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 .
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: “100” [Fig. 1]; “400” [Fig. 4].
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
The amendment filed 15 November 2024 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure [“The present application is the National Phase entry of International Patent Application No. PCT/EP2023/063353, filed May 17, 2023, which claims priority to European Patent Application No. 22173808.1, filed May 17, 2022, the entire contents of both are hereby incorporated by reference into this application” (Applicant’s Specification p. 1:4-7)]. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention. The added material which is not supported by the original disclosure is as follows: incorporation(s) by reference to foreign priority document(s) when added by amendment at the time of entry to the national stage is/are considered new matter [An incorporation by reference statement added after an application’s filing date is not effective because no new matter can be added to an application after its filing date (see 35 U.S.C. 132(a)) (MPEP § 608.01(p)(I)(B)); An international application designating the U.S. has two stages (international and national) with the filing date being the same in both stages. Often the date of entry into the national stage is confused with the filing date. It should be borne in mind that the filing date of the international stage application is also the filing date for the national stage application (MPEP § 1893.03(b))]]. Applicant is required to cancel the new matter in the reply to this Office Action.
Appropriate correction is required.
Claim Objections
Claim(s) 7-9, 13-14, and 19 is/are objected to because of the following informalities:
Claim 7 should read “wherein the vessel is [[as]] a microcirculatory blood vessel” [lines 2-3].
Claim 8 recites the acronym “CMOS camera” [line 2], which should be referred to by its fully spelled out name prior to using an acronym.
Claim 9 should read “according to claim 1” [lines 1-2].
Claim 13 should read “[[0,25]] 0.25 mW/cm2” [line 2].
Claim 14 should read “wherein the method [[is]] further comprises the step of” [line 3].
Claim 19 should read “measuring” [line 3].
Appropriate correction is required.
Claim Interpretation
Examiner Notes: currently, NO limitation invokes interpretation under § 112(f).
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.
Claim(s) 3-4, 12-14, 21, and those dependent therefrom is/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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance:
claim 3 recites the broad recitation “wherein the high-speed camera is configured for capturing at least 5000 fps… of the target”, and the claim also recites “wherein the high-speed camera is configured for capturing… at least 6000 fps of the target” which is the narrower statement of the range/limitation;
claim 4 recites the broad recitation “wherein said length of the vessel is less than 1 mm”, and the claim also recites “wherein said length of the vessel is… less than 0.2 mm” which is the narrower statement of the range/limitation, and the claim also recites “wherein said length of the vessel is… less than 0.16 mm” which is a further narrower statement of the range/limitation;
claim 12 recites the broad recitation “wherein said length of the vessel is less than 1 mm”, and the claim also recites “wherein said length of the vessel is… less than 0.2 mm” which is the narrower statement of the range/limitation, and the claim also recites “wherein said length of the vessel is… less than 0.16 mm” which is a further narrower statement of the range/limitation;
claim 13 recites the broad recitation “the laser irradiation on the target is below 1 mW/cm2”, and the claim also recites “wherein the laser irradiation on the target is… below 0,25 mW/cm2” which is the narrower statement of the range/limitation;
Claim 14 recites the broad recitation “wherein the target is… a retina of a human or animal eye”, and the claim also recites “wherein the target is a portion of a retina… of a human or animal eye” which is the narrower statement of the range/limitation;
claim 21 recites the broad recitation “at least 5000fps… of the target are captured”, and the claim also recites “or at least 6000 fps, of the target are captured” which is the narrower statement of the range/limitation
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The term "nearly" in claim 10 is a relative term which renders the claim indefinite. The term "nearly" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The parameter “100% transmission” is rendered indefinite by the use of the term “nearly”.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4, 6, 9-12, 15-16, and 18-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel (US-20240032790-A1, EFD 21 March 2022) in view of Postnov (“Dynamic Laser Speckle Imaging”, NPL cited and attached by Applicant).
