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 .
Claims 1-20 are the currently pending claims hereby under examination.
Claim Objections
Claim 10 is objected to because of the following informalities:
In claim 10, line 3: "the target object" does not have proper antecedent basis and should be "a target object";
In claim 10, line 3: "the one or more second optical signals” contains a typographical error and should be "the one or more first optical signals"; and
In claim 10, line 4: "the a target object" is grammatically incorrect and should be revised to "the target object”.
Appropriate correction is required.
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 19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Claim 19 recites “the determination of the physical characteristic of the blood vessel” in lines 1-2. However, claim 19 depends from claim 17, and claim 17 does not recite the instruction to determine a physical characteristic of the blood vessel. Because the dependent claim refers to “the determination” of a physical characteristic not previously introduced in the base claim, the scope of the claim is unclear. The Examiner interprets “the determination of the physical characteristic of the blood vessel” as referring to determining a property of the blood vessel, such as distension or pulse wave velocity, based on the detected optical reflection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 1-7 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Reza et al. (US-20160113507-A1), hereto referred as Reza, and further in view of Antonelli et al. (US-20090299197-A1), hereto referred as Antonelli.
Regarding claim 1, Reza teaches a method comprising: transmitting a continuous optical signal toward a skin of the user, the skin being proximate to a blood vessel of the user (Reza, ¶[0116]: "For the receiver arm a continuous wavelength (CW) C-band laser with 100-kHz linewidth...was used" and ¶[0114]: "Detection laser 14 may be a continuous wave laser", Reza expressly and unambiguously teaches that the interrogation or detection optical signal is a continuous-wave (CW) optical signal; Abstract: "an interrogation beam incident on the sample at the excitation location, a portion of the interrogation beam returning from the sample that is indicative of the generated ultrasonic signals" and ¶[0049]: the acoustic signatures are interrogated using "a long-coherence length probe beam...co-focused and co-aligned with the excitation spots on sample 18", Reza teaches that the CW interrogation beam is directed toward the sample at the target location; ¶[0046]: "capable of in vivo optical-resolution photoacoustic microscopy" and ¶[0127]: "FIGS. 19a-19d depict in vivo PARS images of a mouse ear, and FIGS. 23a-23c and 24 show in vivo PARS images of a 100 g rat's ear", Reza teaches that the interrogation beam is used in vivo on the ear tissue of a living subject (the ear is skin-covered tissue directly overlying blood vessels, supporting that the optical signal is directed toward the skin of a living subject); ¶[0109]: “Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal”, Reza teaches that the returning portion of the interrogation beam includes reflection from the oscillating outer tissue surface; ¶[0105]: T_t is “the transmission intensity coefficient at the air-tissue interface”, Reza further teaches that this surface reflection occurs at the air-tissue interface, i.e., the outer surface of the biological tissue, such that the detected returning interrogation beam includes reflection from the tissue surface previously established as the skin of the living subject; ¶[0123]: "FIG. 14a shows multifocus PARS images revealing both capillary beds and bigger blood vessels", Reza teaches that the biological tissue interrogated by the PARS system includes capillary beds and larger blood vessels underlying the interrogated surface, supporting that the interrogated skin surface is proximate to a blood vessel); during the transmitting of the continuous optical signal, causing generation of one or more acoustic signals from a blood vessel of the user by transmitting one or more pulsed optical signals toward the blood vessel (Reza, Abstract: "an excitation beam configured to generate ultrasonic signals in the sample at an excitation location", Reza teaches an excitation beam configured to generate ultrasonic signals in the sample; ¶[0046]: "Photoacoustic imaging is an emerging biomedical imaging modality that uses laser light to excite tissues. Energy absorbed by chromophores or any other absorber is converted to acoustic waves due to thermo-elastic expansion", Reza teaches that laser excitation of tissue generates acoustic waves; ¶[0047]: "at 532-nm excitation wavelength, imaging a capillary with 500 mJ/cm² local fluence would result in an initial pressure on the order of 100 MPa locally", Reza expressly teaches excitation of a capillary, i.e., a blood vessel, to generate an acoustic pressure response; ¶[0060]: "In one example, a nanosecond-pulsed laser was used" and ¶[0133]: "laser pulses should be preferably shorter than 2 µm/1500 m/s=1.3 ns, which would require a laser with pulse widths of a nanosecond or shorter", Reza teaches pulsed laser excitation with nanosecond or shorter pulse widths); during the generation of the one or more acoustic signals, detecting a reflection of the continuous optical signal from the skin of the user (Reza, Abstract: "a portion of the interrogation beam returning from the sample that is indicative of the generated ultrasonic signals" and "a detector that detects the returning portion of the interrogation beam", Reza teaches detecting a returning portion of the interrogation beam from the sample during the photoacoustic process; ¶[0047]: "large optically-focused photoacoustic signals are detected as close to the photoacoustic source as possible, which is done optically by co-focusing an interrogation beam with the excitation spot. A long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities", Reza teaches optical detection of local photoacoustic vibrations using the CW interrogation laser at the excitation site; ¶[0015]: "a portion of the interrogation beam returning from the sample...is indicative of the generated ultrasonic signals", Reza further teaches that the detected return corresponds to interrogation-beam detection at the photoacoustic excitation location; ¶[0109]: "Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal", Reza teaches detecting the reflection of the CW interrogation beam from the tissue surface during acoustic signal generation).
Also regarding claim 1, Reza does not expressly teach based on the detected reflection of the continuous optical signal, determining a physiological parameter of the user. Rather, Reza teaches detecting and processing the returning portion of the interrogation beam, including that "there may be a processor that calculates an image of the sample based on the returning portion of the interrogation beam" (Reza, ¶[0018]). Reza further discloses that photoacoustic imaging may be used for functional imaging applications such as imaging blood oxygen saturation (Reza, ¶[0046]), indicating that the detected interrogation signal can be processed to derive biological information, but Reza does not expressly disclose determining a physiological parameter of the user based on the detected reflection of the continuous optical signal.
Antonelli expressly teaches this limitation. Antonelli teaches a "non-contact method and apparatus for continuously monitoring physiological events such as the anatomical blood pressure waveform" (Antonelli, ¶[0028]). Antonelli teaches directing a continuous-wave laser beam toward the skin over an artery and detecting the reflected beam: "[a] low-power (1 mW), continuous, red laser beam is directed onto the measurement surface. By interfering the detected beam that was reflected by the measurement surface with a reference beam within the LDV, a measure of the surface velocity is obtained" (Antonelli, ¶[0019]). Antonelli teaches that the computer correlates the detected optical return signal to the blood pressure in the underlying artery: "The computer can be calibrated to correlate the velocity and motion of the skin surface to the pressure of the blood in the artery beneath skin surface" (Antonelli, ¶[0037]). Antonelli further teaches that "[i]t is necessary to convert the measured velocity into a skin displacement signal. This is a critical aspect of the invention in order to provide medical personnel a waveform that is similar to those achieved by catheter pressure sensor" (Antonelli, ¶[0043]). Antonelli therefore expressly teaches determining a physiological parameter (blood pressure) based on the detected reflection of a continuous optical signal from skin proximate to a blood vessel.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Reza in view of Antonelli to, based on the detected reflection of the continuous optical signal, determine a physiological parameter of the user. Both Reza and Antonelli use a continuous-wave laser directed at biological tissue over blood vessels as the interrogation modality, and both rely on detecting the reflected or returning CW beam. The combination would have been feasible because Reza already optically detects and processes the returning interrogation beam at the photoacoustic excitation site, while Antonelli demonstrates that such reflected CW optical signals from skin over an artery encode arterial pressure information sufficient to derive blood pressure waveforms equivalent to catheter measurements. A person of ordinary skill in the art would have been motivated to apply Antonelli's signal-processing output framework to Reza's more sensitive PARS interrogation architecture as a predictable extension, yielding the additional benefit of physiological monitoring from the same optical interrogation signal already present in Reza's system, with a reasonable expectation of success given that both systems measure optically detected displacement or pressure signals originating from the same tissue-vessel interaction.
Regarding claim 2, claim 2 further recites a method comprising: determining a physical characteristic of the blood vessel based at least on the detected reflection of the continuous optical signal; and determining the physiological parameter based at least on the physical characteristic of the blood vessel. The modified Reza teaches transmitting a CW interrogation beam toward the skin of the user proximate to a blood vessel, causing generation of acoustic signals from the blood vessel via pulsed optical excitation, detecting the reflection of the CW beam from the skin during acoustic signal generation, and determining a physiological parameter of the user based on that detected reflection. The modified Reza further teaches, through Reza itself, that the returning interrogation beam is processed to characterize subsurface vascular structures: "there may be a processor that calculates an image of the sample based on the returning portion of the interrogation beam" (Reza, ¶[0018]), and that the PARS system is capable of imaging vascular structures including microvessels and larger blood vessels (Reza, ¶[0004]: "Photoacoustic microscopy has shown significant potential for imaging vascular structures from macro-vessels all the way down to micro-vessels"). The modified Reza does not, however, expressly disclose extracting a discrete physical characteristic of the blood vessel from the CW reflection and using that physical characteristic as the specific basis for determining the physiological parameter.
