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 .
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-24 are rejected under 35 U.S.C. 103 as being unpatentable over Behnke-Parks et al. (US 2021/0015511, hereinafter Parks) in the view of Prus et al. (US 2018/0206816).
Regarding claim 1, Parks teaches a method for localizing a biomineralization in a volume, comprising (para. 0027; The invention may be used to detect and/or treat conditions related to acute renal colic, which is a potentially debilitating condition caused by an obstruction of the urinary tract. Discrimination of a target (e.g., a bubble-coated biomineralization) from surrounding objects such as bone, is possible because the present invention allows for localization and positioning on account of the directional alignment available between the external acoustic source and the target biomineralization and microbubble formation):
producing, by an ultrasonic transducer, pulses of produced ultrasonic energy waves having a fundamental frequency (para. 0026; one or more ultrasonic transducers which deliver ultrasonic energy to a target region containing an unwanted biomineralization such as a urinary stone 110 lodged in a patient's ureter 120. the ultrasound source is configured to generate acoustic energy having a center frequency or fundamental being lower than 1 megahertz (MHz), and in a specific non-limiting example a center frequency of about 500 kilohertz (kHz).);
injecting an ensemble of microbubbles proximal to the biomineralization (para. 0029; depicts placement of engineered microbubbles 203 proximally to an undesired biomineralization (e.g., urinary stone) 204 within a ureter 202.);
receiving, by an acoustic receiver, returned ultrasonic energy waves to detect a broadband signal output (para. 0048; the system may be equipped with both the external ultrasound source (transmitter) as well as a passive cavitation detection and monitoring acoustic sensor (receiver). The acoustic sensor may be integrated into the transmitting ultrasound source as a transducer element in an array of a plurality of elements. By selectively detecting at broad-band emissions.);
processing the broadband signal output to isolate diminished frequencies of the broadband signal output (paras. 0042 and 0048; on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone. The IC is quantifiable in a number of ways that generally indicate the amount, intensity, or other severity of the cavitation activity in the microbubble and target environment. In one embodiment, the IC is quantified using an integration of the power spectrum over a specified frequency range. In a non-limiting example, the frequency range includes the frequencies above and below a harmonic of the fundamental treatment frequency causing the microbubble cavitation. The examiner notes that the system process received reflected waves and isolates frequencies generated from collapse of microbubbles);
monitoring the diminished frequencies, with a processor, for a diminished- frequency spectral signature that corresponds with a location of the biomineralization (paras. 0041-0042 and 0048; The power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system; this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone.); and
determining a spatial location of the biomineralization, with the processor, based on the diminished-frequency spectral signature (paras. 0048-0049 and claims 17-19; the acoustic sensor (or the ultrasound source) may comprise one element, or it may comprise a plurality of phased elements as in an array of transducer elements. In this instance the acoustic sensor array may provide localization and distance or depth information regarding the spatial position of the cavitation events (or biomineralization). said controller further configured and arranged to identify and localize the biomineralization and to discriminate said biomineralization from surrounding objects based on the IC signature at or proximal to said biomineralization.).
Although Parks teach isolate diminished frequencies lower than fundamental frequency, however, Parks fails to explicitly teach isolate diminished frequencies of the broadband signal output, the diminished frequencies lower than 50% of the fundamental frequency.
Prus, in the same field of endeavor, teaches isolate diminished frequencies of the broadband signal output, the diminished frequencies lower than 50% of the fundamental frequency (paras. 0040, 0042, 0048, and 0064-0067; The acoustic signals returned from cavitation events may include frequencies at the fundamental frequency and/or a harmonic, ultra-harmonic, and/or sub-harmonic of the fundamental frequency. the term “sub-harmonic” refers to a fractional number between the fundamental frequency and the first harmonic (e.g., f.sub.0/2, f.sub.0/3, f.sub.0/4, etc.). Various types of microbubble cavitation may occur during an ultrasound procedure and each type of the cavitation may have its own spectral “signature” that represents the unique nonlinear response of the bubbles. For example, stable cavitation induced at an intermediate acoustic power (e.g., 5 Watts above the microbubble-generation threshold) may produce a strong sub-harmonic response (i.e., having more components at the sub-harmonic frequencies and/or having larger amplitudes of the sub-harmonic frequencies). the harmonic(s) 314, ultra-harmonic(s) 316 and/or sub-harmonic(s) (not shown) in the spectral signature 310 of the detected echo signal 306 are included when reconstructing the reference signal 322. In one implementation, each harmonic, ultra-harmonic and/or sub-harmonic is processed by its corresponding filter. For example, a filter associated with a k.sup.th-order harmonic of a fundamental frequency may be defined as follows: where A.sup.1(f) and φ.sup.1 (f) represent an amplitude and a phase of the fundamental frequency filter, and k can be an integer or a fraction. Accordingly, the filter associated with the k.sup.th-order harmonic is computed by scaling the filter associated with the fundamental frequency based on the order of the harmonic (i.e., k). This scaled harmonic-frequency filter may improve the resolution and/or signal-to-noise ratio of the harmonic, ultra-harmonic and/or sub-harmonic signals, which may be particularly useful for detecting, for example, stable cavitation where the sub-harmonic is strong and/or inertial cavitation where broadband noise increases and more high-order harmonic frequencies occur. The examiner notes that the system isolates subharmonic frequencies from the broadband signal, where the subharmonic frequencies are less than or equal to one half of the fundamental frequency to localize microbubble cavitation).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the diminished frequency of Parks to incorporate the teaching Prus to include a diminished frequency less than 50% of the fundamental frequency. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. Additionally, sub-harmonic frequencies provide high contrast, cavitation specific component that can be independently reconstructed, compared to background signal, and used to localize cavitation while suppressing tissue and solid reflection from surrounding anatomies.
Regarding claim 2, Parks teaches the method of claim 1, wherein the diminished frequencies are less than the fundamental frequency (para. 0042; The IC is quantifiable in a number of ways that generally indicate the amount, intensity, or other severity of the cavitation activity in the microbubble and target environment. In one embodiment, the IC is quantified using an integration of the power spectrum over a specified frequency range. In a non-limiting example, the frequency range includes the frequencies above and below a harmonic of the fundamental treatment frequency causing the microbubble cavitation.).
However, Parks fails to explicitly teach that the diminished frequencies are less than or equal to 25% of the fundamental frequency.
Prus, in the same field of endeavor, teaches diminished frequencies are less than or equal to 25% of the fundamental frequency (paras. 0040, 0042, 0048, and 0064-0067; The acoustic signals returned from cavitation events may include frequencies at the fundamental frequency and/or a harmonic, ultra-harmonic, and/or sub-harmonic of the fundamental frequency. the term “sub-harmonic” refers to a fractional number between the fundamental frequency and the first harmonic (e.g., f.sub.0/2, f.sub.0/3, f.sub.0/4, etc.). Various types of microbubble cavitation may occur during an ultrasound procedure and each type of the cavitation may have its own spectral “signature” that represents the unique nonlinear response of the bubbles. For example, stable cavitation induced at an intermediate acoustic power (e.g., 5 Watts above the microbubble-generation threshold) may produce a strong sub-harmonic response (i.e., having more components at the sub-harmonic frequencies and/or having larger amplitudes of the sub-harmonic frequencies). the harmonic(s) 314, ultra-harmonic(s) 316 and/or sub-harmonic(s) (not shown) in the spectral signature 310 of the detected echo signal 306 are included when reconstructing the reference signal 322. In one implementation, each harmonic, ultra-harmonic and/or sub-harmonic is processed by its corresponding filter. For example, a filter associated with a k.sup.th-order harmonic of a fundamental frequency may be defined as follows: where A.sup.1(f) and φ.sup.1 (f) represent an amplitude and a phase of the fundamental frequency filter, and k can be an integer or a fraction. Accordingly, the filter associated with the k.sup.th-order harmonic is computed by scaling the filter associated with the fundamental frequency based on the order of the harmonic (i.e., k). This scaled harmonic-frequency filter may improve the resolution and/or signal-to-noise ratio of the harmonic, ultra-harmonic and/or sub-harmonic signals, which may be particularly useful for detecting, for example, stable cavitation where the sub-harmonic is strong and/or inertial cavitation where broadband noise increases and more high-order harmonic frequencies occur. The examiner notes that the system isolates subharmonic frequencies from the broadband signal, where the subharmonic frequencies are less than or equal to one fourth of the fundamental frequency to localize microbubble cavitation).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the diminished frequency of Parks to incorporate the teaching Prus to include a diminished frequency less than or equal to 25% of the fundamental frequency. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. Additionally, sub-harmonic frequencies provide high contrast, cavitation specific component that can be independently reconstructed, compared to background signal, and used to localize cavitation while suppressing tissue and solid reflection from surrounding anatomies.