Regarding claim 1, Patel teaches
A high speed laser speckle contrast imaging system for characterizing pressure wave propagation or pulse wave velocity of one vessel of a biological target, the apparatus comprising:
- a laser source for generating laser radiation [Light emerging from the distal ends 158A, 158B of the fiber optic component 158 was collected with the lens (L1, 134) and relayed via a relay telescope system (defined by the lenses 138, 142, 146) through a polarizing beam splitter 124, and into the back focal plane of an imaging bore 150 (in one example, such bore was a Bioptigen G4 mouse imaging bore, Leica Microsystems, Morrisville, NC)… The bore 150 was structured as an arrangement of lenses optimized for imaging the retina, and was designed to achieve a 40-degree FOV with 1.7 micron lateral resolution and is optimized and AR-coated for light at near infrared (NIR) wavelengths (Patel ¶0053, Fig. 1A)];
- a high-speed camera [This combination makes the object surface 152 appear at infinity, thereby allowing for the surface 152 to be imaged with a camera lens 156 nominally focused at infinity. A 50 mm F/2.0 6MP manual focus Navitar camera lens (1-24424) was used in one experiment to focus the image of the cornea 152 onto a Basler Ace acA2040-180km-NIR camera (a 2048×2048, 180 FPS, NIR camera) used as the detector 132 (Patel ¶0056, Fig. 1A)];
- an optical sub-system configured for 1) guiding the laser radiation from the laser source to the target 2) and for collecting and guiding a back-scattered light from the target to the camera [The schematic of the embodiment 100 of the LSCI imaging optical camera or apparatus is presented in FIG. 1A, in which the illumination arm (or optical illumination system denoted as 110) and the image-collecting arm (or optical light-collecting system labelled 120) are operably combined via a polarizing beam splitter (PBS) 124 (Patel ¶0045, Fig. 1A)];
- a processing unit configured for receiving and processing raw image data from the camera for calculating the pressure wave propagation or pulse wave velocity over a length of said vessel [The operation of image processing (following the collection of data with the embodiment of the LSCI apparatus disclosed above) was performed as discussed by D. D. Patel and D. M. Lipinski in Sci. Rep. 10, 7177 (2020) on MATLAB using a custom script to read raw speckle images, generate speckle contrast maps via either temporal processing (for high spatial/low temporal resolution contrast maps) or spatial processing (for high temporal/low spatial resolution contrast maps), and with the use of Fourier analysis in order to segment retinal arteries from veins and to map time delay in pulse wave propagation (Patel ¶0067), wherein disclosure of the use of MATLAB software is considered to read on the use of a processing unit (computer); While several of these parameters can measured using other techniques, including pulse-oximetry or non-tethered electrocardiogram, results of the present experimentation proved that LSCI uniquely allowed for the simultaneous monitoring of blood flow and pulse wave velocity across multiple vessels within a single field-of-view (FIGS. 7B, 7C). Doing so allowed for comparison of blood flow waveforms between retinal arteries and veins to subsequently measure delays in pulse wave propagation between the retinal arterial and venous circulation (FIGS. 7E, 7F, 7G, 7H) (Patel ¶0079)].
However, Patel fails to explicitly disclose wherein the high-speed camera is configured for capturing at least 1000 frames per second (fps).
Postnov discloses systems for laser speckle imaging, wherein Postnov discloses the utilization of a high-speed camera configured for capturing at least 1000 frames per second (fps) [Utilizing a high-speed camera and recording back-scattered laser light at more than 20,000 frames per second, we introduce the first wide-field dynamic laser speckle imaging (DLSI) in which we are able to quantify the laser speckle intensity temporal auto-correlation function for every pixel individually to obtain a quantitative image of the dynamics of the light scattering particles in the sample. In biomedical applications, the dynamic light scattering particles are typically moving red blood cells (Postnov p. 1); A high-speed camera (1280x1024 pixels, 991 fps, 5 µm pixel size, Fastec IL5-S, USA) was used to record the backscattered light, through a 5x (whole cortex imaging) objective with NA= 0.14 or a 10X (stroke imaging) objective with NA= 0.28 (Mitutoyo, Japan). A polarizer was placed in front of the objective to increase the contrast range. The number of active pixels was reduced to an image stripe of 1280x32 and the exposure time Texposure was set to 31µs, allowing the camera to reach the maximum frame rate of 22,881 frames per second (Postnov p. 13)].
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 system of Patel to employ wherein the high-speed camera is configured for capturing at least 1000 frames per second (fps), so as to enable increased sampling for data analysis, and as this modification would amount to mere simple substitution of one known element for another with similar expected results [substitution of the camera as used by Patel for the camera as used by Postnov to enable higher fps imaging of reflected light] [MPEP § 2143(I)(B)].
