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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/06/2026 has been entered.
Response to Amendment
This action is in response to the remarks filed on 2/06/2026. The amendments filed on 2/06/2026 are entered.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 5, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Dixon et al. (U.S. Pub. No. 20150272601) hereinafter Dixon, in view of Vortman et al. (U.S. Pub. No. 20070016039) hereinafter Vortman ‘039.
Regarding claim 1, primary reference Dixon teaches:
A method for treating soft tissue having a cavitation threshold at which cavitation occurs the method (abstract), comprising:
throughout an entire therapeutic application of ultrasound to the soft-tissue ([0047], ultrasound echo is transmitted and signals are received from one or more isolated microbubbles, throughout a procedure; [0048], “incrementally increasing power of the transmit ultrasound energy to determine a threshold power level where microbubble destruction, such as by cavitation or other form of destruction is observed to start occurring”. This process would include output, monitoring, and energy adjustment throughout the treatment; [0190]-[0191], signals from isolated microbubbles):
outputting a treatment ultrasound pulse sequence at a treatment portion of the soft tissue ([0048], “delivering the microbubbles at full dose and applying the ultrasound energy to the microbubbles at the reduced power level”; [0190]-[0191], treatment ultrasound is provided at the soft tissue with ultrasound treatment pulses (ultrasound applied to target area); [0193]);
monitoring an ultrasonic echo from microbubbles ([0047], ultrasound echo signals are received from one or more isolated microbubbles; [0048], “incrementally increasing power of the transmit ultrasound energy to determine a threshold power level where microbubble destruction, such as by cavitation or other form of destruction is observed to start occurring”; [0190]-[0191], signals from isolated microbubbles); and
adjusting the energy of the ultrasound pulse sequence based on the monitoring to reduce the ultrasonic echo from microbubbles so that the energy of the ultrasound pulse sequence is at a power level below the cavitation threshold ([0047], ultrasound echo signals are received from one or more isolated microbubbles; [0048], “reducing the power of the transmit ultrasound energy to a reduced power level comprising a predetermined percentage of the threshold power level; and delivering the microbubbles at full dose and applying the ultrasound energy to the microbubbles at the reduced power level”; [0190]-[0191], signals from isolated microbubbles during cavitation events is reduced when the device operates at a power level below the cavitation threshold).
Primary reference Dixon further fails to teach:
adjusting the energy so that the energy of the ultrasound pulse sequence is at a power level below the cavitation threshold to reduce the generation of microbubbles
However, the analogous art of Vortman ‘039 of a system for treating tissue within a body using ultrasound energy (abstract) teaches:
throughout an entire therapeutic application of ultrasound to the soft-tissue ([0027], adjustment of energy level below a threshold occurs during an application of ultrasound treatment to the tissue; [0046]-[0054], treatment above a threshold is brief such as not more than 0.1 second, and then adjustment of energy below the cavitation threshold occurs throughout the treatment process)
adjusting the energy so that the energy of the ultrasound pulse sequence is at a power level below the cavitation threshold to reduce the generation of microbubbles ([0027], “the controller 18 may lower the intensity below a threshold to a level at which the generation of microbubbles is minimized in the tissue within the focal zone 38, yet may still necrose, coagulate, or otherwise heat tissue, as explained below. For example, the controller 18 may subsequently lower the intensity to approximately 0 to thereby prevent further formation of microbubbles at the focal zone 38 during a treatment process.”. This forms a power level below the threshold of generation of microbubbles (cavitation threshold) and enables more precise control of microbubble quantities and amount; [0046]-[0047], microbubbles; [0048], an intensity below the intensity used to generate the microbubbles to reduce and lower the generation of microbubbles; [0049]-[0050], multiple transmissions above and below the threshold (cavitation threshold) necessary to generate microbubbles to either increase or reduce generation of microbubbles; [0072]; see also [0004]-[0006]; [0051]-[0054])
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon to incorporate the adjustment of ultrasound energy below a threshold to reduce microbubble generation as taught by Vortman ‘039 because more precise feedback control of the level of microbubbles at the target tissue of interest can provide more efficient and more accurate treatment while reducing the risk of damage to healthy non-targeted tissue (Vortman ‘039, [0072]).
Regarding claim 5, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further teaches:
wherein a frequency of the treatment ultrasound pulse sequence is between 500kHz and 1MHz ([0162], frequency of therapeutic mode is within the claimed range).
