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 statements (IDS) submitted were filed on 02/09/2026 and 02/24/2026. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Response to Amendment
The amendment filed 02/05/2026 has been entered. Claims 5, 8, 10-11, 16, and 299 have been canceled, and new claims 300-308 have been added. Claims 1, 14-15, 30, 52, 57, 64, 68-69, 74, 76, 91, 110, 148, 300-308 remain pending in the application. Applicant’s amendments to the claims and specification have overcome each and every objection and 112(b) rejections previously set forth in the Non-Final Office Action mailed 12/29/2025.
Response to Arguments
Applicant’s arguments with respect to claim 1 and claims depending therefrom 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 any teaching or matter specifically challenged in the argument. Newly cited reference Grayburn (US20140134234) is being relied upon for teaching collapsing a sonoactive agent in an organ.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 76, 91, 110, 300, 302, 304, 306, and 308 are rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627).
Regarding claim 1, Dayton teaches a method of delivering an exogenous payload to a cell in a tissue of an organ of a subject ([0015], [0018], [0054], [0136], wherein the organ is the brain), the method comprising:
a. administering an exogenous payload to the subject ([0015], [0032], wherein the administering of compounds such as peptides and/or nucleic acids comprise administering an exogenous payload);
b. administering a sonoactive agent to the subject ([0016-0018], [0031-0032], [0059], [0081], wherein the carrier particles affected by acoustic streaming/radiation comprise sonoactive agents); and
c. applying an acoustic radiation force (ARF) to the tissue, wherein the ARF enhances delivery of the exogenous payload to the cell in the tissue of an organ of the subject, wherein the ARF is applied using ultrasound acoustic energy at: (i) an ultrasound spatial peak temporal average intensity of 100 mW/cm2 and (iii) a pulse length of greater than 20 microseconds (μs) ([0018], [0049], “Sound propagating through a medium produces a force on particles suspended in the medium, and also upon the medium itself. Ultrasound produces a radiation force that is exerted upon objects in a medium”, [0030], [0054], [0056], “The invention encompasses the use of radiation force along with acoustic streaming to assist localization and/or delivery of carrier particles”, [0136], “One objective of the present invention is to locally deliver new therapeutics to the brain using acoustic streaming and radiation force”, [0081], “acoustic pulse of long pulse length (for example, 10 seconds) is transmitted…it produces a spatial peak-temporal average intensity (I.sub.spta) between about 200 mW/cm2 and 8 W/cm2”).
However, Dayton fails to explicitly teach wherein applying the acoustic radiation force (ARF) to the tissue (i) displaces at least a portion of the tissue by at least 0.01 mm and (ii) generates shear waves in the tissue of the subject.
In an analogous application of acoustic radiation force (ARF) field of endeavor, Trahey teaches such a feature. Trahey teaches transmitting ultrasound into tissue (Abstract, [0005-0006]). Trahey teaches generating shear waves in tissue by applying ARF ([0027-0028]). Trahey teaches the transmitted ultrasound or ARF causes the tissue to be displaced in a range between about 0.1 μm to 300 μm (Claim 28, [0008], [0031], wherein 300 μm equals 0.3 mm). Trahey therefore teaches wherein the ARF displaces the tissue of a subject by at least 0.01 mm and generates shear waves in the tissue of the subject.
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 invention of Dayton to have the ARF generate shear waves and cause the tissue to be displaced in a range between about 0.1 to 300 μm as taught by Trahey (Claim 28, [0008], [0027-0028], [0031]). By generating shear waves and causing tissue displacement, properties and images of the tissue may be determined recognized by Trahey ([0006], [0033]). Moreover, applying ARF which is sufficient to cause displacement of tissue may predictably also cause displacement and/or facilitate movement of therapeutic compounds.
However, the modified combination noted above fails to teach wherein applying the acoustic radiation force (ARF) (iii) collapses the sonoactive agent in the organ.
In an analogous delivering of an exogenous payload to an organ field of endeavor, Grayburn teaches such a feature. Grayburn teaches localized delivery of active agents using a combination of ultrasound and microbubbles ([0003]). Grayburn teaches intravenously injecting microbubbles which have genes incorporated therein ([0083]). Grayburn further teaches destroying the microbubbles within the microvasculature of the target organ by ultrasound ([0081], [0083], “The delivery vehicle-microbubble complex was then injected intravenously and destroyed within the microvasculature of the target organ by ultrasound”). Grayburn therefore teaches wherein the applied acoustic radiation force (from the ultrasound) collapses the sonoactive agent (microbubble) in an organ.