Regarding claim 2, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 1, wherein the vessel is a microcirculatory vessel and wherein the target is a retina of a human or animal eye [FIGS. 1B and 1C provide spot diagrams representing light distribution at the pupil of an eye and at the retina, respectively, when these surfaces are illuminated with light from the source of light delivered to the lens portion of the optical illumination system of the embodiment of FIG. 1A only through one of the multiple distal ends of the optical fiber element of the embodiment (Patel ¶0021)].
Regarding claim 3, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 1, wherein the high-speed camera is configured for capturing at least 5000 fps or at least 6000 fps of the target [See § 103 modification of claim 1 above; Postnov p. 1, 13].
Regarding claim 4, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 1.
However, while Patel discloses wherein the system is directed towards assessing vessels in a subject’s retina/eye in the scale of micrometers [See Patel Fig. 1B-C] and is further adaptable depending on variations in subject anatomy [Patel ¶0021; Another important consideration during the construction of the embodiment 100 of the LSCI apparatus was to maintain the ability to easily modify the opto-mechanical design to allow for imaging of multiple animal species (including humans) despite large variations in anatomy, axial length, pupil size, and refractive index of the target visual systems. In order to achieve this goal, both the illumination 110 and collection 120 arms of the LSCI system 100 were designed to be easily adjustable and constructed from existing commercial parts. As a consequence, the resulting design allows the user to substitute the front optical element (L1, 132) and adjust the illumination path to ensure the ring illumination is imaged into the subject's pupil plane, and thereby to apply the so-restructurable system 100 to multiple species, including humans in clinical applications (Patel ¶0060)], Patel fails to explicitly disclose wherein said length of the vessel is less than 1 mm, or less than 0.2 mm or less than 0.16 mm.
As Patel Fig. 1C is considered to depict the scale of a measured mouse retina in the magnitude of 1500 μm [Patel ¶0065, Fig. 1C] and further depicts analyzed vessels of the retina in Fig. 7B-C [Patel ¶0027, Fig. 7B-C], 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 system of Patel in view of Postnov to employ wherein said length of the vessel is less than 1 mm, or less than 0.2 mm or less than 0.16 mm, as this modification would amount to mere application of a known technique to a known device (method, or product) ready for improvement to yield predictable results [apply the system to vessels in the scale of 1 mm to analyze vessel parameters] [MPEP § 2143(I)(D)].
Regarding claim 6, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 1, wherein the laser source is a highly coherent laser source [A person of ordinary skill in the art will now readily appreciate that, in designing of an illumination system or arm of a given LSCI system, the coherence of the source of light should be taken into account as it is critical to ensure optimal speckle contrast. In the present case, wherein the multimode light propagation through the fiber bundle can reduce spatial coherence—and, therefore, speckle contrast—a wavelength-stabilized laser source (Ondax SureLock, Coherent Inc, Santa Clara CA) operating at about 785 nm with 50 MHz linewidth was chosen as a source of light. This corresponded to a linewidth of approximately 100 fm, or a coherence length of about 6 m, which was expected to easily exceed any modal dispersion in the fiber bundles while still providing sufficient coherence to maximize speckle contrast (Patel ¶0059)].
Regarding claim 9, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according claim 1, wherein the optical sub-system comprises a mirror with a pinhole, or a polarizing beam splitter [Patel ¶0045] or a 9:1 or higher ratio beam splitter.
Regarding claim 10, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 1, wherein the optical sub-system has a nearly 100% transmission [Patel Fig. 1A].
