acts specified in the algorithms described in the present application. These computer program instructions may also be stored in a computer-readable medium (e.g., a non-transitory computer-readable medium) that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable medium produce an article of manufacture including instruction means which implement the function/act specified in the flowchart blocks and algorithms. The computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions/acts specified in the algorithms described in the present application.
Computer processor 28 is typically a hardware device programmed with computer program instructions to produce a special purpose computer. For example, when programmed to perform the algorithms described herein, computer processor 28 typically acts as a special purpose sample-analysis computer processor. Typically, the operations described herein that are performed by computer processor 28 transform the physical state of memory 30, which is a real physical article, to have a different magnetic polarity, electrical charge, or the like depending on the technology of the memory that is used.
There is provided, in accordance with some applications of the present invention, the following inventive concepts:
Inventive concept 1. Apparatus comprising:
a sample carrier configured to carry a sample, and
an optical measurement device configured to perform optical measurements upon the sample, the optical measurement device defining an observation field,
an optical module;
a support for holding a sample carrier; and
a controller configured to:
wherein the sample carrier comprises at least one irregular pattern and the irregular pattern is sized and positioned on a sample carrier surface such that at least one of said ten orientation images or less shows the irregular pattern or a part thereof without searching.
Inventive concept 17. An automated microscope according to inventive concept 16, wherein the irregular pattern is patterned such that any portion of an orientation image that shows the irregular pattern or a part thereof shows a geometric pattern unique to that portion.
Inventive concept 18. An automated microscope according to inventive concept 16, wherein the irregular pattern is sized, shaped and positioned such that one image per pattern is sufficient for determining at least one of a position and orientation of the sample carrier.
Inventive concept 19. A sample carrier for a microscope, comprising at least one chamber configured for containing therein a sample to be analyzed, said chamber comprising:
a cavity with a platform disposed therein and having a platform surface elevated above a floor surface of the cavity; and
a cover covering said cavity spaced from said platform surface;
wherein said platform surface comprises a first mark and a said cover comprises on a surface thereof a second mark, wherein the focusing distance between the first mark and the second mark allows determining a vertical length of the space between said platform surface and a bottom surface of said cover.
Inventive concept 20. A sample carrier for a microscope according to inventive concept 19, wherein the second mark is on the bottom surface of said cover.
Inventive concept 21. A sample carrier for a microscope according to inventive concept 19, wherein the first mark and second mark overlap along the Z axis.
Inventive concept 22. A sample carrier for a microscope according to inventive concept 19, wherein at least one of the first mark and second mark comprises an irregular pattern.
Inventive concept 23. A method for determining a volume of a portion of a fluid sample in a sample carrier of inventive concept 19, comprising:
introducing the fluid sample into said sample carrier such that the sample fills a volume having a height defined between said platform surface and a bottom surface of said cover;
determining an area A of a portion of said platform surface;
focusing an optical module of the microscope on said first mark and registering an indication of the focusing distance F1 for said first mark;
focusing an optical module of the microscope on said second mark and registering an indication of the focusing distance F2 for said second mark; and
determining based on F1, F2 and A, a volume of the fluid sample located on said portion of the platform surface.
The apparatus and methods described herein may be used in conjunction with apparatus and methods described in any one of the following patent applications, all of which are incorporated herein by reference:
It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.
The present application is a continuation of U.S. Ser. No. 16/763,810 to Yorav-Raphael, which is the US national phase application of PCT Application No. PCT/IB2018/058861 to Yorav-Raphael (published as WO 19/097387), filed Nov. 12, 2018, which claims priority from U.S. Provisional Patent Application No. 62/585,621 to Yorav-Raphael, filed Nov. 14, 2017, entitled “Sample carrier for optical measurements.”
| Number | Name | Date | Kind |
|---|---|---|---|
| 3203768 | Tiller et al. | Aug 1965 | A |
| 3603156 | Konkol | Sep 1971 | A |
| 3676076 | Grady | Jul 1972 | A |
| 3786184 | Pieters | Jan 1974 | A |
| 3916205 | Kleinerman | Oct 1975 | A |
| 3967056 | Yata et al. | Jun 1976 | A |
| 4030888 | Yamamoto | Jun 1977 | A |
| 4076419 | Kleker | Feb 1978 | A |
| 4097845 | Bacus | Jun 1978 | A |
| 4199748 | Bacus | Apr 1980 | A |
| 4209548 | Bacus | Jun 1980 | A |
| 4350884 | Dieter | Sep 1982 | A |
| 4453266 | Bacus | Jun 1984 | A |
| 4454235 | Johnson | Jun 1984 | A |
| 4494479 | Drury et al. | Jan 1985 | A |
| 4580895 | Patel | Apr 1986 | A |
| 4700298 | Palcic et al. | Oct 1987 | A |
| 4761381 | Blatt et al. | Aug 1988 | A |
| 4774192 | Terminiello et al. | Sep 1988 | A |
| 4803352 | Bierleutgeb | Feb 1989 | A |
| 4849430 | Fleet | Jul 1989 | A |
| 4851330 | Kohne | Jul 1989 | A |
| 4902101 | Fujihara et al. | Feb 1990 | A |
| 5001067 | Coleman et al. | Mar 1991 | A |
| 5064282 | Curtis | Nov 1991 | A |
| 5229265 | Tometsko | Jul 1993 | A |
| 5300779 | Hillman et al. | Apr 1994 | A |
| 5331958 | Oppenheimer | Jul 1994 | A |