Antonelli expressly teaches that blood flowing through the artery causes the overlying skin to pulsate, and that the CW reflected beam encodes the resulting skin surface displacement: "Blood flowing through the artery directly below the skin causes skin surface 26 to pulsate in a rhythm corresponding to ventricular contractions of the subject's heart. Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position to a position represented by plane 28" (Antonelli, ¶[0030]). Antonelli further teaches that the reflected laser beam is modulated by this skin surface movement: "The reflected laser light beam 34 is modulated by the movement of skin surface 26 by means of a Doppler shift in the optical wavelength, as compared to the original laser beam 32 produced by laser source 14" (Antonelli, ¶[0032]). The skin displacement ΔX is causally determined by and directly corresponds to the dimensional change of the underlying blood vessel, and is thus a physical characteristic of the blood vessel as detected through the overlying tissue. Antonelli further teaches that this displacement signal is obtained from the detected CW reflection by integrating the velocity signal: "The signal processing unit provides skin displacement information, which more directly corresponds to the blood pressure waveform than a measured velocity signal. The blood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]).
As to determining the physiological parameter based on the physical characteristic, Antonelli expressly teaches that the computer uses the detected skin displacement to derive blood pressure: "The computer 30 can be calibrated to correlate the velocity and motion of the skin surface 26 to the pressure of the blood in the artery beneath skin surface 26" (Antonelli, ¶[0037]), and that "[i]t is necessary to convert the measured velocity into a skin displacement signal. This is a critical aspect of the invention in order to provide medical personnel a waveform that is similar to those achieved by catheter pressure sensor" (Antonelli, ¶[0043]). Antonelli thereby expressly teaches determining blood pressure, a physiological parameter, based on the skin displacement physical characteristic derived from the CW reflection.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Antonelli to determine a physical characteristic of the blood vessel based on the detected CW reflection, and to determine the physiological parameter based on that physical characteristic. The modified Reza provides a highly sensitive PARS interrogation architecture in which the returning CW beam encodes subsurface tissue dynamics. Antonelli demonstrates that the CW reflection from skin over an artery directly encodes skin displacement ΔX causally driven by the underlying vessel's dimensional state, and that this physical characteristic can be used to derive blood pressure with accuracy comparable to catheter measurements. A person of ordinary skill in the art would have been motivated to combine these teachings because doing so would yield a more physiologically grounded and clinically meaningful output (specifically, a blood pressure determination anchored to a directly measured physical characteristic of the vessel rather than a purely empirical correlation) with a reasonable expectation of success given that both references operate on the same underlying tissue-vessel interaction and use optically detected signals as the measurement basis.
Regarding claim 3, claim 3 further recites a method wherein the physical characteristic of the blood vessel comprises distension or pulse wave velocity of the blood vessel, and wherein the physiological parameter comprises blood pressure. The modified Reza teaches that the physical characteristic of the blood vessel is skin displacement ΔX caused by pulsation of the underlying artery, and that blood pressure is the physiological parameter derived therefrom. The modified Reza does not, however, expressly characterize the physical characteristic as distension of the blood vessel.
As to blood pressure as the physiological parameter, Antonelli expressly and repeatedly teaches this limitation. Antonelli teaches that "[t]he computer 30 can be calibrated to correlate the velocity and motion of the skin surface 26 to the pressure of the blood in the artery beneath skin surface 26" (Antonelli, ¶[0037]), and that the result is "a highly accurate representative blood pulse waveform" (Antonelli, ¶[0038]). Antonelli further characterizes the output as "a waveform that is similar to those achieved by catheter pressure sensor" (Antonelli, ¶[0043]). Blood pressure is thus expressly taught as the physiological parameter by Antonelli within the modified Reza.
As to distension as the physical characteristic, Antonelli expressly teaches that the pulsation of blood through the artery causes the overlying skin surface to move an amount ΔX from its resting position (Antonelli, ¶[0030]: "Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position to a position represented by plane 28"). This outward displacement of the skin surface is causally and directly produced by the radial expansion of the arterial wall during the cardiac pressure pulse, which is the definition of arterial distension. The skin displacement ΔX detected by the CW reflection thus corresponds to and is a surface manifestation of vessel distension, and one of ordinary skill in the art would understand ΔX as measured by Antonelli to represent vessel distension as recited in the claim. Antonelli further teaches that "[b]lood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]), directly linking the detected displacement (distension) to the blood pressure determination, which is precisely the relationship recited in the claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Antonelli to characterize the physical characteristic of the blood vessel as distension and to determine blood pressure therefrom. The modified Reza's PARS interrogation architecture provides a highly sensitive, non-contact means of detecting the returning CW beam modulated by surface displacement over a blood vessel. Antonelli, already incorporated within the modified Reza, expressly links that surface displacement to the pulsatile radial expansion of the underlying artery and to blood pressure derivation. Applying these teachings to the modified Reza's more sensitive optical detection scheme would be a predictable extension, as it requires no new physical principles and uses the same tissue-vessel-skin displacement relationship already taught by Antonelli. The benefit of this combination is that it provides a specific, physiologically meaningful intermediate quantity (vessel distension) as the basis for blood pressure determination, allowing the measurement to be grounded in a well-characterized arterial mechanics relationship rather than a purely empirical surface calibration, with a reasonable expectation of success given that both references operate on the same pulsatile skin displacement signal produced by the same underlying arterial mechanics.
Regarding claim 4, the modified Reza teaches a method further comprising obtaining an image representation of at least the reflection of the continuous optical signal, wherein the determining of the physical characteristic of the blood vessel is based on the image representation (Reza, ¶[0018]: "there may be a processor that calculates an image of the sample based on the returning portion of the interrogation beam", Reza expressly teaches that the returning portion of the interrogation beam, i.e., the detected reflection of the CW interrogation signal, is processed by a processor to calculate an image of the sample, which is an image representation of at least the reflection of the continuous optical signal as recited in the claim; ¶[0123]: "FIG. 14a shows multifocus PARS images revealing both capillary beds and bigger blood vessels", Reza teaches that the PARS images calculated from the returning interrogation beam reveal vascular structures, constituting an image representation from which the physical characteristic of the blood vessel is determined; ¶[0004]: "Photoacoustic microscopy has shown significant potential for imaging vascular structures from macro-vessels all the way down to micro-vessels", Reza further teaches that characterization of vascular structures, i.e., determining a physical characteristic of the blood vessel, is based on those PARS images, as recited in the claim).
Regarding claim 5, the modified Reza teaches a method wherein the determining of the physical characteristic of the blood vessel comprises determining a displacement of the skin of the user, the physical characteristic of the blood vessel determined based on the displacement of the skin. The modified Reza teaches that the PARS system is capable of detecting surface displacement: "The PARS system is capable of detecting noncontact measurement of the displacement caused by ultrasound signals from an ultrasound transducer" (Reza, ¶[0057]), and that surface oscillations of the tissue caused by pressure modulation are a source of the detected signal from the interrogation beam: "Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal" (Reza, ¶[0109]). It does not, however, expressly teach that the physical characteristic of the blood vessel determined from the detected CW reflection is specifically the displacement of the skin, nor that the physical characteristic of the blood vessel is determined based on that skin displacement.
Antonelli teaches that the CW reflected beam encodes the displacement of the skin surface over the artery: "Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position to a position represented by plane 28" (Antonelli, ¶[0030]), and that "[t]he reflected laser light beam 34 is modulated by the movement of skin surface 26 by means of a Doppler shift in the optical wavelength, as compared to the original laser beam 32 produced by laser source 14" (Antonelli, ¶[0032]). Antonelli further expressly teaches that skin displacement is used as the physical quantity from which the physiological parameter is derived: "The signal processing unit provides skin displacement information, which more directly corresponds to the blood pressure waveform than a measured velocity signal. The blood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]). The skin displacement ΔX is causally produced by the pulsatile radial expansion of the underlying vessel wall and thus directly reflects a physical characteristic of the blood vessel, as recited in the claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Antonelli to determine skin displacement as the physical characteristic of the blood vessel from the detected CW reflection in order determine the physical characteristic. Reza already demonstrates that the PARS interrogation architecture is sensitive to surface displacement caused by subsurface pressure waves, while Antonelli demonstrates that the CW reflected beam from skin over an artery directly encodes skin displacement ΔX driven by the underlying vessel. A person of ordinary skill in the art would have been motivated to apply Antonelli's displacement-extraction framework to the modified Reza's more sensitive optical detection scheme as a predictable extension, yielding the benefit of a direct, quantitative physical measurement of vessel-driven skin motion as the intermediate quantity for physiological parameter determination, with a reasonable expectation of success given that both references rely on the same tissue surface displacement signal produced by the same underlying arterial mechanics.
Regarding claim 6, the modified Reza teaches a method wherein the determining of the displacement of the skin of the user comprises using a focus differential indicative of a distance to the skin, a frequency difference associated with the reflection of the continuous optical signal, a phase difference associated with the reflection of the continuous optical signal, or a combination thereof (Reza, ¶[0047]: "A long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities", Reza expressly teaches that the displacement of the tissue surface is determined interferometrically from the returning CW interrogation beam, which by definition involves detecting a phase difference associated with the reflection of the continuous optical signal as recited in the claim; ¶[0068]: "PARS can be integrated with any interferometry designs such as common path interferometer...Michelson interferometer, Fizeau interferometer, Ramsey interferometer, Sagnac interferometer, Fabry-Perot interferometer and Mach-Zehnder interferometer", Reza further teaches that the interferometric detection of the returning interrogation beam, i.e., the phase and frequency difference readout, is compatible with a broad range of standard interferometer architectures, each of which operates by detecting phase or frequency differences in the reflected optical signal to determine surface displacement).