Regarding claim 11, Patel teaches
A high-speed laser speckle contrast imaging method for characterizing pressure wave or pulse wave velocity in a vessel of a biological target, the method comprising the steps of:
- irradiating the target by laser radiation [Light emerging from the distal ends 158A, 158B of the fiber optic component 158 was collected with the lens (L1, 134) and relayed via a relay telescope system (defined by the lenses 138, 142, 146) through a polarizing beam splitter 124, and into the back focal plane of an imaging bore 150 (in one example, such bore was a Bioptigen G4 mouse imaging bore, Leica Microsystems, Morrisville, NC)… The bore 150 was structured as an arrangement of lenses optimized for imaging the retina, and was designed to achieve a 40-degree FOV with 1.7 micron lateral resolution and is optimized and AR-coated for light at near infrared (NIR) wavelengths (Patel ¶0053, Fig. 1A)];
- capturing frames of the target by a high-speed camera [This combination makes the object surface 152 appear at infinity, thereby allowing for the surface 152 to be imaged with a camera lens 156 nominally focused at infinity. A 50 mm F/2.0 6MP manual focus Navitar camera lens (1-24424) was used in one experiment to focus the image of the cornea 152 onto a Basler Ace acA2040-180km-NIR camera (a 2048×2048, 180 FPS, NIR camera) used as the detector 132 (Patel ¶0056, Fig. 1A)];
- calculating the pressure wave propagation or pulse wave propagation over a length of said vessel, based on raw image data from the camera, using a processing unit [The operation of image processing (following the collection of data with the embodiment of the LSCI apparatus disclosed above) was performed as discussed by D. D. Patel and D. M. Lipinski in Sci. Rep. 10, 7177 (2020) on MATLAB using a custom script to read raw speckle images, generate speckle contrast maps via either temporal processing (for high spatial/low temporal resolution contrast maps) or spatial processing (for high temporal/low spatial resolution contrast maps), and with the use of Fourier analysis in order to segment retinal arteries from veins and to map time delay in pulse wave propagation (Patel ¶0067), wherein disclosure of the use of MATLAB software is considered to read on the use of a processing unit (computer); While several of these parameters can measured using other techniques, including pulse-oximetry or non-tethered electrocardiogram, results of the present experimentation proved that LSCI uniquely allowed for the simultaneous monitoring of blood flow and pulse wave velocity across multiple vessels within a single field-of-view (FIGS. 7B, 7C). Doing so allowed for comparison of blood flow waveforms between retinal arteries and veins to subsequently measure delays in pulse wave propagation between the retinal arterial and venous circulation (FIGS. 7E, 7F, 7G, 7H) (Patel ¶0079)].
However, Patel fails to explicitly disclose wherein at least 1000 frames per second (fps), of the target are captured by the high-speed camera.
Postnov discloses systems for laser speckle imaging, wherein Postnov discloses the utilization of a high-speed camera configured for capturing at least 1000 frames per second (fps) [Utilizing a high-speed camera and recording back-scattered laser light at more than 20,000 frames per second, we introduce the first wide-field dynamic laser speckle imaging (DLSI) in which we are able to quantify the laser speckle intensity temporal auto-correlation function for every pixel individually to obtain a quantitative image of the dynamics of the light scattering particles in the sample. In biomedical applications, the dynamic light scattering particles are typically moving red blood cells (Postnov p. 1); A high-speed camera (1280x1024 pixels, 991 fps, 5 µm pixel size, Fastec IL5-S, USA) was used to record the backscattered light, through a 5x (whole cortex imaging) objective with NA= 0.14 or a 10X (stroke imaging) objective with NA= 0.28 (Mitutoyo, Japan). A polarizer was placed in front of the objective to increase the contrast range. The number of active pixels was reduced to an image stripe of 1280x32 and the exposure time Texposure was set to 31µs, allowing the camera to reach the maximum frame rate of 22,881 frames per second (Postnov p. 13)].
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 method of Patel to employ wherein at least 1000 frames per second (fps), of the target are captured by the high-speed camera, so as to enable increased sampling for data analysis, and as this modification would amount to mere simple substitution of one known element for another with similar expected results [substitution of the camera as used by Patel for the camera as used by Postnov to enable higher fps imaging of reflected light] [MPEP § 2143(I)(B)].
Regarding claim 12, Patel in view of Postnov teaches
The method according to claim 11.
However, while Patel discloses wherein the method is directed towards assessing vessels in a subject’s retina/eye in the scale of micrometers [See Patel Fig. 1B-C] and is further adaptable depending on variations in subject anatomy [Patel ¶¶0021, 0060], Patel fails to explicitly disclose wherein said length of the vessel is less than 1 mm, or less than 0.2 mm or less than 0.16 mm.