Regarding claim 3, Parks teaches the method of claim 1, wherein the fundamental frequency is greater than or equal to about 250 kHz and less than about 1 MHz (para. 0026; the ultrasound source is configured to generate acoustic energy having a center frequency or fundamental being lower than 1 megahertz (MHz), and in a specific non-limiting example a center frequency of about 500 kilohertz (kHz).).
Regarding claim 4, Parks teaches the method of claim 3, wherein the fundamental frequency is less than or equal to about 750 kHz (para. 0026; the ultrasound source is configured to generate acoustic energy having a center frequency or fundamental being lower than 1 megahertz (MHz), and in a specific non-limiting example a center frequency of about 500 kilohertz (kHz).).
Regarding claim 5, Parks teaches the method of claim 3, wherein the fundamental frequency is about 500 kHz (para. 0026; the ultrasound source is configured to generate acoustic energy having a center frequency or fundamental being lower than 1 megahertz (MHz), and in a specific non-limiting example a center frequency of about 500 kilohertz (kHz).).
Regarding claim 6, Parks teaches the method of claim 5, however, fails to explicitly teach wherein the diminished frequencies are greater than or equal to about 20 kHz and less than or equal to about 120 kHz.
Prus, in the same field of endeavor, teaches the diminished frequencies are greater than or equal to about 20 kHz and less than or equal to about 120 kHz (paras. 0040, 0042, 0048, and 0064-0067; The acoustic signals returned from cavitation events may include frequencies at the fundamental frequency and/or a harmonic, ultra-harmonic, and/or sub-harmonic of the fundamental frequency. the term “sub-harmonic” refers to a fractional number between the fundamental frequency and the first harmonic (e.g., f.sub.0/2, f.sub.0/3, f.sub.0/4, etc.). Various types of microbubble cavitation may occur during an ultrasound procedure and each type of the cavitation may have its own spectral “signature” that represents the unique nonlinear response of the bubbles. For example, stable cavitation induced at an intermediate acoustic power (e.g., 5 Watts above the microbubble-generation threshold) may produce a strong sub-harmonic response (i.e., having more components at the sub-harmonic frequencies and/or having larger amplitudes of the sub-harmonic frequencies). the harmonic(s) 314, ultra-harmonic(s) 316 and/or sub-harmonic(s) (not shown) in the spectral signature 310 of the detected echo signal 306 are included when reconstructing the reference signal 322. In one implementation, each harmonic, ultra-harmonic and/or sub-harmonic is processed by its corresponding filter. For example, a filter associated with a k.sup.th-order harmonic of a fundamental frequency may be defined as follows: where A.sup.1(f) and φ.sup.1 (f) represent an amplitude and a phase of the fundamental frequency filter, and k can be an integer or a fraction. Accordingly, the filter associated with the k.sup.th-order harmonic is computed by scaling the filter associated with the fundamental frequency based on the order of the harmonic (i.e., k). This scaled harmonic-frequency filter may improve the resolution and/or signal-to-noise ratio of the harmonic, ultra-harmonic and/or sub-harmonic signals, which may be particularly useful for detecting, for example, stable cavitation where the sub-harmonic is strong and/or inertial cavitation where broadband noise increases and more high-order harmonic frequencies occur. The examiner notes that the system isolates subharmonic frequencies from the broadband signal, where the subharmonic frequencies are less than or equal to one fourth of the fundamental frequency to localize microbubble cavitation. If the frequency is 500 KHz the diminished frequency (Sub harmonic) would be 125 Khz (which is about 120 KHz) or lower based on the fraction K used to isolate the sub harmonic frequency of the fundamental frequency.).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the diminished frequency of Parks to incorporate the teaching Prus to include a diminished frequency less than or equal to about 120 kHz. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. Additionally, sub-harmonic frequencies provide high contrast, cavitation specific component that can be independently reconstructed, compared to background signal, and used to localize cavitation while suppressing tissue and solid reflection from surrounding anatomies.
Regarding claim 7, Parks teaches the method of claim 1, wherein the diminished-frequency spectral signature includes an increased acoustic pressure response of the diminished frequencies when the produced ultrasonic energy waves are aligned with the biomineralization compared to when the produced ultrasonic energy waves are offset from the biomineralization (paras. 0008, 0023, 0041, and 0048; The inertial cavitation (IC) activity and signature of the present microbubbles can be used to detect and localize or spatially align the treatment of biomineralizations such as urinary stones where the microbubbles may attach, accumulate or be concentrated. The microbubbles cavitate in the target region, destructively affecting the biomineralization and potentially breaking it or reducing its mass over time as a result of the cavitation action. Spatial orientation or alignment of the external ultrasound source may be achieved for best results using acoustic signatures and spectral representations of the same. The examiner notes that when the ultrasound source is aligned with biomineralization, the spectral signature reflects the alignment of the ultrasound source with biomineralization).
Regarding claim 8, Parks teaches the method of claim 7, wherein the increased acoustic pressure response of the diminished frequencies occurs when the microbubbles accumulate on a surface of the biomineralization (paras. 0013, 0036, 0041, and 0048; a method for non-invasive targeting of biomineralizations, comprising introducing a plurality of chemically-tagged microbubbles into a target region containing a biomineralization so as to accumulate the microbubbles on a surface of said biomineralization; targeting the microbubbles with ultrasound energy to cause inertial cavitation of the microbubbles; and monitoring an acoustic signature of said microbubbles during their cavitation. FIG. 3 also shows the dynamics of a microbubble subjected to a short burst of ultrasound 307. The bubble radius as a function of time is depicted in 310, which shows the extreme change in bubble size (covering several orders of magnitude) which also results in locally extreme hydrodynamic, acoustic and shock wave behaviors against the surface of the unwanted biomineralization.).
Regarding claim 9, Parks teaches the method of claim 8, wherein the increased acoustic pressure response of the diminished frequencies occurs when the microbubbles form a microbubble cloud and/or a microbubble cluster (paras. 0007 and 0041; a method of placement of a plurality of microbubbles at a target site, then exciting or cavitating the microbubbles with an external acoustic source to generate said bubble dynamics or cavitation events, both at an individual bubble level and at the level of the bubble cluster or cloud as a multi-bubble entity. The acoustic emissions from the insonated microbubbles are used to determine indicia for detection of events of interest, which can be then used to determine or guide a treatment, or to monitor said treatment. the power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system.).
Regarding claim 10, Parks teaches the method of claim 1, wherein the diminished-frequency spectral signature includes an integrated signal of an acoustic pressure of the diminished frequencies (paras. 0042-0043; The IC is quantifiable in a number of ways that generally indicate the amount, intensity, or other severity of the cavitation activity in the microbubble and target environment. In one embodiment, the IC is quantified using an integration of the power spectrum over a specified frequency range. In a non-limiting example, the frequency range includes the frequencies above and below a harmonic of the fundamental treatment frequency causing the microbubble cavitation. a general frequency-dependence of cumulative IC (in kilo Pascals squared, kPa). The IC measure increases with increasing acoustic pressure amplitude of the applied ultrasound energy.).
