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 .
Status of Claims
Claims 1-24 are pending in this application. Claims 1-12, 13, 14, and 16 are withdrawn, and Claims 12, 15, 17-24 have been examined on the merits.
Election/Restrictions
Applicant’s election without traverse of claims 12-24 drawn to Invention II and species B (Claim 15) from Group I in the reply filed on 09/26/25 is acknowledged.
In an Examiner-initiated phone call interview held on 10/29/25 with the attorney Edward Weisz, the species drawn to Claim 15 (primary action includes means for hypo-fractionated stereotactic radiotherapy or proton-therapy) was elected, and the species drawn to claim 13 (primary action includes means for chemical- or radio-pharmaceutical therapy) and claim 16 (primary action includes means for brachytherapy radiation action) have been withdrawn. Claim 14 has also been withdrawn due to its dependency to withdrawn species claim 13.
Claims 1-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention I drawn to a method for increasing an immune response against an existing cancer, and claims 13-14, and 16 are withdrawn being drawn to non-elected species, there being no allowable generic or linking claim.
Information Disclosure Statement
The information disclosure statement filed 10/06/2021 and 04/12/2022 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
Claim Objections
Claims 1 objected to because of the following informalities:
In claim 12, line 4, “APCs/DCs” should be written out as “Antigen-Presenting Cells/Dendritic Cells (APCs/DCs)”.
In claim 12, line 3, “the primary tumor” should be “a primary tumor”
In claim 12, line 5 “the primary cancer cells” should be “primary cancer cells”
In claim 12, line 5 “the interstitial fluid” should be “an interstitial fluid”
In claim 12, line 5 “the primary cancer region” should be “a primary cancer region”
In claim 12 line 8 “the capillary system” should be “a capillary system”
In claim 12, line 8 “the cancer region” should be “the primary cancer region”
In claim 12, line 10 “said micro bubbles” should be “the micro-bubbles”
In claim 12, line 12 “APCs/DCs” should be “the APCs/DCs”
In claim 12, line 12 “TAA” should be “the TAA”
In Claim 12, line 13 “the primary tumor” should be “a primary tumor”
In claim 12, line 13 “the draining lymph nodes” should be “draining lymph nodes”
In claim 17, line 1 “primary action” should be “the primary action”
In Claim 18, line 1 “secondary action” should be “the secondary action”
In claim 18, line 2 “a primary action” should be “the primary action”
In claim 19, line 1 “micro-bubbles” should be “the micro-bubbles”
In claim 19, line 2 “the blood” should be “blood”
In claim 20, line 1, “micro-bubbles” should be “the micro-bubbles”
IN Claim 19, line 3, “incident ultrasound” should be “the incident ultrasound”
In claim 20 line 1 “micro-bubbles” should be “the micro-bubbles”
In claim 20 line 3 “with diameter” should be “with a diameter”
In claim 21, line 5 “the cancer region” should be “the primary cancer region”
In Claim 22, line 4 “the object properties” should be “object properties”
In Claim 22, line 4 “the co-propagating HF pulse” should be “the co-propagating LF and HF pulses”
In Claim 22 line 6, “the scattered signal” should be “a scattered signal”
In Claim 22 line 6 “the cancer region” should be “a cancer region”
In Claim 22 line 7 “micro-bubbles” should be “the micro-bubbles”
In claim 23 line 3 “the vibration amplitude” should be “a vibration amplitude”
In Claim 24 line 2 “the micro-bubble vibration” should be “a micro-bubble vibration”
In Claim 24 line 2 “the corresponding” should be “a corresponding”
In Claim 24 line 3 “the capillary wall” should be “a capillary wall”
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
“means for introducing micro-bubbles” in Claim 12. [0017] describes using vibrations to bring in micro-bubbles, but the system used to introduce the vibrations is not described.
“means for carrying through said secondary action multiple times following a primary action.” In claim 18. Although [0032]-[0033] in the specifications describes carrying through the secondary action multiple times, the means for doing so are not identified.