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 invention of Dayton to deliver the gene filled microbubbles to the microvasculature of the target organ for its destruction within the organ as taught by Grayburn ([0081], [0083]). Genes may predictably be delivered to specific tissues or organs for gene transfection in this manner as recognized by Grayburn ([0083-0084]).
However, the modified combination noted above fails to teach wherein the ARF is applied using ultrasound acoustic energy at: (ii) a duty cycle of less than 5%.
In an analogous destruction of sonoactive agents field of endeavor, Merchant teaches such a feature. Merchant teaches using acoustic radiation force to push microbubbles ([0038]). Merchant teaches inducing transient cavitation of microbubbles via ultrasound ([0038], [0142], [0149]). Merchant teaches ultrasound parameters for inducing transient cavitation include transmitting at a duty cycle of less than 5% ([0143]).
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 invention of Dayton to have the duty cycle be less than 5% as taught by Merchant ([0143]). By using a duty cycle of less than 5%, transient cavitation of microbubbles may be induced as recognized by Merchant ([0143], [0149]), thereby allowing for the release of a payload.
Regarding claim 76, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the ARF displaces the at least the portion of the tissue by at least 0.1 mm.
In an analogous application of acoustic radiation force (ARF) field of endeavor, Trahey teaches such a feature. Trahey teaches generating shear waves by applying ARF ([0027-0028]). Trahey teaches the transmitted ultrasound or ARF causes the tissue to be displaced in a range between about 0.1 μm to 300 μm (Claim 28, [0008], wherein 300 μm equals 0.3 mm). Trahey therefore teaches wherein the ARF displaces at least a portion of a tissue by at least 0.1 mm.
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 invention of Dayton to have the ARF cause the tissue to be displaced in a range between about 0.1 to 300 μm as taught by Trahey (Claim 28, [0008], [0027-0028]). Image of shear wave displacement may be generated as a result as recognized by Trahey ([0006], [0033]). Moreover, by applying ARF which causes displacement of tissue may predictably also cause displacement and/or facilitate movement of therapeutic compounds.
Regarding claim 91, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
Dayton further teaches wherein the exogenous payload comprises a nucleic acid construct ([0032], “The compounds used in this aspect of the invention may comprise … nucleic acids”, [0073], “The compound preferably comprises a therapeutic agent such as, e.g., a drug, nucleic acid, or other therapeutic agent”).
Regarding claim 110, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
Dayton further teaches wherein the acoustic radiation force is applied for at least 10, 20, 30 ,60, 120, 180, 240, 300, 360, 420, 480, 540, or 600 seconds ([0081], wherein an acoustic pulse length of 10 seconds long is at least 10 seconds).
Regarding claim 300, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the administration of the exogenous payload in (a) occurs intravenously.
In an analogous delivering of an exogenous payload to an organ field of endeavor, Grayburn teaches such a feature. Grayburn teaches localized delivery of active agents using a combination of ultrasound and microbubbles ([0003]). Grayburn teaches intravenously injecting microbubbles which have genes incorporated therein for gene transfection ([0083-0084]). Grayburn therefore teaches administration of an exogenous payload (genes) occurring intravenously.
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 invention of Dayton to intravenously inject the exogenously payload as taught by Grayburn ([0083]). By intravenously injecting the payload, the payload may circulate or be moved to the microvasculature of a target organ for targeted delivery for gene transfection as recognized by Grayburn ([0083-0084]).
Regarding claim 302, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the administration of the sonoactive agent in (b) occurs intravenously.
In an analogous delivering of an exogenous payload to an organ field of endeavor, Grayburn teaches such a feature. Grayburn teaches localized delivery of active agents using a combination of ultrasound and microbubbles ([0003]). Grayburn teaches intravenously injecting microbubbles which have genes incorporated therein for gene transfection ([0083-0084]). Grayburn therefore teaches administration of a sonoactive agent (microbubble complex) occurring intravenously.