Regarding claim 11, Parks teaches the method of claim 1, further comprising moving the ultrasound transducer axially with respect to the volume while the ultrasound transducer produces the pulses of produced ultrasonic energy waves (para. 0054; the insonating-listening transducer assembly may be translated across the skin. In another variant of the method, the insonating-listening transducer assembly may be pivoted through various angles at the skin surface.),
wherein the diminished-frequency spectral signature includes:
a first increase in a diminished-frequency response over a first time period, the first increase in the diminished-frequency response compared to a background response signal (figures 3-4, paras. 0027, 0036, 0038, 0041, and 0048; The invention may be used to detect and/or treat conditions related to acute renal colic, which is a potentially debilitating condition caused by an obstruction of the urinary tract. Discrimination of a target (e.g., a bubble-coated biomineralization) from surrounding objects such as bone, is possible because the present invention allows for localization and positioning on account of the directional alignment available between the external acoustic source and the target biomineralization and microbubble formation. a time-dependent change in IC on the ˜1 second timescale is obtained, consisting of an initial biphasic rise-decay ˜500 ms in duration, the amplitude of which showed the expected quadratic dependence on pressure, followed by a long-lived tail. This tail suggests that microbubbles, collectively, can persist through a large number of inertial collapse cycles. T, the power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system. this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone. The examiner notes that the response signals generated from reflection signals are plotted against time that represent a rise in the signal when microbubbles are accumulated around the stone (proximal and distal) and the signals are compared to background signals generated from reflections of surrounding bones. Therefore, the frequency response represent two peaks one proximal to the stone and one distal to the stone over time),
a decrease in the diminished-frequency response over a second time period compared to the diminished-frequency response over the first time period (figures 3-4, paras. 0027, 0036, 0038, 0041, and 0048; The invention may be used to detect and/or treat conditions related to acute renal colic, which is a potentially debilitating condition caused by an obstruction of the urinary tract. Discrimination of a target (e.g., a bubble-coated biomineralization) from surrounding objects such as bone, is possible because the present invention allows for localization and positioning on account of the directional alignment available between the external acoustic source and the target biomineralization and microbubble formation. a time-dependent change in IC on the ˜1 second timescale is obtained, consisting of an initial biphasic rise-decay ˜500 ms in duration, the amplitude of which showed the expected quadratic dependence on pressure, followed by a long-lived tail. This tail suggests that microbubbles, collectively, can persist through a large number of inertial collapse cycles. T, the power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system. this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone. The examiner notes that the response signals generated from reflection signals are plotted against time that represent a rise in the signal when microbubbles are accumulated around the stone (proximal and distal) and the signals are compared to background signals generated from reflections of surrounding bones. Further the microbubbles accumulate on the stones and collapse at max acoustic pressure wave which generates a decay in the signal. Therefore, the frequency response represent two peaks one proximal to the stone and one distal to the stone over time and a decay where the stone is located.), and
a second increase in the diminished-frequency response over a third time period, the second increase in the diminished frequency response compared to the background response signal, wherein: the second time period immediately follows the first time period, and the third time period immediately follows the second time period (figures 3-4, paras. 0009, 0027, 0036, 0038, 0041, and 0048; Successive insonations at various time scales are presented and uniquely exploited by the invention so as to achieve preferred diagnostic and/or therapeutic effects. The invention may be used to detect and/or treat conditions related to acute renal colic, which is a potentially debilitating condition caused by an obstruction of the urinary tract. Discrimination of a target (e.g., a bubble-coated biomineralization) from surrounding objects such as bone, is possible because the present invention allows for localization and positioning on account of the directional alignment available between the external acoustic source and the target biomineralization and microbubble formation. a time-dependent change in IC on the ˜1 second timescale is obtained, consisting of an initial biphasic rise-decay ˜500 ms in duration, the amplitude of which showed the expected quadratic dependence on pressure, followed by a long-lived tail. This tail suggests that microbubbles, collectively, can persist through a large number of inertial collapse cycles. T, the power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system. this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone. The examiner notes that the response signals generated from reflection signals are plotted against time that represent a rise in the signal when microbubbles are accumulated around the stone (proximal and distal) and the signals are compared to background signals generated from reflections of surrounding bones. Therefore, the frequency response represent two peaks one proximal to the stone and one distal to the stone over time).
Regarding claim 12, Parks teaches the method of claim 11, wherein the decrease in the diminished-frequency response over the second time period corresponds to the spatial location of the biomineralization (figures 3-4, paras. 0027, 0036, 0038, 0041, and 0048; The invention may be used to detect and/or treat conditions related to acute renal colic, which is a potentially debilitating condition caused by an obstruction of the urinary tract. Discrimination of a target (e.g., a bubble-coated biomineralization) from surrounding objects such as bone, is possible because the present invention allows for localization and positioning on account of the directional alignment available between the external acoustic source and the target biomineralization and microbubble formation. a time-dependent change in IC on the ˜1 second timescale is obtained, consisting of an initial biphasic rise-decay ˜500 ms in duration, the amplitude of which showed the expected quadratic dependence on pressure, followed by a long-lived tail. This tail suggests that microbubbles, collectively, can persist through a large number of inertial collapse cycles. T, the power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system. this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone. The examiner notes that the response signals generated from reflection signals are plotted against time that represent a rise in the signal when microbubbles are accumulated around the stone (proximal and distal) and the signals are compared to background signals generated from reflections of surrounding bones. Further the microbubbles accumulate on the stones and collapse at max acoustic pressure wave which generates a decay in the signal. Therefore, the frequency response represent two peaks one proximal to the stone and one distal to the stone over time and a decay where the stone is located.).
Regarding claim 13, Parks teaches the method of claim 12, wherein the first and second increases in the diminished- frequency response correspond to a spatial location of microbubbles and/or a microbubble cloud (figures 3-4, paras. 0027, 0036, 0038, 0041, and 0048; The invention may be used to detect and/or treat conditions related to acute renal colic, which is a potentially debilitating condition caused by an obstruction of the urinary tract. Discrimination of a target (e.g., a bubble-coated biomineralization) from surrounding objects such as bone, is possible because the present invention allows for localization and positioning on account of the directional alignment available between the external acoustic source and the target biomineralization and microbubble formation. a time-dependent change in IC on the ˜1 second timescale is obtained, consisting of an initial biphasic rise-decay ˜500 ms in duration, the amplitude of which showed the expected quadratic dependence on pressure, followed by a long-lived tail. This tail suggests that microbubbles, collectively, can persist through a large number of inertial collapse cycles. T, the power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system. this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone. The examiner notes that the response signals generated from reflection signals are plotted against time that represent a rise in the signal when microbubbles are accumulated around the stone (proximal and distal) and the signals are compared to background signals generated from reflections of surrounding bones. Therefore, the frequency response represent two peaks one proximal to the stone and one distal to the stone over time).
Regarding claim 14, Parks teaches the method of claim 1, however, fails to explicitly teach wherein the diminished frequencies are greater than or equal to about 4% of the fundamental frequency.
Prus, in the same field of endeavor, teaches diminished frequencies are greater than or equal to about 4% of the fundamental frequency (paras. 0040, 0042, 0048, and 0064-0067; The acoustic signals returned from cavitation events may include frequencies at the fundamental frequency and/or a harmonic, ultra-harmonic, and/or sub-harmonic of the fundamental frequency. the term “sub-harmonic” refers to a fractional number between the fundamental frequency and the first harmonic (e.g., f.sub.0/2, f.sub.0/3, f.sub.0/4, etc.). Various types of microbubble cavitation may occur during an ultrasound procedure and each type of the cavitation may have its own spectral “signature” that represents the unique nonlinear response of the bubbles. For example, stable cavitation induced at an intermediate acoustic power (e.g., 5 Watts above the microbubble-generation threshold) may produce a strong sub-harmonic response (i.e., having more components at the sub-harmonic frequencies and/or having larger amplitudes of the sub-harmonic frequencies). the harmonic(s) 314, ultra-harmonic(s) 316 and/or sub-harmonic(s) (not shown) in the spectral signature 310 of the detected echo signal 306 are included when reconstructing the reference signal 322. In one implementation, each harmonic, ultra-harmonic and/or sub-harmonic is processed by its corresponding filter. For example, a filter associated with a k.sup.th-order harmonic of a fundamental frequency may be defined as follows: where A.sup.1(f) and φ.sup.1 (f) represent an amplitude and a phase of the fundamental frequency filter, and k can be an integer or a fraction. Accordingly, the filter associated with the k.sup.th-order harmonic is computed by scaling the filter associated with the fundamental frequency based on the order of the harmonic (i.e., k). This scaled harmonic-frequency filter may improve the resolution and/or signal-to-noise ratio of the harmonic, ultra-harmonic and/or sub-harmonic signals, which may be particularly useful for detecting, for example, stable cavitation where the sub-harmonic is strong and/or inertial cavitation where broadband noise increases and more high-order harmonic frequencies occur. The examiner notes that the system isolates subharmonic frequencies from the broadband signal, where the subharmonic frequencies are less than or equal to one fourth of the fundamental frequency to localize microbubble cavitation).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the diminished frequency of Parks to incorporate the teaching Prus to include a diminished frequency greater than or equal to about 4% of the fundamental frequency. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. Additionally, sub-harmonic frequencies provide high contrast, cavitation specific component that can be independently reconstructed, compared to background signal, and used to localize cavitation while suppressing tissue and solid reflection from surrounding anatomies.
