DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/05/2025 has been entered.
Response to Arguments
Rejections under 35 U.S.C. § 112(b)
As described in the advisory action, amendments mean that claims 5 and 8 no longer have antecedent basis issues.
Applicant argues that details added to claim 5 further define the speed measurement unit, however, this argument is not persuasive. The additional limitations are purely functional in nature, not adding sufficient structure to perform the functions attributed to the speed measurement unit, so interpretation under 35 USC § 112(f) remains, and the specification does not adequately define the corresponding structure that performs the optical method or electromagnetic method as part of the speed measurement unit.
Rejections under 35 U.S.C. §§ 102 and 103
Applicant’s arguments have been fully considered, but are moot, as neither Howell nor Ortyn is relied on to teach the newly-claimed limitation of executing correction to offset rotation of the bioparticle.
Specification
The disclosure is objected to because of the following informalities: as amended, paragraph 15 of the specification appears to be saying that a speed of 20 m/s is 24 times larger than a speed of 1 to 5 m/s, which, as a matter of fact, is not true.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
the irradiation unit in claim 1, interpreted as corresponding to the light irradiation unit described in paragraph 23 of the specification, which includes a light source unit and a light guide optical unit, where the light source unit includes one or more light sources and the light guide optical system includes an optical component;
the processing unit and information processing unit in claim 1, interpreted as corresponding to the information processing unit 103 as described in paragraph 32 (a computer, a server computer, or a computing cloud);
the detection unit in claims 1, 18, and 19, interpreted as corresponding to the detection unit described in paragraph 16 (an event-based vision sensor); and
the speed measurement unit in claim 5, which is not disclosed with adequate structure in the written description to perform the function. In the interest of compact prosecution, for the purposes of examination, the speed measurement unit is interpreted as referring to anything capable of performing the claimed function. See rejection under 35 U.S.C. 112(b) below.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 15, and 18-19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 5, claim limitation “a speed measurement unit that measures the relative speed of the bioparticle with respect to the detection unit” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function.
The disclosure only describes the speed measurement unit in functional terms and in terms of its inclusion in detection unit 102 (paragraph 36), but is devoid of any structure that performs the function in the claim. The optical method or electromagnetic method alluded to in the claim as amended is not a structure.
Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Claim 15 recites the limitation "the flow channel" in line 3. As mentioned in the advisory action, there is insufficient antecedent basis for this limitation in the claim. In particular, there is a “predetermined flow channel” introduced in amended claim 1, on which claim 15 depends, which also is recited in claim 15 as amended, but it is unclear whether “the flow channel” is the same as “the predetermined flow channel”. The flow channel is interpreted as not required to be separate from the predetermined flow channel from claim 1.
Claim 18 recites the limitation "the bioparticle" in line 5. There is insufficient antecedent basis for this limitation in the claim. The bioparticle is interpreted as being introduced in that line. While, strictly speaking, “the bioparticle” is not required to also be the subject introduced earlier in claim 18, the prior art rejection below is consistent with such a requirement.
Claim 19 recites the limitation "the bioparticle" in line 5. There is insufficient antecedent basis for this limitation in the claim. The bioparticle is interpreted as being introduced in that line. While, strictly speaking, “the bioparticle” is not required to also be the subject introduced earlier in claim 19, the prior art rejection below is consistent with such a requirement.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 5 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AlA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The claimed limitation lacks an adequate written description as required by 35 U.S.C.112(a) or pre-AIA 35 U.S.C. 112, first paragraph, because an indefinite, unbounded functional limitation would cover all ways of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Howell (Non-Patent Literature “High-speed particle detection and tracking in microfluidic devices using event-based sensing”) in view of Höbel (Foreign Patent Document DE 102016212164 B3).
Regarding claim 19, Howell teaches an information processing method including generating subject information regarding a subject (section Imaging setup, third paragraph, running the MATLAB imaging pipeline) on a basis of an event detected in each of a plurality of pixels that detects a luminance change of light from the subject as the event in a detection unit including the pixels (FIG. 1).
While Howell does not explicitly describe the micrometer-scale polystyrene beads under test as bioparticles, Howell does explicitly state that their results “confirm that event-based cameras can be used to track individual particle behaviours in the size range of commonly used biological cells” (section Particle tracking and velocity mapping, fourth paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the event-based imaging flow cytometry method of Howell with bioparticles, such as cells, in the manner that Howell contemplated.
While Howell does contemplate using a similar method to measure the apparent shape of particles (section “Visualisation and detection of microparticles”, final sentence), which would depend on the rotational state of a non-spherical particle, Howell does not explicitly teach executing correction to offset rotation of the bioparticle.