| 5430542 | Shepherd et al. | Jul 1995 | A |
| 5470751 | Sakata et al. | Nov 1995 | A |
| 5663057 | Drocourt et al. | Sep 1997 | A |
| 5672861 | Fairley et al. | Sep 1997 | A |
| 5674457 | Williamsson et al. | Oct 1997 | A |
| 5745804 | Iwane | Apr 1998 | A |
| 5782770 | Mooradian et al. | Jul 1998 | A |
| 5827190 | Palcic et al. | Oct 1998 | A |
| 5834217 | Levine et al. | Nov 1998 | A |
| 5932872 | Price | Aug 1999 | A |
| 5948686 | Wardlaw et al. | Sep 1999 | A |
| 5978497 | Lee et al. | Nov 1999 | A |
| 5985595 | Krider et al. | Nov 1999 | A |
| 6005964 | Reid et al. | Dec 1999 | A |
| 6027695 | Oldenburg et al. | Feb 2000 | A |
| 6064474 | Lee | May 2000 | A |
| 6074789 | Zelmanovic et al. | Jun 2000 | A |
| 6101104 | Yoon et al. | Aug 2000 | A |
| 6235536 | Wardlaw | May 2001 | B1 |
| 6262798 | Shepherd et al. | Jul 2001 | B1 |
| 6320979 | Melen | Nov 2001 | B1 |
| 6339472 | Hafeman | Jan 2002 | B1 |
| 6350613 | Wardlaw et al. | Feb 2002 | B1 |
| 6448024 | Bruegger | Sep 2002 | B1 |
| 6519355 | Nelson | Feb 2003 | B2 |
| 6554788 | Hunley et al. | Apr 2003 | B1 |
| 6582964 | Samsoondar et al. | Jun 2003 | B1 |
| 6611777 | Samsoondar | Aug 2003 | B2 |
| 6632681 | Chu | Oct 2003 | B1 |
| 6658143 | Hansen | Dec 2003 | B2 |
| 6664528 | Cartlidge et al. | Dec 2003 | B1 |
| 6711516 | Samsoondar | Mar 2004 | B2 |
| 6799119 | Voorhees et al. | Sep 2004 | B1 |
| 6819408 | Scrivens et al. | Nov 2004 | B1 |
| 6831733 | Pettersson | Dec 2004 | B2 |
| 6834237 | Noergaard et al. | Dec 2004 | B2 |
| 6836559 | Abdel-fattah et al. | Dec 2004 | B2 |
| 6842233 | Narisada | Jan 2005 | B2 |
| 6866823 | Wardlaw | Mar 2005 | B2 |
| 6872930 | Cartlidge et al. | Mar 2005 | B2 |
| 6898451 | Wuori | May 2005 | B2 |
| 6903323 | Cartlidge et al. | Jun 2005 | B2 |
| 6929953 | Wardlaw et al. | Aug 2005 | B1 |
| 6949384 | Samsoondar | Sep 2005 | B2 |
| 6955872 | Maples et al. | Oct 2005 | B2 |
| 6956650 | Boas | Oct 2005 | B2 |
| 6989891 | Braig et al. | Jan 2006 | B2 |
| 7027628 | Gagnon | Apr 2006 | B1 |
| 7030351 | Wasserman | Apr 2006 | B2 |
| 7034883 | Rosenqvist | Apr 2006 | B1 |
| 7105795 | Cartlidge et al. | Sep 2006 | B2 |
| 7132636 | Cartlidge | Nov 2006 | B1 |
| 7133547 | Marcelpoil | Nov 2006 | B2 |
| 7151246 | Fein et al. | Dec 2006 | B2 |
| 7155049 | Wetzel | Dec 2006 | B2 |
| 7248716 | Fein et al. | Jul 2007 | B2 |
| 7274810 | Reeves et al. | Sep 2007 | B2 |
| 7283217 | Ikeuchi | Oct 2007 | B2 |
| 7288751 | Cartlidge et al. | Oct 2007 | B2 |
| 7305109 | Gagnon | Dec 2007 | B1 |
| 7324694 | Chapoulaud | Jan 2008 | B2 |
| 7329537 | Qiu | Feb 2008 | B2 |
| 7338168 | Cartlidge et al. | Mar 2008 | B2 |
| 7344890 | Perez et al. | Mar 2008 | B2 |
| 7346205 | Walker, Jr. | Mar 2008 | B2 |
| 7369696 | Arini et al. | May 2008 | B2 |
| 7387898 | Gordon | Jun 2008 | B1 |
| 7411680 | Chang | Aug 2008 | B2 |
| 7417213 | Krief et al. | Aug 2008 | B2 |
| 7385168 | Cartlidge et al. | Sep 2008 | B2 |
| 7425421 | Dertinger | Sep 2008 | B2 |
| 7439478 | Cartlidge et al. | Oct 2008 | B2 |
| 7450223 | Ikeuchi | Nov 2008 | B2 |
| 7450762 | Morell | Nov 2008 | B2 |
| 7460222 | Kalveram | Dec 2008 | B2 |
| 7490085 | Walker et al. | Feb 2009 | B2 |
| 7493219 | Qi | Feb 2009 | B1 |
| 7580120 | Hamada | Aug 2009 | B2 |
| 7599893 | Sapir | Oct 2009 | B2 |
| 7601938 | Cartlidge et al. | Oct 2009 | B2 |
| 7602954 | Marcelpoil | Oct 2009 | B2 |
| 7605356 | Krief | Oct 2009 | B2 |
| 7609369 | Simon-Lopez | Oct 2009 | B2 |
| 7630063 | Padmanabhan | Dec 2009 | B2 |
| 7633604 | Ikeuchi | Dec 2009 | B2 |
| 7638748 | Krief et al. | Dec 2009 | B2 |
| 7663738 | Johansson | Feb 2010 | B2 |
| 7668362 | Olson | Feb 2010 | B2 |
| 7692131 | Fein et al. | Apr 2010 | B2 |
| 7697764 | Kataoka | Apr 2010 | B2 |
| 7702181 | Gouch | Apr 2010 | B2 |
| 7706862 | Alfano et al. | Apr 2010 | B2 |
| 7713474 | Schulman et al. | May 2010 | B2 |
| 7747153 | Ibaraki | Jun 2010 | B2 |
| 7765069 | Ostoich | Jul 2010 | B2 |
| 7777869 | Nerin | Aug 2010 | B2 |
| 7787109 | Dosmann et al. | Aug 2010 | B2 |
| 7796797 | Nakaya et al. | Sep 2010 | B2 |
| 7863552 | Cartlidge et al. | Jan 2011 | B2 |
| 7869009 | Dosmann et al. | Jan 2011 | B2 |
| 7894047 | Hamada | Feb 2011 | B2 |
| 7911617 | Padmanabhan | Mar 2011 | B2 |
| 7925070 | Sumida | Apr 2011 | B2 |
| 7929121 | Wardlaw | Apr 2011 | B2 |
| 7933435 | Hunter | Apr 2011 | B2 |
| 7936913 | Nordell | May 2011 | B2 |
| 7951599 | Levine | May 2011 | B2 |
| 7995200 | Matsumoto | Aug 2011 | B2 |
| 7998435 | Reed et al. | Aug 2011 | B2 |
| 8000511 | Perz | Aug 2011 | B2 |
| 8044974 | Sumida | Oct 2011 | B2 |
| 8045782 | Li | Oct 2011 | B2 |
| 8055471 | Qi | Nov 2011 | B2 |
| 8064680 | Ramoser | Nov 2011 | B2 |
| 8077296 | Wardlaw | Dec 2011 | B2 |
| 8081303 | Levine | Dec 2011 | B2 |
| 8105554 | Kanigan et al. | Jan 2012 | B2 |
| 8125643 | Hansen | Feb 2012 | B2 |
| D655421 | Lee et al. | Mar 2012 | S |
| 8131035 | Grady | Mar 2012 | B2 |
| 8131052 | Alexandrov | Mar 2012 | B2 |
| 8150114 | Svanberg | Apr 2012 | B2 |
| 8154713 | Simon-Lopez | Apr 2012 | B2 |
| 8165385 | Reeves | Apr 2012 | B2 |
| 8175353 | Westphal | May 2012 | B2 |
| 8179597 | Namba et al. | May 2012 | B2 |
| 8184273 | Dosmann | May 2012 | B2 |
| 8192995 | Zhang et al. | Jun 2012 | B2 |
| 8216832 | Battrell et al. | Jul 2012 | B2 |
| 8224058 | Lindberg | Jul 2012 | B2 |
| 8269954 | Levine | Sep 2012 | B2 |
| 8280134 | Hoyt | Oct 2012 | B2 |
| 8310659 | Wardlaw | Nov 2012 | B2 |
| 8320655 | Sarachan | Nov 2012 | B2 |
| 8327724 | Fairs et al. | Dec 2012 | B2 |
| 8331642 | Zerfass | Dec 2012 | B2 |
| 8339586 | Zahniser | Dec 2012 | B2 |
| 8345227 | Zahniser | Jan 2013 | B2 |
| 8351676 | Dai | Jan 2013 | B2 |
| 8363221 | Hansen | Jan 2013 | B2 |
| 8379944 | Grady | Feb 2013 | B2 |
| 8406498 | Ortyn et al. | Mar 2013 | B2 |
| 8428331 | Dimarzio | Apr 2013 | B2 |
| 8432392 | Kim | Apr 2013 | B2 |
| 8477294 | Zahniser | Jul 2013 | B2 |
| 8481303 | Faris et al. | Jul 2013 | B2 |
| 8488111 | Zahniser | Jul 2013 | B2 |
| 8491499 | Choi et al. | Jul 2013 | B2 |
| 8526704 | Dobbe | Sep 2013 | B2 |
| 8570496 | Chen | Oct 2013 | B2 |
| 8582924 | De La | Nov 2013 | B2 |
| 8638427 | Wardlaw | Jan 2014 | B2 |