Regarding claim 15, Parks teaches the method of claim 1, however fails to explicitly teach further comprising amplifying the diminished frequencies of the broadband signal output.
Prus, in the same field of endeavor, teaches amplifying the diminished frequencies of the broadband signal output (figure 1, paras. 0037-0039 and 0041; the transducer array 102 is coupled to the beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasonic beam or field. For n transducer elements, the beamformer 106 may contain n driver circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120; drive circuit drives one of the transducer elements 104. The beamformer 106 receives a radio frequency (RF) input signal, typically in the range from 0.1 MHz to 1.0 MHz, from the frequency generator 110, which may, for example, be a Model DS345 generator available from Stanford Research Systems. The input signal may be split into n channels for the n amplifiers 118 and delay circuits 120 of the beamformer 106. System 100 may be modified in various ways within the scope of the invention. For example, for diagnostic applications, the system may further include a conventional ultrasound detector device (such as a hydrophone) 122 that measures transmitted or reflected ultrasound, and which may provide the signals it receives to the controller 108 for further processing. The reflection and transmission signals may also be used as feedback for the phase and amplitude adjustments of the beamformer 106. The examiner notes that received reflections are sent to the controller then the amplifier for signal amplification).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the diminished frequency of Parks to incorporate the teaching Prus to include an amplified diminished frequencies. Doing so would improve signal resolution and obtain a desired focus or any other desired spatial field patterns as disclosed within Prus in paras. 0037-0039.
Regarding claim 16, Parks teaches the method of claim 1, wherein the processing step includes filtering, in a low-pass filter or a bandpass filter, the broadband signal output to isolate the diminished frequencies (paras. 0042 and 0048; The IC is quantifiable in a number of ways that generally indicate the amount, intensity, or other severity of the cavitation activity in the microbubble and target environment. In one embodiment, the IC is quantified using an integration of the power spectrum over a specified frequency range. In a non-limiting example, the frequency range includes the frequencies above and below a harmonic of the fundamental treatment frequency causing the microbubble cavitation. For example, as shown in the figure, if the ultrasound source frequency is centered at 500 kHz (the fundamental) then we may integrate the spectral distribution around the second harmonic (1500 kHz), omitting the frequencies very near to the harmonic itself. In this non-limiting example, the shaded frequency ranges (1.1 MHz to 1.4 MHz and 1.6 MHz to 1.9 MHz) suitably capture a representative range of spectra while excluding the harmonic itself (1.5 MHz) and surrounding harmonics. this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone. The examiner notes that the filtering out harmonics by omitting only the frequency of the harmonic itself is a bandpass filtering.).
Regarding claim 17, Parks teaches the method of claim 1, wherein the processing step includes performing, with the processor, a fast Fourier transform of the broadband signal output with respect to the diminished frequencies (para. 0041; the power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system. The power spectral density may employ a fast Fourier transform (FFT) and be computed as PSD(f)=Δt/N|f.Math.FFT(p(t))|.sup.2).
Regarding claim 18, Parks teaches a system for localizing a biomineralization in a volume, comprising (para. 0027; The invention may be used to detect and/or treat conditions related to acute renal colic, which is a potentially debilitating condition caused by an obstruction of the urinary tract. Discrimination of a target (e.g., a bubble-coated biomineralization) from surrounding objects such as bone, is possible because the present invention allows for localization and positioning on account of the directional alignment available between the external acoustic source and the target biomineralization and microbubble formation):
an ultrasound device that produces pulses of produced ultrasonic energy waves having a fundamental frequency (para. 0026; one or more ultrasonic transducers which deliver ultrasonic energy to a target region containing an unwanted biomineralization such as a urinary stone 110 lodged in a patient's ureter 120. the ultrasound source is configured to generate acoustic energy having a center frequency or fundamental being lower than 1 megahertz (MHz), and in a specific non-limiting example a center frequency of about 500 kilohertz (kHz).);
a receiver that receives returned ultrasonic energy waves and produces signals that represent the returned ultrasonic energy waves (para. 0048; the system may be equipped with both the external ultrasound source (transmitter) as well as a passive cavitation detection and monitoring acoustic sensor (receiver). The acoustic sensor may be integrated into the transmitting ultrasound source as a transducer element in an array of a plurality of elements. By selectively detecting at broad-band emissions.);
filter configured to receive the signal output of the receiver and to isolate diminished frequencies of the signal output, the diminished frequencies less the fundamental frequency (paras. 0041-0042 and 0048; The IC is quantifiable in a number of ways that generally indicate the amount, intensity, or other severity of the cavitation activity in the microbubble and target environment. In one embodiment, the IC is quantified using an integration of the power spectrum over a specified frequency range. In a non-limiting example, the frequency range includes the frequencies above and below a harmonic of the fundamental treatment frequency causing the microbubble cavitation. Instead of simply detecting reflected ultrasound signals at the source frequency, this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone.);
a catheter configured to inject an ensemble of microbubbles proximal to the biomineralization (para. 0029; depicts placement of engineered microbubbles 203 proximally to an undesired biomineralization (e.g., urinary stone) 204 within a ureter 202. The microbubbles may be injected using a syringe or pump 208 through a catheter 206 as best suits a particular situation. );
and a computer having a microprocessor cause the microprocessor to automatically (para. 0041, the system's processing circuit 230):
determine whether the digital diminished-frequency representations include a diminished-frequency spectral signature that corresponds with a spatial location of a biomineralization in a volume (paras. 0041 and 0048; instead of simply detecting reflected ultrasound signals at the source frequency, this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone).
However, Parks fails to explicitly teach a low-pass filter configured to receive the signal output of the receiver and to isolate diminished frequencies of the signal output, the diminished frequencies less than 50% of the fundamental frequency; an analog-to-digital converter configured to convert the diminished frequencies to digital diminished-frequency representations; a non-volatile computer-readable memory that stores the digital diminished- frequency representations; and a computer having a microprocessor and non-volatile computer-readable memory, the computer operatively coupled to the computer-readable memory, the non-volatile computer-readable memory storing computer-readable instructions that, when executed by the microprocessor, cause the microprocessor to automatically: determine whether the digital diminished-frequency representations include a diminished-frequency spectral signature that corresponds with a spatial location of a biomineralization in a volume, and produce an output control signal that indicates that the diminished- frequency spectral signature is detected.
