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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06 May 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the Examiner.
Response to Arguments
Applicant’s arguments, see pg. 6, filed 15 Apr 2026, with respect to the 35 U.S.C. 112(b) rejections have been fully considered and are persuasive. The 35 U.S.C. 112(b) rejections of 15 Jan 2026 have been withdrawn in view of the amended claims.
Applicant’s arguments, see pg. 6-7, filed 15 Apr 2026, with respect to the 35 U.S.C. 102 and 103 rejections have been considered but are moot because the new ground of rejection does not rely on the prior rejection of record for any teaching or matter specifically challenged in the argument.
Status of Claims
Claims 1-3, 5-13, and 15-22 are currently under examination. Claims 4 and 14 have been cancelled since the Non-Final Office Action of 15 Jan 2026.
Claim Rejections - 35 USC § 112
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 8, 11-13, 15-20, and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 8 recites the limitation “wherein the strength of the at least one signal is adjusted to provide approximately equal levels of ultrasound energy by the first frequency component and the second frequency component of the signal”. First, it is unclear whether “ultrasound energy” in the limitation is the same or different from “ultrasound energy” recited in claim 1, to which claim 8 depends. Second, the antecedent basis for “the signal” in the limitation is unclear. It is unclear whether “the signal” is the same or different from “the at least one signal” also recited in the limitation. For purposes of the examination, the limitation is being given a broadest reasonable interpretation as “wherein the strength of the at least one signal is adjusted to provide approximately equal levels of the ultrasound energy by the first frequency component and the second frequency component of the at least one signal”.
Claim 11 recites the limitation “wherein the first frequency component and the second frequency component of at least one signal used to drive the ultrasound transducer are selected to enhance cavitation of the at least one contrast agent and thereby effect sonothrombolysis within the blood vessel”. It is unclear whether “at least one signal” recited in the limitation is the same or different from “at least one signal having a first frequency component and a second frequency component” also recited in claim 11, lines 7-9. Claims 12-13, 15-20, and 22 inherit the deficiency by the nature of their dependency on claim 11. For purposes of the examination, the limitation is being given a broadest reasonable interpretation as “wherein the first frequency component and the second frequency component of the at least one signal used to drive the ultrasound transducer are selected to enhance cavitation of the at least one contrast agent and thereby effect sonothrombolysis within the blood vessel”.
Claim 17 recites the limitation “wherein the function generator is configured for adjusting a strength of the signal according to each frequency component”. The antecedent basis for “the signal” in the limitation is unclear. It is unclear whether “the signal” is the same or different from “at least one signal” recited in claim 11, to which claim 17 depends. For purposes of the examination, the limitation is being given a broadest reasonable interpretation as “wherein the function generator is configured for adjusting a strength of the at least one signal according to each frequency component”.
Claim 18 recites the limitation “wherein the function generator is configured for adjusting the strength of the at least one signal to provide approximately equal levels of ultrasound energy by the first frequency component and the second frequency component of the signal”. First, it is unclear whether “ultrasound energy” in the limitation is the same or different from “ultrasound energy” recited in claim 11, to which claim 18 depends. Second, the antecedent basis for “the signal” in the limitation is unclear. It is unclear whether “the signal” is the same or different from “the at least one signal” also recited in the limitation. For purposes of the examination, the limitation is being given a broadest reasonable interpretation as “wherein the function generator is configured for adjusting the strength of the at least one signal to provide approximately equal levels of the ultrasound energy by the first frequency component and the second frequency component of the at least one signal”.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 6-8, 10-11, 16-18, and 20-22 are rejected under 35 U.S.C. 103 as being unpatentable over Suo et al. (Suo et al. Microbubble mediated dual-frequency high intensity focused ultrasound thrombolysis: An In vitro study. Applied Physics Letters. (2017). 110:023703. doi: 10.1063/1.4973857. A copy attached to this Office action.) – hereinafter referred to as Suo (2017) – in view of Suo et al. (Suo et al. Thrombolysis using multi-frequency high intensity focused ultrasound at MHz range: an in vitro study. Physics in Medicine & Biology. (2015). 60:7403-7418. doi: 10.1088/0031-9155/60/18/7403. A copy attached to this Office action.) – hereinafter referred to as Suo (2015).