Regarding claim 21, primary reference Dixon teaches:
An apparatus for therapeutic ultrasound (abstract) comprising:
an ultrasonic transducer providing an ultrasound pulse sequence and adapted to couple the ultrasonic pulse sequence into soft tissue ([0048], “delivering the microbubbles at full dose and applying the ultrasound energy to the microbubbles at the reduced power level”; [0161]-[0162], ultrasound source forms transducer for treatment; [0181], transducer; [0190]-[0191], treatment ultrasound is provided at the soft tissue with ultrasound treatment pulses (ultrasound applied to target area); [0193]);
a treatment monitor monitoring an ultrasonic echo from microbubbles ([0047], ultrasound echo signals are received from one or more isolated microbubbles; [0048], “incrementally increasing power of the transmit ultrasound energy to determine a threshold power level where microbubble destruction, such as by cavitation or other form of destruction is observed to start occurring”; [0190]-[0191], signals from isolated microbubbles);
a control system controlling output power of the treatment ultrasound pulse sequence throughout an entire therapeutic application of ultrasound to the soft-tissue by the ultrasonic transducer ([0047], ultrasound echo is transmitted and signals are received from one or more isolated microbubbles, throughout a procedure; [0048], “incrementally increasing power of the transmit ultrasound energy to determine a threshold power level where microbubble destruction, such as by cavitation or other form of destruction is observed to start occurring”. This process would include output, monitoring, and energy adjustment throughout the treatment; [0190]-[0191], signals from isolated microbubbles):
according to feedback from the treatment monitor to reduce the ultrasonic echo from microbubbles so that the energy of the ultrasound pulse sequence is at a level beneath a cavitation threshold ([0047], ultrasound echo signals are received from one or more isolated microbubbles; [0048], “reducing the power of the transmit ultrasound energy to a reduced power level comprising a predetermined percentage of the threshold power level; and delivering the microbubbles at full dose and applying the ultrasound energy to the microbubbles at the reduced power level”; [0190]-[0191], signals from isolated microbubbles during cavitation events is reduced when the device operates at a power level below the cavitation threshold).
Primary reference Dixon further fails to teach:
to reduce the ultrasonic echo from microbubbles so that the energy of the ultrasound pulse sequence is at a level beneath a cavitation threshold to reduce the generation of microbubbles
However, the analogous art of Vortman ‘039 of a system for treating tissue within a body using ultrasound energy (abstract) teaches:
throughout an entire therapeutic application of ultrasound to the soft-tissue ([0027], adjustment of energy level below a threshold occurs during an application of ultrasound treatment to the tissue; [0046]-[0054], treatment above a threshold is brief such as not more than 0.1 second, and then adjustment of energy below the cavitation threshold occurs throughout the treatment process)
to reduce the ultrasonic echo from microbubbles so that the energy of the ultrasound pulse sequence is at a level beneath a cavitation threshold to reduce the generation of microbubbles ([0027], “the controller 18 may lower the intensity below a threshold to a level at which the generation of microbubbles is minimized in the tissue within the focal zone 38, yet may still necrose, coagulate, or otherwise heat tissue, as explained below. For example, the controller 18 may subsequently lower the intensity to approximately 0 to thereby prevent further formation of microbubbles at the focal zone 38 during a treatment process.”. This forms a power level below the threshold of generation of microbubbles (cavitation threshold) and enables more precise control of microbubble quantities and amount; [0046]-[0047], microbubbles; [0048], an intensity below the intensity used to generate the microbubbles to reduce and lower the generation of microbubbles; [0049]-[0050], multiple transmissions above and below the threshold (cavitation threshold) necessary to generate microbubbles to either increase or reduce generation of microbubbles; [0072]; see also [0004]-[0006]; [0051]-[0054])
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon to incorporate the adjustment of ultrasound energy below a threshold to reduce microbubble generation as taught by Vortman ‘039 because more precise feedback control of the level of microbubbles at the target tissue of interest can provide more efficient and more accurate treatment while reducing the risk of damage to healthy non-targeted tissue (Vortman ‘039, [0072]).
Claims 2-4 and 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039 as applied to claim 1 above, and further in view of Konofagou et al. (U.S. Pub. No. 20210283428) hereinafter Konofagou ‘428.
Regarding claim 2, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
wherein a peak negative pressure of the treatment ultrasound pulse sequence being less than or equal to 20 MPa
However, the analogous art of Konofagou ‘428 of an ultrasound treatment technique for modulating and stimulating target tissue of interest (abstract) teaches:
wherein a peak negative pressure of the treatment ultrasound pulse sequence being less than or equal to 20 MPa ([0061], peak negative pressures are within the claimed range).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the peak negative pressure as taught by Konofagou ‘428 because it provides sufficient energy levels for providing a treatment stimulation to a target tissue of interest, without damaging healthy tissue and leading to unwanted side effects (Konofagou, [0061]).