Prus, in the same field of endeavor, teaches Prus, in the same field of endeavor, teaches a low-pass filter configured to receive the signal output of the receiver and to isolate diminished frequencies of the signal output, the diminished frequencies less than 50% of the fundamental frequency (paras. 0040, 0042, and 0048; The acoustic signals returned from cavitation events may include frequencies at the fundamental frequency and/or a harmonic, ultra-harmonic, and/or sub-harmonic of the fundamental frequency. the term “sub-harmonic” refers to a fractional number between the fundamental frequency and the first harmonic (e.g., f.sub.0/2, f.sub.0/3, f.sub.0/4, etc.). Various types of microbubble cavitation may occur during an ultrasound procedure and each type of the cavitation may have its own spectral “signature” that represents the unique nonlinear response of the bubbles. For example, stable cavitation induced at an intermediate acoustic power (e.g., 5 Watts above the microbubble-generation threshold) may produce a strong sub-harmonic response (i.e., having more components at the sub-harmonic frequencies and/or having larger amplitudes of the sub-harmonic frequencies). the harmonic(s) 314, ultra-harmonic(s) 316 and/or sub-harmonic(s) (not shown) in the spectral signature 310 of the detected echo signal 306 are included when reconstructing the reference signal 322. In one implementation, each harmonic, ultra-harmonic and/or sub-harmonic is processed by its corresponding filter. For example, a filter associated with a k.sup.th-order harmonic of a fundamental frequency may be defined as follows: where A.sup.1(f) and φ.sup.1 (f) represent an amplitude and a phase of the fundamental frequency filter, and k can be an integer or a fraction. Accordingly, the filter associated with the k.sup.th-order harmonic is computed by scaling the filter associated with the fundamental frequency based on the order of the harmonic (i.e., k). This scaled harmonic-frequency filter may improve the resolution and/or signal-to-noise ratio of the harmonic, ultra-harmonic and/or sub-harmonic signals, which may be particularly useful for detecting, for example, stable cavitation where the sub-harmonic is strong and/or inertial cavitation where broadband noise increases and more high-order harmonic frequencies occur. The examiner notes that the system isolates subharmonic frequencies from the broadband signal, where the subharmonic frequencies are less than or equal to one half of the fundamental frequency to localize microbubble cavitation using low pass filter);
an analog-to-digital converter configured to convert the diminished frequencies to digital diminished-frequency representations (figures 1 and 2A, paras. 0037-0039 and 0051; The beamformer 106 receives a radio frequency (RF) input signal, typically in the range from 0.1 MHz to 1.0 MHz, from the frequency generator 110, which may, for example, be a Model DS345 generator available from Stanford Research Systems. System 100 may be modified in various ways within the scope of the invention. For example, for diagnostic applications, the system may further include a conventional ultrasound detector device (such as a hydrophone) 122 that measures transmitted or reflected ultrasound, and which may provide the signals it receives to the controller 108 for further processing. The reflection and transmission signals may also be used as feedback for the phase and amplitude adjustments of the beamformer 106. The examiner notes that the signals are converted to digital signals that can be processed by the controller);
a non-volatile computer-readable memory that stores the digital diminished- frequency representations (para. 0051; the signal library is stored in a database 204 in memory 206. The memory 206 may include or consist essentially of one or more volatile or non-volatile storage devices, e.g., random-access memory (RAM) devices such as DRAM, SRAM, etc., read-only memory (ROM) devices, magnetic disks, optical disks, flash memory devices, and/or other solid-state memory devices. All or a portion of the memory 206 may be located remotely from the ultrasound system 100 and/or the imager 112, e.g., as one or more storage devices connected to ultrasound system 100 and/or the imager 112 via a network (e.g., Ethernet, WiFi, a cellular telephone network, the Internet, or any local- or wide-area network or combination of networks capable of supporting data transfer and communication). As utilized herein, the term “storage” broadly connotes any form of digital storage, e.g., optical storage, magnetic storage, semiconductor storage, etc. The database 204 may store the reference signals and the various types of microbubble cavitation (or pointers thereto). For example, the database 204 may be organized as a series of records each of which classifies a reference signal (i.e., a spectral signature) as a particular type of cavitation, and which may contain pointers to the file or files encoding the reference signal in a suitable manner, e.g., as an uncompressed binary file, a .wav file, a compressed signal file, etc. The examiner notes that the memory is a digital storage memory);
and a computer having a microprocessor and non-volatile computer-readable memory, the computer operatively coupled to the computer-readable memory, the non-volatile computer-readable memory storing computer-readable instructions that, when executed by the microprocessor, cause the microprocessor to automatically (paras. 0038, 0051, and 0068-0069; the controller 108, which may provide the computational functions through software, hardware, firmware, hardwiring, or any combination thereof. For example, the controller 108 may utilize a general-purpose or special-purpose digital data processor programmed with software in a conventional manner, whether integrated within a controller of the imager, a cavitation detection device 113 and/or an ultrasound system, or provided by a separate external controller or other computational entity or entities, may be structured in one or more modules implemented in hardware, software, or a combination of both. For embodiments in which the functions are provided as one or more software programs, the programs may be written in any of a number of high level languages such as FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and/or HTML. Additionally, the software can be implemented in an assembly language directed to the microprocessor resident on a target computer (e.g., the controller); for example, the software may be implemented in Intel 80x86 assembly language if it is configured to run on an IBM PC or PC clone. The software may be embodied on an article of manufacture including, but not limited to, a floppy disk, a jump drive, a hard disk, an optical disk, a magnetic tape, a PROM, an EPROM, EEPROM, field-programmable gate array, or CD-ROM. Embodiments using hardware circuitry may be implemented using, for example, one or more FPGA, CPLD or ASIC processors.): determine whether the digital diminished-frequency representations include a diminished-frequency spectral signature that corresponds with a spatial location of a biomineralization in a volume (paras. 0064-0069; methods 820 for determining the real-time presence, type and/or location of microbubble cavitation using a signal library having portions of reference signals corresponding to various types of cavitation in accordance with various embodiments. In a first step 822, during an ultrasound procedure, an emitted acoustic signal reflected from the tissue is detected using a portion of the transducer array and/or a separate detection device 122. In a second step 824, one or more portions of reference signals serve as windows moving along the received acoustic signal; the portion of the received signal that has the closest match to one of the portions of reference signals is identified. In other words, each type of cavitation is associated with a portion of signals indicative of that type of cavitation, and a received signal is simultaneously or sequentially analyzed against multiple signal portions in a moving-window fashion to determine which of multiple cavitation types may be present.), and produce an output control signal that indicates that the diminished- frequency spectral signature is detected (paras. 0064-0069; If the received acoustic echo signal (for example, a signal 808 received at a time t.sub.2) includes a portion 810 that is identified to match the reference signal 802, it indicates that the cavitation type associated with the reference signal 802 has occurred.).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the system of Parks to incorporate the teaching Prus to include a low pass filter to isolate diminished frequency less than 50% of the fundamental frequency, an analog to digital converter, and a memory. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. Additionally, sub-harmonic frequencies provide high contrast, cavitation specific component that can be independently reconstructed, compared to background signal, and used to localize cavitation while suppressing tissue and solid reflection from surrounding anatomies. The use of analog to digital converter and a memory allows the signals to be converted to digital signals for processing and storage.
Regarding claim 19, Parks teaches the system of claim 18, further comprising: however, fails to explicitly disclose a preamplifier having an input electrically coupled to an output of the receiver, the preamplifier having an output electrically coupled to an input of the low-pass filter; and a gain amplifier having an input electrically coupled to an output of the low-pass filter, the gain amplifier having an output electrically coupled to an input of the analog- to-digital converter.