Regarding claim 1, Suo (2017) discloses a method for sonothrombolysis mediated with at least one contrast agent (at least Abstract: dual-frequency focused ultrasound mediated by microbubbles (MBs) for thrombolysis), the method comprising:
administering the at least one contrast agent towards a blood clot (Fig. 1 and pg. 023703-2: MBs were produced and delivered to the clot site);
selecting a first frequency component and a second frequency component of at least one signal used to drive an ultrasound transducer to enhance cavitation of the at least one contrast agent and thereby effect sonothrombolysis of the blood clot (Fig. 1 and pg. 023703-2: two center frequencies of 1.5 MHz and 1.45 MHz were chosen for excitation by 1.5 MHz HIFU transducer for thrombolysis);
controlling application of ultrasound energy to the at least one contrast agent towards the blood clot (Fig. 1 and pg. 023703-2: high intensity focused ultrasound (HIFU) transducer was moved along the length of the clot to treat the entire clot), wherein controlling the application of the ultrasound energy includes driving the ultrasound transducer with the at least one signal having the first frequency component and the second frequency component (Fig. 1 and pg. 023703-2: two center frequencies of 1.5 MHz and 1.45 MHz were chosen for excitation in thrombolysis, and all thrombolysis experiments were repeated 5 times).
It is noted that Suo (2017) does not explicitly disclose that the contrast agent delivery and the ultrasound energy application were performed within a blood vessel of a patient, but does disclose that the contrast agent delivery and the ultrasound energy application being directed to a blood clot contained within a syringe, mimicking a blood clot within a blood vessel in a patient (see Fig. 1 and pg. 023703-1). Therefore, Suo (2017)’s method is capable of being performed on a blood vessel of a patient for sonothrombolysis of a clot.
Suo (2017) does not disclose:
wherein the first frequency component is a constant frequency component and the second frequency component includes a plurality of frequency steps within a range of frequencies.
In the same field of sonothrombolysis, Suo (2015), however, teaches:
selecting and applying first frequency component and second frequency component (Fig. 1 and pg. 7407: 2.3. Experiment procedure: dual frequency excitation were generated and performed), wherein the first frequency component is a constant frequency component and the second frequency component includes a plurality of frequency steps within a range of frequencies (Fig. 1 and pg. 7407: 2.3. Experiment procedure: dual frequency excitation of 1.5 MHz + 1.475 MHz, 1.5 MHz + 1.45 MHz, 1.5 MHz + 1.4 MHz, wherein 1.5 MHz is the constant frequency component and 1.475 MHz, 1.45 MHz, and 1.4 MHz are frequency steps).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Suo (2017)’s method to include Suo (2015)’s method of applying second frequency component of frequency steps. One of ordinary skill in the art would have combined the elements, and the combination would have yielded a reasonable expectation of success since both Suo (2017) and Suo (2015) are directed to dual-frequency sonothrombolysis. The motivation for the combination would have been since “the generated difference frequencies could excite large size bubbles which collapse and break into a large number of small fragments (smaller bubbles) … (and) the wider range of frequencies generated from the nonlinear interactions could be more energy efficient in producing cavitation as it is a random pressure, frequency dependent phenomena (in vivo)”, as taught by Suo (2015; pg. 7414).
Regarding claim 6, Suo (2017) in view of Suo (2015) discloses all limitations of claim 1, as discussed above, and Suo (2017) further discloses:
wherein the at least one contrast agent comprises at least one nanodroplet and/or at least one microbubble (Fig. 1 and pg. 023703-2: MBs were produced and delivered to the clot site for thrombolysis).
Regarding claim 7, Suo (2017) in view of Suo (2015) discloses all limitations of claim 1, as discussed above, and Suo (2017) further discloses:
wherein a strength of the at least one signal is adjusted according to each frequency component (Fig. 1: Function Generator and pg. 023703-02: signals generated from a function generator and two center frequencies of 1.5 MHz and 1.45 MHz emitted by the 1.5 MHz HIFU transducer, thus the strength must be adjusted to emit at different frequencies by the same transducer).
Regarding claim 8, Suo (2017) in view of Suo (2015) discloses all limitations of claim 7, as discussed above, and Suo (2017) further discloses:
wherein the strength of the at least one signal is adjusted to provide approximately equal levels of ultrasound energy by the first frequency component and the second frequency component of the signal (pg. 023703-2: output powers at different input levels were calibrated to ensure that the output powers were the same for SFFU and DFFU).