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 invention of Dayton to intravenously inject the sonoactive agent or gene carrier as taught by Grayburn ([0083]). By intravenously carrier carrying the payload (genes), the payload may circulate or be moved to the microvasculature of a target organ for targeted delivery for gene transfection as recognized by Grayburn ([0083-0084]).
Regarding claim 304, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
Dayton teaches the invention further comprising imaging the tissue with ultrasound to confirm a presence of the sonoactive agent in the tissue ([0032], “imaging of the carrier particle or of target site”, [0057], “acoustic streaming in cooperation with ultrasonic imaging, to allow a user to observe the area being treated”, [0079], [0082-0083], “These therapeutic pulses in one embodiment are interleaved with the imaging pulses”, [0123], “with ultrasound imaging used to define the region to be treated and to monitor the inflow of the delivery vehicle”).
Regarding claim 306, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the sonoactive agent comprises a plurality of microbubbles.
In an analogous delivering of an exogenous payload to an organ field of endeavor, Grayburn teaches such a feature. Grayburn teaches localized delivery of active agents using a combination of ultrasound and microbubbles ([0003]). Grayburn teaches incorporating genes into gas-filled microbubbles to form a microbubble complex for gene delivery and transfection ([0083-0084]). Grayburn teaches wherein the microbubble complex comprising a plurality of microbubbles is destroyed via ultrasound in the microvasculature of the target organ ([0083]).
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 invention of Dayton to incorporate the genes into a plurality of microbubbles as taught by Grayburn ([0083]). The microbubbles may form a delivery vehicle for the genes for ultrasound-targeted delivery as recognized by Grayburn ([0083]).
Regarding claim 308, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 91.
However, Dayton fails to teach wherein the nucleic acid construct comprises DNA, and wherein delivery of the DNA to the cell induces expression of a therapeutic protein.
In an analogous delivering of an exogenous payload to an organ field of endeavor, Grayburn teaches such a feature. Grayburn teaches localized delivery of active agents using a combination of ultrasound and microbubbles ([0003]). Grayburn teaches delivering a bioactive agent such as genetic material to a target organ by using ultrasound targeted microbubble destruction (UTMD) ([0047-0049]). Grayburn teaches an example in which the bioactive agent may comprise a plasmid DNA comprising genetic material encoding therapeutic protein such as hormones and insulin ([0050]). Grayburn teaches wherein the level of gene expression (i.e. insulin) may be increased from the delivery of the microbubbles containing the plasmid DNA ([0062], [0080-0081], [0084]).
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 invention of Dayton to have the payload comprise a plasmid DNA for encoding and inducing the expression of a therapeutic protein as taught by Grayburn ([0050], [0062], [0080-0081], [0084]).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claim 1 above, and further in view of Miao ‘037 (US20210370037) and Sylvester (US20210050125). Miao ‘037 is cited in the IDS filed 06/09/2025.
Regarding claim 14, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the exogenous payload is delivered to cells in two tissue samples of the organ.
In an analogous method of distributing a payload across an organ field of endeavor, Miao ‘037 teaches such a feature. Miao ‘037 teaches ultrasound mediated gene delivery, delivering genes to the liver (Fig. 27A-27B, Abstract, [0003], [0010], [0027-0028], [0043]). Miao ‘037 shows spatial gene distribution plots across two samples in figures 27A and 27B, (Fig. 27A & Fig. 27B, [0043]). As shown in figures 27A and 27B, the gene payload is expressed or distributed throughout the organ in the two tissue samples of the organ, thus indicating delivery of the payload to cells in the two tissue samples of the organ.
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 invention of Dayton to have the payload be delivered to and expressed throughout the organ in two tissue samples as taught by Miao ‘037 (Figs. 27A & 27B, [0043]). Having the payload be expressed throughout the organ evidenced by two samples may indicate uniform and thus effective distribution/delivery of the payload or gene.
However, the modified combination noted above fails to explicitly teach wherein the two tissue samples of the organ are taken from opposite ends of the organ.
In an analogous taking of samples field of endeavor, Sylvester teaches such a feature. Sylvester teaches taking samples from opposite sides of a tank to check for solution homogeneity ([0167]).
