DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/04/2026 has been entered.
Response to Amendment
The amendment filed on 10/01/2025 has been entered. Claims 1, 11 and 14 have been amended. Claims 1-4 and 6-21 remain pending.
Previous objection issued for Claim 14 has been overcome. Previous 112b rejections issued for Claims 1 and 11 have been overcome.
Response to Arguments
In Remarks, Page 9, regarding Claims 1 and 11, Applicant argues that the reference Levenberg uses acoustic sensitive materials, and relies on a cavitation mechanism but not thermal effect of ultrasound, so modification of Levenberg by Thanou would change the principle of operation of Levenberg. Examiner respectfully disagrees. Even though Levenberg utilizes the cavitation mechanism of ultrasound, it is a widely known fact to a PHOSITA that ultrasound can have both cavitation effect and thermal effect. Using the thermal mechanism instead would not change the principle of operation of Levenberg, because the modified method would still use the same technology of focused ultrasound. Further, Levenberg in Para 0013 cited a previous patent application “Australian Patent Application Publication No. 2018201765A1 … using high intensity focused ultrasound (HIFU)” and commented that “The proposed process is able to be utilized in bioprinting to produce tissue and organ cell formations using biocompatible materials and whereby the formations are able to be produced in-vivo within the patient”, which explicitly discloses the idea of using HIFU for in-vivo bioprinting. Furthermore, Thanou discloses “… inducing hyperthermia, in particular using ultrasound (US), such as focused ultrasound (FUS), usually at high intensity (HIFU) …”, which suggests that focused ultrasound in Levenberg can be modified to “high intensity (HIFU)” without changing its principle of operation.
In Remarks, Page 10, regarding Claims 1 and 11, Applicant argues that the Office Action does not explain how the benefit of localized delivery of drugs to cancer tumors provided via Thanou’s method of drug-carrying thermosensitive lipid particles would provide any motivation to use a thermosensitive lipid nanoparticle to carry crosslinking agents in Levenberg’s bioprinting techniques. Examiner respectfully disagrees. As cited in the Office Action, Page 6, Thanou discloses using lipid nanoparticle that undergoes phase transition at a particular temperature, which makes drug to be released in a more controlled manner, and discloses using focused ultrasound, which is the same technique as Levenberg. The reference Mammadov is provided as evidence that the field had recognized the value of HIFU and its thermal effect in accurately controlling bioprinting. To a PHOSITA, it is beneficial to use a more quantifiable metric – temperature – to more closely monitor and control the process of polymerization.
In Remarks, Page 11, regarding Claim 19, Applicant argues that, first, “neither Martin nor Thanou describes using a thermosensitive carrier particle that encapsulates any type of crosslinking agent”, and second, the Office Action “does not explain how the benefit of localized delivery of drugs to cancer tumors in Thanou’s method of drug-carrying thermosensitive lipid particles would provide any motivation to use a thermosensitive lipid nanoparticle to encapsulate a thermal crosslinker in Martin’s composite material for tissue regeneration”. Examiner respectfully disagrees. As cited in the Office Action, Pages 25-26, Martin discloses using at least “a free radical polymerization initiator” as a type of crosslinking agent, and Thanou discloses using at least “thermo-sensitive particles” as a type of carrier particle. The modification of Martin by Thanou includes at least encapsulating crosslinking agent inside thermosensitive carrier particles, and when compared to originally disclosed method in Martin, this modification has the benefit of, as cited in the Office Action, Page 27, achieving precisely-controlled release of agent at a temperature level that can be efficiently achieved and is safe for human body. For example, with the modified method, the implanted material’s effect can be activated in a controlled manner (e.g. after more waiting time or additional adjustment for location of the implant) by using focused ultrasound to achieve optimal treatment outcome.
In Remarks, Page 12, regarding Claims 17 and 21, Applicant argues that Levenberg discourages bioprinting methods that cause a temperature increase at the bioprinting site. Examiner respectfully disagrees. Levenberg’s disclosure in Para 0084 “the polymerization effect is through cavitation and not thermal polymerization” is clearly just to specify the mechanism utilized by its disclosed method, and should not be regarded as a “discouragement” of using ultrasound's thermal effect. Instead, when Levenberg refers to “Australian Patent Application Publication No. 2018201765A1 … using high intensity focused ultrasound (HIFU)” in Para 0013, Levenberg explicitly supports that HIFU can be used for in vivo bioprinting, as “The proposed process is able to be utilized in bioprinting to produce tissue and organ cell formations using biocompatible materials and whereby the formations are able to be produced in-vivo within the patient”.