Prus, in the same field of endeavor, teaches a preamplifier having an input electrically coupled to an output of the receiver, the preamplifier having an output electrically coupled to an input of the low-pass filter (figures 1 and 2A, paras. 0037-0039; The transducer array 102 is coupled to the beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasonic beam or field. For n transducer elements, the beamformer 106 may contain n driver circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120; drive circuit drives one of the transducer elements 104. The amplification or attenuation factors α.sub.1-α.sub.n and the phase shifts a.sub.1-a.sub.n imposed by the beamformer 106 serve to transmit and focus ultrasonic energy through the patient's skull 114 onto a selected region of the patient's brain, and account for wave distortions induced in the skull 114 and soft brain tissue. The amplification factors and phase shifts are computed using the controller 108, which may provide the computational functions through software, hardware, firmware, hardwiring, or any combination thereof. System 100 may be modified in various ways within the scope of the invention. For example, for diagnostic applications, the system may further include a conventional ultrasound detector device (such as a hydrophone) 122 that measures transmitted or reflected ultrasound, and which may provide the signals it receives to the controller 108 for further processing. The examiner notes that the amplifier is connected to the ultrasound detector device and the controller which preforms low pass filtering of the signals); and a gain amplifier having an input electrically coupled to an output of the low-pass filter, the gain amplifier having an output electrically coupled to an input of the analog- to-digital converter (figures 1 and 2A, paras. 0037-0039; The transducer array 102 is coupled to the beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasonic beam or field. For n transducer elements, the beamformer 106 may contain n driver circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120; drive circuit drives one of the transducer elements 104. The amplification or attenuation factors α.sub.1-α.sub.n and the phase shifts a.sub.1-a.sub.n imposed by the beamformer 106 serve to transmit and focus ultrasonic energy through the patient's skull 114 onto a selected region of the patient's brain, and account for wave distortions induced in the skull 114 and soft brain tissue. The amplification factors and phase shifts are computed using the controller 108, which may provide the computational functions through software, hardware, firmware, hardwiring, or any combination thereof. System 100 may be modified in various ways within the scope of the invention. For example, for diagnostic applications, the system may further include a conventional ultrasound detector device (such as a hydrophone) 122 that measures transmitted or reflected ultrasound, and which may provide the signals it receives to the controller 108 for further processing. The examiner notes that the amplifier is connected to the ultrasound detector device (which is part of the beamformer which preforms the analog to digital conversion) and the controller which preforms low pass filtering of the signals).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the system of Parks to incorporate the teaching Prus to include a low pass filter to isolate diminished frequency less than 50% of the fundamental frequency, an analog to digital converter, and an amplifier. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. Additionally, sub-harmonic frequencies provide high contrast, cavitation specific component that can be independently reconstructed, compared to background signal, and used to localize cavitation while suppressing tissue and solid reflection from surrounding anatomies. The use of analog to digital converter and a memory allows the signals to be converted to digital signals for processing and storage.
Regarding claim 20, Parks teaches the system of claim 18, however, fails to explicitly teach a field-programmable gate array (FPGA) in electrical communication with the memory, the FPGA configured to produce a trigger signal to store the digital diminished-frequency representations in the memory.
Prus, in the same field of endeavor, teaches a field-programmable gate array (FPGA) in electrical communication with the memory, the FPGA configured to produce a trigger signal to store the digital diminished-frequency representations in the memory (Figure 2A, paras. 0047, 0051 and 0068-0069; hardware circuitry may be implemented using, for example, one or more FPGA, CPLD or ASIC processors.).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the system of Parks to incorporate the teaching Prus to include FPGA. Doing so would enable generating reconstructed echo signal 322 resulting from microbubble cavitation may have a higher signal-to-noise ratio than the original received signal . The echo signal may then be stored in a library and used as a reference signal for detecting the presence of microbubble cavitation during an ultrasound procedure as disclosed within Prus in para. 0047.
Regarding claim 21, Parks teaches the system of claim 18, however fails to explicitly teach the analog-to-digital converter is a first analog-to-digital converter, the non-volatile computer-readable memory is a first non-volatile computer- readable memory, and the system further comprises: a high-pass filter configured to receive the signal output of the receiver and to isolate the fundamental and harmonic frequencies of the signal output; a second analog-to-digital converter configured to convert the fundamental and harmonic frequencies to digital fundamental and harmonic representations; and a second non-volatile computer-readable memory that stores the digital fundamental and harmonic representations, wherein the computer-readable instructions, when executed by the microprocessor, further cause the microprocessor to produce a diagnostic image on a display screen in electrical communication with the computer, the diagnostic image corresponding to the digital fundamental and harmonic representations.
Prus, in the same field of endeavor, teaches analog-to-digital converter is a first analog-to-digital converter (figures 1 and 2A, paras. 0037-0039 and 0051; The beamformer 106 receives a radio frequency (RF) input signal, typically in the range from 0.1 MHz to 1.0 MHz, from the frequency generator 110, which may, for example, be a Model DS345 generator available from Stanford Research Systems. System 100 may be modified in various ways within the scope of the invention. For example, for diagnostic applications, the system may further include a conventional ultrasound detector device (such as a hydrophone) 122 that measures transmitted or reflected ultrasound, and which may provide the signals it receives to the controller 108 for further processing. The reflection and transmission signals may also be used as feedback for the phase and amplitude adjustments of the beamformer 106. The examiner notes that the signals are converted to digital signals that can be processed by the controller),
the non-volatile computer-readable memory is a first non-volatile computer- readable memory (para. 0051; the signal library is stored in a database 204 in memory 206. The memory 206 may include or consist essentially of one or more volatile or non-volatile storage devices, e.g., random-access memory (RAM) devices such as DRAM, SRAM, etc., read-only memory (ROM) devices, magnetic disks, optical disks, flash memory devices, and/or other solid-state memory devices. All or a portion of the memory 206 may be located remotely from the ultrasound system 100 and/or the imager 112, e.g., as one or more storage devices connected to ultrasound system 100 and/or the imager 112 via a network (e.g., Ethernet, WiFi, a cellular telephone network, the Internet, or any local- or wide-area network or combination of networks capable of supporting data transfer and communication). As utilized herein, the term “storage” broadly connotes any form of digital storage, e.g., optical storage, magnetic storage, semiconductor storage, etc. The database 204 may store the reference signals and the various types of microbubble cavitation (or pointers thereto). For example, the database 204 may be organized as a series of records each of which classifies a reference signal (i.e., a spectral signature) as a particular type of cavitation, and which may contain pointers to the file or files encoding the reference signal in a suitable manner, e.g., as an uncompressed binary file, a .wav file, a compressed signal file, etc. The examiner notes that the memory is a digital storage memory), and the system further comprises:
a high-pass filter configured to receive the signal output of the receiver and to isolate the fundamental and harmonic frequencies of the signal output (paras. 0040, 0042, and 0048; The acoustic signals returned from cavitation events may include frequencies at the fundamental frequency and/or a harmonic, ultra-harmonic, and/or sub-harmonic of the fundamental frequency. Various types of microbubble cavitation may occur during an ultrasound procedure and each type of the cavitation may have its own spectral “signature” that represents the unique nonlinear response of the bubbles. the harmonic(s) 314, ultra-harmonic(s) 316 and/or sub-harmonic(s) (not shown) in the spectral signature 310 of the detected echo signal 306 are included when reconstructing the reference signal 322. In one implementation, each harmonic, ultra-harmonic and/or sub-harmonic is processed by its corresponding filter. For example, a filter associated with a k.sup.th-order harmonic of a fundamental frequency may be defined as follows: where A.sup.1(f) and φ.sup.1 (f) represent an amplitude and a phase of the fundamental frequency filter, and k can be an integer or a fraction. Accordingly, the filter associated with the k.sup.th-order harmonic is computed by scaling the filter associated with the fundamental frequency based on the order of the harmonic (i.e., k). This scaled harmonic-frequency filter may improve the resolution and/or signal-to-noise ratio of the harmonic, ultra-harmonic and/or sub-harmonic signals, which may be particularly useful for detecting, for example, stable cavitation where the sub-harmonic is strong and/or inertial cavitation where broadband noise increases and more high-order harmonic frequencies occur. The examiner notes that the system isolates harmonic, ultra-harmonic and/or sub-harmonic signals from the broadband signal, using high pass and low pass filters);
a second analog-to-digital converter configured to convert the fundamental and harmonic frequencies to digital fundamental and harmonic representations (figures 1 and 2A, paras. 0037-0039 and 0051; The beamformer 106 receives a radio frequency (RF) input signal, typically in the range from 0.1 MHz to 1.0 MHz, from the frequency generator 110, which may, for example, be a Model DS345 generator available from Stanford Research Systems. System 100 may be modified in various ways within the scope of the invention. For example, for diagnostic applications, the system may further include a conventional ultrasound detector device (such as a hydrophone) 122 that measures transmitted or reflected ultrasound, and which may provide the signals it receives to the controller 108 for further processing. The reflection and transmission signals may also be used as feedback for the phase and amplitude adjustments of the beamformer 106. The examiner notes that the signals are converted to digital signals that can be processed by the controller); and
a second non-volatile computer-readable memory that stores the digital fundamental and harmonic representations, wherein the computer-readable instructions, when executed by the microprocessor, further cause the microprocessor to produce a diagnostic image on a display screen in electrical communication with the computer, the diagnostic image corresponding to the digital fundamental and harmonic representations (paras. 0038, 0042-0043; the spectral signature associated with each type of cavitation is “learned” based on measurements acquired during previous ultrasound delivery. For example, during a prior ultrasound procedure, the ultrasound system 100, the imager 112 and/or the cavitation detector 113 may detect and monitor the generation of cavitation events in tissue. If a type of cavitation is detected, at least some of the transducer elements 104 and/or a separate detector device 122 are used to measure ultrasound emitted from the microbubbles; the resulting signals may be transmitted to the controller 108 to obtain spectral information associated with the microbubble cavitation. Thus, a mapping between various types of cavitation events and their spectral signatures can be established.).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the system of Parks to incorporate the teaching Prus to include a high pass filter, an analog to digital converter, and a memory. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. The use of analog to digital converter and a memory allows the signals to be converted to digital signals for processing and storage.