Regarding claim 7, the modified Reza teaches a method wherein the one or more pulsed optical signals comprise one or more optical signals emitted by a first light source, the continuous optical signal comprises a continuous optical signal emitted by a second light source, and the first light source and the second light source are disposed at different locations of a device (Reza, ¶[0060]: "In one example, a nanosecond-pulsed laser was used", Reza expressly teaches a dedicated pulsed laser source for generating the excitation optical signals, corresponding to the first light source as recited in the claim; ¶[0116]: "For the receiver arm a continuous wavelength (CW) C-band laser with 100-kHz linewidth (TLK-L1550R, Thorlabs Inc., New Jersey) was used", Reza expressly teaches a dedicated CW laser source for the interrogation beam, corresponding to the second light source as recited in the claim; ¶[0114] and FIG. 20: Reza depicts the experimental PARS system in FIG. 20, showing pulsed laser 12 and detection laser 14 as entirely separate, spatially distinct components within the system architecture, with their respective beams combined only downstream at dual beam combiner 2218 before reaching the sample, expressly teaching that the first and second light sources occupy different locations within the device; ¶[0118] and FIG. 22: Reza further depicts in FIG. 22 an alternative system configuration in which "pulse laser 12 provides an additional beam to polarization maintaining single mode fiber 2402, lens system 42, and then to beam combiner unit 30" while continuous wave lasers 2404 and 2406 provide separate beams that are likewise combined at beam combiner unit 30 before reaching sample 18, again expressly teaching two light sources disposed at different locations within the device as recited in the claim).
Regarding claim 17, Reza teaches that a non-transitory computer-readable apparatus comprising a storage medium, the storage medium comprising a plurality of instructions configured to, when executed by a control system, cause an apparatus to (Reza, ¶[0051]: the PARS detection unit 22 is described as comprising "a photodiode 46, amplifier 48, data acquisition unit 50 and a computer", Reza expressly teaches that the PARS system includes a computer as an integral component of the detection and data processing architecture; ¶[0018]: "there may be a processor that calculates an image of the sample based on the returning portion of the interrogation beam" and claim 9: "a processor that calculates an image of the sample based on the returning portion of the interrogation beam", Reza further teaches that the computer executes defined processing operations on the detected optical return signal; a computer of the type expressly disclosed in Reza at ¶[0051] necessarily and implicitly comprises a non-transitory computer-readable storage medium, such as a hard disk drive, ROM, or flash memory, on which the instructions controlling the data acquisition and processing operations are stored, as such storage is a fundamental and inseparable architectural component of any computer; a person of ordinary skill in the art would therefore have understood that the computer disclosed in Reza at ¶[0051] constitutes a non-transitory computer-readable apparatus comprising a storage medium on which instructions for performing the recited steps are stored, and that configuring such stored instructions to cause the apparatus to perform the steps described below requires no inventive step beyond the express teachings of Reza): transmit a continuous optical signal toward a skin of the user, the skin being proximate to a blood vessel of the user (Reza, ¶[0116]: "For the receiver arm a continuous wavelength (CW) C-band laser with 100-kHz linewidth...was used" and ¶[0114]: "Detection laser 14 may be a continuous wave laser", Reza expressly and unambiguously teaches that the interrogation or detection optical signal is a continuous-wave (CW) optical signal; Abstract: "an interrogation beam incident on the sample at the excitation location, a portion of the interrogation beam returning from the sample that is indicative of the generated ultrasonic signals" and ¶[0049]: the acoustic signatures are interrogated using "a long-coherence length probe beam...co-focused and co-aligned with the excitation spots on sample 18", Reza teaches that the CW interrogation beam is directed toward the sample at the target location; ¶[0046]: "capable of in vivo optical-resolution photoacoustic microscopy" and ¶[0127]: "FIGS. 19a-19d depict in vivo PARS images of a mouse ear, and FIGS. 23a-23c and 24 show in vivo PARS images of a 100 g rat's ear", Reza teaches that the interrogation beam is used in vivo on the ear tissue of a living subject (the ear is skin-covered tissue directly overlying blood vessels, supporting that the optical signal is directed toward the skin of a living subject); ¶[0109]: “Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal”, Reza teaches that the returning portion of the interrogation beam includes reflection from the oscillating outer tissue surface; ¶[0105]: T_t is “the transmission intensity coefficient at the air-tissue interface”, Reza further teaches that this surface reflection occurs at the air-tissue interface, i.e., the outer surface of the biological tissue, such that the detected returning interrogation beam includes reflection from the tissue surface previously established as the skin of the living subject; ¶[0123]: "FIG. 14a shows multifocus PARS images revealing both capillary beds and bigger blood vessels", Reza teaches that the biological tissue interrogated by the PARS system includes capillary beds and larger blood vessels underlying the interrogated surface, supporting that the interrogated skin surface is proximate to a blood vessel); during the transmitting of the continuous optical signal, cause generation of one or more acoustic signals from a blood vessel of the user by transmitting one or more pulsed optical signals toward the blood vessel (Reza, Abstract: "an excitation beam configured to generate ultrasonic signals in the sample at an excitation location", Reza teaches an excitation beam configured to generate ultrasonic signals in the sample; ¶[0046]: "Photoacoustic imaging is an emerging biomedical imaging modality that uses laser light to excite tissues. Energy absorbed by chromophores or any other absorber is converted to acoustic waves due to thermo-elastic expansion", Reza teaches that laser excitation of tissue generates acoustic waves; ¶[0047]: "at 532-nm excitation wavelength, imaging a capillary with 500 mJ/cm² local fluence would result in an initial pressure on the order of 100 MPa locally", Reza expressly teaches excitation of a capillary, i.e., a blood vessel, to generate an acoustic pressure response; ¶[0060]: "In one example, a nanosecond-pulsed laser was used" and ¶[0133]: "laser pulses should be preferably shorter than 2 µm/1500 m/s=1.3 ns, which would require a laser with pulse widths of a nanosecond or shorter", Reza teaches pulsed laser excitation with nanosecond or shorter pulse widths); during the generation of the one or more acoustic signals, detect a reflection of the continuous optical signal from the skin of the user (Reza, Abstract: "a portion of the interrogation beam returning from the sample that is indicative of the generated ultrasonic signals" and "a detector that detects the returning portion of the interrogation beam", Reza teaches detecting a returning portion of the interrogation beam from the sample during the photoacoustic process; ¶[0047]: "large optically-focused photoacoustic signals are detected as close to the photoacoustic source as possible, which is done optically by co-focusing an interrogation beam with the excitation spot. A long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities", Reza teaches optical detection of local photoacoustic vibrations using the CW interrogation laser at the excitation site; ¶[0015]: "a portion of the interrogation beam returning from the sample...is indicative of the generated ultrasonic signals", Reza further teaches that the detected return corresponds to interrogation-beam detection at the photoacoustic excitation location; ¶[0109]: "Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal", Reza teaches detecting the reflection of the CW interrogation beam from the tissue surface during acoustic signal generation).
Also regarding claim 17, Reza does not expressly teach determining a physiological parameter of the user based on the detected reflection of the continuous optical signal. Rather, Reza teaches detecting and processing the returning portion of the interrogation beam, including that "there may be a processor that calculates an image of the sample based on the returning portion of the interrogation beam" (Reza, ¶[0018]). Reza further discloses that photoacoustic imaging may be used for functional imaging applications such as imaging blood oxygen saturation (Reza, ¶[0046]), indicating that the detected interrogation signal can be processed to derive biological information, but Reza does not expressly disclose determining a physiological parameter of the user based on the detected reflection of the continuous optical signal.
Antonelli expressly teaches this limitation. Antonelli teaches a "non-contact method and apparatus for continuously monitoring physiological events such as the anatomical blood pressure waveform" (Antonelli, ¶[0028]). Antonelli teaches directing a continuous-wave laser beam toward the skin over an artery and detecting the reflected beam: "[a] low-power (1 mW), continuous, red laser beam is directed onto the measurement surface. By interfering the detected beam that was reflected by the measurement surface with a reference beam within the LDV, a measure of the surface velocity is obtained" (Antonelli, ¶[0019]). Antonelli teaches that the computer correlates the detected optical return signal to the blood pressure in the underlying artery: "The computer 30 can be calibrated to correlate the velocity and motion of the skin surface 26 to the pressure of the blood in the artery beneath skin surface" (Antonelli, ¶[0037]). Antonelli further teaches that "[i]t is necessary to convert the measured velocity into a skin displacement signal. This is a critical aspect of the invention in order to provide medical personnel a waveform that is similar to those achieved by catheter pressure sensor" (Antonelli, ¶[0043]). Antonelli therefore expressly teaches determining a physiological parameter (blood pressure) based on the detected reflection of a continuous optical signal from skin proximate to a blood vessel.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Antonelli to determine a physiological parameter of the user based on the detected reflection of the continuous optical signal. Both Reza and Antonelli use a continuous-wave laser directed at biological tissue over blood vessels as the interrogation modality, and both rely on detecting the reflected or returning CW beam. The combination would have been feasible because Reza already optically detects and processes the returning interrogation beam at the photoacoustic excitation site, while Antonelli demonstrates that such reflected CW optical signals from skin over an artery encode arterial pressure information sufficient to derive blood pressure waveforms equivalent to catheter measurements. A person of ordinary skill in the art would have been motivated to apply Antonelli's signal-processing output framework to Reza's more sensitive PARS interrogation architecture as a predictable extension, yielding the additional benefit of physiological monitoring from the same optical interrogation signal already present in Reza's system, with a reasonable expectation of success given that both systems measure optically detected displacement or pressure signals originating from the same tissue-vessel interaction.