| 8712142 | Rajpoot | Apr 2014 | B2 |
| 8736824 | Matsui | May 2014 | B2 |
| 8744165 | Liu | Jun 2014 | B2 |
| 8778687 | Levine | Jul 2014 | B2 |
| 8787650 | Muragame | Jul 2014 | B2 |
| 8792693 | Satish | Jul 2014 | B2 |
| 8837803 | Wang et al. | Sep 2014 | B2 |
| 8849024 | Shinoda | Sep 2014 | B2 |
| 8873827 | Mcculloch | Oct 2014 | B2 |
| 8877458 | Maurer | Nov 2014 | B2 |
| 8878923 | Henderson | Nov 2014 | B2 |
| 8885154 | Wardlaw | Nov 2014 | B2 |
| 8885912 | Sui | Nov 2014 | B2 |
| 8891851 | Spaulding | Nov 2014 | B2 |
| 8922761 | Zahniser | Dec 2014 | B2 |
| 8942458 | Takahashi | Jan 2015 | B2 |
| 8964171 | Zahniser | Feb 2015 | B2 |
| 8992750 | Beaty | Mar 2015 | B1 |
| 8994930 | Levine | Mar 2015 | B2 |
| 9012868 | Courtney et al. | Apr 2015 | B2 |
| 9041792 | Van Leeuwen | May 2015 | B2 |
| 9050595 | Miller et al. | Jun 2015 | B2 |
| 9064301 | Zie et al. | Jun 2015 | B2 |
| 9046473 | Levine | Sep 2015 | B2 |
| 9176121 | Winkelman et al. | Nov 2015 | B2 |
| 9186843 | Chan et al. | Nov 2015 | B2 |
| 9240043 | Christiansen | Jan 2016 | B2 |
| 9322767 | Ehrenkranz | Apr 2016 | B2 |
| 9329129 | Pollak et al. | May 2016 | B2 |
| 9342734 | Lin et al. | May 2016 | B2 |
| 9404852 | Braig et al. | Aug 2016 | B2 |
| 9470609 | Wimberger-friedl | Oct 2016 | B2 |
| 9477875 | Ohya | Oct 2016 | B2 |
| 9522396 | Bachelet | Dec 2016 | B2 |
| 9528978 | Yamada | Dec 2016 | B2 |
| 9588033 | Zahniser et al. | Mar 2017 | B2 |
| 9767343 | Jones et al. | Sep 2017 | B1 |
| 9820990 | Pak et al. | Nov 2017 | B2 |
| 9934571 | Ozaki | Apr 2018 | B2 |
| 10024858 | Smith et al. | Jul 2018 | B2 |
| 10061972 | Champlin | Aug 2018 | B2 |
| 10093957 | Pollak et al. | Oct 2018 | B2 |
| 10169861 | Ozaki et al. | Jan 2019 | B2 |
| 10176565 | Greenfield | Jan 2019 | B2 |
| 10281386 | Hsu et al. | May 2019 | B2 |
| 10482595 | Yorav-Raphael et al. | Nov 2019 | B2 |
| 10488644 | Eshel et al. | Nov 2019 | B2 |
| 10508983 | Kendall et al. | Dec 2019 | B2 |
| 10640807 | Pollak et al. | May 2020 | B2 |
| 10663712 | Eshel et al. | May 2020 | B2 |
| 10843190 | Bachelet et al. | Nov 2020 | B2 |
| 11199690 | Eshel et al. | Dec 2021 | B2 |
| 20020009711 | Wada et al. | Jan 2002 | A1 |
| 20020028158 | Wardlaw | Mar 2002 | A1 |
| 20020028471 | Oberhardt | Mar 2002 | A1 |
| 20030017085 | Kercso et al. | Jan 2003 | A1 |
| 20030161514 | Curry | Aug 2003 | A1 |
| 20030170613 | Straus | Sep 2003 | A1 |
| 20030197925 | Hamborg | Oct 2003 | A1 |
| 20030224522 | de Jong et al. | Dec 2003 | A1 |
| 20030227612 | Fein et al. | Dec 2003 | A1 |
| 20030227673 | Nakagawa | Dec 2003 | A1 |
| 20030231791 | Torre-Bueno et al. | Dec 2003 | A1 |
| 20040122216 | Nielsen | Jun 2004 | A1 |
| 20040132171 | Rule et al. | Jul 2004 | A1 |
| 20040170312 | Soenksen | Sep 2004 | A1 |
| 20040185447 | Maples et al. | Sep 2004 | A1 |
| 20040218804 | Affleck et al. | Nov 2004 | A1 |
| 20040240050 | Ogihara | Dec 2004 | A1 |
| 20040241677 | Lin et al. | Dec 2004 | A1 |
| 20050089208 | Dong et al. | Apr 2005 | A1 |
| 20050109959 | Wasserman et al. | May 2005 | A1 |
| 20050175992 | Aberl et al. | Aug 2005 | A1 |
| 20050286800 | Gouch | Dec 2005 | A1 |
| 20060002817 | Bohm | Jan 2006 | A1 |
| 20060003458 | Golovchenko et al. | Jan 2006 | A1 |
| 20060045505 | Zeineh et al. | Mar 2006 | A1 |
| 20060051778 | Kallick | Mar 2006 | A1 |
| 20060063185 | Vannier | Mar 2006 | A1 |
| 20060187442 | Chang et al. | Aug 2006 | A1 |
| 20060190226 | Jojic et al. | Aug 2006 | A1 |
| 20060222567 | Kloepfer et al. | Oct 2006 | A1 |
| 20060223052 | MacDonald et al. | Oct 2006 | A1 |
| 20060223165 | Chang et al. | Oct 2006 | A1 |
| 20070252984 | Van Beek et al. | Jan 2007 | A1 |
| 20070054350 | Walker, Jr. | Mar 2007 | A1 |
| 20070076190 | Nakaya et al. | Apr 2007 | A1 |
| 20070161075 | Gleich | Jul 2007 | A1 |
| 20070172956 | Magari et al. | Jul 2007 | A1 |
| 20070243117 | Wardlaw et al. | Oct 2007 | A1 |
| 20070250301 | Vaisberg et al. | Oct 2007 | A1 |
| 20080020128 | van Ryper | Jan 2008 | A1 |
| 20080059135 | Murugkar et al. | Mar 2008 | A1 |
| 20080118399 | Fleming | May 2008 | A1 |
| 20080187466 | Wardlaw et al. | Aug 2008 | A1 |
| 20080212069 | Goldberg et al. | Sep 2008 | A1 |
| 20080260369 | Ibaraki | Oct 2008 | A1 |
| 20080273776 | Krief et al. | Nov 2008 | A1 |
| 20080305514 | Alford et al. | Dec 2008 | A1 |
| 20090066934 | Gao et al. | Mar 2009 | A1 |
| 20090075324 | Pettersson | Mar 2009 | A1 |
| 20090086314 | Namba | Apr 2009 | A1 |
| 20090128618 | Fahn et al. | May 2009 | A1 |
| 20090185734 | Lindberg et al. | Jul 2009 | A1 |
| 20090191098 | Beard et al. | Jul 2009 | A1 |
| 20090195688 | Henderson et al. | Aug 2009 | A1 |
| 20090213214 | Yamada | Aug 2009 | A1 |
| 20090258347 | Scott | Oct 2009 | A1 |
| 20090269799 | Winkelman et al. | Oct 2009 | A1 |
| 20090291854 | Wiesinger-Mayr et al. | Nov 2009 | A1 |
| 20100003265 | Scheffler et al. | Jan 2010 | A1 |
| 20100068747 | Herrenknecht | Mar 2010 | A1 |
| 20100104169 | Yamada | Apr 2010 | A1 |
| 20100112631 | Hur et al. | May 2010 | A1 |
| 20100120129 | Amshey et al. | May 2010 | A1 |
| 20100136556 | Friedberger et al. | Jun 2010 | A1 |
| 20100136570 | Goldberg et al. | Jun 2010 | A1 |
| 20100152054 | Love | Jun 2010 | A1 |
| 20100157086 | Segale et al. | Jun 2010 | A1 |
| 20100172020 | Price | Jul 2010 | A1 |
| 20100192706 | Fairs | Aug 2010 | A1 |
| 20100232675 | Ortyn et al. | Sep 2010 | A1 |
| 20100234703 | Sterling et al. | Sep 2010 | A1 |
| 20100253907 | Korb | Oct 2010 | A1 |
| 20100254596 | Xiong | Oct 2010 | A1 |
| 20100256323 | Perz | Oct 2010 | A1 |
| 20100256918 | Chen et al. | Oct 2010 | A1 |
| 20100272334 | Yamada et al. | Oct 2010 | A1 |
| 20100295998 | Sakai et al. | Nov 2010 | A1 |
| 20100300563 | Ramunas et al. | Dec 2010 | A1 |
| 20110007178 | Kahlman | Jan 2011 | A1 |
| 20110009163 | Fletcher | Jan 2011 | A1 |
| 20110030458 | Park et al. | Feb 2011 | A1 |
| 20110059481 | Wardlaw et al. | Mar 2011 | A1 |
| 20110102571 | Yoneyama | May 2011 | A1 |
| 20110123398 | Carrhilo et al. | May 2011 | A1 |
| 20110144480 | Lu et al. | Jun 2011 | A1 |
| 20110149097 | Danuser et al. | Jun 2011 | A1 |
| 20110151502 | Kendall et al. | Jun 2011 | A1 |
| 20110178716 | Krockenberger et al. | Jul 2011 | A1 |