Regarding claim 3, the combined references of Dixon, Vortman ‘039, and Konofagou ‘428 teach all of the limitations of claim 2. Primary reference Dixon further fails to teach:
wherein a peak negative pressure of the treatment ultrasound pulse sequence being less than or equal to 15 MPa
However, the analogous art of Konofagou ‘428 of an ultrasound treatment technique for modulating and stimulating target tissue of interest (abstract) teaches:
wherein a peak negative pressure of the treatment ultrasound pulse sequence being less than or equal to 15 MPa ([0061], peak negative pressures are within the claimed range).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon, Vortman ‘039, and Konofagou ‘428 to incorporate the peak negative pressure as taught by Konofagou ‘428 because it provides sufficient energy levels for providing a treatment stimulation to a target tissue of interest, without damaging healthy tissue and leading to unwanted side effects (Konofagou ‘428, [0061]).
Regarding claim 4, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
wherein a peak positive pressure of the treatment ultrasound pulse sequence being less than or equal to 60 MPa
However, the analogous art of Konofagou ‘428 of an ultrasound treatment technique for modulating and stimulating target tissue of interest (abstract) teaches:
wherein a peak positive pressure of the treatment ultrasound pulse sequence being less than or equal to 60 MPa ([0061], peak positive pressures are within the claimed range).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the peak positive pressure as taught by Konofagou ‘428 because it provides sufficient energy levels for providing a treatment stimulation to a target tissue of interest, without damaging healthy tissue and leading to unwanted side effects (Konofagou ‘428, [0061]).
Regarding claim 7, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
wherein a duty cycle of the treatment ultrasound pulse sequence is less than or equal to 2%
However, the analogous art of Konofagou ‘428 of an ultrasound treatment technique for modulating and stimulating target tissue of interest (abstract) teaches:
wherein a duty cycle of the treatment ultrasound pulse sequence is less than or equal to 2% ([0062], duty cycle overlaps the claimed range).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the duty cycle range as taught by Konofagou ‘428 because it provides sufficient energy levels for providing a treatment stimulation to a target tissue of interest, without damaging healthy tissue and leading to unwanted side effects (Konofagou ‘428, [0061]).
Regarding claim 8, the combined references of Dixon, Vortman ‘039, and Konofagou ‘428 teach all of the limitations of claim 7. Primary reference Dixon further fails to teach:
wherein a duty cycle of the treatment ultrasound pulse sequence is less than or equal to 1%
However, the analogous art of Konofagou ‘428 of an ultrasound treatment technique for modulating and stimulating target tissue of interest (abstract) teaches:
wherein a duty cycle of the treatment ultrasound pulse sequence is less than or equal to 1% ([0062], duty cycle overlaps the claimed range).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon, Vortman ‘039, and Konofagou ‘428 to incorporate the duty cycle range as taught by Konofagou ‘428 because it provides sufficient energy levels for providing a treatment stimulation to a target tissue of interest, without damaging healthy tissue and leading to unwanted side effects (Konofagou ‘428, [0061]).
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039, as applied to claim 1 above, and further in view of Pernot et al. (U.S. Pub. No. 20190126317) hereinafter Pernot.
Regarding claim 6, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
wherein a pulse repetition frequency (PRF) of the treatment ultrasound pulse sequence is between 250Hz and 750Hz
However, the analogous art of Pernot of an ultrasound imaging and therapy device for treatment of target tissue regions of interest (abstract) teaches:
wherein a pulse repetition frequency (PRF) of the treatment ultrasound pulse sequence is between 250Hz and 750Hz ([0042], pulse repetition frequency overlaps the claimed range).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the pulse repetition frequency as taught by Pernot because it provides a set of energy that forms a burst in order to generate sufficient energy at a target location for treatment of affected tissue (Pernot, [0042]). This leads to improved treatment efficacy and enhanced clinical outcomes.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039 as applied to claim 1 above, and further in view of Slayton et al. (U.S. Pub. No. 20150202468) hereinafter Slayton.
Regarding claim 9, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
wherein pulse length of the treatment pulse is less than or equal to 15 µsec
However, the analogous art of Slayton of a method for controlling acoustic energy deposition within tissue objects of interest (abstract; [0030]) teaches:
wherein pulse length of the treatment pulse is less than or equal to 15 µsec ([0006]-[0007], pulse duration is within the claimed range for the ultrasound treatment pulse in a picosecond range; [0056]; see also claims 23-24).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the pulse length as taught by Slayton because it provides sufficient energy at a target location for treatment of affected tissue (Slayton, [0006]-[0007]; [0056]). This leads to improved treatment efficacy and enhanced clinical outcomes.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039 as applied to claim 1 above, and further in view of Tyler et al. (U.S. Pub. No. 20160038770) hereinafter Tyler.
Regarding claim 10, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
wherein a number of pulses in the treatment ultrasound pulse sequence is 10 to 50 pulses
However, the analogous art of Tyler of an ultrasound treatment system (abstract) teaches:
wherein a number of pulses in the treatment ultrasound pulse sequence is 10 to 50 pulses ([0077], number of pulses is within the claimed range, “The number of pulses for pulsed transcranial ultrasound neuromodulation waveforms is between about 1 pulse and about 125,000 pulses”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the number of pules as taught by Tyler because it provides sufficient energy at a target location for treatment of affected tissue (Tyler, [0077]). This leads to improved treatment efficacy and enhanced clinical outcomes.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039 as applied to claim 1 above, and further in view of Ebbini et al. (U.S. Pub. No. 20130144165) hereinafter Ebbini.