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 invention of Dayton in view of Miao ‘037 to have the two samples be taken from opposite ends as taught by Sylvester ([0167]). By having the samples be taken at opposite ends and for both samples to show gene expression throughout, it can be ensured that the payload is distributed evenly or in a homogenous manner as recognized by Sylvester ([0167]).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), Merchant (US20080014627), Miao ‘037 (US20210370037), and Sylvester (US20210050125) as applied to claim 14 above, and further in view of Kalady (US20130345077).
Regarding claim 15, Dayton in view of Trahey, Grayburn, Merchant, Miao ‘037, and Sylvester teaches the invention as claimed above in claim 14.
However, Dayton fails to teach wherein the two tissue samples are 1 cm3 or 1 g in size.
In an analogous method sample taking, Kalady teaches such a feature. Kalady teaches determining gene expression levels by performing biopsy to retrieve samples ([0055]). Kalady teaches the biopsy sample generally has a size ranging from 5 mm3 to 1 cm3 ([0055]). Kalady therefore teachings wherein samples may be samples sized 1 cm3.
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 invention of Dayton to have the two tissue samples be sized 1 cm3 as taught by Kalady ([0055]). By using samples sized 1 cm3, a person may sufficiently determine gene expression levels from said samples as recognized by Kalady ([0055]).
Claims 30 and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claim 1 above, and further in view of Genstler (US20160082243).
Regarding claim 30, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the pulse length is from 200 to 5000 μs.
In an analogous method for delivering a payload by applying acoustic radiation forces field of endeavor, Genstler teaches such a feature. Genstler teaches a catheter system configured to enhance delivery of therapeutic compounds using ultrasound ([0043-0046]). Genstler teaches the catheter (10) includes an ultrasound radiating member ([0047], [0056]). Genstler teaches the ultrasound emitted may have a pulse duration or width (i.e. pulse length) between about 0.1 milliseconds and about 25 milliseconds ([0099-0100], [0110], wherein 0.1 to 25 milliseconds includes values between 200-5000 microseconds). Genstler further teaches varying power/physiological parameters to apply acoustic radiation force to media to enhance the therapeutic effects of ultrasound ([0123]). Genstler therefore teaches wherein ARF may be applied at an ultrasound pulse length from 200 to 5000 microseconds.
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 invention of Dayton to apply ultrasound at a pulse length between about 0.1 to 25 milliseconds as taught by Genstler ([0099-0100], [0110]). By using such a pulse length, the effect of a therapeutic compound may be enhanced as recognized by Genstler ([0108], [0110]).
Regarding claim 52, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the ultrasound acoustic energy is applied at a pulse repetition frequency of 0.5 to 5 Hz.
In an analogous method for delivering a payload by applying acoustic radiation forces field of endeavor, Genstler teaches such a feature. Genstler teaches a catheter system configured to enhance delivery of therapeutic compounds using ultrasound ([0043-0046]). Genstler teaches the catheter (10) includes an ultrasound radiating member ([0047], [0056]). Genstler teaches the effect of a therapeutic compound may be enhanced by using a certain pulse repetition frequency and teaches in one embodiment the PRF may be about 5 Hz ([0099], [0108]). Moreover Genstler teaches varying power/physiological parameters to apply acoustic radiation force to media to enhance the therapeutic effects of ultrasound ([0123]).
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 invention of Dayton to have the ARF be applied at a pulse repetition frequency (PRF) of about 5 Hz as taught by Genstler ([0099], [0108]). The effect of a therapeutic compound may be enhanced by having the PRF be 5 Hz as recognized by Genstler ([0108]).
Claims 57 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claim 1 above, and further in view of Lanza (US20050175541).
Regarding claim 57, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the ultrasound acoustic energy is applied at a mechanical index of 0.4 to 3.0.
In an analogous method for delivering a payload by applying acoustic radiation forces field of endeavor, Lanza teaches such a feature. Lanza teaches using acoustic radiation force to facilitate transport of therapeutic compounds to cells (Abstract, [0014], [0155]). Lanza teaches delivering ultrasound energy using a mechanical index of about 1.0 to about 1.9, thereby generating acoustic radiation forces ([0027], [0151], wherein the experiment performed used a mechanical index of 1.9, [0155]).