| 20110212486 | Yamada | Sep 2011 | A1 |
| 20110243794 | Wardlaw | Oct 2011 | A1 |
| 20110249910 | Henderson | Oct 2011 | A1 |
| 20110275111 | Pettigrew et al. | Nov 2011 | A1 |
| 20120002195 | Wu et al. | Jan 2012 | A1 |
| 20120021951 | Hess et al. | Jan 2012 | A1 |
| 20120030618 | Leong et al. | Feb 2012 | A1 |
| 20120044342 | Hing et al. | Feb 2012 | A1 |
| 20120058504 | Li et al. | Mar 2012 | A1 |
| 20120092477 | Kawano et al. | Apr 2012 | A1 |
| 20120120221 | Dong et al. | May 2012 | A1 |
| 20120169863 | Bachelet et al. | Jul 2012 | A1 |
| 20120225446 | Wimberger-Friedl et al. | Sep 2012 | A1 |
| 20120237107 | Tawfik et al. | Sep 2012 | A1 |
| 20120312957 | Loney et al. | Dec 2012 | A1 |
| 20120320045 | Yao | Dec 2012 | A1 |
| 20130023007 | Zahniser et al. | Jan 2013 | A1 |
| 20130078668 | Levine et al. | Mar 2013 | A1 |
| 20130130262 | Battrell et al. | May 2013 | A1 |
| 20130169948 | Xie | Jul 2013 | A1 |
| 20130170730 | Yu et al. | Jul 2013 | A1 |
| 20130176551 | Wardlaw et al. | Jul 2013 | A1 |
| 20130177974 | Mamghani et al. | Jul 2013 | A1 |
| 20130203082 | Gonda et al. | Aug 2013 | A1 |
| 20130273968 | Rhoads et al. | Oct 2013 | A1 |
| 20130284924 | Mizuochi et al. | Oct 2013 | A1 |
| 20130290225 | Kamath et al. | Oct 2013 | A1 |
| 20130323757 | Poher | Dec 2013 | A1 |
| 20140139625 | Mathuis et al. | May 2014 | A1 |
| 20140139630 | Kowalevicz | May 2014 | A1 |
| 20140185906 | Ding et al. | Jul 2014 | A1 |
| 20140186859 | Calderwood et al. | Jul 2014 | A1 |
| 20140205176 | Obrien et al. | Jul 2014 | A1 |
| 20140347459 | Greenfield et al. | Nov 2014 | A1 |
| 20140347463 | Lin | Nov 2014 | A1 |
| 20150037806 | Pollak et al. | Feb 2015 | A1 |
| 20150124082 | Kato et al. | May 2015 | A1 |
| 20150190063 | Zakharov et al. | Jul 2015 | A1 |
| 20150246170 | Miao et al. | Sep 2015 | A1 |
| 20150278575 | Allano et al. | Oct 2015 | A1 |
| 20150302237 | Ohya et al. | Oct 2015 | A1 |
| 20150316477 | Pollak et al. | Nov 2015 | A1 |
| 20160042507 | Turner | Feb 2016 | A1 |
| 20160187235 | Fine | Jun 2016 | A1 |
| 20160208306 | Pollak et al. | Jul 2016 | A1 |
| 20160246046 | Yorav-Raphael et al. | Aug 2016 | A1 |
| 20160250312 | Longley | Sep 2016 | A1 |
| 20160279633 | Bachelet et al. | Sep 2016 | A1 |
| 20170052110 | Malissek et al. | Feb 2017 | A1 |
| 20170160185 | Minemura et al. | Jun 2017 | A1 |
| 20170218425 | Chen et al. | Aug 2017 | A1 |
| 20170307496 | Zahniser et al. | Oct 2017 | A1 |
| 20170328924 | Jones et al. | Nov 2017 | A1 |
| 20180246313 | Eshel et al. | Aug 2018 | A1 |
| 20180296102 | Satish et al. | Oct 2018 | A1 |
| 20180297024 | Tran | Oct 2018 | A1 |
| 20190002950 | Pollak et al. | Jan 2019 | A1 |
| 20190087953 | Yorav-Raphael et al. | Mar 2019 | A1 |
| 20190130567 | Greenfield et al. | May 2019 | A1 |
| 20190145963 | Zait et al. | May 2019 | A1 |
| 20190302099 | Pollak et al. | Oct 2019 | A1 |
| 20190347467 | Ohsaka et al. | Nov 2019 | A1 |
| 20200034967 | Yorav-Raphael et al. | Jan 2020 | A1 |
| 20200049970 | Eshel et al. | Feb 2020 | A1 |
| 20200111209 | Greenfield et al. | Apr 2020 | A1 |
| 20200249458 | Eshel et al. | Aug 2020 | A1 |
| Number | Date | Country |
|---|---|---|
| 2655024 | Jan 2008 | CA |
| 1918501 | Feb 2007 | CN |
| 101501785 | Aug 2009 | CN |
| 101403650 | Jun 2010 | CN |
| 102282467 | Dec 2011 | CN |
| 0073551 | Mar 1983 | EP |
| 0479231 | Apr 1992 | EP |
| 1381229 | Jan 2003 | EP |
| 1698883 | Sep 2006 | EP |
| 2145684 | Jan 2010 | EP |
| 2211165 | Jul 2010 | EP |
| 3001174 | Mar 2016 | EP |
| 3 123 927 | Feb 2017 | EP |
| 3482189 | May 2019 | EP |
| 1 873 232 | Feb 2020 | EP |
| 2329014 | Mar 1999 | GB |
| 61198204 | Sep 1986 | JP |
| 9-54083 | Feb 1997 | JP |
| H11-73903 | Mar 1999 | JP |
| 2000-199845 | Jul 2000 | JP |
| 2002-516982 | Jun 2002 | JP |
| 2004-144526 | May 2004 | JP |
| 2004-257768 | Sep 2004 | JP |
| 2006-301270 | Nov 2006 | JP |
| 2007-040814 | Feb 2007 | JP |
| 2009-180539 | Aug 2009 | JP |
| 2013-515264 | May 2013 | JP |
| 2013-541767 | Nov 2013 | JP |
| 2014-41139 | Mar 2014 | JP |
| 2016-70658 | May 2016 | JP |
| 2017-209530 | Nov 2017 | JP |
| 1985005446 | Dec 1985 | WO |
| 1996001438 | Jan 1996 | WO |
| 1996012981 | May 1996 | WO |
| 1996013615 | May 1996 | WO |
| 2000006765 | Feb 2000 | WO |
| 2000052195 | Aug 2000 | WO |
| 2000055572 | Sep 2000 | WO |
| 2003081525 | Feb 2003 | WO |
| 2003056327 | Jul 2003 | WO |
| 2003073365 | Sep 2003 | WO |
| 2004111610 | Dec 2004 | WO |
| 2005121863 | Dec 2005 | WO |
| 2006121266 | Nov 2006 | WO |
| 2008063135 | May 2008 | WO |
| 2010036827 | Apr 2010 | WO |
| 2010056740 | May 2010 | WO |
| 2010116341 | Oct 2010 | WO |
| 2010126903 | Nov 2010 | WO |
| 2011056658 | May 2011 | WO |
| 2011076413 | Jun 2011 | WO |
| 2011123070 | Oct 2011 | WO |
| 2011143075 | Nov 2011 | WO |
| 2012000102 | Jan 2012 | WO |
| 2012029269 | Mar 2012 | WO |
| 2012030313 | Mar 2012 | WO |
| 2012090198 | Jul 2012 | WO |
| 2012154333 | Nov 2012 | WO |
| 2013041951 | Mar 2013 | WO |
| 2013098821 | Jul 2013 | WO |
| 2014159620 | Oct 2014 | WO |
| 2014188405 | Nov 2014 | WO |
| 2015001553 | Jan 2015 | WO |
| 2015029032 | Mar 2015 | WO |
| 2015089632 | Jun 2015 | WO |
| 2016030897 | Mar 2016 | WO |
| 2017195208 | Nov 2016 | WO |
| 2017046799 | Mar 2017 | WO |
| 2017168411 | Oct 2017 | WO |
| 2017195205 | Nov 2017 | WO |
| 2018009920 | Jan 2018 | WO |
| 2019035084 | Feb 2019 | WO |
| 2019097387 | May 2019 | WO |
| 2019102277 | May 2019 | WO |
| 2019198094 | Oct 2019 | WO |
| 2021079305 | Apr 2021 | WO |
| 2021079306 | Apr 2021 | WO |
| Entry |
|---|
| “Blood specimens:Microscopic Examination”, Centers for Disease Control and Prevention CDC, Diagnostic Procedures, 2009, http://www.dpd.cdc.gov/dpdx/HTML/Frames/DiagnosticProcedures/body_dp_bloodexamin.htm, 2 pages. |
| Agero, U., Mesquita, L.G., Neves, B.R.A., Gazzinelli, R.T. and Mesquita, O.N., 2004, “Defocusing microscopy”, Microscopy research and technique, 65(3), pp. 159-165. |
| Ahirwar, Neetu et al., “Advanced Image Analysis Based System for Automatic Detection and Classification of Malarial Parasite in Blood Images”, International Journal of Information Technology and Knowledge Management Jan.-Jun. 2012, vol. 5, No. 1, pp. 59-64, Serial Publications Pvt. Ltd, India. |