Regarding claim 10, Suo (2017) in view of Suo (2015) discloses all limitations of claim 1, as discussed above, and Suo (2017) further discloses:
wherein the ultrasound transducer comprises a forward-viewing ultrasound transducer (Fig. 1: 1.5 MHz Focused Transducer “forward-viewing” towards the blood clot).
Regarding claim 21, Suo (2017) in view of Suo (2015) discloses all limitations of claim 7, as discussed above, and Suo (2015) further teaches (also see claim 1 above):
wherein the range of frequencies is lower than a frequency of the first frequency component (pg. 7407: 2.3. Experiment procedure: dual frequency excitation of 1.5 MHz + 1.475 MHz, 1.5 MHz + 1.45 MHz, 1.5 MHz + 1.4 MHz, thus frequency steps of 1.475 MHz, 1.45 MHz, and 1.4 MHz are lower than the constant first frequency component of 1.5 MHz).
Regarding claim 11, Suo (2017) discloses a system for sonothrombolysis mediated with at least one contrast agent (at least Abstract: dual-frequency focused ultrasound mediated by microbubbles (MBs) for thrombolysis; Fig. 1), the system comprising:
an ultrasound transducer (Fig. 1: 1.5 MHz Focused Transducer); and
a function generator (Fig. 1: Function Generator) connected to the ultrasound transducer (Fig. 1: Function Generator connected to 1.5 MHz Focused Transducer), the function generator configured for controlling application of ultrasound energy towards a blood clot (Fig. 1 and pg. 023703-2: signals generated from a function generator for thrombolysis) includes driving the ultrasound transducer with at least one signal having a first frequency component and a second frequency component different from the first frequency component (Fig. 1 and pg. 023703-2: two center frequencies of 1.5 MHz and 1.45 MHz were chosen for excitation in thrombolysis),
wherein the first frequency component and the second frequency component of at least one signal used to drive the ultrasound transducer are selected to enhance cavitation of the at least one contrast agent and thereby effect sonothrombolysis of the blood clot (Fig. 1 and pg. 023703-2: two center frequencies of 1.5 MHz and 1.45 MHz were chosen for excitation by 1.5 MHz HIFU transducer for thrombolysis).
It is noted that Suo (2017) does not explicitly disclose that the contrast agent delivery and the ultrasound energy application were performed within a blood vessel of a patient, but does disclose that the contrast agent delivery and the ultrasound energy application being directed to a blood clot contained within a syringe, mimicking a blood clot within a blood vessel in a patient (see Fig. 1 and pg. 023703-1). Therefore, Suo (2017)’s method is capable of being performed on a blood vessel of a patient for sonothrombolysis of a clot.
Suo (2017) does not disclose:
wherein the first frequency component is a constant frequency component and the second frequency component includes a plurality of frequency steps within a range of frequencies.
In the same field of sonothrombolysis, Suo (2015), however, teaches:
selecting and applying first frequency component and second frequency component (Fig. 1 and pg. 7407: 2.3. Experiment procedure: dual frequency excitation were generated and performed), wherein the first frequency component is a constant frequency component and the second frequency component includes a plurality of frequency steps within a range of frequencies (Fig. 1 and pg. 7407: 2.3. Experiment procedure: dual frequency excitation of 1.5 MHz + 1.475 MHz, 1.5 MHz + 1.45 MHz, 1.5 MHz + 1.4 MHz, wherein 1.5 MHz is the constant frequency component and 1.475 MHz, 1.45 MHz, and 1.4 MHz are frequency steps).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Suo (2017) to include Suo (2015)’s method of applying second frequency component of frequency steps. One of ordinary skill in the art would have combined the elements (i.e., applying ultrasound frequency components comprising frequency steps, as disclosed by Suo (2015)), and the combination would have yielded a reasonable expectation of success since both Suo (2017) and Suo (2015) are directed to dual-frequency sonothrombolysis. The motivation for the combination would have been since “the generated difference frequencies could excite large size bubbles which collapse and break into a large number of small fragments (smaller bubbles) … (and) the wider range of frequencies generated from the nonlinear interactions could be more energy efficient in producing cavitation as it is a random pressure, frequency dependent phenomena (in vivo)”, as taught by Suo (2015; pg. 7414).