As Patel Fig. 1C is considered to depict the scale of a measured mouse retina in the magnitude of 1500 μm [Patel ¶0065, Fig. 1C] and further depicts analyzed vessels of the retina in Fig. 7B-C [Patel ¶0027, Fig. 7B-C], 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 method of Patel in view of Postnov to employ wherein said length of the vessel is less than 1 mm, or less than 0.2 mm or less than 0.16 mm, as this modification would amount to mere application of a known technique to a known device (method, or product) ready for improvement to yield predictable results [apply the system to vessels in the scale of 1 mm to analyze vessel parameters] [MPEP § 2143(I)(D)].
Regarding claim 15, Patel in view of Postnov teaches
The method according to claim 14, further comprising the step of calculating accurate time-stamp based average contrast frames by averaging contrast frames belonging to a same time-stamp cycle [Patel Fig. 7B-C, E-F], or a same phase, of a heart beat or calculating time-stamp based temporal contrast frames from raw data belonging to a same time-stamp cycle.
Regarding claim 16, Patel in view of Postnov teaches
The method according to claim 11, further comprising the step of obtaining nodes for one or more vessels in the target by segmentation and skeletonization of temporal contrast frames for different surrogate exposure times [Fourier analysis was applied to measure change in heart rate under 2% isoflurane (451.2 bpm) and 5% isoflurane (270.6 bpm) (FIG. 7D). Mean speckle contrast was measured in the arterial (red) and venous (blue) ROIs drawn in FIGS. 7B, 7C to plot variation in speckle contrast over time under 2% isoflurane (FIG. 7E) and 5% isoflurane (FIG. 7F). The time delay between pulse wave propagation from retinal artery to retinal vein is highlighted in FIGS. 7E through F. Fourier analysis is applied to create a map pulse wave propagation time delay over the entire field-of-view under 2% isoflurane (FIG. 7G) and 5% isoflurane (FIG. 7H). Time delay measurements in FIGS. 7G through H are relative to time measured in each respective, red circular ROI (Patel ¶0027, Fig. 7A-H), wherein the pulse waves as measured along the red/blue regions of interest is considered to be measured between a first “node” and a second “node”].
Regarding claim 18, Patel in view of Postnov teaches
The method according to claim 11, further comprising the steps of: based on quantitative time-stamp based average blood flow index and based on a final vessel mask, calculating a low-noise quantitative time- stamp based average blood flow index obtained by segmentation-based spatial averaging of quantitative time-stamp based average blood flow index, such that dynamics of different vessels are not mixed with each other [Patel ¶0027, Fig. 7A-H, wherein the vessels as analyzed by Patel are considered to be not mixed with each other].
Regarding claim 19, Patel in view of Postnov teaches
The method according to claim 11, further comprising the steps of: based on low-noise quantitative time-stamp average based blood flow index and a vessel mask, measure ng a foot-to-foot pulse wave delay between nodes of each vessel [Patel ¶0027, Fig. 7A-H, wherein graphing pulse wave propagation over time is considered to read on the claimed limitation]; calculating per vessel pulse wave velocity (PWV) [Patel ¶0079]; and calculating microcirculatory stiffness [Patel ¶0078].
Regarding claim 20, Patel in view of Postnov teaches
The system of claim 1, configured to execute any one of the following steps:
- irradiating the target by laser radiation [Patel ¶0053];
- capturing at least 1000 frames per second (fps), of the target by a high-speed camera [See § 103 modification of claim 1 above; Patel ¶0056; Postnov p. 1, 13]; and
- calculating the pressure wave propagation or pulse wave propagation over a length of said vessel, based on raw image data from the camera, using a processing unit [Patel ¶¶0067, 0079].
Regarding claim 21, Patel in view of Postnov teaches
The method according to claim 11, wherein at least 5000 fps, or at least 6000 fps, of the target are captured by a high-speed camera [See § 103 modification of claim 11 above; Postnov p. 1, 13].
Regarding claim 22, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 6, wherein the laser source is a Near-Infra-Red (NIR) laser source [Patel ¶0053].
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel in view of Postnov, as applied to claim 1 above, in further view of Lin (US-20180206734-A1).
Regarding claim 5, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 1.
However, while Patel discloses wherein the processing unit is further configured to extract stiffness of the vessel [The ability to reliably perform LSCI at high frame rates by modulating exposure duration and laser power to ensure mean pixel intensity falls in the linear range (15-135 AU) enables the quantification of several parameters of systemic vascular and cardiac health (i.e. heart rate, pulse wave propagation, cardiac contractility, vessel stiffness, and peripheral resistance) which are difficult and laborious to achieve with other advanced ocular imaging modalities (Patel ¶0078)], Patel in view of Postnov fails to explicitly disclose wherein the extracted stiffness of the vessel is based on the pulse wave velocity.