| Anand, A., et al. “Automatic Identification of Malaria-Infected RBC with Digital Holographic Microscopy Using Correlation Algorithms.” Photonics Journal, IEEE 4.5 (2012): 1456-1464. |
| Bacus, J.W., 1985, “Cytometric approaches to red blood cells”, Pure and Applied AL Chemistry, 57(4), pp. 593-598. |
| Biéler, Sylvain et al. “Improved detection of Trypanosoma brucei by lysis of red blood cells, concentration and LED fluorescence microscopy”; Acta Tropica; vol. 121, Issue 2, Feb. 2012, pp. 135-140. |
| Merchant et al., “The Essential Guide to Image Processing”, Chapter 27, Computer Assisted Microscopy, pp. 777-831; Academic Press, 2009. |
| Bravo-Zanoguera, M.E., Laris, C.A., Nguyen, L.K., Oliva, M. and Price, J.H., 2007, “Dynamic autofocus for continuous-scanning time-delay-and-integration image acquisition in automated microscopy”, Journal of biomedical optics, 12(3), pp. 034011-034011. |
| Brenner et al., “An Automated Microscope for Cytologic Research a Preliminary Evaluation”, The Journal of Histochecmistry and Cytochemistry, vol. 24, No. 1, pp. 100-111, 1976. |
| Briggs, C., et al., “Continuing developments with the automated platelet count”, Blackwell Publishing Ltd, International Journal of Laboratory Hematology, Jan. 18, 2007, pp. 77-91, vol. 29 (15 pages total). |
| Centers for Disease Control and Prevention, “DPDx—Laboratory Identification of Parasitic Diseases of Public Health Concern” <http://www.cdc.gov/dpdx/diagnosticProcedures/blood/microexam.html>, Nov. 29, 2013, 4 pages. |
| Cervantes, Serena , Jacques Prudhomme, David Carter, Krishna G Gopi, Qian Li, Young-Tae Chang, and Karine G Le Roch, “High-content live cell imaging with RNA probes: advancements in high-throughput antimalarial drug discovery”, BMC Cell Biology 2009, 10:45, https://bmcmolcellbiol.biomedcentral.com/track/pdf/10.1186/1471-2121-10-45, (Jun. 10, 2009), 9 pages. |
| Chiodini, P.L. et al., “Rapid diagnosis of malaria by fluorescence microscopy”, The Lancet, vol. 337, Issue 8741, pp. 624-625, Mar. 9, 1991. |
| Chong, Shau Poh, Shilpa Pant, and Nanguang Chen, “Line-scan Focal Modulation Microscopy for Rapid Imaging of Thick Biological Specimens”, SPIE/OSA/IEEE Asia Communications and Photonics, International Society for Optics and Photonics, 2011, 5 pages. |
| Emma Eriksson et al: “Automated focusing of nuclei for time lapse experiments on single cells using holographic optical tweezers”, Optics Express , vol. 17, No. 7, Mar. 24, 2009, pp. 5585-5594. |
| F. Boray Tek et al. “Parasite detection and identification for automated thin blood film malaria diagnosis”, Computer Vision and Image Understanding, vol. 114, Issue 1, Jan. 2010, pp. 21-32. |
| Fohlen-Walter, Anne PhD, et al., “Laboratory Identification of Cryoglobulinemia From Automated Blood Cell Counts, Fresh Blood Samples, and Blood Films”, American Society for Clinical Pathology, Am J Clin Pathol, 2002, pp. 606-614, vol. 117 (9 pages total). |
| Frean, John. “Microscopic Determination of Malaria Parasite Load: Role of Image Analysis”, Microscopy: Science, technology, Applications, and Education, (2010), pp. 862-866. |
| Gallo, V., Skorokhod, O.A., Schwarzer, E, and Arese, P. “Simultaneous determination of phagocytosis of Plasmodium falciparum-parasitized and non-parasitized red blood cells by flow cytometry”, Malaria Journal 2012, 11:428, 11 pages. |
| Garcia, et al. “Laboratory Diagnosis of Blood-borne Parasitic Diseases; Approved Guideline”, NCCLS Documents M115-a, Jun. 2000, 13 pages. |
| Gordon, Andrew et al., “Single-cell quantification of molecules”, Nature Methods 4, Jan. 21, 2007, pp. 175-181. |
| Gordon, Andrew et al. “Supplementary Note to Gordon et al: “Single-cell quantification of molecules”” Nature Methods, Jan. 21, 2007, pp. 1-35. |
| Groen, F.C.A., et al. “A comparison of different focus functions for use in autofocus algorithms”, Cytometry, Alan Liss, New York, US, vol. 6, No. 2, Mar. 1, 1985 (Mar. 1, 1985) pp. 81-91. |
| Guy, Rebecca, Paul Liu, Peter Pennefather and Ian Crandall, “The use of fluorescence enhancement to improve the microscopic diagnosis of falciparum malaria”, Malaria Journal 2007 6:89, https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-6-89, (Jul. 9, 2007), 8 pages. |
| Houri-Yafin, A., et al. “An enhanced computer vision platform for clinical diagnosis of malaria” Malaria Control and Elimination, 2016, p. 138, Vo. 5, Issue 1, omics International, India, 5 pages. |
| Jager et al. “Five-minute Giemsa stain for rapid detection of malaria parasites in blood smears”, Tropical Doctor, Vo. 41, pp. 33-35, Jan. 2011. |
| Jahanmehr,S A H et al., “Simple Technique for Fluorescence Staining of Blood Cells with Acridine Orange”, Journal of Clinical Pathology, Feb. 12, 1987, pp. 926-929 (4 pages total). |
| Joanny, Fanny, Held Jana, and Benjamin Mordmullera, “In Vitro Activity of Fluorescent Dyes against Asexual Blood Stages of Plasmodium falciparum”, 'DOI: 10.1128/AAC.00709-12, vol. 56, No. 11, Nov. 2012, pp. 5982-5985. |
| Kawamoto, F. and P.F.Billingsley, “Rapid diagnosis of malaria by fluorescence microscopy”, Parasitology Today, 8.2 (1992): pp. 69-71. |
| Kawamoto,F. “Rapid diagnosis of malaria by fluorescence microscopy with light microscope and interference filter”, The Lancet, vol. 337, pp. 200-202, Jan. 26, 1991. |
| Keiser, J. et al., “Acridine Orange for malaria diagnosis: its diagnostic performance, its promotion and implementation in Tanzania, and the implications for malaria control”, Annals of Tropical Medicine and parasitology, 96.7, (2002), pp. 643-654. |
| Knesel, “Roche Image Analysis Systems, Inc.”, Acta Cytologica, vol. 40, pp. 60-66, (1996). |
| Kumar, Amit et al. “Enhanced Identification of Malarial Infected Objects using Otsu Algorithm from Thin Smear Digital Images”, International Journal of Latest Research in Science and Technology, vol. 1,Issue 2, pp. 159-163, Jul.-Aug. 2012). |
| Le, Minh-Tam et al., “A novel semi-automatic image processing approach to determine Plasmodium falciparum parasitemia in Giemsa-stained thin blood smears”, BMC Cell Biology, published Mar. 28, 2008, 12 pages. |