In Remarks, Page 12, regarding Claims 17 and 21, Applicant argues that the Office Action's rationale for modifying Levenberg to incorporate crosslinking agents that induce thermal crosslinking is not supported by Thanou, and that Thanou does not describe the application of HIFU to generate gels of a “desired shape and size”. Clarification needs to be made here. In the Office Action, Pages 17, the benefit for the modification is phrased as “precise and localized change of temperature can be conveniently achieved by HIFU, as evidenced by Thanou, so that gels of desired shape and size can be generated”. Here, what Thanou evidences is that HIFU achieves precise and localized change of temperature, but not either inducing thermal crosslinking or gels of desired shape and size.
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.
Claims 1, 3-4, 6-7, 10-12 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Levenberg et al (US 20220288278 A1; hereafter Levenberg), in view of Thanou et al (US 20180178043 A1; hereafter Thanou).
With regard to Claim 1, Levenberg discloses a method, comprising:
obtaining a biopolymer mixture (said acoustic-sensitive material) including prepolymer material (pre-polymer) and a crosslinking agent (cross-linker) encapsulated in carrier particles (micro-capsules)( Levenberg, Page 17, Claim 10; “said acoustic-sensitive material comprises a solution of pre-polymer and acoustic-sensitive cross-linker loaded micro-capsules.”);
delivering the biopolymer mixture to a subcutaneous or deep tissue target location of a subject (Levenberg, Para 0080; “… performing printing and/or polymerization at any location inside the patient, including all deep tissues and internal organs, with the material being transported to the area in a single injection.”); and
transmitting with a bioprinting device (Levenberg, Para 0113; “… focused ultrasound (FUS) for 3D printing/bioprinting”), via transcutaneous application, radiation to the subcutaneous or deep tissue target location, the radiation configured to cause the carrier particles to release at least some of the crosslinking agent (calcium), the released crosslinking agent configured to cause the prepolymer material to form into a gel or polymeric matrix (Levenberg, Para 0114; “by applying FUS, the liposomes permeability increases, and the calcium is released locally and induce the ionic crosslinking of the alginate as part of patterned 3D printed alginate”).
Levenberg does not clearly and explicitly disclose using thermosensitive carrier particles, or using one or more high-intensity focused ultrasound (HIFU) transducers to cause the thermosensitive carrier particles to increase in temperature that further causes the particles to release agent.
Thanou in the same field of endeavor discloses using thermosensitive carrier particles (Thanou, Para 0235; “the lipid nanoparticle of the present invention is thermosensitive, i.e. undergoes a phase transition at a particular temperature.”), and using one or more high-intensity focused ultrasound (HIFU) transducers to cause the thermosensitive carrier particles to increase in temperature that further causes the particles to release agent (Thanou, Para 0006; “The invention contemplates a method of inducing hyperthermia, in particular using ultrasound (US), such as focussed ultrasound (FUS), usually at high intensity (HIFU), on a subject”; Para 0072; “The hyperthermia protocol can therefore heat the tissue or site of interest, and so can heat the thermosensitive (e.g. liposome) particles drug delivery systems, to cause the release of the drug and/or API at or near that site.” These disclosures show that HIFU is used to heat thermosensitive particles for releasing drug or agent). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg, as suggested by Thanou, in order to use HIFU to release agent from thermosensitive carrier particles. One of ordinary skill in the art would have been motivated to make the modification for the benefit of enabling localized and controlled release of agent from carrier particles by using temperature as a quantitative metric (Thanou, Para 0400; “FUS is a non-invasive method that can be used to induce deep and localised hyperthermia in a controlled manner (12)”).
With regard to Claim 3, Levenberg and Thanou disclose the method of Claim 1. Levenberg further discloses wherein the carrier particles comprise vesicles, micelles, bubbles, or polymers (Levenberg, Page 3, Example 21; “… micro-capsules comprise liposomes including said cross-linker.”).