Lin discloses systems for measuring pulse wave velocity, wherein Lin discloses that it is known that pulse wave velocity is an index of arterial stiffness [It is generally accepted that both PTT and PWV can be regarded as indices of arterial stiffness (Lin ¶0073)].
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 system of Patel in view of Postnov to employ wherein the extracted stiffness of the vessel is based on the pulse wave velocity, as pulse wave velocity is understood to be an index of arterial stiffness.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel in view of Postnov, as applied to claim 1 above, as evidenced by Fondi et al. (“Measurement of Retinal Vascular Caliber From Optical Coherence Tomography Phase Images”, NPL attached), hereinafter Fondi.
Regarding claim 7, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 1, wherein the vessel is as microcirculatory blood vessel, in a retina of a human or animal eye [Patel ¶0021].
However, while Patel discloses wherein the system is directed towards assessing vessels in a subject’s retina/eye in the scale of micrometers [See Patel Fig. 1B-C] and is further adaptable depending on variations in subject anatomy [Patel ¶¶0021, 0060], Patel fails to explicitly disclose wherein the microcirculatory blood vessel is of diameter size less than 100 micrometers.
Fondi discloses that human retinal vessels have diameters that are less than 100 micrometers [A total of 214 retinal vessels were evaluated under breathing room air. The average vessel diameter in OCT images was 83.8 ± 28.2 μm; the average vessel diameter in RVA images was 86.6 ± 28.0 μm. The difference of 2.8 ± 10.7 μm was statistically significant (P < 0.001). During 100% oxygen breathing, a total of 101 vessels were evaluated. Again, the retinal vessel diameters were smaller when evaluated using OCT (81.0 ± 22.4 μm) as compared with RVA (85.5 ± 26.0 μm; t-test P = 0.001) (Fondi p. 123)].
As Patel is directed towards measurements performed on human retinal vessels, Fondi is considered to provide evidence that the microcirculatory blood vessels as analyzed by the system of Patel in view of Postnov are of diameter size less than 100 micrometers.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel in view of Postnov, as applied to claim 1 above, as evidenced by FASTEC (“DATA SHEET April 2018 IL5/TS5”, NPL attached), and in further view of Beiley et al. (“Design and characterization of 1.1 micron pixel image sensor with high near infrared quantum efficiency”, NPL attached), hereinafter Beiley.
Regarding claim 8, Patel in view of Postnov teaches
The high-speed laser speckle contrast imaging system according to claim 1, wherein the camera is a high sensitivity CMOS camera, at a near infra-red spectrum, and wherein said camera has a pixel size of at least 5 micrometres and wherein said camera has a near to zero delay between frames, such that the delay is negligible compared to an exposure time of the camera, and wherein the camera has a pixel size such that a speckle to pixel size ratio is below 2 [See § 103 modification of claim 1 above; A high-speed camera (1280×1024 pixels, 991 fps, 5 μm pixel size, Fastec IL5-S, USA) was used to record the backscattered light… The number of active pixels was reduced to an image stripe of 1280×32 and the exposure time Texposure was set to 31μs, allowing the camera to reach the maximum frame rate of 22,881 frames per second. Coherent light was delivered to the object using a free space volume holographic grating (VHG) stabilized laser diode21 (785nm, LD785-SEV300, Tholrabs, USA) operated at the recommended settings… The size of the speckle on the camera was adjusted by altering the pupil diameter of an iris in the detection path to achieve a speckle to pixel size ratio of approximately 2 (Postnov p. 13)].
However, Patel in view of Postnov, as presently applied fails to explicitly disclose wherein the camera is a CMOS camera having a sensitivity of at least 1600 ISO, and at least 50% quantum efficiency.
FASTEC further defines the Fastec IL5-S camera as used by Postnov as being a CMOS camera having a sensitivity of at least 1600 ISO [Sensor 12-bit CMOS sensor with 5µm square pixels, color or monochrome… Light Sensitivity 1600 to 12,800* ISO monochrome, 800 to 6400* ISO color (depending on mode) (FASTEC p. 8)]. Such that Patel in view of Postnov, as evidenced by FASTEC, teaches wherein the camera is a CMOS camera having a sensitivity of at least 1600 ISO.