In the same field of endeavor of measuring particles using flow cytometry, Höbel does teach executing correction to offset rotation of the bioparticle (Description, sentence 2, which describes using the rotation angles of images to make the images coincide, removing the offset due to movement and rotation). By offsetting one particle image onto another, Höbel is able to track that particle and obtain a better signal to noise ratio.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the information processing method of Howell with the rotational offset correction of Höbel to better track the particles under test and improve signal to noise ratio.
Claim(s) 1-18 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Howell (Non-Patent Literature “High-speed particle detection and tracking in microfluidic devices using event-based sensing”) in view of Ortyn (US Patent 6608682) and Höbel (Foreign Patent Document DE 102016212164 B3).
Regarding claim 1, Howell teaches a biological sample analysis system including:
an irradiation unit that irradiates a particle in a sample with light (FIG. 2 A, Illumination.);
a detection unit (FIG. 2 A, Event-based camera) including a plurality of pixels that each detects, as an event, a luminance change of light emitted from the bioparticle by irradiation with the light (FIG. 1 demonstrates the function of an event-based camera); and
a processing unit that generates bioparticle information regarding the bioparticle on a basis of the event detected by each of the pixels (section Imaging setup, third paragraph, running the MATLAB imaging pipeline);
and a predetermined flow channel (FIG. 2 C) wherein the predetermined flow channel is straight with a width of 1 mm or less (section Results, first paragraph, specifies a channel with widths of 360 µm and 60 µm along its two cross-sectional axes. Also see FIG. 3, which has a 200 µm scale bar that is substantially less than a fifth as long as the channel is wide in the region of interest (even at the right-hand edge of the region of interest, the channel is only about half a mm wide)).
While Howell does not explicitly describe the samples used as biological samples, nor the micrometer-scale polystyrene beads therein as bioparticles, Howell does explicitly state that their results “confirm that event-based cameras can be used to track individual particle behaviours in the size range of commonly used biological cells” (section Particle tracking and velocity mapping, fourth paragraph). Further, a claim for an apparatus generally does not distinguish patentably over the prior art due to recitations of the material or article worked upon by the apparatus. See MPEP 2115.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the event-based imaging flow cytometer of Howell with bioparticles, such as cells, in the manner that Howell contemplated.
While the flow channel disclosed by Howell is spiraled rather than straight, Howell does contemplate the use of sensor systems like the one Howell used with other channel designs (COL. 3, sentences 1-2).
In the same field of endeavor of imaging and analyzing small moving objects, such as cells, Ortyn does teach a straight flow cell (FIG. 25, flow cell 306). By not including the spiral like that of Howell, Ortyn avoids the inertial separation of the particles across the fluid stream, allowing the whole width of the flow channel to be used for all sizes of particles. Note that it is generally considered obvious, when a particular function is not desired, to remove both an element (such as the curvature of a flow channel) and its undesired function (such as inertial particle separation). See MPEP 2144.04 II A.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the event-based imaging flow cytometer of Howell without the spiral of the flow cell, following the example of Ortyn, to avoid inertial It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the event-based imaging flow cytometer of Howell without the spiral of the flow cell, following the example of Ortyn, to avoid inertial particle separation if inertial particle separation is not a desired function, for example, to more efficiently use the entire width of the flow cell for imaging of particles of all sizes. Note that Ortyn also describes the use of cells, a type of bioparticle, in the sample (abstract).
While Howell does contemplate using a similar means to measure the apparent shape of particles (section “Visualisation and detection of microparticles”, final sentence), which would depend on the rotational state of a non-spherical particle, Howell does not explicitly teach executing correction to offset rotation of the bioparticle.
In the same field of endeavor of measuring particles using flow cytometry, Höbel does teach an information processing unit that executes correction to offset rotation of the bioparticle (Description, sentence 2, which describes using the rotation angles of images to make the images coincide, removing the offset due to movement and rotation). By offsetting one particle image onto another, Höbel is able to track that particle and obtain a better signal to noise ratio.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the event-based flow cytometry method of Howell, as modified by Ortyn, with the rotational offset correction of Höbel to better track the particles under test and improve signal to noise ratio.
Regarding claim 2, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 1 (as described above).