Regarding claim 11, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
wherein an exposure duration of the treatment ultrasound pulse sequence is less than 60 sec
However, the analogous art of Ebbini of an ultrasound system for both imaging and therapy delivery (abstract) teaches:
wherein an exposure duration of the treatment ultrasound pulse sequence is less than 60 sec ([0257], exposure duration is either 15 or 5 seconds which is less than 60 seconds as claimed).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the exposure duration as taught by Ebbini because it provides a sufficiently long exposure time to determine the energy heat within the tissue structures of interest. This enables accurate modelling of treatment progress, leading to improved clinical outcomes (see Ebbini, [0257]).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039 as applied to claim 1 above, and further in view of Guha et al. (U.S. Pub. No. 20200398084) hereinafter Guha.
Regarding claim 12, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
wherein the treatment ultrasound pulse sequence is applied to at least one of a breast cancer tissue, liver cancer tissue, and pancreas cancer tissue
However, the analogous art of Guha of a cancer treatment system utilizing low energy ultrasound immune priming (abstract) teaches:
wherein the treatment ultrasound pulse sequence is applied to at least one of a breast cancer tissue, liver cancer tissue, and pancreas cancer tissue ([0067], breast, pancreas, or liver cancer tumor tissue).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the treatment of cancer tissue regions as taught by Guha because a sub-ablative dose of energy can generate an immunogenic response when combined with other therapies which provides enhanced clinical outcomes without a high intensity ultrasound energy destroying healthy tissue (Guha, [0005]-[0006]).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039 as applied to claim 1 above, and further in view of Fan et al. (U.S. Pub. No. 20130345565) hereinafter Fan.
Regarding claim 14, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1. Primary reference Dixon further fails to teach:
further comprising the step of adjusting the treatment ultrasound pulse sequence during treatment based on a monitoring of a destruction of the fibrotic extracellular matrix measurement
However, the analogous art of Fan of an acoustic absorption coefficient measurement for ultrasound therapy treatment (abstract) teaches:
further comprising the step of adjusting the treatment ultrasound pulse sequence during treatment based on a monitoring of a destruction of the fibrotic extracellular matrix measurement ([0016], absorption parameter is measured which is indicative of levels of liver fibrosis and other extracellular matrix measurements. This parameter, when monitored during a treatment, provides an adjustment of the ultrasound therapy settings, which teaches to changing the pulse sequence based upon destruction as indicated by the absorption parameter; [0078]-[0082], further teach to the real-time monitoring characteristic of absorption parameter measurements, which teaches to the “during treatment” limitation and additional subsequent transmissions change the settings based upon the measured parameters that indicate liver fibrosis levels)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the adjusting of the treatment pulse settings as in light of fibrosis measurements indicative of treatment destruction as taught by Fan because greater absorption by tissue may allow for lower amplitude, shorter duration, smaller aperture, or other decrease in power delivered for treatment. Lesser absorption may alter treatment planning to include application of more acoustic power to provide the desired dose (Fan, [0078]). This enables a more precise array of treatment settings, enhancing the treatment efficiency and reducing side effects.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039, in further view of Sarvazyan (U.S. Pub. No. 20110144493) hereinafter Sarvazyan.