“means for injecting fluid micro-droplets into the blood” and “means for evaporating said micro-droplets by incident ultrasound.” In claim 19. Although [0043] describes the injection of fluid micro-droplets, the means for doing so are not identified. Further, [0036] describes the evaporation, the means for doing so are not clarified, nor is it clear if the PFC droplets are the micro-droplets
“means for injection into the blood” in claim 20. Although [0043] describes the injection, the means for doing so are not identified.
“means for transmitting pulse complexes comprising co-propagating and overlapping” and “means for utilizing the nonlinear manipulation of the object properties” in claim 22. Although [0044] describes the co-propagation, the means for doing so are not specified.
“means for determining the vibration amplitude of said micro-bubbles with ultrasound” and “means for using the measured amplitude as input for adjusting the transmit amplitude” in claim 23. Although [0050] describes the vibration amplitudes, the means for determining the vibration amplitudes are not specified.
“means for determining a relation between the micro-bubble vibration amplitude and the corresponding maximal amplitude of the capillary wall vibrations.” In claim 24. Although [0050] describes the vibration amplitudes and their relations, the means for determining the vibration amplitudes are not specified.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
This application includes one or more claim limitations that use the word “means” or “step” but are nonetheless not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph because the claim limitation(s) recite(s) sufficient structure, materials, or acts to entirely perform the recited function. Such claim limitation(s) is/are:
“means for ultrasound vibration of said micro-bubbles” in claim 21. Specifications [0036] recites “an intra-capillary micro-bubble 109 that for the purpose of the invention is set into volume vibrations by an incoming ultrasound beam”, thus further describing the means for ultrasound vibration.
Because this/these claim limitation(s) is/are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are not being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof.
If applicant intends to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to remove the structure, materials, or acts that performs the claimed function; or (2) present a sufficient showing that the claim limitation(s) does/do not recite sufficient structure, materials, or acts to perform the claimed function.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12, 15, 17-24 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 12 recites the limitation of “means for introducing micro-bubbles”. It is unclear what modality or system is being used to introduce the micro-bubbles. Although the use of vibrations with incident ultrasound beams is recited, the system is still not clearly defined. For purposes of examination, the limitation will be construed as any ultrasound probe or ultrasound-producing system. However, further clarification is required.
Claim 17 recites the limitation of “means for carrying through multiple primary actions with selected intervals in time”. It is unclear what the multiple primary actions would refer to, as there is only a primary action being referred to in Claim 12. For purposes of examination, “multiple primary actions” will be interpreted as the primary action being carried through with selected intervals in time. However, further clarification is required.
Claim 19 recites the limitation of “evaporating said micro-droplets by incident ultrasound”. It is unclear if the evaporating of micro-droplets is accomplished by the incident ultrasound beams in claim 12, or if this is an incident ultrasound that is to be differentiated from the incident ultrasound beams that induce vibrations in micro-bubbles. For purposes of examination, the limitation will be construed as a different ultrasound beam. However, further clarification is required.
Claim 20 recites the limitation “introducing micro-bubbles includes means for injection into the blood of one”. It is unclear if the micro-bubbles are being introduced through an injection, which is separate from the micro-droplets in claim 19, as the specifications describe the micro-droplets (PFC oil droplets) to be evaporated into micro-bubbles [0036]. For purposes of examination, the limitation will be construed as a separate embodiment of introducing micro-bubbles through the listed injections. However, further clarification is required.
Claim 22 recites the limitation of “transmitting pulse complexes comprising co-propagating and overlapping, low frequency (LF) and high frequency (HF) pulses,”. It is unclear what modality is producing the low and high frequencies or if they are correlated with the frequencies mentioned in claim 21. For purposes of examination, the limitation will be construed as an ultrasound transducer capable of producing both frequencies, which is the same modality used for claim 21 for vibrating and imaging the micro-bubbles. However, further clarification is required.