Howell further teaches that the bioparticle moves in a first direction with respect to the detection unit (FIG. 3, generally parallel to the x axis),
the plurality of pixels includes two or more first pixels arranged adjacent to or separated from each other in the first direction (FIG. 3, multiple pixels exist along the x direction),
the detection unit outputs event data including information of time at which an event has been detected in each of the pixels (section titled Event-data collection and pre-processing, first paragraph), and
the processing unit aligns the pieces of information of time of a series of event data for each of the first pixels output from the detection unit by detecting the luminance change of light emitted from the bioparticle by each of the first pixels (FIG. 7 shows data for several specific particles aligned across time as they move through the pixels), and generates the bioparticle information by processing the series of event data from each of the first pixels with the pieces of information of time aligned (FIG. 7 shows some of that information).
Regarding claim 3, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 2 (as described above).
Howell further teaches that the event data further includes at least one of position information of a pixel that has detected the event (FIG. 3. Note that the events are plotted based on their position) and polarity information of the event detected in the pixel (FIG. 1).
Regarding claim 4, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 2 (as described above).
Howell further teaches that the processing unit aligns the pieces of information of time of the series of event data for each of the first pixels on a basis of a relative speed of the bioparticle with respect to the detection unit (FIG. 8 B aligns information based on speed to produce the probability density function) and an interval between the first pixels in the first direction (section titled Imaging setup, first paragraph. Also see scale bars in FIG. 3.).
Regarding claim 5, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the (as described above).
Howell further teaches a speed measurement unit that measures the relative speed of the bioparticle with respect to the detection unit using at least one of an optical method and an electromagnetic method (used to determine average fluid velocity in FIG. 5 and individual particle velocity in FIG. 7. The caption of FIG. 5 notes that the it is a distribution of particles detected in a video recorded with an event-based camera. Recording a video is an optical technique. Note that optical techniques are inherently electromagnetic, as optical signals (i.e., light) are a form of electromagnetic radiation.).
Regarding claim 6, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 2 (as described above).
Howell further teaches that the processing unit aligns the pieces of information of time of the series of event data for each of the first pixels on a basis of a difference in time at which each of the first pixels has detected the luminance change of light emitted from the bioparticle (FIG. 4).
Regarding claim 7, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 6 (as described above).
Howell further teaches that the processing unit aligns the pieces of information of time of the series of event data for each of the first pixels on a basis of a difference in time at which each of the first pixels has detected the luminance change of light emitted from the bioparticle in two or more pixel columns parallel to the first direction (note in FIG. 4 C that each of the three particles is shown as multiple pixels tall).
Regarding claim 8, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 2 (as described above).
Howell further teaches that the biological sample containing the bioparticle is delivered to the predetermined flow channel (FIG. 2 C), and
the processing unit aligns the pieces of information of time of the series of event data for each of the first pixels on a basis of a control value of a liquid delivery system that delivers the biological sample to the predetermined flow channel (section Microfluidic setup, first paragraph, describes how experiments were performed for varying flow rates with their corresponding velocities and Reynolds numbers. FIG. 6 shows data aligned based on those values.).
Regarding claim 9, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 2 (as described above).
Howell further teaches that the processing unit generates the bioparticle information on a basis of a result of adding or dividing the series of event data for each of the first pixels in which the pieces of information of time are aligned on a time axis (FIG. 4 shows a process of dividing the relatively continuous time of the asynchronous event data into discrete frames.).
Regarding claim 10, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the (as described above).
Howell further teaches that the processing unit reconstructs the luminance change of light emitted from the bioparticle on a basis of the result of adding or dividing the series of event data for each of the first pixels in which the pieces of information of time are aligned on a time axis, and generates the bioparticle information on a basis of the reconstructed luminance change (section Event-data collection and pre-processing, second paragraph, describes doing analysis after the process of dividing the relatively continuous time of the asynchronous event data into discrete frames.).
Regarding claim 11, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 10 (as described above).
Howell further teaches that the processing unit reconstructs the luminance change of light emitted from the bioparticle for each of the first pixels for each of two or more pixel columns parallel to the first direction, and generates the bioparticle information on a basis of the luminance change for each of the first pixels in each of the two or more reconstructed pixel columns (FIG. 3. Note that the data comprises multiple rows and multiple columns of pixels, and that each of the particles is multiple pixels across.).
Regarding claim 12, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 1 (as described above).
Howell further teaches that the processing unit generates the bioparticle information using machine learning (section Particle tracking and velocity mapping, determining the particle tracks includes a training step, which is used to track which particle is which from one frame to the next and thereby determine the particle information) from a series of event data for each of the pixels output from the detection unit by detecting the luminance change of light emitted from the bioparticle by each of the pixels (FIG. 1).
Regarding claim 13, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 1 (as described above).