Regarding claim 16, Suo (2017) in view of Suo (2015) discloses all limitations of claim 11, as discussed above, and Suo (2017) further discloses:
wherein the at least one contrast agent comprises at least one nanodroplet and/or at least one microbubble (Fig. 1 and pg. 023703-2: MBs were produced and delivered to the clot site for thrombolysis).
Regarding claim 17, Suo (2017) in view of Suo (2015) discloses all limitations of claim 1, as discussed above, and Suo (2017) further discloses:
wherein the function generator (Fig. 1: Function Generator) is configured for adjusting a strength of the signal according to each frequency component (pg. 023703-02: signals generated from a function generator and two center frequencies of 1.5 MHz and 1.45 MHz emitted by the 1.5 MHz HIFU transducer, thus the strength must be adjusted to emit at different frequencies by the same transducer).
Regarding claim 18, Suo (2017) in view of Suo (2015) discloses all limitations of claim 17, as discussed above, and Suo (2017) further discloses:
wherein the function generator (Fig. 1: Function Generator) is configured for adjusting the strength of the at least one signal to provide approximately equal levels of ultrasound energy by the first frequency component and the second frequency component of the signal (pg. 023703-2: output powers at different input levels were calibrated to ensure that the output powers were the same for SFFU and DFFU).
Regarding claim 20, Suo (2017) in view of Suo (2015) discloses all limitations of claim 11, as discussed above, and Suo (2017) further discloses:
wherein the ultrasound transducer comprises a forward-viewing ultrasound transducer (Fig. 1: 1.5 MHz Focused Transducer “forward-viewing” towards the blood clot).
Regarding claim 22, Suo (2017) in view of Suo (2015) discloses all limitations of claim 11, as discussed above, and Suo (2015) further teaches (also see claim 11 above):
wherein the range of frequencies is lower than a frequency of the first frequency component (pg. 7407: 2.3. Experiment procedure: dual frequency excitation of 1.5 MHz + 1.475 MHz, 1.5 MHz + 1.45 MHz, 1.5 MHz + 1.4 MHz, thus frequency steps of 1.475 MHz, 1.45 MHz, and 1.4 MHz are lower than the constant first frequency component of 1.5 MHz).
Claims 2-3, 9, 12-13, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Suo (2017) in view of Suo (2015), as applied to claims 1 and 11 above respectively, and further in view of Jiang et al. (US PG Pub No. 2021/0007759, provided by the Applicant in the IDS of 30 Jan 2025 and 11 Feb 2025) – hereinafter referred to as Jiang.
Regarding claim 2, Suo (2017) in view of Suo (2015) discloses all limitations of claim 1 above, and Suo (2017) does not disclose:
inserting the ultrasound transducer into the blood vessel adjacent to the at least one contrast agent before controlling the application of the ultrasound energy.
In the same field of sonothrombolysis, Jiang, however, teaches:
inserting the ultrasound transducer into the blood vessel adjacent to the at least one contrast agent before controlling the application of the ultrasound energy (Fig. 9: piezoelectric transducer and laser-generated ultrasound transducer adjacent a blood clot and microbubbles; [0093]: ultrasound transducers used to excite the injected microbubble contrast agents (MCA) or nanodroplets to cause enhanced cavitation-induced microstreaming).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Suo (2017)’s method to include Jiang’s method of inserting the ultrasound transducer into a blood vessel. One of ordinary skill in the art would have combined the elements, and the combination would have yielded a reasonable expectation of success since both Suo (2017) and Jiang are directed to sonothrombolysis. The motivation for the combination would have been to provide an in vivo “intravuasclar thrombolysis”, as taught by Jiang (Abstract).
Regarding claim 12, Suo (2017) in view of Suo (2015) discloses all limitations of claim 11 above, and Suo (2017) does not disclose:
wherein the ultrasound transducer is configured for being inserted into the blood vessel adjacent to the at least one contrast agent.