Claim 23 recites the limitation of “means for determining the vibration amplitude of said micro-bubbles with ultrasound”. It is unclear if ultrasound is the same incident ultrasound recited in Claim 12, or if it is a new ultrasound transducer for determining amplitude. For purposes of examination, the limitation will be construed as the same incident ultrasound in Claim 12, which is adjusted to determine the vibration amplitude. However, further clarification is required. Further, Claim 23 recites the limitation of “means for using the measured amplitude as input for adjusting the transmit amplitude of said ultrasound beams to obtain a bubble vibration amplitude close to a specified value”. It is unclear what the plurality of ultrasound beams refer to, nor what a specified value would be. For purposes of examination, the limitation of the ultrasound beams will be construed to be the incident ultrasound in Claim 12, where the incident ultrasound will be adjusted according to the micro-bubble amplitude, and a specified value will be any value that induces the micro-droplets to be micro-bubbles. However, further clarification is required.
Claim 24 recites the limitation of “means for determining a relation between the micro-bubble vibration amplitude and the corresponding maximal amplitude of the capillary wall vibrations.” It is unclear how the relation is determined. For purposes of examination, the limitation will be construed to be any mathematical relation between a micro-bubble vibration amplitude and a vessel wall vibration amplitude. However, further clarification is required.
The remaining claims are also rejected based on their dependency to the independent claim 12.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 12, 17-18, 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dimcevski (“A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer”, 2016, Journal of Controlled Release, 243 172-181)
Regarding Claim 12,
Dimcevski teaches a system for increasing immune response against an existing cancer in a patient (corresponding disclosure in at least [pg. 1, “Introduction”], where the system is to improve immune response against cancer (chemotherapeutic efficacy) “to evaluate a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance status and prolonging survival”), comprising
a) means for a primary action on the primary tumor of the patient that generates professional antigen-presenting cells APCs/DCs with tumor associated antigens (TAA) of the primary cancer cells in the interstitial fluid of the primary cancer region (corresponding disclosure in at least [pg. 2, “Chemotherapeutic and microbubble dosage”], where there is a primary action (chemotherapy) on the primary tumor of the patient; [0032] in the present application’s specifications recites that chemo-therapy would produce professional APCs/DCs, so as the prior art uses chemotherapy (gemcitabine hydrochloride), by the specifications, the prior art methods would also produce APCs/DCs “We used the standard recommended treatment protocol of gemcitabine hydrochloride”)
b) means that for a selectable delay after the start of said primary action performs one or more secondary actions, said means comprising i) means for introducing micro-bubbles into the tumor capillary system of the cancer region (corresponding disclosure in at least [pg. 3, “Chemotherapeutic and microbubble dosage”], where microbubbles were introduced later entering into the tumor/cancer region “Maximum plasma concentration of gemcitabine is achieved after 30 min at which point sonoporation with Sonovue® was initiated to ensure maximal possible tumour exposures. Clinically approved SonoVue® ultrasound contrast agent was used as the microbubble for sonoporation”),
ii) means for vibrating said micro-bubbles with incident ultrasound beams with appropriate frequency and amplitude, for the purpose of increasing flow of lymphatic fluid containing APCs/DCs with TAA from the primary tumor to the draining lymph nodes (DLNs) (corresponding disclosure in at least [pg. 3, “Ultrasound scanner configuration”], where vibrating is induced using ultrasound; the ultrasound center frequency is at 1.9 MHz, which aligns with the specifications of the present application [0051] of the optimal frequency between 0.1-2 MHz. The aligning similarity would indicate increase flow of lymphatic fluid containing APCs/DCs for the prior art “The ultrasound scanner configuration was programmed to maximise the duty cycle, with short broadband linear pulse in order excite as many microbubbles as possible… The center frequency of 1.9 MHz was ideal as it was close to the natural resonance of the SonoVue® microbubbles”).
Regarding Claim 17,
Dimcevski further teaches where said means for primary action includes means for carrying through multiple primary actions with selected intervals in time (corresponding disclosure in at least [pg. 3, 2.2 “Chemotherapeutic and microbubble dosage”], where the primary action (treatment) is carried out with select intervals in time “Specifically, an initial phase of intravenous gemcitabine infusion was administered at a frequency of one cycle per week for seven weeks followed by a one-week pause”).