With regard to Claim 4, Levenberg and Thanou disclose the method of Claim 3. Levenberg further discloses wherein the carrier particles comprise vesicles including liposomes encapsulating the crosslinking agent (Levenberg, Page 3, Example 21; “… micro-capsules comprise liposomes including said cross-linker.”); and
the radiation is configured to cause the liposomes to increase in temperature (Levenberg, Para 0013; “Ultrasound waves penetrate plurality of mediums with matching acoustic impedance with the HIFU transducer concentrating energy into a focal point to stimulate temperat[ure] increase at desired location.”) and release the crosslinking agent (Levenberg, Para 0114; “… by applying FUS, the liposomes permeability increases, and the calcium is released locally …”).
With regard to Claim 6, Levenberg and Thanou disclose all the limitations of Claim 1 as discussed above, but do not disclose wherein the HIFU radiation is configured to heat the subcutaneous or deep tissue target location to between 39°C and 43°C.
Thanou further discloses wherein the HIFU radiation is configured to heat the subcutaneous or deep tissue target location to between 39°C and 43°C (Thanou, Para 0040; “Preferably, the temperature of the tissue or desired body part is raised or increased to 39°C to 42°C, such as to from 40°C to 41°C. Suitably, the temperature of the desired site does not exceed 42°C or 43°C.”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as further suggested by Thanou, in order to heat the tissue target location to the abovementioned range of temperature. One of ordinary skill in the art would have been motivated to make the modification for the benefit of avoiding tissue damage by hyperthermia (Thanou, Para 527; “Lower power settings may also be used to induce sub-lethal (normally <43°C.), highly localised hyperthermia that does not damage tissues directly.”).
With regard to Claim 7, Levenberg and Thanou disclose the method of Claim 1. Levenberg further discloses wherein:
the prepolymer material is loaded with drugs or cells (Levenberg, Abstract; “the at least one additional component is one or more of at least one releasable drug within said acoustic-sensitive material and/or a plurality of cells within said acoustic-sensitive material.”); and
the gel formed from the prepolymer material is configured, in the subcutaneous or deep tissue target location, to provide a controlled release of the drugs for a therapeutic application (Levenberg, Para 0083; “the implant is configured for controlled release of drugs …, polymerization by general ultrasound induction … in deep tissues...”) or to encapsulate the cells for tissue regeneration (Levenberg, Para 0080; “by combining tissue-specific and/or therapeutic cells with the injected material, the invention serves as a platform for cell-based therapies for tissue regeneration and augmentation.”).
With regard to Claim 10, Levenberg and Thanou disclose the method of Claim 1. Levenberg further discloses wherein transmitting with the bioprinting device, via transcutaneous application, the radiation to the subcutaneous or deep tissue target location comprises: transmitting with one or more transducers of the bioprinting device, along a predetermined trajectory (controlling the spatial position of the US focal point), the radiation to the subcutaneous or deep tissue target location to cause the prepolymer material to form into a pattern (desired pattern) of the gel defined by the predetermined trajectory (Levenberg, Para 0113; “FUS is used to induce polymerization of the acoustic-sensitive material at a localized volume (using for example a cavitation mechanism), and/or by controlling the spatial position of the US focal point the object is printed layer by layer and/or in any other desired pattern.”).
With regard to Claim 11, Levenberg discloses a system for in vivo bioprinting, the system comprising:
a biopolymer mixture (said acoustic-sensitive material) including prepolymer material (pre-polymer) and a crosslinking agent (cross-linker) encapsulated in carrier particles (micro-capsules) (Levenberg, Page 17, Claim 10; “said acoustic-sensitive material comprises a solution of pre-polymer and acoustic-sensitive cross-linker loaded micro-capsules.”); and
a bioprinting device (Levenberg, Para 0113; “… focused ultrasound (FUS) for 3D printing/bioprinting”) comprising one or more focused ultrasound transducers, the one or more transducers configured to transmit, via transcutaneous application, radiation to a subcutaneous or deep tissue target location of a subject that the biopolymer mixture is delivered to, the radiation configured to cause the carrier particles to release at least some of the crosslinking agent (calcium), the released crosslinking agent configured to cause the prepolymer material to form into a gel or polymeric matrix (Levenberg, Para 0114; “by applying FUS, the liposomes permeability increases, and the calcium is released locally and induce the ionic crosslinking of the alginate as part of patterned 3D printed alginate”).