Regarding claim 18, claim 18 further recites that the plurality of instructions are further configured to, when executed by the control system, cause the apparatus to: determine a physical characteristic of the blood vessel based at least on the reflection of the continuous optical signal, wherein the physical characteristic of the blood vessel comprises a distension experienced by the blood vessel during the generation of the one or more acoustic signals, or a pulse wave velocity (PWV) of the blood vessel; and determine the physiological parameter of the user based on the physical characteristic of the blood vessel, wherein the physiological parameter of the user comprises a blood pressure of the user. The modified Reza teaches that the returning interrogation beam is processed to characterize subsurface vascular structures: "there may be a processor that calculates an image of the sample based on the returning portion of the interrogation beam" (Reza, ¶[0018]), and that the PARS system is capable of imaging vascular structures including microvessels and larger blood vessels (Reza, ¶[0004]: "Photoacoustic microscopy has shown significant potential for imaging vascular structures from macro-vessels all the way down to micro-vessels"). However, the modified Reza does not expressly teach that the instructions cause the apparatus to determine a discrete physical characteristic of the blood vessel from the CW reflection and to determine the physiological parameter based on that physical characteristic, nor that the physical characteristic comprises a distension experienced by the blood vessel during the generation of the one or more acoustic signals, nor that the physiological parameter comprises blood pressure of the user.
Antonelli expressly teaches all of these limitations. As to determining a physical characteristic of the blood vessel based on the reflection of the continuous optical signal, Antonelli teaches that the CW reflected beam encodes the displacement of the skin surface over the underlying artery: "Blood flowing through the artery directly below the skin causes skin surface 26 to pulsate in a rhythm corresponding to ventricular contractions of the subject's heart. Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position to a position represented by plane 28" (Antonelli, ¶[0030]), and that "[t]he reflected laser light beam 34 is modulated by the movement of skin surface 26 by means of a Doppler shift in the optical wavelength, as compared to the original laser beam 32 produced by laser source 14" (Antonelli, ¶[0032]). Antonelli further teaches that skin displacement is extracted from the detected CW optical return: "The signal processing unit provides skin displacement information, which more directly corresponds to the blood pressure waveform than a measured velocity signal. The blood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]).
As to the physical characteristic comprising a distension experienced by the blood vessel during the generation of the one or more acoustic signals, the skin displacement ΔX detected by the CW reflection is causally and directly produced by the radial expansion of the arterial wall during the cardiac pressure pulse, which is the definition of arterial distension experienced by the blood vessel. One of ordinary skill in the art would understand ΔX as measured by Antonelli to represent a distension experienced by the blood vessel as recited in the claim, occurring during the generation of the pulsatile acoustic signals driven by the underlying arterial mechanics.
As to determining the physiological parameter of the user based on the physical characteristic, and the physiological parameter comprising blood pressure of the user, Antonelli expressly teaches that the computer uses the detected skin displacement to derive blood pressure: "The computer 30 can be calibrated to correlate the velocity and motion of the skin surface 26 to the pressure of the blood in the artery beneath skin surface 26" (Antonelli, ¶[0037]), and that "[i]t is necessary to convert the measured velocity into a skin displacement signal. This is a critical aspect of the invention in order to provide medical personnel a waveform that is similar to those achieved by catheter pressure sensor" (Antonelli, ¶[0043]). Antonelli thereby expressly teaches determining blood pressure of the user, the physiological parameter, based on the distension experienced by the blood vessel as derived from the CW reflection.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza to configure the stored instructions to cause the apparatus to determine a distension experienced by the blood vessel from the detected CW reflection as the physical characteristic, and to determine blood pressure of the user from that physical characteristic. The modified Reza provides a highly sensitive PARS interrogation architecture in which the returning CW beam encodes subsurface tissue dynamics, and Antonelli demonstrates that the CW reflection from skin over an artery directly encodes skin displacement ΔX driven by the pulsatile radial expansion of the underlying vessel, and that blood pressure can be derived from that displacement with accuracy comparable to catheter measurements. A person of ordinary skill in the art would have been motivated to implement Antonelli's two-step determination framework in the stored instructions of the combined system as a predictable extension, yielding the benefit of a physiologically grounded blood pressure output anchored to a directly measured physical characteristic of the blood vessel rather than a purely empirical surface calibration, with a reasonable expectation of success given that both references rely on the same tissue-vessel-skin displacement relationship and use the same class of reflected CW optical return signal as the measurement basis.
Regarding claim 19, the modified Reza teaches that the determination of a displacement of the skin of the user using a focus differential indicative of a distance to the skin, a frequency difference associated with the reflection of the continuous optical signal, a phase difference associated with the reflection of the continuous optical signal, or a combination thereof (Reza, ¶[0047]: "A long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities", Reza expressly teaches that the displacement of the tissue surface is determined interferometrically from the returning CW interrogation beam, which by definition involves detecting a phase difference associated with the reflection of the continuous optical signal as recited in the claim, satisfying the phase difference alternative of the disjunctive; ¶[0068]: "PARS can be integrated with any interferometry designs such as common path interferometer...Michelson interferometer, Fizeau interferometer, Ramsey interferometer, Sagnac interferometer, Fabry-Perot interferometer and Mach-Zehnder interferometer", Reza further teaches that the interferometric detection of the returning interrogation beam is compatible with a broad range of standard interferometer architectures, each of which operates by detecting phase differences in the reflected optical signal to determine surface displacement).
Also regarding claim 19, the modified Reza does not explicitly teach that the determination of the physical characteristic of the blood vessel comprising determination of a displacement of the skin of the user. Rather, the modified Reza teaches that the PARS system is capable of detecting surface displacement caused by subsurface acoustic pressure: "The PARS system is capable of detecting noncontact measurement of the displacement caused by ultrasound signals from an ultrasound transducer" (Reza, ¶[0057]), and that surface oscillations caused by pressure modulation modulate the CW reflection detected by the receiver: "Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal" (Reza, ¶[0109]). The modified Reza does not, however, expressly teach that the instructions cause the apparatus to determine a displacement of the skin of the user as the physical characteristic of the blood vessel, nor that the physical characteristic of the blood vessel is determined based on that skin displacement.
Antonelli expressly teaches this limitation. Antonelli teaches that the CW reflected beam encodes the displacement of the skin surface over the underlying artery: "Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position to a position represented by plane 28" (Antonelli, ¶[0030]), and that "[t]he reflected laser light beam 34 is modulated by the movement of skin surface 26 by means of a Doppler shift in the optical wavelength, as compared to the original laser beam 32 produced by laser source 14" (Antonelli, ¶[0032]). Antonelli further expressly teaches that skin displacement is extracted from the detected CW optical return as the physical quantity from which the physiological parameter is derived: "The signal processing unit provides skin displacement information, which more directly corresponds to the blood pressure waveform than a measured velocity signal. The blood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]). The skin displacement ΔX is causally produced by the pulsatile radial expansion of the underlying blood vessel and thus directly reflects a physical characteristic of the blood vessel, establishing that the physical characteristic of the blood vessel is determined based on the displacement of the skin as recited in the claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Antonelli to configure the stored instructions to cause the apparatus to determine a displacement of the skin of the user as the physical characteristic of the blood vessel from the detected CW reflection. Reza already demonstrates that the PARS interrogation architecture is sensitive to surface displacement caused by subsurface pressure waves, while Antonelli demonstrates that the CW reflected beam from skin over an artery directly encodes skin displacement ΔX driven by the dynamics of the underlying blood vessel. A person of ordinary skill in the art would have been motivated to apply Antonelli's displacement-extraction framework to the more sensitive optical detection scheme of the combined system as a predictable extension, yielding the benefit of a direct, quantitative physical measurement of vessel-driven skin motion as the intermediate quantity for physiological parameter determination, with a reasonable expectation of success given that both references rely on the same tissue surface displacement signal produced by the same underlying arterial mechanics.
Claims 8 and 10-16 are rejected under 35 U.S.C. 103 as being unpatentable over Reza et al. (US-20160113507-A1), hereto referred as Reza, and further in view of Antonelli et al. (US-20090299197-A1), hereto referred as Antonelli, and further in view of Page et al. (US-20050054907-A1), hereto referred as Page.
The modified Reza teaches claim 1 as described above.
Regarding claim 8, claim 8 further recites a method wherein the device comprises a wearable device, and further comprises a receiver configured to detect the reflection of the continuous optical signal. As to a receiver configured to detect the reflection of the continuous optical signal, the modified Reza expressly teaches this limitation through Reza itself (Reza, Abstract: "a detector that detects the returning portion of the interrogation beam", Reza expressly teaches a detector that receives the reflection of the CW interrogation beam from the sample, constituting a receiver configured to detect the reflection of the continuous optical signal as recited in the claim; ¶[0117]: "the reflected light back through the wave-plate creating 90° polarization which then reflects at the polarizing beam-splitter in order to guide the maximum possible intensity of reflected light to a 150 MHz-bandwidth InGaAs photodiode (PDA10CF, Thorlabs Inc., New Jersey)", Reza further expressly teaches a specific photodiode receiver configured to detect the returning reflected interrogation beam). The modified Reza does not, however, expressly teach that the device is a wearable device. Reza teaches a benchtop optical microscopy system.