Regarding Claim 18,
Dimcevski further teaches where said means for secondary action includes means for carrying through said secondary action multiple times following a primary action (corresponding disclosure in at least [pg. 3, 2.2 “Chemotherapeutic and microbubble dosage” ], where after the primary action, the secondary action (injection of microbubbles) was carried out multiple times “The expected in-vivo life time of microbubbles was 4–5 min, hence we chose to inject boluses every 3.5 min to ensure microbubbles were present continuously throughout the whole treatment”).
Regarding Claim 20,
Dimcevski further teaches where said means for introducing micro-bubbles includes means for injection into the blood of one of i) ultrasound contrast agent micro- bubbles and ii) micro-bubbles with diameter above 5 microns (corresponding disclosure in at least [pg. 2, 1. “Introduction”], where it’s stated that ultrasound contrast agent microbubbles are injected “we initiated an open label phase I, single centre, safety evaluation study in PDAC patients by combining an ultrasound contrast agent and gemcitabine under sonication at clinical diagnostic conditions”).
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.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Dimcevski (“A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer”, 2016, Journal of Controlled Release, 243 172-181) in view of Mirjolet (“Impact of proton therapy on antitumor immune response”, 2021, Scientific Reports, 11 13444)
Regarding Claim 15, Dimcevski teaches the limitations of Claim 12, but does not teach where said means for primary action includes means for hypo-fractionated stereotactic radiotherapy or proton-therapy
Mirjolet, in a similar field of endeavor, teaches a similar concept (cancer treatment) of where said means for primary action includes means for hypo-fractionated stereotactic radiotherapy or proton-therapy (corresponding disclosure in at least [pg. 2, “Results”], where the used method of therapy is proton therapy “A single dose of 16.4 Gy proton therapy was delivered to the CT26 tumors of immunocompetent BALB/c mice”).
It would have been obvious to a person having ordinary skill in the art before the effective filing date to have incorporated proton therapy as the primary action as taught by Mirjolet. One of the ordinary skill in the art would have been motivated to incorporate this because proton therapy is another commonly used form of cancer treatment, which would induce the APC/DC response.
Claims 19, 21, 23 are rejected under 35 U.S.C. 103 as being unpatentable over Dimcevski (“A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer”, 2016, Journal of Controlled Release, 243 172-181) in view of Strohm (“Vaporization of perfluorocarbon droplets using optical irradiation”, 2011, Biomedical Optics Express, Vol 2 No 6).
Regarding Claim 19, Dimcevski teaches the limitations of Claim 12, and further teaches
where said means for introducing micro-bubbles includes means for injecting fluid micro-droplets into the blood (corresponding disclosure in at least [pg. 3, ], where the SonoVue contrast agent, which are tiny microbubbles (microdroplets) are injected into the blood of the patient “The expected in-vivo life time of microbubbles was 4–5 min, hence we chose to inject boluses every 3.5 min to ensure microbubbles were present continuously throughout the whole treatment” ) and the incident ultrasound (corresponding disclosure in at least []) ,but does not teach the means for evaporating said micro-droplets
Strohm, in a similar field of endeavor, teaches a similar concept (microbubbles) of means for evaporating said micro-droplets by incident ultrasound (corresponding disclosure in at least [pg. 3, 1. “Introduction”], where the droplets are irradiated for evaporation (vaporization) for resulting bubbles “We then demonstrate that laser light may be used to vaporize nanoparticle-loaded PFC droplets when irradiated above a threshold laser fluence, and confirm that the resulting bubbles can be detected via ultrasound methods”).
It would have been obvious to a person having ordinary skill in the art before the effective filing date to have incorporated evaporating microdroplets for introducing microbubbles as taught by Strohm. One of the ordinary skill in the art would have been motivated to incorporate this because the microdroplets can circulate to the cancer region and then generate microbubbles to occlude capillaries and arteries.