Levenberg does not clearly and explicitly disclose using thermosensitive carrier particles, or using one or more high-intensity focused ultrasound (HIFU) transducers to cause the thermosensitive carrier particles to increase in temperature that further causes the particles to release agent.
Thanou in the same field of endeavor discloses using thermosensitive carrier particles (Thanou, Para 0235; “the lipid nanoparticle of the present invention is thermosensitive, i.e. undergoes a phase transition at a particular temperature.”), and using one or more high-intensity focused ultrasound (HIFU) transducers to cause the thermosensitive carrier particles to increase in temperature that further causes the particles to release agent (Thanou, Para 0006; “The invention contemplates a method of inducing hyperthermia, in particular using ultrasound (US), such as focussed ultrasound (FUS), usually at high intensity (HIFU), on a subject”; Para 0072; “The hyperthermia protocol can therefore heat the tissue or site of interest, and so can heat the thermosensitive (e.g. liposome) particles drug delivery systems, to cause the release of the drug and/or API at or near that site.” These disclosures show that HIFU is used to heat thermosensitive particles for releasing drug or agent). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg, as suggested by Thanou, in order to use HIFU to release agent from thermosensitive carrier particles. One of ordinary skill in the art would have been motivated to make the modification for the benefit of enabling localized and controlled release of agent from carrier particles by using temperature as a quantitative metric (Thanou, Para 0400; “FUS is a non-invasive method that can be used to induce deep and localised hyperthermia in a controlled manner (12)”).
With regard to Claim 12, Levenberg and Thanou disclose all the limitations of Claim 11, but do not explicitly and clearly disclose wherein:
the biopolymer mixture further includes a contrast agent; and
the system further comprises an imaging device configured to capture an image of the subcutaneous or deep tissue target location of the subject during gelation of the prepolymer material after the biopolymer mixture is delivered to the subcutaneous or deep tissue target location.
Thanou further discloses wherein:
the biopolymer mixture further includes a contrast agent (Thanou, Para 0082; “The API and/or the delivery system (particles) thus preferably comprise a label, or an imaging and/or contrast agent.”); and
the system further comprises an imaging device configured to capture an image of the subcutaneous or deep tissue target location of the subject during gelation of the prepolymer material (Thanou, Para 0081; “The method may thus involve simultaneous hyperthermia and (e.g. NIRF and/or MRI) imaging.” As hyperthermia and imaging are performed simultaneously, the modification of Levenberg by Thanou would necessarily involve imaging during gelation of the prepolymer material.) after the biopolymer mixture is delivered to the subcutaneous or deep tissue target location (Thanou, Para 0123; “FIG. 25: Comparisons of in vivo and excised IGROV-1 tumours labeled XL750-herceptin NIRF from mice treated with no, 1, 2, or 3 rounds of FUS hyperthermia to the right hand tumour.” Here “NIRF” is near infra-red fluorescence imaging, and “XL750” is the fluorescence dye or contrast agent for enhancing images.). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as further suggested by Thanou, in order to include an imaging contrast agent and perform imaging during gelation. One of ordinary skill in the art would have been motivated to make the modification for the benefit of ensuring the administered agents (e.g. polymer, drug or cells) to be delivered to the target location precisely and with effective amount (Thanou, Para 0156; “Since the lipid nanoparticle of the present invention can comprise imaging label(s) (e.g. MRI and/or NIRF), it is possible to monitor the lipid nanoparticles in vivo.”).
With regard to Claim 14, Levenberg and Thanou disclose a system of Claim 11. Levenberg further discloses wherein the bioprinting device comprises:
a controller configured to cause the one or more transducers to transmit, along a predetermined trajectory (controlling the spatial position of the US focal point), the radiation to the subcutaneous or deep tissue target location to cause the prepolymer material to form into a pattern (desired pattern) of the gel defined by the predetermined trajectory (Levenberg, Para 0113; “FUS is used to induce polymerization of the acoustic-sensitive material at a localized volume (using for example a cavitation mechanism), and/or by controlling the spatial position of the US focal point the object is printed layer by layer and/or in any other desired pattern.”).
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Levenberg and Thanou, in view of Bassett et al (US 20220143276 A1; hereafter Bassett).