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 invention of Dayton to apply acoustic radiation force at a mechanical index of about 1.9 as taught by Lanza ([0027], [0151], [0155]). By using a mechanical index of 1.9, acoustic radiation force may help facilitate delivery of therapeutic compounds as recognized by Lanza ([0007], [0151], [0155]).
Regarding claim 68, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the ultrasound acoustic energy is applied at a mechanical index of at least 2.1.
In an analogous method for delivering a payload by applying acoustic radiation forces field of endeavor, Lanza teaches such a feature. Lanza teaches using acoustic radiation force to facilitate transport of therapeutic compounds to cells (Abstract, [0014], [0155]). Lanza teaches wherein using certain mechanical indexes may be effective for enhancing delivery of a therapeutic agent ([0021], [0023]) and further teaches wherein in some instances, mechanical indexes of greater than 1.9 may be used ([0027]). Lanza therefore teaches wherein ARF may be applied at a mechanical index of at least 2.1 (wherein mechanical indexes greater than 1.9 include at least 2.1).
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 invention of Dayton to use mechanical indexes greater than 1.9 as taught by Lanza ([0027]). Mechanical indexes of greater than 1.9 may enhance delivery of a therapeutic agent as recognized by Lanza ([0021], [0023], [0027]).
Claim 64 is rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claim 1 above, and further in view of Yu (US20230381548).
Regarding claim 64, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the duty cycle is from 0.01% to 1.0%.
In an analogous method for delivering a payload by applying acoustic radiation forces field of endeavor, Yu teaches such a feature. Yu teaches transmitting acoustic radiation forces into brain tissue (Abstract, [0012], [0015]). Yu teaches wherein the invention may facilitate drug delivery ([0019], [0055], [0086], [0092-0093]). Yu teaches wherein the duty cycle of the applied ultrasound treatment pulse may be less than or equal to 1% to exert shear stress on the tissue (Claim 8, [0027], [0088]). Yu therefore teaches wherein ARF is applied at a duty cycle from 0.01% to 1.0%.
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 invention of Dayton to use a duty cycle of less than 1% when applying ARF as taught by Yu (Claim 8, [0027], [0088]). Using a low duty cycle may help minimize and prevent undesired heating effects on tissue as recognized by Yu ([0088-0090], [0118], [0123]).
Claims 69 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claim 1 above, and further in view of Li (US20230058977).
Regarding claim 69, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the ultrasound acoustic energy is applied at a thermal index of less than 1.0.
In an analogous method for delivering a payload by applying acoustic radiation forces field of endeavor, Li teaches such a feature. Li teaches applying ultrasound energy at a target site in a subject, thereby delivering a therapeutic agent to the target site ([0093]). Li teaches wherein the applied ultrasound energy enhances delivery of the therapeutic agent within the subject ([0108]). Li teaches, for enhancing delivery of therapeutic agents, wherein the applied ultrasound energy causes mechanical shear forces to be imparted onto the tissue/barrier surface, causing sonoporation, thereby teaching wherein the applied ultrasound energy results in acoustic radiation force as shear waves are generated in the tissue ([0367]). Li teaches performing sonoporation using a thermal index of 0.1 ([0523]). Li therefore teaches wherein ultrasound energy is applied at a thermal index of less than 1.0.
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 invention of Dayton to apply ultrasound energy at a thermal index of 0.1 as taught by Li ([0367], [0523]). By using such a low thermal index, the risks for tissue damage as caused by heating or a rise in temperature may be minimized/prevented.
Regarding claim 74, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach wherein the applying the ARF does not increase a temperature of the tissue by more than 0.5 °C.
In an analogous method for delivering a payload by applying acoustic radiation forces field of endeavor, Li teaches such a feature. Li teaches applying ultrasound energy at a target site in a subject, thereby delivering a therapeutic agent to the target site ([0093]). Li teaches wherein the applied ultrasound energy enhances delivery of the therapeutic agent within the subject ([0108]). Li teaches, for enhancing delivery of therapeutic agents, wherein the applied ultrasound energy causes mechanical shear forces to be imparted onto the tissue/barrier surface, causing sonoporation, thereby teaching wherein the applied ultrasound energy results in acoustic radiation force as shear waves are generated in the tissue ([0367]). Li teaches performing sonoporation using a thermal index of 0.1 ([0523]). A thermal index of 0.1 indicates that the ultrasound is estimated to cause about a 0.1 degree Celsius rise in temperature. Therefore Li teaches wherein the application of the ARF would not cause an increase of the temperature of tissue by more than 0.5 °C.