Page teaches a "portable, non-invasive system[] for blood analyte measurement integrated with a common article worn about the body" (Page, ¶[0065]) in which all measurement components including an optical source and acoustic detector are integrated within a rigid wristwatch case: "a rigid case operable for containing; a processing unit in communication with an optical source; and an acoustic detector...the bottom side suitable for supporting said acoustic detector and said optical source whereby they may be coupled to human tissue" (Page, claim 1, FIG. 5). Page further teaches that the wristwatch case "may form an enclosed space of between one and ten cubic centimeters such that the article may be easily worn about the body" (Page, ¶[0057]), and that the apparatus "is held in good and intimate contact with respect to the top of the wrist where excellent measurement may be made" (Page, ¶[0061]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Page to implement the photoacoustic measurement system in a wearable form factor. Page expressly demonstrates that photoacoustic measurement systems employing an optical source and a detector can be miniaturized and integrated into a wristwatch-sized wearable article for continuous, non-invasive physiological monitoring. A person of ordinary skill in the art would have been motivated to apply Page's wearable integration approach to the modified Reza's PARS architecture because doing so would yield the direct benefit of enabling continuous, unobtrusive physiological monitoring without requiring a stationary benchtop setup, with a reasonable expectation of success given that both references employ the same fundamental photoacoustic measurement principle using an optical source directed toward tissue and a detector receiving the optical return signal.
Regarding claim 10, Reza teaches a user device comprising: a first light source system configured to transmit one or more first optical signals toward the target object, the one or more first optical signals configured to generate one or more acoustic signals from the target object (Reza, Abstract: "an excitation beam configured to generate ultrasonic signals in the sample at an excitation location", Reza teaches an excitation beam configured to generate ultrasonic signals in the sample, constituting a first light source system transmitting optical signals that generate acoustic signals from the target object; ¶[0046]: "Photoacoustic imaging is an emerging biomedical imaging modality that uses laser light to excite tissues. Energy absorbed by chromophores or any other absorber is converted to acoustic waves due to thermo-elastic expansion", Reza teaches that laser excitation of tissue generates acoustic waves; ¶[0047]: "at 532-nm excitation wavelength, imaging a capillary with 500 mJ/cm² local fluence would result in an initial pressure on the order of 100 MPa locally", Reza expressly teaches excitation of a capillary to generate an acoustic pressure response; ¶[0060]: "In one example, a nanosecond-pulsed laser was used" and ¶[0133]: "laser pulses should be preferably shorter than 2 µm/1500 m/s=1.3 ns, which would require a laser with pulse widths of a nanosecond or shorter", Reza teaches pulsed laser excitation with nanosecond or shorter pulse widths); a second light source system configured to transmit a second optical signal toward a skin of the user, the skin being proximate to the target object of the user (Reza, ¶[0116]: "For the receiver arm a continuous wavelength (CW) C-band laser with 100-kHz linewidth...was used" and ¶[0114]: "Detection laser 14 may be a continuous wave laser", Reza expressly teaches that the interrogation or detection optical signal is a continuous-wave (CW) optical signal emitted by a dedicated detection laser, constituting a second light source system; Abstract: "an interrogation beam incident on the sample at the excitation location, a portion of the interrogation beam returning from the sample that is indicative of the generated ultrasonic signals" and ¶[0049]: the acoustic signatures are interrogated using "a long-coherence length probe beam...co-focused and co-aligned with the excitation spots on sample 18", Reza teaches that the CW interrogation beam is directed toward the sample at the target location; ¶[0046]: "capable of in vivo optical-resolution photoacoustic microscopy" and ¶[0127]: "FIGS. 19a-19d depict in vivo PARS images of a mouse ear, and FIGS. 23a-23c and 24 show in vivo PARS images of a 100 g rat's ear", Reza teaches that the interrogation beam is used in vivo on the ear tissue of a living subject; ¶[0109]: “Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal”, Reza teaches that the returning portion of the interrogation beam includes reflection from the oscillating outer tissue surface; ¶[0105]: T_t is “the transmission intensity coefficient at the air-tissue interface”, Reza further teaches that this surface reflection occurs at the air-tissue interface, i.e., the outer surface of the biological tissue, such that the detected returning interrogation beam includes reflection from the tissue surface previously established as the skin of the living subject; ¶[0123]: "FIG. 14a shows multifocus PARS images revealing both capillary beds and bigger blood vessels", Reza teaches that the biological tissue interrogated by the PARS system includes capillary beds and larger blood vessels underlying the interrogated surface, supporting that the interrogated skin surface is proximate to a target object comprising a blood vessel); a receiver configured to detect a reflection of the second optical signal from the skin of the user during the generation of the one or more acoustic signals, the reflection of the second optical signal indicative of a physiological parameter of the user (Reza, Abstract: "a portion of the interrogation beam returning from the sample that is indicative of the generated ultrasonic signals" and "a detector that detects the returning portion of the interrogation beam", Reza teaches a detector configured to receive the returning portion of the CW interrogation beam from the sample during the photoacoustic process, constituting a receiver configured to detect a reflection of the second optical signal from the skin; ¶[0047]: "large optically-focused photoacoustic signals are detected as close to the photoacoustic source as possible, which is done optically by co-focusing an interrogation beam with the excitation spot. A long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities", Reza teaches optical detection of local photoacoustic vibrations using the CW interrogation laser at the excitation site; ¶[0109]: "Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal", Reza teaches detecting the reflection of the CW interrogation beam from the tissue surface during acoustic signal generation).
Also regarding claim 10, Reza does not expressly teach that the detected reflection of the second optical signal is used to derive a physiological parameter of the user. Reza discloses processing of the returning interrogation beam to form images and to detect photoacoustic signals (Reza, ¶[0018]), but does not expressly disclose processing the CW return to extract a physiological parameter such as blood pressure.
Antonelli expressly teaches this limitation. Antonelli teaches a "non-contact method and apparatus for continuously monitoring physiological events such as the anatomical blood pressure waveform" (Antonelli, ¶[0028]). Antonelli teaches directing a continuous-wave laser beam toward the skin over an artery and detecting the reflected beam: "[a] low-power (1 mW), continuous, red laser beam is directed onto the measurement surface. By interfering the detected beam that was reflected by the measurement surface with a reference beam within the LDV, a measure of the surface velocity is obtained" (Antonelli, ¶[0019]). Antonelli further teaches that the signal processor derives blood pressure waveform information from the detected reflected beam: "The computer can be calibrated to correlate the velocity and motion of the skin surface to the pressure of the blood in the artery beneath skin surface" (Antonelli, ¶[0037]), and that "[u]tilizing the pulsation velocity of skin surface over time, computer can plot a highly accurate representative blood pulse waveform" (Antonelli, ¶[0038]). Antonelli therefore expressly teaches that a reflected CW optical signal from the skin over an artery is processed to derive blood pressure waveform information, establishing that such a reflected signal is indicative of a physiological parameter of the user.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Reza in view of Antonelli to configure the receiver to detect a reflection of the second optical signal that is indicative of a physiological parameter of the user. Reza already provides a dual-optical-source architecture in which a CW interrogation beam is reflected from tissue and detected by a photodetector, and Antonelli demonstrates that a reflected CW optical signal from skin over an artery encodes blood pressure waveform information sufficient to derive arterial pressure equivalent to catheter measurements. A person of ordinary skill in the art would have been motivated to apply Antonelli's output-processing framework to Reza's more sensitive PARS optical return detection architecture as a predictable extension, yielding the additional benefit of continuous physiological monitoring from the same reflected CW optical signal already detected in Reza's system, with a reasonable expectation of success given that both references detect a reflected continuous-wave optical beam from tissue overlying blood vessels and process that return signal to extract physiological information.
Also regarding claim 10, the modified Reza does not expressly teach a wearable structure securable to the user and comprising the first light source system, the second light source system, and the receiver. Reza teaches a benchtop optical microscopy system and does not disclose miniaturization or integration into a body-worn device.
Page teaches a "portable, non-invasive system[] for blood analyte measurement integrated with a common article worn about the body" (Page, ¶[0065]) in which all measurement components including an optical source and acoustic detector are integrated within a rigid wristwatch case: "a rigid case operable for containing; a processing unit in communication with an optical source; and an acoustic detector...the bottom side suitable for supporting said acoustic detector and said optical source whereby they may be coupled to human tissue" (Page, claim 1, FIG. 5). Page further teaches that the wristwatch case "may form an enclosed space of between one and ten cubic centimeters such that the article may be easily worn about the body" (Page, ¶[0057]), and that the apparatus "is held in good and intimate contact with respect to the top of the wrist where excellent measurement may be made" (Page, ¶[0061]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Page to implement the photoacoustic physiological monitoring system in a wearable structure securable to the user. Reza and Antonelli together provide the optical source and optical return detection architecture for deriving physiological parameters, and Page expressly demonstrates that photoacoustic sensing hardware, including an optical source and detector, may be miniaturized and integrated into a compact body-worn device. A person of ordinary skill in the art would have been motivated to apply Page's wearable integration approach to the combined Reza-Antonelli architecture because doing so would yield the direct benefit of enabling continuous, unobtrusive physiological monitoring without requiring a stationary benchtop setup, with a reasonable expectation of success given that Page expressly demonstrates the integration of photoacoustic optical sources and detectors into a body-worn physiological monitoring device.