Regarding Claim 21, Dimcevski teaches the limitations of Claim 12 and further teaches
where said means for vibrating said micro-bubbles includes - means for ultrasound vibration of said micro-bubbles at a frequency lower than 2 MHz (corresponding disclosure in at least [pg. 3, “Ultrasound scanner configuration”], where vibrating is induced using ultrasound; the ultrasound center frequency is at 1.9 MHz “The ultrasound scanner configuration was programmed to maximise the duty cycle, with short broadband linear pulse in order excite as many microbubbles as possible… The center frequency of 1.9 MHz was ideal as it was close to the natural resonance of the SonoVue® microbubbles” and further in ), but does not teach means for imaging the cancer region and said micro-bubbles at a frequency higher than 2 MHz.
Strohm, in a similar field of endeavor, teaches a similar concept of means for imaging the cancer region and said micro-bubbles at a frequency higher than 2 MHz (corresponding disclosure in at least [pg. 4, 3.2 “Photoacoustic Microscope”], where the ultrasound imaging was at a frequency higher than 2 MHz “For the ultrasound pulse-echo measurements, 10 Vpp pulses were generated at a pulse repetition frequency of up to 500 kHz using a monocycle pulse generator with a center frequency of 300 MHz”).
It would have been obvious to a person having ordinary skill in the art before the effective filing date to have incorporated the use of an ultrasound transducer of a frequency higher than 2 MHz for microbubble imaging as taught by Strohm. One of the ordinary skill in the art would have been motivated to incorporate this because microbubbles are typically imaged at higher frequencies for spatial resolution purposes.
Regarding Claim 23, Dimcevski teaches the limitations of Claim 12, but does not teach where said means for vibrating said micro-bubbles includes - means for determining the vibration amplitude of said micro-bubbles with ultrasound, and - means for using the measured amplitude as input for adjusting the transmit amplitude of said ultrasound beams to obtain a bubble vibration amplitude close to a specified value.
Strohm, in a similar field of endeavor, teaches a similar concept where said means for vibrating said micro-bubbles includes - means for determining the vibration amplitude of said micro-bubbles with ultrasound (corresponding disclosure in at least [pg. 5, 5.5 “Measurements], where the amplitude of the microbubbles were determined via ultrasound “The envelope of the signal at each x-y position of a single droplet was found by using the Hilbert transform of the recorded ultrasound data, from which the maximum signal amplitude was determined”), and
- means for using the measured amplitude as input for adjusting the transmit amplitude of said ultrasound beams to obtain a bubble vibration amplitude close to a specified value (corresponding disclosure in at least [pg. 6, 4.2 “Photoacoustic Signals”], where the signal amplitude of the input was adjusted to obtain a bubble vibration close to a specified value (the amplitude was increased to induce the vaporization, which is the specified value) “The photoacoustic signal c-scan of a single 6.9 µm diameter droplet with high PbS loading, measured at 200 MHz as a function of laser fluence is shown in Fig. 2. The signal amplitude increased with increasing laser fluence, until vaporization occurred in the last frame.”).
It would have been obvious to a person having ordinary skill in the art before the effective filing date to have incorporated determining the amplitude of the microbubbles and adjusting the input accordingly to match the microbubbles as taught by Strohm. One of the ordinary skill in the art would have been motivated to incorporate this because by matching the amplitude of the microbubbles, the optimal vibration can be induced for therapy purposes.
Claims 22 are rejected under 35 U.S.C. 103 as being unpatentable over Dimcevski (“A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer”, 2016, Journal of Controlled Release, 243 172-181) and Strohm (“Vaporization of perfluorocarbon droplets using optical irradiation”, 2011, Biomedical Optics Express, Vol 2 No 6) as applied in Claim 21, and in further view of Eisenbrey (“Sensitization of Hypoxic Tumors to Radiation Therapy Using Ultrasound-Sensitive Oxygen Microbubbles”, 2018, International Journal of Radiation Oncology, Vol 101, No 1).