Regarding claim 22, Parks teaches the system of claim 18, wherein the ultrasound device and the receiver are coaxially aligned such that the produced ultrasonic energy waves from the ultrasound device pass through the receiver before passing into the volume (para. 0048; the system may be equipped with both the external ultrasound source (transmitter) as well as a passive cavitation detection and monitoring acoustic sensor (receiver). The acoustic sensor may be integrated into the transmitting ultrasound source as a transducer element in an array of a plurality of elements, or the acoustic sensor may be implemented as a stand-alone sensor such as a hydrophone which is suitably placed with respect to the ultrasound source and target region.).
Regarding claim 23, Parks teaches the system of claim 18, however, fails to explicitly teach wherein the diminished frequencies are greater than or equal to about 4% of the fundamental frequency.
Prus, in the same field of endeavor, teaches diminished frequencies are greater than or equal to about 4% of the fundamental frequency (paras. 0040, 0042, 0048, and 0064-0067; The acoustic signals returned from cavitation events may include frequencies at the fundamental frequency and/or a harmonic, ultra-harmonic, and/or sub-harmonic of the fundamental frequency. the term “sub-harmonic” refers to a fractional number between the fundamental frequency and the first harmonic (e.g., f.sub.0/2, f.sub.0/3, f.sub.0/4, etc.). Various types of microbubble cavitation may occur during an ultrasound procedure and each type of the cavitation may have its own spectral “signature” that represents the unique nonlinear response of the bubbles. For example, stable cavitation induced at an intermediate acoustic power (e.g., 5 Watts above the microbubble-generation threshold) may produce a strong sub-harmonic response (i.e., having more components at the sub-harmonic frequencies and/or having larger amplitudes of the sub-harmonic frequencies). the harmonic(s) 314, ultra-harmonic(s) 316 and/or sub-harmonic(s) (not shown) in the spectral signature 310 of the detected echo signal 306 are included when reconstructing the reference signal 322. In one implementation, each harmonic, ultra-harmonic and/or sub-harmonic is processed by its corresponding filter. For example, a filter associated with a k.sup.th-order harmonic of a fundamental frequency may be defined as follows: where A.sup.1(f) and φ.sup.1 (f) represent an amplitude and a phase of the fundamental frequency filter, and k can be an integer or a fraction. Accordingly, the filter associated with the k.sup.th-order harmonic is computed by scaling the filter associated with the fundamental frequency based on the order of the harmonic (i.e., k). This scaled harmonic-frequency filter may improve the resolution and/or signal-to-noise ratio of the harmonic, ultra-harmonic and/or sub-harmonic signals, which may be particularly useful for detecting, for example, stable cavitation where the sub-harmonic is strong and/or inertial cavitation where broadband noise increases and more high-order harmonic frequencies occur. The examiner notes that the system isolates subharmonic frequencies from the broadband signal, where the subharmonic frequencies are less than or equal to one fourth of the fundamental frequency to localize microbubble cavitation).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the diminished frequency of Parks to incorporate the teaching Prus to include a diminished frequency greater than or equal to about 4% of the fundamental frequency. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. Additionally, sub-harmonic frequencies provide high contrast, cavitation specific component that can be independently reconstructed, compared to background signal, and used to localize cavitation while suppressing tissue and solid reflection from surrounding anatomies.
Regarding claim 24, Parks teaches a system for localizing a biomineralization in a volume, comprising (para. 0027; The invention may be used to detect and/or treat conditions related to acute renal colic, which is a potentially debilitating condition caused by an obstruction of the urinary tract. Discrimination of a target (e.g., a bubble-coated biomineralization) from surrounding objects such as bone, is possible because the present invention allows for localization and positioning on account of the directional alignment available between the external acoustic source and the target biomineralization and microbubble formation):
an ultrasound device that produces pulses of produced ultrasonic energy waves having a fundamental frequency (para. 0026; one or more ultrasonic transducers which deliver ultrasonic energy to a target region containing an unwanted biomineralization such as a urinary stone 110 lodged in a patient's ureter 120. the ultrasound source is configured to generate acoustic energy having a center frequency or fundamental being lower than 1 megahertz (MHz), and in a specific non-limiting example a center frequency of about 500 kilohertz (kHz).);
a receiver that receives returned ultrasonic energy waves and produces signals that represent the returned ultrasonic energy waves (para. 0048; the system may be equipped with both the external ultrasound source (transmitter) as well as a passive cavitation detection and monitoring acoustic sensor (receiver). The acoustic sensor may be integrated into the transmitting ultrasound source as a transducer element in an array of a plurality of elements. By selectively detecting at broad-band emissions.);
a catheter configured to inject an ensemble of microbubbles proximal to the biomineralization(para. 0029; depicts placement of engineered microbubbles 203 proximally to an undesired biomineralization (e.g., urinary stone) 204 within a ureter 202. The microbubbles may be injected using a syringe or pump 208 through a catheter 206 as best suits a particular situation. ); and
and a computer having a microprocessor cause the microprocessor to automatically (para. 0041, the system's processing circuit 230):
perform a fast Fourier transform of the digital frequency representations with respect to diminished frequencies that are less the fundamental frequency to isolate the diminished frequencies (paras. 0041-0042 and 0048; the power spectral density (PSD) of acoustic signature measured from the excitation and inertial cavitation events in the cluster, cloud or group of a large plurality of microbubbles. A Fourier transform may be applied using the system's processing circuit 230 to the acoustic signature of the cavitation events in the target region, and the resulting spectrum can be plotted, analyzed or processed by human operators or machines in the present system. The power spectral density may employ a fast Fourier transform (FFT) and be computed as PSD(f)=Δt/N|f.Math.FFT(p(t))|.sup.2. The IC is quantifiable in a number of ways that generally indicate the amount, intensity, or other severity of the cavitation activity in the microbubble and target environment. In one embodiment, the IC is quantified using an integration of the power spectrum over a specified frequency range. In a non-limiting example, the frequency range includes the frequencies above and below a harmonic of the fundamental treatment frequency causing the microbubble cavitation.), determine whether a diminished-frequency signal corresponding to the diminished frequencies includes a diminished-frequency spectral signature that corresponds with a spatial location of a biomineralization in a volume (paras. 0041 and 0048; instead of simply detecting reflected ultrasound signals at the source frequency, this invention relies on detection of IC signals arising from the collapse of microbubbles that selectively accumulate near the urinary stone in the ureter. By selectively detecting at broad-band emissions and filtering out harmonics of the input ultrasound frequency, direct reflections from the surrounding bones are discriminated against, providing greatly enhanced detection of the urinary stone).