Regarding claim 11, claim 11 further recites a control system, the control system configured to: determine a physical characteristic of the target object based at least on the reflection of the second optical signal; and determine the physiological parameter of the user based on the physical characteristic of the target object. The modified Reza teaches that the returning interrogation beam encodes information about the sample at the excitation location, and that a processor calculates information about the sample based on the returning portion of the interrogation beam (Reza, ¶[0018]). Reza further teaches that the PARS system detects surface oscillations caused by the photoacoustic pressure, with the detected interrogation beam return reflecting modulation of the tissue surface (Reza, ¶[0109]: "Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal"). The modified Reza therefore already teaches a processor receiving the CW optical return signal and computing information about the tissue sample from it.
The modified Reza does not, however, expressly teach that the control system determines a physical characteristic of the target object from the CW reflection, or that the physiological parameter is then derived from that physical characteristic, as a distinct two-step determination.
Antonelli expressly teaches both steps. As to the physical characteristic, Antonelli teaches that the reflected CW laser beam is processed to determine the displacement of the skin surface over the underlying artery: "The signal processing unit provides skin displacement information, which more directly corresponds to the blood pressure waveform than a measured velocity signal. The blood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]). Antonelli further teaches that "Blood flowing through the artery directly below the skin causes skin surface 26 to pulsate in a rhythm corresponding to ventricular contractions of the subject's heart. Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position" (Antonelli, ¶[0030]), expressly identifying skin surface displacement ΔX as the physical characteristic determined from the reflected CW optical signal. As to the physiological parameter being derived from that physical characteristic, Antonelli expressly teaches the second step as well: "The computer can be calibrated to correlate the velocity and motion of the skin surface to the pressure of the blood in the artery beneath skin surface" (Antonelli, ¶[0037]), and "[i]t is necessary to convert the measured velocity into a skin displacement signal. This is a critical aspect of the invention in order to provide medical personnel a waveform that is similar to those achieved by catheter pressure sensor" (Antonelli, ¶[0043]). Antonelli therefore expressly teaches a two-step determination in which skin surface displacement ΔX is first derived from the reflected CW optical signal as the physical characteristic of the target object, and blood pressure is then determined from that physical characteristic as the physiological parameter.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have configured the control system of the modified Reza in view of Antonelli to determine a physical characteristic of the target object based at least on the reflection of the second optical signal and determine the physiological parameter of the user based on the physical characteristic of the target object. Reza already provides a processor that receives and processes the CW optical return signal from the tissue surface, and Antonelli demonstrates that such a return signal encodes tissue surface displacement information that is directly correlated to arterial blood pressure. A person of ordinary skill in the art would have been motivated to implement Antonelli's two-step determination framework (first extracting surface displacement as a physical characteristic, then correlating that displacement to blood pressure as the physiological parameter) in the control system of the combined device, because doing so produces a more physiologically meaningful and clinically useful output from the CW optical return signal already present in the system, with a reasonable expectation of success given that Antonelli expressly demonstrates this determination using the same class of reflected CW optical signal from skin over an artery.
Regarding claim 12, claim 12 further recites a device wherein the physical characteristic of the target object comprises a distension experienced by the target object during the generation of the one or more acoustic signals, or a pulse wave velocity (PWV) of the target object, and wherein the physiological parameter of the user comprises a blood pressure of the user. The modified Reza teaches that blood flowing through the artery causes the overlying skin surface to pulsate and that the CW reflected beam encodes the resulting skin surface displacement as the physical characteristic of the target object: "Blood flowing through the artery directly below the skin causes skin surface 26 to pulsate in a rhythm corresponding to ventricular contractions of the subject's heart. Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position to a position represented by plane 28" (Antonelli, ¶[0030]). This outward displacement of the skin surface is causally and directly produced by the radial expansion of the arterial wall during the cardiac pressure pulse, which is the definition of arterial distension experienced by the target object during the generation of the acoustic signals. The skin displacement ΔX detected from the CW optical reflection thus corresponds to and is a surface manifestation of that distension, and one of ordinary skill in the art would understand ΔX as measured by Antonelli to represent a distension experienced by the target object as recited in the claim. It further teaches that the blood pressure waveform is obtained by integrating the velocity signal to obtain surface displacement: "The signal processing unit provides skin displacement information, which more directly corresponds to the blood pressure waveform than a measured velocity signal. The blood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]), directly linking the detected displacement (distension of the target object) to the blood pressure determination, which is precisely the relationship recited in the claim. The modified Reza does not, however, expressly characterize the physical characteristic as distension of the blood vessel.
As to blood pressure as the physiological parameter, Antonelli expressly and repeatedly teaches this limitation. Antonelli teaches that "[t]he computer 30 can be calibrated to correlate the velocity and motion of the skin surface 26 to the pressure of the blood in the artery beneath skin surface 26" (Antonelli, ¶[0037]), and that the result is "a highly accurate representative blood pulse waveform" (Antonelli, ¶[0038]). Antonelli further characterizes the output as "a waveform that is similar to those achieved by catheter pressure sensor" (Antonelli, ¶[0043]). Blood pressure is thus expressly taught as the physiological parameter by Antonelli within the modified Reza.
As to distension as the physical characteristic, Antonelli expressly teaches that the pulsation of blood through the artery causes the overlying skin surface to move an amount ΔX from its resting position (Antonelli, ¶[0030]: "Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position to a position represented by plane 28"). This outward displacement of the skin surface is causally and directly produced by the radial expansion of the arterial wall during the cardiac pressure pulse, which is the definition of arterial distension. The skin displacement ΔX detected by the CW reflection thus corresponds to and is a surface manifestation of vessel distension, and one of ordinary skill in the art would understand ΔX as measured by Antonelli to represent vessel distension as recited in the claim. Antonelli further teaches that "[b]lood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]), directly linking the detected displacement (distension) to the blood pressure determination, which is precisely the relationship recited in the claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further configured the control system of the modified Reza as further modified by Page to determine a distension experienced by the target object during the generation of the one or more acoustic signals as the physical characteristic from the detected CW reflection, and to determine blood pressure of the user from that distension. Reza's PARS interrogation architecture provides a highly sensitive, non-contact means of detecting the returning CW beam modulated by surface displacement over the target object. Antonelli, already incorporated within the combination, expressly links that surface displacement to the pulsatile radial expansion of the underlying artery (i.e., distension experienced by the target object during acoustic signal generation) and to blood pressure derivation. Applying these teachings to the control system of the combined device to extract distension specifically as the physical characteristic, and blood pressure of the user as the physiological parameter derived therefrom, would be a predictable extension requiring no new physical principles and using the same tissue-vessel-skin displacement relationship already taught by Antonelli. The benefit of this combination is that it grounds the blood pressure determination in a specific, physiologically meaningful intermediate quantity (distension of the target object) governed by well-characterized arterial mechanics, rather than a purely empirical surface calibration, with a reasonable expectation of success given that all three references operate on the same pulsatile tissue-vessel interaction and that Antonelli expressly demonstrates this distension-to-blood-pressure determination using the same class of reflected CW optical return signal.
Regarding claim 13, claim 13 further recites a device wherein the determination of the physical characteristic of the target object comprises determination of a displacement of the skin, the physical characteristic of the target object determined based on the displacement of the skin. The modified Reza teaches that the PARS system is capable of detecting surface displacement: "The PARS system is capable of detecting noncontact measurement of the displacement caused by ultrasound signals from an ultrasound transducer" (Reza, ¶[0057]), and that surface oscillations of the tissue caused by pressure modulation are a source of the detected signal from the interrogation beam: "Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal" (Reza, ¶[0109]). The modified Reza does not expressly teach that the control system's determination of the physical characteristic of the target object specifically comprises determination of a displacement of the skin, nor that the physical characteristic of the target object is determined based on that skin displacement, as a distinct two-step operation.
Antonelli teaches that the CW reflected beam encodes the displacement of the skin surface over the underlying artery: "Skin surface 26 moves an amount ΔX, as indicated by numeral 24, from its initial position to a position represented by plane 28" (Antonelli, ¶[0030]), and that "[t]he reflected laser light beam 34 is modulated by the movement of skin surface 26 by means of a Doppler shift in the optical wavelength, as compared to the original laser beam 32 produced by laser source 14" (Antonelli, ¶[0032]). Antonelli further expressly teaches that skin displacement is extracted from the detected CW optical return as the quantity from which the physiological parameter is derived: "The signal processing unit provides skin displacement information, which more directly corresponds to the blood pressure waveform than a measured velocity signal. The blood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]). As to the physical characteristic of the target object being determined based on that skin displacement, the skin displacement ΔX is causally produced by the pulsatile radial expansion of the underlying target object and thus directly reflects a physical characteristic of the target object, establishing that the physical characteristic of the target object is determined based on the displacement of the skin as recited in the claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Antonelli to determine a displacement of the skin as the basis for the physical characteristic of the target object. Reza already demonstrates that the PARS interrogation architecture is sensitive to surface displacement caused by subsurface pressure waves, while Antonelli demonstrates that the CW reflected beam from skin over an artery directly encodes skin displacement ΔX driven by the dynamics of the underlying target object. A person of ordinary skill in the art would have been motivated to apply Antonelli's displacement-extraction framework to the more sensitive optical detection scheme of the combined device as a predictable extension, yielding the benefit of a direct, quantitative physical measurement of target-object-driven skin motion as the intermediate quantity for physiological parameter determination, with a reasonable expectation of success given that all three references rely on the same tissue surface displacement signal produced by the same underlying arterial mechanics.