| Leif, “Methods for Preparing Sorted Cells as Monolayer Specimens”, Springer Lab Manuals, Section 7—Chapter 5, pp. 592-619, (2000). |
| Life Technologies Corporation, “Counting blood cells with Countless Automated Cell Counter” found at http://www.lifetechnologies.com/content/dam/LifeTech/migration/files/cell-tissue-analysis/pdfs.par.83996.file.dat/w-082149-countless-application-blood-cells.pdf, 4 pages, (2009). |
| Matcher, S.J., et al. “Use of the water absorption spectrum to quantify tissue chromophore concentration changes in near-infrared spectroscopy”, Physics in Medicine & Biology, vol. 39, No. 1, 1994 pp. 177-196, IOP Publishing Ltd., UK. |
| Mendiratta, D.K. et al. Evaluation of different methods for diagnosis of P. falciparum malaria; Indian J Med Microbiol. Jan. 24, 2006, (1), pp. 49-51. |
| Moody , “Rapid Diagnostic Tests for Malaria Parasites”, Clinical Microbiology Reviews, vol. 15, No. 1, pp. 66-78, 12 (2002). |
| Moon S, Lee S, Kim H, Freitas-Junior LH, Kang M, Ayong L, et al. (2013) “An Image Analysis Algorithm for Malaria Parasite Stage Classification and Viability Quantification”, PLoS ONE 8(4): e61812. https://doi.org/10.1371/journal.pone.0061812, 12 pages. |
| Ortyn, William E., et al. “Extended Depth of Field Imaging for High Speed Cell Analysis”, Cytometry Part A 71.4, 2007), pp. 215-231. |
| Osibote, O. A., et al. “Automated focusing in bright-field microscopy for tuberculosis detection”, Journal of Microscopy 240.2 (2010), pp. 155-163. |
| Pasini, Erica M. et al. “A novel live-dead staining methodology to study malaria parasite viability”, Malaria Journal 2013, 12:190, 10 pages. |
| Piruska, Aigars et al., “The autofluorescence of plastic materials and chips measured under laser irradiation” Lab on a Chip, 2005, 5, pp. 1348-1354, published Nov. 1, 2005. |
| Poon et al., “Automated Image Detection and Segmentation in Blood Smears”, Cytometry, 1992, 13, pp. 766-774. |
| Price Jeffrey H. and David A. Gough, “Comparison of phase-contrast and fluorescence digital autofocus for scanning microscopy”, Cytometry 16.4 (1994), pp. 283-297. |
| Purwar, Yashasvi, et al. “Automated and Unsupervised Detection of Malarial Parasites in Microscopic Images”, Malaria Journal, 10.1, 364, (2011), 10 pages. |
| Rappaz, Benjamin et al., “Comparative study of human erythrocytes by digital holographic microscopy, confocal microscopy, and impedance volume analyzer”, Cytometry Part A, 2008, vol. 73, Issue 10, pp. 895-903, John Wiley & Sons, US. |
| Roma, P. M. S., et al. “Total three-dimensional imaging of phase objects using defocusing microscopy Application to red blood cells”, Applied Physics Letters 104,25 (2014): 251107, 7 pages. |
| Ross, Nichoals E., et al., “Automated image processing method for the diagnosis and classification of malaria on thin blood smears”, Medical and Biological Engineering and Computing, May 2006, vol. 44, Issue 5, pp. 427-436, Springer Publishing Company, US. |
| Sheikh , H., Bin Zhu, Micheli-Tzanakou, E. (1996) “Blood cell identification using neural networks”, Proceedings of the IEEE 22nd Annual Northeast Bioengineering Conference, pp. 119-120. |
| Shen, Feimo, Louis Hodgson and Klaus Hahn, “Digital autofocus method for automated microscopy”, Methods in Enzymology, vol. 414, 2006, pp. 620-632. |
| Shute G. T. and T. M. Sodeman, “Identification of malaria parasites by fluorescence microscopy and acridine orange staining”, Bulletin of the World Health Organ, 1973; 48(5), pp. 591-596. |
| Sun,Yu, S. Duthaler and B.J. Nelson, “Autofocusing algorithm selection in computer microscopy”, 2005 IEEE/RSJ International Conference on Intelligent Robots and Systems, 7 pages. |
| Tek, F. Boray, Andrew G. Dempster, and Izzet Kale, “Computer Vision for Microscopy Diagnosis of Malaria”, Malaria Journal 8.1, (2009): 153, 14 pages. |
| Thung, Ferdian, and Iping Supriana Suwardi, “Blood Parasite Identification Using Feature Based Recognition”, Electrical Engineering and Informatics (ICEEI), 2011 International Conference on IEEE, 2011, 7 pages. |
| Unitaid “Malaria Diagnostic Technology And Market Landscape, 2nd Edition” (2014), 148 pages. |
| Vink, J.P et al., “An automatic vision-based malaria diagnosis system”, Journal of Microscopy 250.3 (2013), pp. 166-178. |
| Wissing, Frank et al. “Illumination of the Malaria Parasite Plasmodium falciparum AltersIntracellular pH”, Implications for Live Cell Imaging; published Jul. 24, 2002,JBS Papers in Press, vol. 277 No. 40, pp. 27747-37755. |
| Wright, J H. “A Rapid Method for the Differential Staining of Blood Films and Malarial Parasites” Journal of medical research, vol. 7,1, (1902): pp. 138-144. |
| Wu, Caicai et al., “Feasibility study of the spectroscopic measurement of oxyhemoglobin using whole blood without pre-treatment”, The Analyst, Mar. 1998, pp. 477-481, vol. 123 (5 pages total). |
| Wu, Qiang, Fatima Mechant, and Kenneth Castleman, “Microscope Image Processing. Chapter 16, Autofocusing”, pp. 441-467, Academic Press, 2010. |
| Xu, Lili, Asok Chaudhuri, “Plasmodium yoelii: A differential fluorescent technique using Acridine Orange to identify infected erythrocytes and reticulocytes in Duffy knockout mouse”, Experimental Parasitology, vol. 110, Issue 1, May 2005, pp. 80-87, https://www.sciencedirect.com/science/article/pii/S001448940500038X, (May 31, 2005). |
| Yang, Ming, and Li Luo, “A Rapid Auto-Focus Method in Automatic Microscope”, Signal Processing, 2008. ICSP 2008. 9th International Conference on IEEE,2008, pp. 502-505. |
| Yao, LN et al. “Pathogen identification and clinical diagnosis for one case infected with Babesia”. Chinese journal of parasitology parasitic diseases, Aug. 2012, pp. 118-121. |
| Yazdanfar, S., Kenny, K.B., Tasimi, K., Corwin, A.D., Dixon, E.L. and Filkins, R.J., 2008, “Simple and robust image-based autofocusing for digital microscopy”, Optics express, 16(12), pp. 8670-8677. |
| “Zahniser et al., Automated Slide Preparation System for the Clinical Laboratory”, Cytometry, vol. 26, No. 10, pp. 60-64, (1996). |
| U.S. Appl. No. 61/427,809, filed Dec. 29, 2010. |
| U.S. Appl. No. 61/870,106, filed Aug. 26, 2013. |
| U.S. Appl. No. 62/042,388, filed Aug. 27, 2014. |