With regard to Claim 2, Levenberg and Thanou disclose all the limitations of Claim 1, but do not disclose wherein:
the biopolymer mixture further includes a contrast agent mixed into the prepolymer material; and
the method further comprises: capturing, using an imaging device, during gelation of the prepolymer material, an image of the subcutaneous or deep tissue target location, the image enhanced by the contrast agent.
Thanou further discloses wherein the method further comprises: capturing, using an imaging device, during gelation of the prepolymer material (Thanou, Para 0081; “The method may thus involve simultaneous hyperthermia and (e.g. NIRF and/or MRI) imaging.” As hyperthermia and imaging are performed simultaneously, the modification of Levenberg by Thanou would necessarily involve imaging during gelation of the prepolymer material.), an image of the subcutaneous or deep tissue target location, the image enhanced by the contrast agent (Thanou, Para 0123; “FIG. 25: Comparisons of in vivo and excised IGROV-1 tumours labeled XL750-herceptin NIRF from mice treated with no, 1, 2, or 3 rounds of FUS hyperthermia to the right hand tumour.” Here “NIRF” is near infra-red fluorescence imaging, and “XL750” is the fluorescence dye or contrast agent for enhancing images.). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as further suggested by Thanou, in order to image the target location during the polymerization process. One of ordinary skill in the art would have been motivated to make the modification for the benefit of ensuring the administered agents (e.g. polymer, drug or cells) to be delivered to the target location precisely and with effective amount (Thanou, Para 0156; “Since the lipid nanoparticle of the present invention can comprise imaging label(s) (e.g. MRI and/or NIRF), it is possible to monitor the lipid nanoparticles in vivo.”).
Levenberg and Thanou, as discussed in Claim 1 and further disclosed above by Thanou, do not disclose wherein the biopolymer mixture further includes a contrast agent mixed into the prepolymer material.
Bassett in the same field of endeavor discloses wherein the biopolymer mixture further includes a contrast agent mixed into the prepolymer material (Bassett, Para 0046; “one or both crosslinkable precursor solutions may contain contrast agents or other means for visualizing the hydrogel implant.”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Bassett, in order to mix a contrast agent into the prepolymer material. One of ordinary skill in the art would have been motivated to make the modification for the benefit of ensuring the prepolymer material to be injected to the correct target location and with the correct amount prior to the polymerization process (Bassett, Para 0137; “The presence of the visualization agent in application may enable the user to detect when the cavity has been sufficiently filled with material through the presence of excess exiting the target cavity.”).
Claims 8, 17 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Levenberg and Thanou, in view of Martin et al (US 20190060516 A1; hereafter Martin).
With regard to Claim 8, Levenberg and Thanou disclose all the limitations of Claim 1 as discussed above, but do not explicitly and clearly disclose wherein:
the prepolymer material is electrically conductive; and
the gel formed from the prepolymer material is electrically conductive.
Martin in the same field of endeavor discloses wherein:
the prepolymer material is electrically conductive (Martin, Para 0183; “These applications involve modification of the hydrogel composition so as to contain a conductive species.”); and
the gel formed from the prepolymer material is electrically conductive (Martin, Para 0183; “… to render the hydrogel compositions of the invention electrically conductive …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Martin, in order to use electrically conductive prepolymer material to form electrically conductive gel. One of ordinary skill in the art would have been motivated to make the modification for the benefit of enabling physiological measurements that rely on electrical signals such as ECG for heart and EMG for muscles (Martin, Para 0183; “… the hydrogel composition may be used to attach a transcutaneous nerve stimulation electrode, an electrosurgical return electrode, or an EKG electrode to a patient's skin or mucosal tissue.”).
With regard to Claim 17, Levenberg and Thanou disclose a system of Claim 11, including the limitation of increasing temperature at the subcutaneous or deep tissue target location caused by the HIFU radiation, but do not explicitly and clearly disclose wherein: in response to temperature increase, the crosslinking agent is configured to induce thermal crosslinking of the prepolymer material.
Martin in the same field of endeavor discloses wherein: in response to temperature increase, the crosslinking agent is configured to induce thermal crosslinking of the prepolymer material (Martin, Para 0184; “The gel/hydrogel polymers may be covalently crosslinked to other polymers or to the nanostructures, either intramolecularly or intermolecularly or through covalent bonds. … The crosslinks may be formed using any suitable means, including using heat …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Martin, in order to use thermal crosslinking to form gel or polymeric matrix. One of ordinary skill in the art would have been motivated to make the modification for the benefit that precise and localized change of temperature can be conveniently achieved by HIFU, as evidenced by Thanou, so that gels of desired shape and size can be generated.