Regarding claim 14, the modified Reza teaches that the determination of the displacement of the skin of the user is based on a focus differential indicative of a distance to the skin, a change in frequency associated with the reflection of the second optical signal, a phase difference associated with the reflection of the second optical signal, or a combination thereof (Reza, ¶[0047]: "A long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities", Reza expressly teaches that the displacement of the tissue surface is determined interferometrically from the returning CW interrogation beam, which by definition involves detecting a phase difference associated with the reflection of the second optical signal as recited in the claim; ¶[0068]: "PARS can be integrated with any interferometry designs such as common path interferometer...Michelson interferometer, Fizeau interferometer, Ramsey interferometer, Sagnac interferometer, Fabry-Perot interferometer and Mach-Zehnder interferometer", Reza further teaches that the interferometric detection of the returning interrogation beam is compatible with a broad range of standard interferometer architectures, each of which operates by detecting phase or frequency differences in the reflected optical signal to determine surface displacement).
Regarding claim 15, the modified Reza teaches that the target object comprises a blood vessel of the user (Reza, ¶[0047]: "at 532-nm excitation wavelength, imaging a capillary with 500 mJ/cm² local fluence would result in an initial pressure on the order of 100 MPa locally", Reza expressly teaches that the target object excited by the pulsed optical signals is a capillary, i.e., a blood vessel of the subject; ¶[0123]: "FIG. 14a shows multifocus PARS images revealing both capillary beds and bigger blood vessels", Reza further teaches that the PARS system images both capillary beds and larger blood vessels as the target objects of the system; ¶[0004]: "Photoacoustic microscopy has shown significant potential for imaging vascular structures from macro-vessels all the way down to micro-vessels", Reza expressly identifies vascular structures, i.e., blood vessels of a subject, as the target objects for photoacoustic interrogation; ¶[0127]: "FIGS. 19a-19d depict in vivo PARS images of a mouse ear, and FIGS. 23a-23c and 24 show in vivo PARS images of a 100 g rat's ear", Reza teaches that the target objects are blood vessels of a living subject imaged in vivo); the one or more first optical signals comprise pulsed laser signals (Reza, ¶[0060]: "In one example, a nanosecond-pulsed laser was used", Reza expressly teaches a pulsed laser as the source of the excitation optical signals directed toward the target object; ¶[0114]: "a 1 ns pulse width, frequency doubled ytterbium-doped fiber laser (IPG Photonics Inc.) with a pulse repetition rate (PRR) of 40 kHz", Reza further expressly teaches a specific pulsed laser used as the first optical signal source; ¶[0133]: "laser pulses should be preferably shorter than 2 µm/1500 m/s=1.3 ns, which would require a laser with pulse widths of a nanosecond or shorter", Reza confirms that the first optical signals are pulsed laser signals with nanosecond-scale pulse durations as recited in the claim); the second optical signal comprises a continuous laser signal (Reza, ¶[0114]: "Detection laser 14 may be a continuous wave laser", Reza expressly teaches that the detection or interrogation optical signal is emitted by a continuous wave laser, constituting a continuous laser signal as recited in the claim; ¶[0116]: "For the receiver arm a continuous wavelength (CW) C-band laser with 100-kHz linewidth (TLK-L1550R, Thorlabs Inc., New Jersey) was used", Reza further expressly teaches a specific CW laser as the source of the second optical signal); the receiver comprises a photodetector configured to determine a frequency or a phase of the reflection of the continuous laser signal while the pulsed laser signals are transmitted toward the target object of the user (Reza, ¶[0117]: "the reflected light back through the wave-plate creating 90° polarization which then reflects at the polarizing beam-splitter in order to guide the maximum possible intensity of reflected light to a 150 MHz-bandwidth InGaAs photodiode (PDA10CF, Thorlabs Inc., New Jersey)", Reza expressly teaches that the receiver is a photodetector, specifically an InGaAs photodiode, that receives the reflection of the CW interrogation laser signal from the sample; ¶[0047]: "A long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities", Reza expressly teaches that the photodetector determines the phase of the CW reflection interferometrically during the photoacoustic excitation event, i.e., while the pulsed laser signals are transmitted toward the target object, satisfying the phase alternative of the disjunctive as recited in the claim; ¶[0068]: "PARS can be integrated with any interferometry designs such as common path interferometer...Michelson interferometer, Fizeau interferometer, Ramsey interferometer, Sagnac interferometer, Fabry-Perot interferometer and Mach-Zehnder interferometer", Reza further teaches that the photodetector operates within interferometric architectures that detect phase differences in the reflected optical signal to determine surface displacement).
Regarding claim 16, the modified Reza teaches that the displacement of the skin determined based on a focus differential indicative of a distance to the skin, a difference in the frequency associated with the reflection of the continuous laser signal, a phase difference associated with the reflection of the continuous laser signal, or a combination thereof (Reza, ¶[0047]: "A long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities", Reza expressly teaches that the displacement of the tissue surface is determined interferometrically from the returning CW interrogation beam, which by definition involves detecting a phase difference associated with the reflection of the continuous laser signal as recited in the claim, satisfying the phase difference alternative of the disjunctive; ¶[0068]: "PARS can be integrated with any interferometry designs such as common path interferometer...Michelson interferometer, Fizeau interferometer, Ramsey interferometer, Sagnac interferometer, Fabry-Perot interferometer and Mach-Zehnder interferometer", Reza further teaches that the interferometric detection of the returning interrogation beam is compatible with a broad range of standard interferometer architectures, each of which operates by detecting phase differences in the reflected optical signal to determine surface displacement).
Also regarding claim 16, with respect to the device further comprising a control system configured to determine the physiological parameter of the user based on a displacement of the skin during the generation of the one or more acoustic signals, the modified Reza teaches that the PARS system is capable of detecting surface displacement caused by subsurface acoustic pressure: "The PARS system is capable of detecting noncontact measurement of the displacement caused by ultrasound signals from an ultrasound transducer" (Reza, ¶[0057]), and that surface oscillations caused by pressure modulation modulate the CW reflection detected by the receiver: "Surface pressure modulation can cause surface oscillations and the reflection of the interrogation beam from this oscillating surface can be a source of detected signal" (Reza, ¶[0109]). The modified Reza does not expressly teach that the control system is configured to determine the physiological parameter of the user based on the detected skin displacement.
Antonelli expressly teaches this limitation. Antonelli teaches that the detected CW reflection is processed to extract skin displacement: "The signal processing unit provides skin displacement information, which more directly corresponds to the blood pressure waveform than a measured velocity signal. The blood pressure waveform can be obtained by integrating the velocity signal to obtain surface displacement" (Antonelli, ¶[0020]). Antonelli further teaches that the control system uses the skin displacement to derive the physiological parameter: "The computer 30 can be calibrated to correlate the velocity and motion of the skin surface 26 to the pressure of the blood in the artery beneath skin surface 26" (Antonelli, ¶[0037]), and that "[i]t is necessary to convert the measured velocity into a skin displacement signal. This is a critical aspect of the invention in order to provide medical personnel a waveform that is similar to those achieved by catheter pressure sensor" (Antonelli, ¶[0043]). Antonelli thereby expressly teaches a control system configured to determine blood pressure, a physiological parameter of the user, based on skin displacement during the detection of pulsatile tissue motion, which occurs during the generation of the acoustic signals.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Antonelli to determine the physiological parameter of the user based on skin displacement. Reza already provides a receiver that detects the interferometrically encoded CW reflection modulated by tissue surface displacement during photoacoustic excitation, and Antonelli demonstrates that this class of detected skin displacement signal directly encodes arterial pressure information sufficient to derive blood pressure waveforms equivalent to catheter measurements. A person of ordinary skill in the art would have been motivated to implement Antonelli's displacement-to-physiological-parameter determination framework in the control system of the combined device as a predictable extension, yielding the benefit of a continuous, non-contact physiological parameter output derived from the same skin displacement signal already detected by the PARS receiver, with a reasonable expectation of success given that all three references rely on the same tissue surface displacement produced by the same underlying arterial mechanics.
Claims 9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Reza et al. (US-20160113507-A1), hereto referred as Reza, and further in view of Antonelli et al. (US-20090299197-A1), hereto referred as Antonelli, and further in view of Ruan et al. (US-20190336007-A1), hereto referred as Ruan.
The modified Reza teaches claim 1 as described above. The modified Reza teaches claim 17 as described above.
Regarding claim 9, the modified Reza teaches a method wherein the continuous optical signal has a wavelength of up to 1550 nm, and wherein the pulsed optical signals have a wavelength in the range of 450-850 nm and a duration of up to 500 ns (Reza, ¶[0116]: "For the receiver arm a continuous wavelength (CW) C-band laser with 100-kHz linewidth (TLK-L1550R, Thorlabs Inc., New Jersey) was used", Reza expressly teaches a CW interrogation laser operating at 1550 nm, directly within the recited wavelength of up to 1550 nm; ¶[0134]: "A wavelength of 1550 nm may be used with a 532 nm excitation light because it is spectrally different...and because it is a key band in optical communications where a plethora of components are available", Reza further confirms 1550 nm as the interrogation wavelength and provides the rationale for that selection, establishing the recited CW wavelength limitation; ¶[0047]: "at 532-nm excitation wavelength, imaging a capillary with 500 mJ/cm2 local fluence would result in an initial pressure on the order of 100 MPa locally", Reza expressly teaches a 532 nm pulsed excitation source, squarely within the recited pulsed wavelength range of 450-850 nm; ¶[0114]: "a 1 ns pulse width, frequency doubled ytterbium-doped fiber laser (IPG Photonics Inc.) with a pulse repetition rate (PRR) of 40 kHz", Reza expressly teaches 1 ns pulsed laser operation, well within the recited pulsed duration of up to 500 ns; ¶[0133]: "laser pulses should be preferably shorter than 2 µm/1500 m/s=1.3 ns, which would require a laser with pulse widths of a nanosecond or shorter", Reza further confirms that nanosecond-scale pulse durations satisfy the stress confinement requirements of the photoacoustic technique, establishing the recited pulsed duration limitation).