In the same field of sonothrombolysis, Jiang, however, teaches:
the ultrasound transducer is configured for being inserted into the blood vessel adjacent to the at least one contrast agent (Fig. 9: piezoelectric transducer and laser-generated ultrasound transducer adjacent a blood clot and microbubbles; [0093]: ultrasound transducers used to excite the injected microbubble contrast agents (MCA) or nanodroplets to cause enhanced cavitation-induced microstreaming).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the system of Suo (2017) to include Jiang’s method of inserting the ultrasound transducer into a blood vessel. One of ordinary skill in the art would have combined the elements (i.e., performing an in vivo sonothrombolysis, as disclosed by Jiang), and the combination would have yielded a reasonable expectation of success since both Suo (2017) and Jiang are directed to sonothrombolysis. The motivation for the combination would have been to provide an in vivo “intravuasclar thrombolysis”, as taught by Jiang (Abstract).
Regarding claims 3 and 13, Suo (2017) in view of Suo (2015) and Jiang discloses all limitations of claims 2 and 12 above respectively, and Jiang further teaches:
wherein the ultrasound transducer is housed in a catheter (Fig. 6 and [0078]: first ultrasonic transducer arrangement 1 and third ultrasonic transducer arrangement 7 are at the distal end 275 of catheter 3).
Regarding claims 9 and 19, Suo (2017) in view of Suo (2015) discloses all limitations of claims 1 and 11 above respectively, and Suo (2017) does not disclose:
wherein the ultrasound transducer comprises at least one piezoelectric element.
In the same field of sonothrombolysis, Jiang, however, teaches:
the ultrasound transducer (Fig. 6: first ultrasonic transducer arrangement 1) comprising at least one piezoelectric element ([0081]: transducer arrangement 1 comprising transducer elements of piezoelectric material).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Suo (2017)’s method/system to include Jiang’s piezoelectric transducer. One of ordinary skill in the art would have combined the elements (i.e., utilizing a piezoelectric transducer, as disclosed by Jiang), and the combination would have yielded a reasonable expectation of success since both Suo (2017) and Jiang are directed to sonothrombolysis. The motivation for the combination would have been since a piezoelectric element provides a “higher acoustic power, and smaller capacitance which leads to good electrical impedance matching with relatively low electrical impedance at the resonance of the transducer device”, as taught by Jiang ([0086]).
Allowable Subject Matter
Claims 5 and 15 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
When claims 5 and 15 are each considered as a whole, prior arts do not disclose, neither individually nor in combination, at least selecting and applying ultrasound frequency components for sonothrombolysis using a contrast agent, wherein the ultrasound frequency components comprises a constant first center frequency of about 750 kHz and varying second frequencies ranging from about 450 kHz to about 650 kHz at 50 kHz intervals. In particular, Suo (2015), a prior art made of record above, discloses applying a constant center frequency of 1.5 MHz and varying second frequencies ranging from 1.4 MHz to 1.475 MHz for sonothrombolysis in vitro (see pg. 7407), but does not disclose applying lower varying frequencies in kHz to effect sonothrombolysis within a blood vessel. Additionally, Shaw et al. (Shaw et al. Tissue Plasminogen Activator Concentration Dependence of 120 kHz Ultrasound Enhanced Thrombolysis-Revised #1. Ultrasound in Medical Biology. (2008). 34(11): 1783–1792. doi: 10.1016/j.ultrasmedbio.2008.03.020. A copy attached to this Office action.), another prior art being made of record herein, discloses applying a 120 kHz frequency for sonothrombolysis (see pg. 4: Methods), but also does not disclose applying specifically a constant first center frequency of about 750 kHz and varying second frequencies ranging from about 450 kHz to about 650 kHz at 50 kHz intervals for sonothrombolysis.
The technical advantage of the claimed invention is “Frequencies 450 kHz, 500 KHz, 550 kHz, 600 kHz, and 650 kHz … represent[s] relatively high sensitivities as the secondary frequency components combined with the center frequency (i.e., 750 kHz) … The dual-frequency technique using ultrasound transducer 102 achieved effective treatment for both un-treatment and retracted clots with a lysis mass reduction up to 58% and 32%, respectively, after a 30 min treatment, corresponding to 46% and 85% lysis rate increase, respectively, compared with the signal=frequency treatment method.” (pg. 15-17 of the specification of the instant application).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Younhee Choi whose telephone number is (571)272-7013. The examiner can normally be reached M-F 9AM-5PM EST.
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/Y.C./Examiner, Art Unit 3797
/ANHTUAN T NGUYEN/Supervisory Patent Examiner, Art Unit 3795
7/13/26
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