Howell further teaches that the bioparticle information includes at least one of image data of the bioparticle reconstructed on a basis of the detected event (FIG. 3 and elsewhere), a feature amount of the bioparticle extracted from at least one of the detected event and the image data, and attribute information of the bioparticle generated from at least one of the event, the image data, and the feature amount (FIG. 6 B shows distance to inner wall, an attribute of a particle at a given time, based on reconstructed image data).
Regarding claim 14, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 1 (as described above).
Howell further teaches that the bioparticle is a cell or a non-cellular bioparticle (the setup is usable with non-cellular bioparticles as evidenced by its use with non-cellular particles. Note that intended use of a claimed device only limits the claim insofar as it restricts the structure of the device itself. Additionally, the particles used are explicitly characterized as being in the size range of cells commonly studied by such devices.).
Also see claim 1 above regarding the biological nature of the bioparticle, where the kind of bioparticle Howell references is a cell.
Regarding claim 15, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 1 (as described above).
Howell further teaches that the irradiation unit irradiates a predetermined spot on the predetermined flow channel with the light (FIG. 2 C, region of interest labeled ROI), and the bioparticle moves in the flow channel so as to pass through the predetermined spot (the flow has to pass through the ROI to get from the input port of the flow channel located at the center of the spiral to the output ports. Also note that measurements are made there.).
Regarding claim 16, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 1 (as described above).
Howell further teaches that the bioparticle is labeled with one or more fluorescent dyes (section Bead preparation), the irradiation unit irradiates the bioparticle with the light including excitation light in one or more wavelength ranges (abstract, a microscope arc lamp of a standard fluorescence microscope is used for fluorescence imaging. Fluorescence imaging requires irradiating the image target with excitation light in one or more wavelength ranges. ), and that the detection unit detects a luminance change as an event (FIG. 1).
Howell does not explicitly teach a spectroscopic optical system that disperses light emitted from the bioparticle.
In the same field of endeavor of fluorescent imaging flow cytometry, Ortyn teaches a spectroscopic optical system that disperses light emitted from the bioparticle (FIG. 25, dichroic filters 301-305) and a detection unit detecting each of the beams of light dispersed by the spectroscopic optical system (FIG. 25, detectors 321-325 collectively). By using dispersive optics, Ortyn distinguishes between multiple fluorescence colors, which can come from multiple dyes.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the event-based imaging flow cytometer of Howell with the dispersive optics of Ortyn to gain the benefit of using multiple fluorescent dyes to mark particles under study to distinguish them.
Regarding claim 17, Howell, as modified by Ortyn and Höbel, teaches or renders obvious the biological sample analysis system according to claim 16 (as described above).
Howell does not explicitly teach the use of multiple detectors.
In the same field of endeavor of fluorescent imaging flow cytometry, Ortyn teaches that the detection unit includes a plurality of detectors disposed for the beams of light dispersed by the spectroscopic optical system on a one-to-one basis (FIG. 25, detectors 321-325). Using multiple detectors allows Ortyn to detect images independently for each of the dispersed beams.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the event-based imaging flow cytometer of Howell with the multiple detectors of Ortyn to gain the benefit of capturing multiple images simultaneously.
Regarding claim 18, Howell teaches an information processing device including a processing unit (section Imaging setup, third paragraph, the computer running MATLAB) that generates subject information regarding a subject (by running MATLAB) on a basis of an event detected in each of a plurality of pixels that detects a luminance change of light from the subject as the event in a detection unit including the pixels (FIG. 1); and
a flow channel (FIG. 2 C) wherein the flow channel is with a width of 1 mm or less (section Results, first paragraph, specifies a channel with widths of 360 µm and 60 µm along its two cross-sectional axes. Also see FIG. 3, which has a 200 µm scale bar that is substantially less than a fifth as long as the channel is wide in the region of interest (even at the right-hand edge of the region of interest, the channel is only about half a mm wide)).
While the flow channel disclosed by Howell is spiraled rather than straight, Howell does contemplate the use of sensor systems like the one Howell used with other channel designs (COL. 3, sentences 1-2).
In the same field of endeavor of imaging and analyzing small moving objects, such as cells, Ortyn does teach a straight flow cell (FIG. 25, flow cell 306). By not including the spiral like that of Howell, Ortyn avoids the inertial separation of the particles across the fluid stream, allowing the whole width of the flow channel to be used for all sizes of particles. Note that it is generally considered obvious, when a particular function is not desired, to remove both an element (such as the curvature of a flow channel) and its undesired function (such as inertial particle separation). See MPEP 2144.04 II A.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the event-based imaging flow cytometer of Howell without the spiral of the flow cell, following the example of Ortyn, to avoid inertial particle separation if inertial particle separation is not a desired function, for example, to more efficiently use the entire width of the flow cell for imaging of particles of all sizes.