Also regarding claim 9, the modified Reza does not expressly teach a method wherein the continuous optical signal has a duration of up to 10 microseconds. Rather, the modified Reza discloses a truly continuous wave interrogation laser with no stated gating, windowing, or bounded measurement period applied to the CW beam itself.
Ruan discloses a non-invasive optical physiological measurement system that directs source light into an anatomical structure and detects the returning signal during discrete measurement periods. Ruan expressly teaches that each measurement period should be constrained to a duration at or below the speckle decorrelation time of the tissue, and identifies 10 microseconds as a preferred upper bound for that period: "each of the measurement period(s) may be equal to or less than 100 microseconds, and preferably, equal to or less than 10 microseconds" (Ruan, ¶[0013]). Ruan further explains the physical basis for this constraint: the speckle decorrelation time of tissue "rapidly decreases with the depth of the tissue, and in particular, scales superlinearly with the depth into tissue, falling to microseconds or below as the tissue depth extends to the multi-centimeter range," and accordingly establishes that "the measurement period z may be equal to or less than 100 µs (equivalent to a uni-directional sweep rate of 10 KHz), and preferably equal to or less than 10 µs" (Ruan, ¶[0079]). Ruan further applies this constraint explicitly in a worked example in which the measurement period is set to 10 microseconds, confirming operability of the recited duration (Ruan, ¶[0120]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Ruan to apply a bounded measurement window of up to 10 microseconds to the CW interrogation beam of the PARS system. Reza itself makes clear that the quality of the CW interrogation signal during each acquisition window is critical to system performance: ¶[0047] expressly states that "a long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities." Reza thereby identifies coherence integrity of the CW interrogation beam during the detection window as a recognized design constraint of the PARS architecture. A person of ordinary skill in the art would have understood that limiting the duration of each interrogation window is a direct and predictable means of preserving that coherence quality, because tissue is a dynamic medium in which any relative motion between the interrogation beam and the tissue surface degrades phase and amplitude stability over time. Ruan expressly teaches that bounding the optical measurement period to 10 microseconds or less is an effective solution to this class of coherence-preservation problem in optical tissue measurements, and provides the physical and empirical basis for that bound (Ruan, ¶[0013], ¶[0079], ¶[0120]). A person of ordinary skill in the art would have been motivated to apply Ruan's measurement period teaching to the CW interrogation window of the modified Reza's PARS system as a predictable and well-motivated design choice, yielding the direct benefit of improved interferometric signal fidelity by constraining each acquisition to a duration over which the coherence of the CW interrogation beam is reliably preserved, with a reasonable expectation of success given that both references employ interferometric detection of a CW optical beam interrogating tissue and share the same underlying concern for maintaining optical coherence quality during the measurement acquisition.
Regarding claim 20, the modified Reza teaches a non-transitory computer-readable apparatus wherein: the continuous optical signal comprises a continuous optical signal emitted by a second light source, wherein the continuous optical signal emitted by the second light source comprises an optical signal having a wavelength of up to 1550 nm generated by a second laser (Reza, ¶[0116]: "For the receiver arm a continuous wavelength (CW) C-band laser with 100-kHz linewidth (TLK-L1550R, Thorlabs Inc., New Jersey) was used", Reza expressly teaches a CW laser operating at 1550 nm as the second light source, directly within the recited wavelength of up to 1550 nm; ¶[0134]: "A wavelength of 1550 nm may be used with a 532 nm excitation light because it is spectrally different...and because it is a key band in optical communications where a plethora of components are available", Reza further confirms 1550 nm as the interrogation wavelength and provides the rationale for that selection, establishing the recited CW wavelength limitation; ¶[0114]: "Detection laser 14 may be a continuous wave laser", Reza expressly teaches that the second light source is a dedicated continuous wave laser, constituting the second laser as recited in the claim); the one or more pulsed optical signals comprise one or more optical signals emitted by a first light source, wherein the one or more pulsed optical signals emitted by the first light source comprise one or more optical signals having a wavelength of 450-850 nm each generated by a first laser configured to obtain a photoacoustic response from the blood vessel over a second duration up to 500 nanoseconds during the first duration (Reza, ¶[0047]: "at 532-nm excitation wavelength, imaging a capillary with 500 mJ/cm² local fluence would result in an initial pressure on the order of 100 MPa locally", Reza expressly teaches a 532 nm pulsed excitation source, squarely within the recited pulsed wavelength range of 450-850 nm; ¶[0046]: "Energy absorbed by chromophores or any other absorber is converted to acoustic waves due to thermo-elastic expansion", Reza teaches that the pulsed excitation laser is configured to obtain a photoacoustic response from the biological target, i.e., a blood vessel, as recited in the claim; ¶[0114]: "a 1 ns pulse width, frequency doubled ytterbium-doped fiber laser (IPG Photonics Inc.) with a pulse repetition rate (PRR) of 40 kHz", Reza expressly teaches 1 ns pulsed laser operation, well within the recited second duration of up to 500 nanoseconds; ¶[0133]: "laser pulses should be preferably shorter than 2 µm/1500 m/s=1.3 ns, which would require a laser with pulse widths of a nanosecond or shorter", Reza further confirms that nanosecond-scale pulse durations satisfy the stress confinement requirements of the photoacoustic technique, establishing the recited pulsed duration limitation); the first light source and the second light source are disposed at different locations of a device (Reza, ¶[0114] and FIG. 20: Reza depicts the experimental PARS system in FIG. 20, showing pulsed laser 12 and detection laser 14 as entirely separate, spatially distinct components within the system architecture, with their respective beams combined only downstream at dual beam combiner 2218 before reaching the sample, expressly teaching that the first and second light sources occupy different locations within the device; ¶[0118] and FIG. 22: Reza further depicts in FIG. 22 an alternative system configuration in which pulse laser 12 provides an additional beam to polarization maintaining single mode fiber 2402, lens system 42, and then to beam combiner unit 30, while continuous wave lasers 2404 and 2406 provide separate beams that are likewise combined at beam combiner unit 30 before reaching sample 18, again expressly teaching two light sources disposed at different locations within the device as recited in the claim).
Also regarding claim 20, the modified Reza does not expressly teach that the continuous optical signal is generated by the second laser over a first duration up to 10 microseconds. Rather, the modified Reza discloses a truly continuous wave interrogation laser with no stated gating, windowing, or bounded measurement period applied to the CW beam itself.
Ruan discloses a non-invasive optical physiological measurement system that directs source light into an anatomical structure and detects the returning signal during discrete measurement periods. Ruan expressly teaches that each measurement period should be constrained to a duration at or below the speckle decorrelation time of the tissue, and identifies 10 microseconds as a preferred upper bound for that period: "each of the measurement period(s) may be equal to or less than 100 microseconds, and preferably, equal to or less than 10 microseconds" (Ruan, ¶[0013]). Ruan further explains the physical basis for this constraint: the speckle decorrelation time of tissue "rapidly decreases with the depth of the tissue, and in particular, scales super-linearly with the depth into tissue, falling to microseconds or below as the tissue depth extends to the multi-centimeter range," and accordingly establishes that "the measurement period z may be equal to or less than 100 µs (equivalent to a uni-directional sweep rate of 10 KHz), and preferably equal to or less than 10 µs" (Ruan, ¶[0079]). Ruan further applies this constraint explicitly in a worked example in which the measurement period is set to 10 microseconds, confirming operability of the recited duration (Ruan, ¶[0120]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the modified Reza in view of Ruan to configure the stored instructions to cause the second laser to generate the CW interrogation signal over a bounded first duration of up to 10 microseconds. Reza itself makes clear that the quality of the CW interrogation signal during each acquisition window is critical to system performance: ¶[0047] expressly states that "a long-coherence length interrogation laser is preferably used with low amplitude and phase noise to read-out the large local photoacoustic vibrations interferrometrically using a novel architecture designed to optimize received signal intensities." Reza thereby identifies coherence integrity of the CW interrogation beam during the detection window as a recognized design constraint of the PARS architecture. A person of ordinary skill in the art would have understood that limiting the duration of each interrogation window is a direct and predictable means of preserving that coherence quality, because tissue is a dynamic medium in which any relative motion between the interrogation beam and the tissue surface degrades phase and amplitude stability over time. Ruan expressly teaches that bounding the optical measurement period to 10 microseconds or less is an effective solution to this class of coherence-preservation problem in optical tissue measurements, and provides the physical and empirical basis for that bound (Ruan, ¶[0013], ¶[0079], ¶[0120]). A person of ordinary skill in the art would have been motivated to apply Ruan's measurement period teaching to the CW interrogation window of the combined system as a predictable and well-motivated design choice, yielding the direct benefit of improved interferometric signal fidelity by constraining each acquisition to a duration over which the coherence of the CW interrogation beam is reliably preserved, with a reasonable expectation of success given that both references employ interferometric detection of a CW optical beam interrogating tissue and share the same underlying concern for maintaining optical coherence quality during the measurement acquisition.
Conclusion
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/AARON MERRIAM/Examiner, Art Unit 3791
/MATTHEW KREMER/Primary Examiner, Art Unit 3791
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