However, Parks fails to explicitly teach isolate diminished frequencies of the signal output, the diminished frequencies less than 50% of the fundamental frequency; an analog-to-digital converter configured to convert the signals to digital frequency representations; a non-volatile computer-readable memory that stores the digital diminished- frequency representations; and a computer having a microprocessor and non-volatile computer-readable memory, the computer operatively coupled to the computer-readable memory, the non-volatile computer-readable memory storing computer-readable instructions that, when executed by the microprocessor, cause the microprocessor to automatically: determine whether the digital diminished-frequency representations include a diminished-frequency spectral signature that corresponds with a spatial location of a biomineralization in a volume, and produce an output control signal that indicates that the diminished- frequency spectral signature is detected.
Prus, in the same field of endeavor, teaches Prus, in the same field of endeavor, teaches isolate diminished frequencies of the signal output, the diminished frequencies less than 50% of the fundamental frequency (paras. 0040, 0042, and 0048; The acoustic signals returned from cavitation events may include frequencies at the fundamental frequency and/or a harmonic, ultra-harmonic, and/or sub-harmonic of the fundamental frequency. the term “sub-harmonic” refers to a fractional number between the fundamental frequency and the first harmonic (e.g., f.sub.0/2, f.sub.0/3, f.sub.0/4, etc.). Various types of microbubble cavitation may occur during an ultrasound procedure and each type of the cavitation may have its own spectral “signature” that represents the unique nonlinear response of the bubbles. For example, stable cavitation induced at an intermediate acoustic power (e.g., 5 Watts above the microbubble-generation threshold) may produce a strong sub-harmonic response (i.e., having more components at the sub-harmonic frequencies and/or having larger amplitudes of the sub-harmonic frequencies). the harmonic(s) 314, ultra-harmonic(s) 316 and/or sub-harmonic(s) (not shown) in the spectral signature 310 of the detected echo signal 306 are included when reconstructing the reference signal 322. In one implementation, each harmonic, ultra-harmonic and/or sub-harmonic is processed by its corresponding filter. For example, a filter associated with a k.sup.th-order harmonic of a fundamental frequency may be defined as follows: where A.sup.1(f) and φ.sup.1 (f) represent an amplitude and a phase of the fundamental frequency filter, and k can be an integer or a fraction. Accordingly, the filter associated with the k.sup.th-order harmonic is computed by scaling the filter associated with the fundamental frequency based on the order of the harmonic (i.e., k). This scaled harmonic-frequency filter may improve the resolution and/or signal-to-noise ratio of the harmonic, ultra-harmonic and/or sub-harmonic signals, which may be particularly useful for detecting, for example, stable cavitation where the sub-harmonic is strong and/or inertial cavitation where broadband noise increases and more high-order harmonic frequencies occur. The examiner notes that the system isolates subharmonic frequencies from the broadband signal, where the subharmonic frequencies are less than or equal to one half of the fundamental frequency to localize microbubble cavitation using low pass filter);
an analog-to-digital converter configured to convert the signals to digital frequency representations (figures 1 and 2A, paras. 0037-0039 and 0051; The beamformer 106 receives a radio frequency (RF) input signal, typically in the range from 0.1 MHz to 1.0 MHz, from the frequency generator 110, which may, for example, be a Model DS345 generator available from Stanford Research Systems. System 100 may be modified in various ways within the scope of the invention. For example, for diagnostic applications, the system may further include a conventional ultrasound detector device (such as a hydrophone) 122 that measures transmitted or reflected ultrasound, and which may provide the signals it receives to the controller 108 for further processing. The reflection and transmission signals may also be used as feedback for the phase and amplitude adjustments of the beamformer 106. The examiner notes that the signals are converted to digital signals that can be processed by the controller);
a non-volatile computer-readable memory that stores the digital frequency representations (para. 0051; the signal library is stored in a database 204 in memory 206. The memory 206 may include or consist essentially of one or more volatile or non-volatile storage devices, e.g., random-access memory (RAM) devices such as DRAM, SRAM, etc., read-only memory (ROM) devices, magnetic disks, optical disks, flash memory devices, and/or other solid-state memory devices. All or a portion of the memory 206 may be located remotely from the ultrasound system 100 and/or the imager 112, e.g., as one or more storage devices connected to ultrasound system 100 and/or the imager 112 via a network (e.g., Ethernet, WiFi, a cellular telephone network, the Internet, or any local- or wide-area network or combination of networks capable of supporting data transfer and communication). As utilized herein, the term “storage” broadly connotes any form of digital storage, e.g., optical storage, magnetic storage, semiconductor storage, etc. The database 204 may store the reference signals and the various types of microbubble cavitation (or pointers thereto). For example, the database 204 may be organized as a series of records each of which classifies a reference signal (i.e., a spectral signature) as a particular type of cavitation, and which may contain pointers to the file or files encoding the reference signal in a suitable manner, e.g., as an uncompressed binary file, a .wav file, a compressed signal file, etc. The examiner notes that the memory is a digital storage memory);
and a computer having a microprocessor and non-volatile computer-readable memory, the computer operatively coupled to the computer-readable memory, the non-volatile computer-readable memory storing computer-readable instructions that, when executed by the microprocessor, cause the microprocessor to automatically (paras. 0038, 0051, and 0068-0069; the controller 108, which may provide the computational functions through software, hardware, firmware, hardwiring, or any combination thereof. For example, the controller 108 may utilize a general-purpose or special-purpose digital data processor programmed with software in a conventional manner, whether integrated within a controller of the imager, a cavitation detection device 113 and/or an ultrasound system, or provided by a separate external controller or other computational entity or entities, may be structured in one or more modules implemented in hardware, software, or a combination of both. For embodiments in which the functions are provided as one or more software programs, the programs may be written in any of a number of high level languages such as FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and/or HTML. Additionally, the software can be implemented in an assembly language directed to the microprocessor resident on a target computer (e.g., the controller); for example, the software may be implemented in Intel 80x86 assembly language if it is configured to run on an IBM PC or PC clone. The software may be embodied on an article of manufacture including, but not limited to, a floppy disk, a jump drive, a hard disk, an optical disk, a magnetic tape, a PROM, an EPROM, EEPROM, field-programmable gate array, or CD-ROM. Embodiments using hardware circuitry may be implemented using, for example, one or more FPGA, CPLD or ASIC processors.): determine whether the digital diminished-frequency representations include a diminished-frequency spectral signature that corresponds with a spatial location of a biomineralization in a volume (paras. 0064-0069; methods 820 for determining the real-time presence, type and/or location of microbubble cavitation using a signal library having portions of reference signals corresponding to various types of cavitation in accordance with various embodiments. In a first step 822, during an ultrasound procedure, an emitted acoustic signal reflected from the tissue is detected using a portion of the transducer array and/or a separate detection device 122. In a second step 824, one or more portions of reference signals serve as windows moving along the received acoustic signal; the portion of the received signal that has the closest match to one of the portions of reference signals is identified. In other words, each type of cavitation is associated with a portion of signals indicative of that type of cavitation, and a received signal is simultaneously or sequentially analyzed against multiple signal portions in a moving-window fashion to determine which of multiple cavitation types may be present.), and produce an output control signal that indicates that the diminished- frequency spectral signature is detected (paras. 0064-0069; If the received acoustic echo signal (for example, a signal 808 received at a time t.sub.2) includes a portion 810 that is identified to match the reference signal 802, it indicates that the cavitation type associated with the reference signal 802 has occurred.).
It would have been obvious to an ordinary skilled in the art before the invention was made to modify the system of Parks to incorporate the teaching Prus to include a low pass filter to isolate diminished frequency less than 50% of the fundamental frequency, an analog to digital converter, and a memory. Doing so would improve signal to noise ratio and suppresses broadband noise and non-cavitation reflection as disclosed within Prus in paras. 0042 and 0049. Additionally, sub-harmonic frequencies provide high contrast, cavitation specific component that can be independently reconstructed, compared to background signal, and used to localize cavitation while suppressing tissue and solid reflection from surrounding anatomies. The use of analog to digital converter and a memory allows the signals to be converted to digital signals for processing and storage.
Conclusion
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/ZAINAB MOHAMMED ALDARRAJI/ Patent Examiner, Art Unit 3797