Regarding Claim 22, Dimcevski and Strohm teach the limitations of Claim 21, but do not teach where said means for imaging comprises - means for transmitting pulse complexes comprising co-propagating and overlapping, low frequency (LF) and high frequency (HF) pulses, said LF pulses are used to nonlinearly manipulate the object properties observed by the co-propagating HF pulse, and
means for utilizing the nonlinear manipulation of the object properties by the LF pulse on the scattered signal by the co-propagating HF pulse to produce images of the cancer region and micro-bubbles.
Eisenbrey, in a similar field of endeavor, teaches a similar concept (radiation therapy in combination with microbubbles) of where said means for imaging comprises - means for transmitting pulse complexes comprising co-propagating and overlapping, low frequency (LF) and high frequency (HF) pulses, said LF pulses are used to nonlinearly manipulate the object properties observed by the co-propagating HF pulse, and means for utilizing the nonlinear manipulation of the object properties by the LF pulse on the scattered signal by the co-propagating HF pulse to produce images of the cancer region and micro-bubbles (corresponding disclosure in at least [pg. 3, “Oxygen Delivery Experiments”], where a sequency of LF (low intensity) and HF (high intensity) propagations were used to produce images (monitor) “A flash-destruction-replenishment sequence was used to first monitor microbubble perfusion into the tumor with lower-intensity (mechanical index Z 0.09) nonlinear ultrasound, followed by a higher-intensity series of destructive pulses (mechanical index Z 1.39) for 4 seconds… By use of identical imaging parameters (imaging depth of 3 cm and focal distance of 2 cm), destructive transmit parameters at the focus were found to be 4.2 MHz 1.6 microsecond pulses transmitted at a derated peak negative pressure of 2.5 MPa at a pulse repetition frequency of approximately 38 Hz”).
It would have been obvious to a person having ordinary skill in the art before the effective filing date to have incorporated the LF and HF pulses co-propagating to produce images of the cancer region and microbubbles as taught by Eisenbrey. One of the ordinary skill in the art would have been motivated to incorporate this because it provides both the therapeutic pulses as well as the imaging capabilities of the ultrasound to observe during therapy.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Dimcevski (“A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer”, 2016, Journal of Controlled Release, 243 172-181) and Strohm (“Vaporization of perfluorocarbon droplets using optical irradiation”, 2011, Biomedical Optics Express, Vol 2 No 6) as applied in Claim 23, and in further view of Khodabakhshi (Pulsating Microbubble in a Micro-vessel and Mechanical Effect on Vessel Wall: A Simulation Study, 2021, J Biomedic Phys Eng, 11(5) 629-640)
Regarding Claim 24, the combined references of Dimcevski and Strohm teach the limitations of Claim 23, but do not teach means for determining a relation between the micro-bubble vibration amplitude and the corresponding maximal amplitude of the capillary wall vibrations.
Khodabakhshi, in a similar field of endeavor, teaches a similar concept (microbubbles propogated by ultrasound), of means for determining a relation between the micro-bubble vibration amplitude and the corresponding maximal amplitude of the capillary wall vibrations (corresponding disclosure in at least [pg. 6, “The effects of acoustic pressure”], where the relationship between microbubbles and the surrounding vessel wall (capillary wall) is determined “When the acoustic frequency approaches the resonance frequency of microbubble, the microbubble will oscillate more vigorously and with the highest amplitude, thus result in the increased shear stress. In the current model, shear stress exerted on the vessel wall at bubble resonance frequency is approximately 7 times greater than that of the same bubble oscillating by 1 MHz acoustic frequency.”).
It would have been obvious to a person having ordinary skill in the art before the effective filing date to have incorporated determining a relation between the micro-bubble vibration amplitude and the corresponding maximal amplitude of the capillary wall vibrations as taught by Khodabakhshi. One of the ordinary skill in the art would have been motivated to incorporate this because determining the size of the microbubble and the vibration amplitude of the wall and their relation provides the most optimal stress for therapeutic purposes while avoiding possible damages.
Conclusion
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/K.E.K./ Examiner, Art Unit 3797
/SERKAN AKAR/Primary Examiner, Art Unit 3797