Beiley discloses near infrared image sensors, wherein Beiley discloses that quantum efficiency is a result effective variable in that changing quantum efficiency changes sensitivity of the image sensor [High sensitivity is quantified by the external quantum efficiency (QE), which is the product of optical absorption efficiency (OE) and internal quantum efficiency (IQE), and should be as close to 100% as possible]. 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 system of Patel in view of Postnov to employ wherein the camera has at least 50% quantum efficiency, as a matter of routine optimization since it has been held that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456. 105 USPQ 233, 235 (CCPA 1955).
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel in view of Postnov, as applied to claim 12 above, in further view of Detter et al. (“Fluorescent Cardiac Imaging: A Novel Intraoperative Method for Quantitative Assessment of Myocardial Perfusion During Graded Coronary Artery Stenosis”, NPL cited and attached by Applicant), hereinafter Detter.
Regarding claim 13, Patel in view of Postnov teaches
The method according to claim 12.
However, while Patel acknowledges permissible exposure of laser irradiation of the target [To ensure that thermal injury to the retina was avoided, laser power levels were kept below the Group 1 limits defined by ophthalmic and lens standards such as, for example, ANSI z80.36:2016. For the used 785-nm light source and a retinal FOV of 50 degrees (producing about 1 6 mm of arc length on mouse retina, as modeled in Zemax), this limit was computed to be 22.1 mW, restricted by the “Retinal infrared radiation thermal hazard” defined in the standards (Patel ¶0065)], Patel in view of Postnov fails to explicitly disclose wherein the laser irradiation on the target is below 1 mW/cm2, or below 0,25 mW/cm2, such that the irradiation is below a maximum permissible exposure for the target.
Detter discloses methods for operating infrared imaging devices, wherein Detter discloses that laser irradiation at 1 mW/cm2 has no hazardous potential to require the use of eye protection [Eye protection is not required in the operating room because the laser light energy is dispersed and the light remitted from the tissue surface (30% of the incident light) has no hazardous potential (I=1 mW/cm2) (Detter p. 1008)].
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 method of Patel in view of Postnov to employ wherein the laser irradiation on the target is below 1 mW/cm2, or below 0,25 mW/cm2, such that the irradiation is below a maximum permissible exposure for the target to limit hazardous potential of the laser irradiation.
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel in view of Postnov and Detter, as applied to claim 13 above, in further view of Lin (US-20180206734-A1).
Regarding claim 14, Patel in view of Postnov and Detter teaches
The method according to claim 13, wherein the target is a portion of a retina or a retina of a human or animal eye [Patel ¶0021], wherein a stiffness of said vessel is calculated [Patel ¶0078], and wherein the method is further comprising the step of, based on raw image data, calculating spatial contrast frames [Mean speckle contrast was measured in the arterial (red) and venous (blue) ROIs drawn in FIGS. 7B, 7C to plot variation in speckle contrast over time under 2% isoflurane (FIG. 7E) and 5% isoflurane (FIG. 7F) (Patel ¶0027, Fig. 7B-C, E-F)].
However, Patel in view of Postnov and Detter fails to explicitly disclose wherein the extracted stiffness of the vessel is based on the pulse wave velocity.
Lin discloses systems for measuring pulse wave velocity, wherein Lin discloses that it is known that pulse wave velocity is an index of arterial stiffness [Lin ¶0073].
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 system of Patel in view of Postnov and Detter to employ wherein the extracted stiffness of the vessel is based on the pulse wave velocity, as pulse wave velocity is understood to be an index of arterial stiffness.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel in view of Postnov, as applied to claim 11 above, in further view of Postnov (“Dynamic light scattering imaging”, NPL cited and attached by Applicant), hereinafter Postnov II.