Regarding claim 15, primary reference Dixon teaches:
A method for controlled mechanical disruption of fibrotic extracellular matrix in a human tissue having a cavitation threshold at which cavitation occurs (abstract), comprising:
throughout an entire therapeutic application of ultrasound to the soft-tissue ([0047], ultrasound echo is transmitted and signals are received from one or more isolated microbubbles, throughout a procedure; [0048], “incrementally increasing power of the transmit ultrasound energy to determine a threshold power level where microbubble destruction, such as by cavitation or other form of destruction is observed to start occurring”. This process would include output, monitoring, and energy adjustment throughout the treatment; [0190]-[0191], signals from isolated microbubbles):
outputting a treatment ultrasound pulse sequence at a treatment portion of the fibrotic extracellular matrix at a power level below the cavitation threshold ([0048], “delivering the microbubbles at full dose and applying the ultrasound energy to the microbubbles at the reduced power level”; [0190]-[0191], treatment ultrasound is provided at the soft tissue with ultrasound treatment pulses (ultrasound applied to target area); [0193])
Primary reference Dixon further fails to teach:
outputting a treatment ultrasound pulse sequence at a treatment portion of the fibrotic extracellular matrix at a power level below the cavitation threshold independent of the presence of microbubbles; and
monitoring an amount of disruption of tissue in the treatment portion with ultrasound at a power level below the cavitation threshold and adjusting the duration of the treatment ultrasound pulse sequence based on the monitored amount of disruption in the treatment portion
However, the analogous art of Vortman ‘039 of a system for treating tissue within a body using ultrasound energy (abstract) teaches:
throughout an entire therapeutic application of ultrasound to the soft-tissue ([0027], adjustment of energy level below a threshold occurs during an application of ultrasound treatment to the tissue; [0046]-[0054], treatment above a threshold is brief such as not more than 0.1 second, and then adjustment of energy below the cavitation threshold occurs throughout the treatment process)
outputting a treatment ultrasound pulse sequence at a treatment portion of the fibrotic extracellular matrix at a power level below the cavitation threshold independent of the presence of microbubbles ([0027], “the controller 18 may lower the intensity below a threshold to a level at which the generation of microbubbles is minimized in the tissue within the focal zone 38, yet may still necrose, coagulate, or otherwise heat tissue, as explained below. For example, the controller 18 may subsequently lower the intensity to approximately 0 to thereby prevent further formation of microbubbles at the focal zone 38 during a treatment process.” This forms a power level below the threshold of generation of microbubbles (cavitation threshold) and enables more precise control of microbubble quantities and amount. The necrosing, coagulating, and heating of tissue can continue independent of the presence of microbubbles; [0028]; [0044], “The acoustic energy 15 may be focused on the target tissue 42 to raise the temperature of the target tissue 42 sufficiently to coagulate and/or necrose the tissue 42, while minimizing damage to surrounding healthy tissue.” Provides for treatment independent of microbubble presence; [0046]-[0048], an intensity below the intensity used to generate the microbubbles to reduce and lower the generation of microbubbles. Microbubbles enhance acoustic energy deposited to a particular region, but tissue disruption can be delivered independent of the presence of the microbubbles; [0049]-[0050], multiple transmissions above and below the threshold (cavitation threshold) necessary to generate microbubbles to either increase or reduce generation of microbubbles; [0054]-[0072], further teach to treatment protocol and monitoring of treatment; Examiner notes that the limitation of “independent of the presence of microbubbles” only requires that the disruption of the tissue in the treatment portion must occur whether there are microbubbles or not, which Vortman ‘039 teaches to. If the applicant intends to claim that no microbubbles are present during a treatment, this must be positively recited within the claim); and
monitoring an amount of disruption of tissue in the treatment portion with ultrasound at a power level below the cavitation threshold and adjusting the duration of the treatment ultrasound pulse sequence based on the monitored amount of disruption in the treatment portion and to reduce the generation of microbubbles ([0027], “the controller 18 may lower the intensity below a threshold to a level at which the generation of microbubbles is minimized in the tissue within the focal zone 38, yet may still necrose, coagulate, or otherwise heat tissue, as explained below. For example, the controller 18 may subsequently lower the intensity to approximately 0 to thereby prevent further formation of microbubbles at the focal zone 38 during a treatment process.” This forms a power level below the threshold of generation of microbubbles (cavitation threshold) and enables more precise control of microbubble quantities and amount. The necrosing, coagulating, and heating of tissue can continue independent of the presence of microbubbles; [0028]; [0031], [0032], duration at each treatment site; [0033]; [0034]-[0044], describe the generation and use of a treatment plan for tissues; [0048], an intensity below the intensity used to generate the microbubbles to reduce and lower the generation of microbubbles; [0049]-[0050], multiple transmissions above and below the threshold (cavitation threshold) necessary to generate microbubbles to either increase or reduce generation of microbubbles; [0045]-[0051], teach to sequences that include disruption of the tissue during treatment below the cavitation threshold and adjusting the amount of treatment parameters based upon the disruption of the tissue; [0054]-[0071], teach to the treatment monitoring and adjustment of parameters such as amount of doses at a target site (treatment duration) based upon the thermal doses at the tissue regions which represent a measurement of tissue disruption)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon to incorporate the adjustment of ultrasound energy below a threshold to treat independent of microbubble presence and provide customized treatment durations as taught by Vortman ‘039 because more precise feedback control of the level of microbubbles at the target tissue of interest can provide more efficient and more accurate treatment while reducing the risk of damage to healthy non-targeted tissue (Vortman ‘039, [0072]).
Primary reference Dixon further fails to teach:
Introducing a therapeutic material exclusive of microbubbles into the soft tissue
However, the analogous art of Sarvazyan of a ultrasound diagnostic and therapeutic device (abstract) teaches:
Introducing a therapeutic material exclusive of microbubbles into the soft tissue ([0020], injection of a drug for tissue treatment of HIFU ultrasound; [0050], drug injected intro treatment site prior to initiation of HIFU treatment step; [0061]; [0063])
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the non-microbubble therapeutic material introduction as taught by Sarvazyan because ultrasound enhanced drug delivery can lead to better targeting of diseased tissues, leading to improved clinical outcomes with reduced side effects (Sarvazyan, [0061]; [0063]).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039, in further view of Sarvazyan as applied to claim 15 above, and further in view of Guha.