| An International Preliminary Report on Patentability dated Feb. 28, 2017, which issued during the prosecution of Applicant's PCT/IL2015/050864. |
| An International Search Report and a Written Opinion dated Jul. 27, 2012 for International Application No. PCT/IL2011/000973. |
| An International Search Report and a Written Opinion both dated Apr. 18, 2013, for International Application No. PCT/IL2012/050556. |
| An International Search Report and a Written Opinion both dated Feb. 12, 2015, for International Application No. PCT/IL2014/050770. |
| An International Search Report and a Written Opinion both dated Jan. 15, 2016, for International Application No. PCT/IL2015/050864. |
| An International Search Report and a Written Opinion both dated Jan. 23, 2017. which issued during the prosecution of Applicant's PCT/IL2016/051025. |
| An International Search Report and a Written Opinion both dated Oct. 30, 2014 , for International Application No. PCT/IL2014/050585. |
| An International Search Report and a Written Opinion both dated Sep. 24, 2014, for International Application No. PCT/IL2012/050423. |
| An International Search Report and Written Opinion in International Application No. PCT/IB2018/058861, dated Apr. 8, 2019. |
| An International Search Report and Written Opinion, dated Aug. 30, 2017 from the International Bureau in counterpart International application No. PCT/IL2017/050526. |
| An International Search Report and Written Opinion, dated Aug. 8, 2017 from the International Bureau in counterpart International application No. PCT/IL2017/050523. |
| An International Search Report and Written Opinion, dated May 18, 2017 from the International Bureau in counterpart International application No. PCT/IL2017/050363. |
| Notice of Allowance dated Mar. 2, 2020, which issued during the prosecution of U.S. Appl. No. 16/657,473. |
| An Office Action dated Apr. 2, 2015, which issued during the prosecution of U.S. Appl. No. 13/338,291. |
| An Office Action dated Apr. 4, 2019 which issued during the prosecution of U.S. Appl. No. 14/914,329. |
| An Office Action dated Aug. 4, 2017. which issued during the prosecution of U.S. Appl. No. 14/369,251. |
| An Office Action dated Feb. 22, 2018 which issued during the prosecution of U.S. Appl. No. 14/369,251. |
| An Office Action dated Jan. 10, 2018. which issued during the prosecution of U.S. Appl. No. 15/083,610. |
| An Office Action dated Jan. 28, 2019 which issued during the prosecution of U.S. Appl. No. 15/174,490. |
| An Office Action dated Jul. 11, 2017. which issued during the prosecution of U.S. Appl. No. 15/174,672. |
| An Office Action dated Jun. 13, 2017. which issued during the prosecution of U.S. Appl. No. 14/285,672. |
| An Office Action dated Jun. 15, 2018 from the United States Patent and Trademark Office in copending U.S. Appl. No. 14/369,251. |
| An Office Action dated Jun. 29, 2018 from the United States Patent and Trademark Office in copending U.S. Appl. No. 15/174,490. |
| An Office Action dated Jun. 4, 2019, which issued during the prosecution of U.S. Appl. No. 14/369,251. |
| An Office Action dated Jun. 5, 2019, which issued during the prosecution of U.S. Appl. No. 15/174,490. |
| An Office Action dated Mar. 2, 2017, which issued during the prosecution of U.S. Appl. No. 14/369,251. |
| An Office Action dated Nov. 16, 2018 which issued during the prosecution of U.S. Appl. No. 14/914,329. |
| An Office Action dated Oct. 29, 2014, which issued during the prosecution of U.S. Appl. No. 13/338,291. |
| An Office Action dated Oct. 5, 2016, which issued during the prosecution of U.S. Appl. No. 14/285,672. |
| An Office Action dated Sep. 25, 2015, which issued during the prosecution of U.S. Appl. No. 13/338,291. |
| An Office Action dated Dec. 21, 2018, issued by the United States Patent and Trademark Office in the prosecution of U.S. Appl. No. 14/369,251. |
| Notice of Allowance dated Dec. 30, 2015 , which issued during the prosecution of U.S. Appl. No. 14/440,864. |
| Notice of Allowance dated Jan. 11, 2016, which issued during the prosecution of U.S. Appl. No. 14/440,864. |
| Notice of Allowance dated Jan. 19, 2016, which issued during the prosecution of U.S. Appl. No. 13/338,291. |
| Notice of Allowance dated Mar. 10, 2016, which issued during the prosecution of U.S. Appl. No. 13/338,291. |
| Notice of Allowance dated Jul. 10, 2019 , which issued during the prosecution of US Patent Application No. U.S. Appl. No. 15/506,997. |
| Notice of Allowance dated Mar. 20, 2019, which issued during the prosecution of U.S. Appl. No. 15/506,997. |
| A European Examination Report dated Dec. 9, 2019. which issued during the prosecution of Applicant's European App No. 16782094.3. |
| A European Examination Report dated Feb. 1, 2019. which issued during the prosecution of Applicant's European App No. 17717000.8. |
| A European Examination Report dated Sep. 3, 2019. which issued during the prosecution of Applicant's European App No. 17717000.8. |
| A European Examination Report dated Apr. 8, 2020. which issued during the prosecution of Applicant's European App No. 17717000.8. |
| A European Examination Report dated Apr. 6, 2020. which issued during the prosecution of Applicant's European App No. 17726036.1. |
| A European Examination Report dated Feb. 11, 2020. which issued during the prosecution of Applicant's European App No. 17728277.9. |
| Saraswat, et al. “Automated microscopic image analysis for leukocytes identification: A survey”, ABV-Indian Institute of Information Technology and Management, Gwalior, India, Micron, 2014, vol. 65, pp. 20-33. |
| Hiremath, P.S,. et al., “Automated Identification and Classification of White Blood Cells (Leukocytes) in Digital Microscopic Images”, IJCA Special Issue on “Recent Trends in Image Processing and Pattern Recognition” RTIPPR, 2010, pp. 59-63. |
| Witt, et al. “Establishing traceability of photometric absorbance values for accurate measurements of the haemoglobin concentration in blood.”, Metrologia 50 (2013) 539-548. |
| Putzu, et al., “Leucocyte classification for leukaemia detection using image processing techniques.”, Artificial Intelligence in Medicine, vol. 63, No. 3, Nov. 1, 2014, pp. 1-31. |