Regarding claim 17, Patel in view of Postnov teaches
The method according to claim 11, further comprising the steps of calculating a quantitative blood flow index as a function of time and space coordinates or a quantitative time-stamp based average blood flow index, using spatial contrast frames or time-stamp based average contrast frames and fitted parameters [Mean speckle contrast was measured in the arterial (red) and venous (blue) ROIs drawn in FIGS. 7B, 7C to plot variation in speckle contrast over time under 2% isoflurane (FIG. 7E) and 5% isoflurane (FIG. 7F). The time delay between pulse wave propagation from retinal artery to retinal vein is highlighted in FIGS. 7E through F. Fourier analysis is applied to create a map pulse wave propagation time delay over the entire field-of-view under 2% isoflurane (FIG. 7G) and 5% isoflurane (FIG. 7H) (Patel ¶0027); While several of these parameters can measured using other techniques, including pulse-oximetry or non-tethered electrocardiogram, results of the present experimentation proved that LSCI uniquely allowed for the simultaneous monitoring of blood flow and pulse wave velocity across multiple vessels within a single field-of-view (FIGS. 7B, 7C). Doing so allowed for comparison of blood flow waveforms between retinal arteries and veins to subsequently measure delays in pulse wave propagation between the retinal arterial and venous circulation (FIGS. 7E, 7F, 7G, 7H). Upon comparing blood flow between a retinal artery and retinal vein, we observe in increase in pulse wave propagation time from 11.68 ms under 2% isoflurane to 32.11 ms under 5% isoflurane (FIGS. 7G, 7H) (Patel ¶0079)].
However, while Patel discloses obtaining average spatial contrast frames from multi-exposure surrogate frames for different surrogate exposure times [Patel ¶0027, Fig. 7A-H], Patel in view of Postnov fails to explicitly disclose the step of calculating dynamic (ρ) and/or static scattering component, dynamics regime (n) and offset (C), based on fitting average spatial contrast frames obtained from multi-exposure surrogate frames for different surrogate exposure times with up to 3 light scattering models, and wherein the light scattering models are at least one in the following selection: multiple scattering ordered motion or single scattering unordered motion, multiple scattering unordered motion, single scattering ordered motion.
Postnov II discloses methods for analyzing laser speckle contrast imaging, wherein Postnov discloses calculating dynamic (ρ) and/or static scattering component, dynamics regime (n) and offset (C), based on fitting spatial contrast frames obtained for different exposure times with up to 3 light scattering models, and wherein the light scattering models are at least one in the following selection: multiple scattering ordered motion or single scattering unordered motion, multiple scattering unordered motion, single scattering ordered motion [For each of the complexity levels, we identify the best-fitting form of the field correlation function and then use the F test to compare the performance of all models (fig. S3). The final DLSI model, which provides the best fit overall and includes all of the mentioned parameters, is (Equation 1) where… ρ represents the fraction of the dynamic scattering component, (1 − ρ) represents the fraction of the static scattering component, and C is an offset caused by measurement noise. X depends on the second type of dynamics with a value of 0.5 for multiple scattering from unordered motion (MUn = 0.5 ) (3, 29) or 2 for single scattering from ordered motion (SOn = 2 ) (3, 19). d represents the influence of the n = X com-ponent compared with the single scattering from unordered or multiple scattering from ordered dynamics (SU/MOn = 1) (3, 8). Applying the model to the g2(τ) measured from the mouse brain, we obtained the correlation time τc, static scattering estimate 1 − ρ , and the dynamic scattering regime, which ranges from MUn = 0.5 to SU/MOn = 1 and from SU/MOn = 1 to SOn = 2 (Postnov II p. 1-2, Fig. 1F); Knowing the dynamic light scattering regime and the form of the field correlation function g1(τ) is critical for the correct interpretation of the blood flow and blood flow changes by dynamic light scattering and LSCI methods (Postnov II p. 3)].
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 method of Patel in view of Postnov to employ the step of calculating dynamic (ρ) and/or static scattering component, dynamics regime (n) and offset (C), based on fitting average spatial contrast frames obtained from multi-exposure surrogate frames for different surrogate exposure times with up to 3 light scattering models, and wherein the light scattering models are at least one in the following selection: multiple scattering ordered motion or single scattering unordered motion, multiple scattering unordered motion, single scattering ordered motion, so as to enable accurate interpretation of blood flow and blood flow changes.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEVERO ANTONIO P LOPEZ whose telephone number is (571)272-7378. The examiner can normally be reached M-F 9-6 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Charles Marmor II can be reached at (571) 272-4730. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SEVERO ANTONIO P LOPEZ/Examiner, Art Unit 3791
Prosecution Insights