Regarding claim 16, the combined references of Dixon, Vortman ‘039, and Sarvazyan teach all of the limitations of claim 15. Primary reference Dixon further fails to teach:
wherein the fibrotic extracellular matrix is of at least one of a breast cancer tissue, liver cancer tissue, and pancreas cancer tissue
However, the analogous art of Guha of a cancer treatment system utilizing low energy ultrasound immune priming (abstract) teaches:
wherein the fibrotic extracellular matrix is of at least one of a breast cancer tissue, liver cancer tissue, and pancreas cancer tissue ([0067], breast, pancreas, or liver cancer tumor tissue).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon, Vortman ‘039, and Sarvazyan to incorporate the treatment of cancer tissue regions as taught by Guha because a sub-ablative dose of energy can generate an immunogenic response when combined with other therapies which provides enhanced clinical outcomes without a high intensity ultrasound energy destroying healthy tissue (Guha, [0005]-[0006]).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039, in further view of Sarvazyan as applied to claim 15 above, and further in view of Burdette (U.S. Pat. No. 10,183,183) hereinafter Burdette.
Regarding claim 18, the combined references of Dixon, Vortman ‘039, and Sarvazyan teach all of the limitations of claim 15. Primary reference Dixon further fails to teach:
Wherein the monitoring of an amount of fibrotic extracellular matrix disruption further comprising the step of monitoring a collagen density in the fibrotic extracellular matrix and adjusting the treatment ultrasound pulse sequence based on the collagen density in the fibrotic extracellular matrix in the treatment portion
However, the analogous art of Burdette of an apparatus and method for modifying collagen sing ultrasound transducers (abstract) teaches:
Wherein the monitoring of an amount of fibrotic extracellular matrix disruption further comprising the step of monitoring a collagen density in the fibrotic extracellular matrix and adjusting the treatment ultrasound pulse sequence based on the collagen density in the fibrotic extracellular matrix in the treatment portion (col 13, line 1 through col 14, line 67 includes the measurement and imaging of collagen density in real time during the treatment procedure. Further adjustments of the ultrasound treatment pulse is made based upon the collagen density measurements in the target regions of interest; see also col 15, lines 1-10).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon, Vortman ‘039, and Sarvazyan to incorporate the monitoring of collagen density within the target tissue region of interest and changing the ultrasound treatment parameters based upon the measurements as taught by Burdette because it can enable differentiation of how extensively regions are treated with the ultrasound energy, leading to improved treatment consistently and optimal treatment results (Burdette, col 14, lines 34-41).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Tosaya et al. (U.S. Pub. No. 20050020945) hereinafter Tosaya, in view of Levy (U.S. Pub. No. 20200391019) hereinafter Levy, in further view of Cannata et al. (U.S. Pub. No. 20200164231) hereinafter Cannata.
Regarding claim 19, primary reference Tosaya teaches:
A method for controlled mechanical disruption of fibrotic extracellular matrix in a human tissue having a cavitation threshold initiating cavitation (abstract), comprising:
Introducing a therapeutic material exclusive of a bubble cloud, into the soft tissue during therapeutic application of ultrasound ([0028]-[0029], drug forms a therapeutic material introduced into the tissue region exclusive of a bubble cloud; figure 1, drug 9; [0037], drug; [0039]; [0052]-[0057]; [0095]; [0099]);
Throughout the entire therapeutic application of ultrasound to the soft tissue ([0052]-[0057], ultrasound mediated drug delivery providing for enhanced transport through the blood brain barrier among other extracellular regions; [0095]; [0099], “At least some of the therapeutic acoustic or vibratory energy may open at least a portion of the blood-brain barrier, arachnoid-villi or arachnoid membrane, at least temporarily, for enhanced passage at least one of inwards or outwards, of medicaments, drugs, byproducts of the deposition therapy process itself or of a disease species. Further, the therapeutic acoustic or vibratory energy is at least one of: (a) below the unaided cavitation threshold and therefore blood brain barrier opening via unaided cavitation mechanisms is largely avoided”; [0130], ultrasound for driving or transporting the drug without cavitation, forms an additional teaching to power level below the unaided cavitation threshold; [0131]-[0133]; claim 11; claim 23)
outputting a treatment ultrasound pulse sequence at a treatment portion of the soft-tissue, without initiation of a bubble cloud and at a power level below the cavitation threshold, to disrupt fibrotic extracellular matrix impeding transport of the therapeutic material ([0052]-[0057], ultrasound mediated drug delivery providing for enhanced transport through the blood brain barrier among other extracellular regions; [0095]; [0099], “At least some of the therapeutic acoustic or vibratory energy may open at least a portion of the blood-brain barrier, arachnoid-villi or arachnoid membrane, at least temporarily, for enhanced passage at least one of inwards or outwards, of medicaments, drugs, byproducts of the deposition therapy process itself or of a disease species. Further, the therapeutic acoustic or vibratory energy is at least one of: (a) below the unaided cavitation threshold and therefore blood brain barrier opening via unaided cavitation mechanisms is largely avoided”; [0130], ultrasound for driving or transporting the drug without cavitation, forms an additional teaching to power level below the unaided cavitation threshold; [0131]-[0133]; claim 11; claim 23)
Primary reference Tosaya further fails to teach:
further comprising the step of monitoring an amount of penetration of therapeutics into the human tissue in the treatment portion and adjusting the treatment ultrasound pulse sequence based on the amount of penetration of therapeutics into the human tissue in the treatment portion.