| Varga, et al., “An automated scoring procedure for the micronucleus test by image analysis”, Mutagenesis vol. 19 No. 5 pp. 391-397, 2004. |
| Ran, Qiong et al. “Spatial-spectral blood cell classification with microscopic hyperspectral imagery”, Proc. SPIE 10461, AOPC 2017: Optical Spectroscopy and Imaging, 1046102 (Oct. 24, 2017) (12 pages total). |
| Omucheni et al. “Application of principal component analysis to multispectral-multimodal optical image analysis for malaria diagnostics”, Malaria Journal 2014, 13:485 http://www.malariajournal.com/content/13/1/485 (11 pages total). |
| Ben-Suliman-2018—“Computerized Counting-Based System for Acute Lymphoblastic Leukemia Detection in Microscopic Blood Images” 27th International Conference on Artificial Neural Networks, Rhodes, Greece, Oct. 4-7, 2018, Proceedings, Part II, pp. 167-178. |
| An Office Action dated Dec. 8, 2020 for Japanese Patent Application No. 2018/512961. |
| An Examination Report dated Dec. 7, 2020 for Australian Patent Application No. 2016322966. |
| An Office Action dated Jan. 11, 2021 for U.S. Appl. No. 16/098,893. |
| An Examination Report dated Apr. 29, 2021 for Australian Patent Application No. 2016322966. |
| International Search Report issued for PCT Application No. PCT/IB2020/059924 dated Mar. 22, 2021. |
| International Search Report issued for PCT Application No. PCT/IB2020/059925 dated Mar. 26, 2021. |
| Invitation to pay fees and Partial Search Report issued for PCT Application No. PCT/IB2020/059924 dated Jan. 28, 2021. |
| Invitation to pay fees and Partial Search Report issued for PCT Application No. PCT/IB2020/059925 dated Feb. 4, 2021. |
| A Japanese Office Action dated Mar. 30, 2021, which issued during the prosecution of Application No. 2018/558180. |
| An Office Action dated Mar. 9, 2021 for U.S. Appl. No. 16/088,321. |
| An Office Action dated Jan. 29, 2021 for U.S. Appl. No. 16/099,270. |
| An Office Action dated Aug. 24, 2020 for U.S. Appl. No. 16/098,893. |
| A Chinese Office Action and dated May 22, 2020. which issued during the prosecution of Chinese Application No. 201680053431.1. |
| A Restriction Requirement issued by the USPTO dated Aug. 24, 2020 for U.S. Appl. No. 16/088,321. |
| An Extended European Search Report issued for European Patent Application No. 21164814.2 dated Jun. 9, 2021. |
| Third Office Action dated Jul. 12, 2021 which issued during the prosecution of Chinese Patent Application No. 201680053431.1. |
| Non-Final Office Action dated Jul. 27, 2021, which issued during the prosecution of U.S. Appl. No. 16/851,686. |
| Non-Final Office Action dated Aug. 19, 2021, which issued during the prosecution of U.S. Appl. No. 16/098,893. |
| Non-Final Office Action dated Sep. 1, 2021 which issued during the prosecution of U.S. Appl. No. 16/088,321. |
| First Office Action dated Aug. 4, 2021 which issued during the prosecution of Chinese Patent Application No. 201780027908.3. |
| An Examination Report dated Mar. 4, 2021 which issued during the prosecution of Indian Patent Application No. 201817036130. |
| An Examination Report dated May 5, 2021 which issued during the prosecution of Indian Patent Application No. 201817012117. |
| Notice of Allowance dated Aug. 3, 2021, which issued during the prosecution of U.S. Appl. No. 16/851,410. |
| An International Search Report and Written Opinion for Application No. PCT/IB2020/061731 dated Feb. 10, 2021. |
| Invitation to pay fees and Partial Search Report issued for PCT Application No. PCT/IB2020/061732 dated Mar. 10, 2021. |
| Invitation to pay fees and Partial Search Report issued for PCT Application No. PCT/IB2020/061736 dated Mar. 12, 2021. |
| Invitation to pay fees and Partial Search Report issued for PCT Application No. PCT/IB2020/061728 dated Mar. 15, 2021. |
| International Search Report issued for PCT Application No. PCT/IB2020/061724 dated Mar. 10, 2021. |
| An International Search Report and Written Opinion for PCT Application No. PCT/IB2020/061732 dated May 7, 2021. |
| International Search Report and Written Opinion for PCT Application No. PCT/IB2020/061728 dated May 7, 2021. |
| International Search Report and Written Opinion for PCT Application No. PCT/IB2020/061736 dated May 3, 2021. |
| Non-Final Office Action dated Jun. 17, 2021 which issued during the prosecution of U.S. Appl. No. 16/851,410. |
| A Final Office Action dated Jun. 17, 2021 which issued during the prosecution of U.S. Appl. No. 16/088,321. |
| Notice of Allowance dated May 19, 2021 which issued during the prosecution of U.S. Appl. No. 16/099,270. |
| A Restriction Requirement issued by the USPTO dated Oct. 19, 2020 for U.S. Appl. No. 16/099,270. |
| Non-Final Office Action dated Oct. 6, 2021, which issued during the prosecution of U.S. Appl. No. 17/063,320. |
| A European Examination Report issued for European Patent Application No. 17728277.9 dated Dec. 23, 2021. |
| A Non-Final Office Action dated May 26, 2022 which issued during the prosecution of U.S. Appl. No. 17/083,775. |
| An Office Action dated Feb. 16, 2022 which issued during the prosecution of U.S. Appl. No. 16/088,321. |
| An Office Action dated May 6, 2022 which issued during the prosecution of U.S. Appl. No. 16/763,810. |
| Examination Report issued by the Indian Patent Office dated Jun. 28, 2022 in Indian Patent Application No. 202047019700. |
| Notice of Allowance dated Nov. 10, 2021, which issued during the prosecution of U.S. Appl. No. 16/851,686. |
| Notice of Allowance dated Jan. 21, 2022, which issued during the prosecution of U.S. Appl. No. 16/098,893. |
| Notice of Allowance dated Nov. 5, 2021, which issued during the prosecution of U.S. Appl. No. 16/851,410. |
| Supplemental Notice of Allowance dated Nov. 12, 2021, which issued during the prosecution of U.S. Appl. No. 16/851,686. |
| Office Action dated Nov. 25, 2022 issued by the United States Patent Office in U.S. Appl. No. 17/082,483. |
| Number | Date | Country | |
|---|---|---|---|
| 20210072526 A1 | Mar 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62585621 | Nov 2017 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16763810 | US | |
| Child | 17083659 | US |