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 invention of Dayton to apply ultrasound energy and/or ARF at a thermal index of 0.1 as taught by Li ([0367], [0523]). By using such a low thermal index, the risks for tissue damage as caused by heating or a rise in temperature may be minimized/prevented, and modifying Dayton to use a thermal index of 0.1 would predictably result wherein the applied ARF would not increase the temperature of the tissue by more than 0.5 °C since the thermal index of 0.1 would limit the temperature increase to about 0.1 °C.
Claim 148 is rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claim 1 above, and further in view of Atala (US20030215459). Atala is cited in the IDS filed 06/09/2025.
Regarding claim 148, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 1.
However, Dayton fails to teach the invention further comprising: delivering a subsequent dose of the exogenous payload to the subject, and applying a subsequent acoustic radiation force (ARF) to the subject at least 4 hours after a first application of ARF, wherein the first application of ARF is the applying of ARF in (c).
In an analogous ultrasound enhanced delivery of a payload field of endeavor, Atala teaches such a feature. Atala teaches applying ultrasound energy to a subject such that cell transfection is promoted (Abstract). Atala teaches a repeated application of gene formulation and ultrasound energy may be provided for example after a week (weekly intervals) to ensure adequate levels of gene expression ([0045]). Atala therefore teaches delivering a subsequent dose of a payload to a subject and applying subsequent ultrasound to the subject at least 4 hours (i.e. a week) after a first application.
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 invention of Dayton to treat the subject at regular intervals such as weekly as taught by Atala ([0045]). By applying the treatment at regular intervals, adequate levels of gene expression may be ensured as recognized by Atala ([0045]). Dayton teaches wherein applying ultrasound comprises applying ARF. Therefore, Dayton modified by the teachings of Atala would predictably result wherein a second or subsequent ARF is applied to the subject at least 4 hours after the first application of ARF.
Claims 301 and 303 are rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claims 300 and 302 respectively above, and further in view of Fisher (US20120195935).
Regarding claim 301, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 300.
However, Dayton fails to teach wherein the intravenous administration of the exogenous payload occurs through a peripheral vein or a peripheral artery of the subject.
In an analogous method of delivery of a payload field of endeavor, Fisher teaches such a feature. Fisher teaches viral gene therapy assisted by microbubbles (Abstract, [0061], [0066], [0099]). Fisher teaches the microbubbles carry the viral gene to a target site where the virus is released from the microbubble ([0051]). Fisher teaches wherein the microbubbles may be injected in peripheral veins and this method may be beneficial for cancer gene therapy of potentially inaccessible tumors ([0052], [0090]). Fisher teaches wherein microbubbles injected in the peripheral veins may be used for enhancing delivery, i.e. gene delivery, to a target tissue ([0090]). Fisher therefore teaches wherein intravenous administration of an exogenous payload (gene) occurs through a peripheral vein of a subject.
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 invention of Dayton to have the payload be injected from the peripheral vein as taught by Fisher ([0052], [0090]). Injection via the peripheral veins may be beneficial/helpful for cancer gene therapy of potentially inaccessible tumors as recognized by Fisher ([0052]).
Regarding claim 303, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 302.
However, Dayton fails to teach wherein the intravenous administration of the sonoactive agent in (b) occurs through a peripheral vein or peripheral artery of the subject.
In an analogous method of delivery of a payload field of endeavor, Fisher teaches such a feature. Fisher teaches viral gene therapy assisted by microbubbles (Abstract, [0061], [0066], [0099]). Fisher teaches the microbubbles carry the viral gene to a target site where the virus is released from the microbubble ([0051]). Fisher teaches wherein the microbubbles may be injected in peripheral veins and this method may be beneficial for cancer gene therapy of potentially inaccessible tumors ([0052], [0090]). Fisher teaches wherein microbubbles injected in the peripheral veins may be used for enhancing delivery, i.e. gene delivery, to a target tissue ([0090]). Fisher teaches once systemic delivery of the microbubbles is achieved, the microbubbles can be disrupted locally by using ultrasound, thereby releasing the payload at only a desired location ([0045]). Fisher therefore teaches wherein intravenous administration of a sonoactive agent occurs through a peripheral vein of a subject.