However, the analogous art of Levy of an ultrasound treatment system for treatment of target tissues of interest (abstract) teaches:
further comprising the step of monitoring an amount of penetration of therapeutics into the human tissue in the treatment portion and adjusting the treatment ultrasound pulse sequence based on the amount of penetration of therapeutics into the human tissue in the treatment portion ([0014], therapeutic agent teaches to the drug delivery of primary reference Tosaya; [0019]-[0020], therapeutic agent drugs; [0042], “administration of the therapeutic agent(s) and/or microbubbles” teaches to drug of primary reference Tosaya; [0046]-[0047]; [0049]-[0054], teaches to the monitoring of therapeutic agent in the target region, which forms a monitoring of the penetration into the human tissue region and adjusting the treatment based upon the monitoring (see particularly, [0051]); [0055]-[0057]; [0059]; [0062]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Tosaya to incorporate the monitoring of a level of therapeutics within the target tissue of interest as taught by Levy because it provides a closed-loop, real-time feedback system that offers information about the target/non-target region and/or exogenous agent so as to allow a treatment adjustment/optimization (Levy, [0051]).
Primary reference Tosaya further fails to teach:
monitoring an amount of penetration of therapeutics into the human tissue in the treatment portion by analyzing ultrasound speckle
However, the analogous art of Cannata of histotripsy treatment system for treating tissues of interest (abstract) teaches:
monitoring an amount of penetration of therapeutics into the human tissue in the treatment portion by analyzing ultrasound speckle ([0147]-[0149], “this method enables continuously monitored in real time drug delivery”, drug delivery is monitored and tracked via the imaging system, and “the nature of the feedback received can be used to adjust acoustic parameters (and associated system parameters) to optimize the drug delivery”; [0150], speckle monitoring as in “In one embodiment, this method may be used to monitor the acoustic cavitation/histotripsy process for enhanced drug delivery where treatment sites/tissue is temporally disrupted, and tissue damage/erosion is not desired.”; [0151])
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Tosaya and Levy to incorporate the speckle tracking of enhanced drug delivery in a tissue of interest as taught by Cannata because it enables quicker and more accurate tracking of tissue damage/erosion during a drug delivery process, which leads to reduced side-effects such as damage to healthy tissue (Cannata, [0150]).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Dixon, in view of Vortman ‘039 as applied to claim 1 above, and further in view of Vortman et al. (U.S. Pub. No. 20210170205) hereinafter Vortman ‘205.
Regarding claim 20, the combined references of Dixon and Vortman ‘039 teach all of the limitations of claim 1 above. Dixon further fails to teach:
wherein the treatment ultrasound pulse sequence includes first and second ultrasonic pulses at predetermined phases, different frequencies, and different angles of propagation
However, the analogous art of Vortman ‘205 of an ultrasound pulsed treatment device (abstract) teaches:
wherein the treatment ultrasound pulse sequence includes first and second ultrasonic pulses at predetermined phases, different frequencies, and different angles of propagation ([0041], “In a second step 404, ultrasound parameters (e.g., amplitudes, phases, frequencies, steering angle(s), application duration, etc.) are determined based on the target/non-target information acquired in step 402 so as to generate one or more foci at one or more sub-regions in a target region or at one or more target regions” these ultrasound parameters are provided across pulses, which include first and second pulses and a plurality of phases, frequencies and steering angles. Therefore, this includes the predetermined phases, different frequencies, and different angles of propagation as claimed).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ultrasound treatment method below a cavitation threshold of Dixon and Vortman ‘039 to incorporate the different ultrasound parameters across ultrasound pulses as taught by Vortman ‘205 because it enables targeting at one or more foci within a region of interest, leading to improved treatment accuracy and better efficiency without damaging healthy tissues (Vortman ‘205, [0041]).
Response to Arguments
Applicant's arguments filed 2/06/2026 have been fully considered but they are not persuasive. Responses to each of the applicant’s arguments are detailed below.