While Howell does contemplate using a similar means to measure the apparent shape of particles (section “Visualisation and detection of microparticles”, final sentence), which would depend on the rotational state of a non-spherical particle, Howell does not explicitly teach executing correction to offset rotation of the bioparticle.
In the same field of endeavor of measuring particles using flow cytometry, Höbel does teach an information processing unit that executes correction to offset rotation of the bioparticle (Description, sentence 2, which describes using the rotation angles of images to make the images coincide, removing the offset due to movement and rotation). By offsetting one particle image onto another, Höbel is able to track that particle and obtain a better signal to noise ratio.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the event-based flow cytometry information processing device of Howell, as modified by Ortyn, with the rotational offset correction of Höbel to better track the particles under test and improve signal to noise ratio.
Regarding claim 20, Howell teaches a biological sample analysis method including:
irradiating a bioparticle in a biological sample with light (FIG. 2 A, Illumination. Note that intending to use an irradiation unit to illuminate a bioparticle in a biological sample does not impose a structural requirement on the irradiation unit that would distinguish that irradiation unit from one used to illuminate a nonbiological particle of similar size in a non-biological fluid);
wherein the bioparticle flows through a flow channel wherein the flow channel is with a width of 1 mm or less (section Results, first paragraph, specifies a channel with widths of 360 µm and 60 µm along its two cross-sectional axes. Also see FIG. 3, which has a 200 µm scale bar that is substantially less than a fifth as long as the channel is wide in the region of interest (even at the right-hand edge of the region of interest, the channel is only about half a mm wide));
detecting, as an event, a luminance change of light emitted from the bioparticle by irradiation with the light in each of a plurality of pixels (FIG. 1 demonstrates the function of an event-based camera); and
generating bioparticle information regarding the bioparticle on a basis of the event detected by each of the pixels (section Imaging setup, third paragraph, running the MATLAB imaging pipeline).
While Howell does not explicitly describe the samples used as biological samples, nor the micrometer-scale polystyrene beads therein as bioparticles, Howell does explicitly state that their results “confirm that event-based cameras can be used to track individual particle behaviours in the size range of commonly used biological cells” (section Particle tracking and velocity mapping, fourth paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the event-based imaging flow cytometer of Howell with bioparticles, such as cells, in the manner that Howell contemplated.
While the flow channel disclosed by Howell is spiraled rather than straight, Howell does contemplate the use of sensor systems like the one Howell used with other channel designs (COL. 3, sentences 1-2).
In the same field of endeavor of imaging and analyzing small moving objects, such as cells, Ortyn does teach a straight flow cell (FIG. 25, flow cell 306). By not including the spiral like that of Howell, Ortyn avoids the inertial separation of the particles across the fluid stream, allowing the whole width of the flow channel to be used for all sizes of particles. Note that it is generally considered obvious, when a particular function is not desired, to remove both an element (such as the curvature of a flow channel) and its undesired function (such as inertial particle separation). See MPEP 2144.04 II A.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the event-based imaging flow cytometer of Howell without the spiral of the flow cell, following the example of Ortyn, to avoid inertial particle separation if inertial particle separation is not a desired function, for example, to more efficiently use the entire width of the flow cell for imaging of particles of all sizes. Note that Ortyn also describes the use of cells, a type of bioparticle, in the sample (abstract).
While Howell does contemplate using a similar method to measure the apparent shape of particles (section “Visualisation and detection of microparticles”, final sentence), which would depend on the rotational state of a non-spherical particle, Howell does not explicitly teach executing correction to offset rotation of the bioparticle.
In the same field of endeavor of measuring particles using flow cytometry, Höbel does teach executing correction to offset rotation of the bioparticle (Description, sentence 2, which describes using the rotation angles of images to make the images coincide, removing the offset due to movement and rotation). By offsetting one particle image onto another, Höbel is able to track that particle and obtain a better signal to noise ratio.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the biological sample analysis method of Howell, as modified by Ortyn, with the rotational offset correction of Höbel to better track the particles under test and improve signal to noise ratio.
Conclusion
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/PAUL SCHNASE/Examiner, Art Unit 2877
/TARIFUR R CHOWDHURY/Supervisory Patent Examiner, Art Unit 2877
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