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 invention of Dayton to have the carrier particle be injected from the peripheral vein as taught by Fisher ([0052], [0090]). Injection via the peripheral veins may be beneficial/helpful for cancer gene therapy of potentially inaccessible tumors as recognized by Fisher ([0052]).
Claim 305 is rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claim 304 above, and further in view of Miao ‘037 (US20210370037).
Regarding claim 305, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 304.
However, Dayton fails to explicitly teach wherein imaging of the tissue occurs prior to the applying of the ARF in (c).
In an analogous method of distributing a payload across an organ field of endeavor, Miao ‘037 teaches such a feature. Miao ‘037 teaches ultrasound mediated gene delivery, delivering genes to the liver (Fig. 27A-27B, Abstract, [0003], [0010], [0027-0028], [0043]). Miao ‘037 teaches wherein the therapeutic compound and/or adjunct compound comprises microbubbles (MBs) ([0101]). Miao ‘037 teaches visualizing a target liver lobe using ultrasound imaging before ultrasound treatment to verify the location of the microbubble solution and the required direction to apply ultrasound therapeutic energy ([0198]). Moreover, Miao ‘037 teaches wherein the application of the treatment or ultrasound energy destroys the microbubbles ([0198]). Miao ‘037 therefore teaches ultrasound imaging of the tissue prior to the application of therapeutic ultrasound (ARF) configured to destroy/collapse the sonoactive agent.
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 invention of Dayton to perform ultrasound imaging of the tissue prior to applying the ARF or therapeutic ultrasound as taught by Miao ‘037 ([0198]). By imaging the tissue prior to applying ARF, the location of the microbubble solution may be verified and also the required direction of the ultrasound energy (ARF) may be verified as recognized by Miao ‘037 ([0198]).
Claim 307 is rejected under 35 U.S.C. 103 as being unpatentable over Dayton (US20070071683) in view of Trahey (US20040068184), Grayburn (US20140134234), and Merchant (US20080014627) as applied to claim 306 above, and further in view of Kaplitt (WO2021022208).
Regarding claim 307, Dayton in view of Trahey, Grayburn, and Merchant teaches the invention as claimed above in claim 306.
However, Dayton fails to teach wherein in (c), the ARF is applied to a first location in the organ, wherein subsequent to applying of the ARF to the first location in the organ in (c), the exogenous payload is delivered to a second location in the organ, and wherein the second location is distal from the first location.
In an analogous method for delivery of an exogenous payload field of endeavor, Kaplitt teaches such a feature. Kaplitt teaches targeted gene therapy to treat neurological diseases and teaches wherein the target may be a peripheral organ or the brain (Title, Page 2 line 5 – Page 3 line 5). Kaplitt teaches delivering a viral vector or payload to one brain region in a single treatment, followed by delivery of a second payload to a second brain region or different site in a second treatment, and wherein the treatment sessions may be separate by several days or weeks (Page 3 lines 12-21, Page 4 lines 6-24). Moreover, Kaplitt teaches wherein ultrasound is used for delivery of the payloads in each treatment (Page 3 lines 13-14, Page 4 lines 7-12). Kaplitt further teaches wherein any method that allows for targeted delivery of the payload may be employed (Page 18 lines 28-31). Dayton in view of Kaplitt therefore teaches applying ultrasound (ARF) to a first and second location in an organ (brain) and subsequent to applying ARF to a first location (first brain region), delivering the payload to a second location (second brain region). The regions being different regions/sites mean they’re distal to one another.
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 invention of Dayton to deliver a pair of payloads to different regions of the brain in separate sessions as taught by Kaplitt (Page 3 lines 12-21, Page 4 lines 6-24). By delivering the pair of payloads to the brain in the manner taught by Kaplitt, neurological diseases or disorders may be treated as recognized by Kaplitt (Page 21 lines 10-21).
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.
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/TOMMY T LY/ Examiner, Art Unit 3797
/SERKAN AKAR/Primary Examiner, Art Unit 3797