Regarding the applicant’s arguments on pages 6-7 of the remarks, the applicant argues that independent claims 1, 15, and 21 includes limitations directed to the outputting, monitoring, and adjusting occurring throughout an entire therapeutic ultrasound application to the soft tissue. The applicant argues that Vortman teaches to the generation of microbubbles during a first part of a treatment and which are then sustained during a period of time where no microbubbles are generated. The applicant argues that the present amendments change the scope such that no microbubbles are generated during the therapy throughout the entire procedure. Examiner notes that the current broadest reasonable interpretation of independent claim 1 does not preclude the generation of microbubbles during a first part of treatment as taught by the Vortman reference. There are no elements within claim 1 that completely limit generation of microbubbles. The claim does not limit the output ultrasound treatment pulses to be always below the cavitation threshold, only that it must be adjusted below the cavitation threshold to reduce the generation of microbubbles. This parallels the applicant’s interpretation of the Vortman reference, as it includes the same adjustment of the energy of the ultrasound pulse sequence below the threshold as claimed. Furthermore, claim 1 includes monitoring ultrasound echo from microbubbles, which would not be possible without either an initial generation of microbubbles during a pulse sequence or a later mid-treatment temporary increase of ultrasound energy beyond the microbubble generation threshold. Either of these situations would then enable the adjustment of energy to a power level below the cavitation threshold as claimed. Examiner notes that without this current interpretation of the claim, any reference that would merely teach to low-energy non cavitation ultrasound therapy would then be sufficient to never outputting energy beyond a cavitation threshold as there would be no adjustment necessary. For these reasons, the applicant’s arguments directed to independent claims 1, 15, and 21 are not persuasive.
Regarding the applicant’s argument on page 7 of the remarks, the applicant makes additional remarks directed to the therapeutic material amendment to independent claim 15. The arguments with respect to claim 15 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for the teaching and matter specifically challenged in the argument.
Regarding the applicant’s arguments on pages 8-9 of the remarks, the applicant argues that the combined prior art references fail to teach to the limitations of independent claim 19. The applicant argues that the limitation of ultrasonic energy below the unaided cavitation threshold does not describe ultrasound treatments that do not require microbubbles or that cannot create cavitation. It is the current interpretation of the Tosaya reference that the teachings of the unaided cavitation being “inertial” cavitation caused by the treatment sequence of the ultrasound pulses ([0075]; [0099]). One of ordinary skill in the art would look to the teachings of [0099] wherein the acoustic energy is “below the unaided cavitation threshold” which forms an output of the ultrasound pulse sequence as designed to be below the cavitation threshold and teaches to the limitations as claimed. The applicant provides a reference to reduced power-threshold cavitation administered agents, but this is an optional configuration of the types of administered drugs in paragraph [0135] that is not considered to be read into the cited portions of the Tosaya reference. The applicant further argues that the Tosaya reference does not teach to precluding cavitation throughout the entirety of the treatment and references paragraphs [0127] and [0183] describing short periods of time. The paragraphs following [0127] only appear to address cavitation as a potential aid and paragraphs following [0183] discusses output power of the system without referencing cavitation or microbubbles. Therefore, the arguments directed to these paragraphs are not persuasive because it does not overcome the other cited portions of the reference. The applicant argues that the reference teaches to mixed protocols of cavitation and non-cavitation as in paragraphs [0071]-[0074], but these discussions of continuous wave and pulse wave operation details do not teach away from the positive reciting of “Further, the therapeutic acoustic or vibratory energy is at least one of: (a) below the unaided cavitation threshold” in paragraph [0099] as cited in the current rejections. One of ordinary skill in the art would understand this as referring to a limitation for the entire treatment and therefore would teach to the amended claim.
Further regarding the applicant’s arguments on page 8-9 of the remarks, the applicant argues that Tosaya describes a range of treatment options above and below the cavitation threshold and therefore discloses a wide range of teachings that form a genus that fail to teach to the applicant’s claimed species of the present invention. The examiner’s interpretation of the Tosaya reference is that it includes multiple teachings of various species of treatments for different drug delivery situations. Therefore, the cited portions of the Tosaya reference form a species that also teaches to the claimed invention. The Tosaya reference provides specific positive recitation of treatment below the unaided cavitation threshold ([0099]) in the cited paragraphs that support this interpretation and do not merely disclose broad language that may include ultrasound below a cavitation threshold as part of a generically referenced genus. For these reasons, the applicant’s arguments directed to independent claim 19 are not persuasive.
For these reasons, the applicant’s arguments have been considered but are not persuasive.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN A FRITH whose telephone number is (571)272-1292. The examiner can normally be reached M-Th 8:00-5:30 Second Fri 8:00-4:30.
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/SEAN A FRITH/Primary Examiner, Art Unit 3798