With regard to Claim 21, Levenberg and Thanou disclose all the limitations of Claim 1, including the limitation of increasing temperature at the subcutaneous or deep tissue target location caused by the HIFU radiation, but do not explicitly and clearly disclose wherein: in response to temperature increase, the released crosslinking agent induces thermal crosslinking of the prepolymer material to form into the gel or polymeric matrix.
Martin in the same field of endeavor discloses wherein: in response to temperature increase, the released crosslinking agent induces thermal crosslinking of the prepolymer material to form into the gel or polymeric matrix (Martin, Para 0184; “The gel/hydrogel polymers may be covalently crosslinked to other polymers or to the nanostructures, either intramolecularly or intermolecularly or through covalent bonds. … The crosslinks may be formed using any suitable means, including using heat …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Martin, in order to use thermal crosslinking to form gel or polymeric matrix. One of ordinary skill in the art would have been motivated to make the modification for the benefit that precise and localized change of temperature can be conveniently achieved by HIFU, as evidenced by Thanou, so that gels of desired shape and size can be generated.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Levenberg and Thanou, in view of Tamayol et al (US 20200123485 A1; hereafter Tamayol).
With regard to Claim 9, Levenberg and Thanou disclose all the limitations of Claim 1 as discussed above, but do not clearly and explicitly disclose wherein the prepolymer material is bioadhesive; and
the gel formed from the prepolymer material is configured to seal an internal wound of the subject at the subcutaneous or deep tissue target location.
Tamayol in the same field of endeavor discloses wherein the prepolymer material is bioadhesive (Tamayol, Para 0080; “GelMA also adheres to various tissues if directly crosslinked on their surface.”); and
the gel formed from the prepolymer material is configured to seal an internal wound of the subject at the subcutaneous or deep tissue target location (Tamayol, Para 0015; “The hydrogel formulation has a composition effective to generate, upon the curing, a scaffold structure in the situs to facilitate muscle hypertrophy and/or new muscle fibers in the situs.”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Tamayol, in order to form bio-adhesive gel to seal an internal wound. One of ordinary skill in the art would have been motivated to make the modification for the benefit of using the method for sealing internal wound or tissue repair in a non-invasive way.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Levenberg and Thanou, in view of Park et al (US 20150064114 A1; hereafter Park).
With regard to Claim 13, Levenberg and Thanou disclose all the limitations of Claim 12 as discussed above, but do not explicitly and clearly disclose wherein the imaging device comprises an ultrasound imaging device.
Park in the same field of endeavor discloses wherein the imaging device comprises an ultrasound imaging device (Park, Para 0025; “Imaging technologies may guide the administration HIFU, and thus HIFU may be classified, e.g., as ultrasound-guided HIFU …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Park, in order to use ultrasound to capture an image of the target location. One of ordinary skill in the art would have been motivated to make the modification for the benefit of monitoring the polymerization process in real time to achieve the desired outcome.
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Levenberg and Thanou, in view of Kim et al (US 20200061904 A1; hereafter Kim).
With regard to Claim 15, Levenberg and Thanou disclose all the limitations of Claim 14 as discussed above, but do not clearly and explicitly disclose wherein:
the bioprinting device comprises an array of HIFU transducers including the one or more HIFU transducers; and
the controller is configured to cause the HIFU transducers of the array of HIFU transducers to operate in an order associated with the predetermined trajectory.
Kim in the same field of endeavor discloses wherein:
the bioprinting device comprises an array of HIFU transducers including the one or more HIFU transducers (Kim, Para 0022; “the ultrasound transducer may include a plurality of 2-dimensional array units, each array unit may include a plurality of single integrated ultrasound devices arranged in rows and columns”. Para 0047; “The ultrasound transducer T refers to a sound source for focusing ultrasound onto a target focal point desired by a user with a desired intensity.” Para 0075; “High-intensity focused ultrasound may be used …” The disclosure shows that the transducer can be adjusted by a user to a desired intensity, and be high-intensity focused ultrasound.); and
the controller is configured to cause the HIFU transducers of the array of HIFU transducers to operate in an order associated with the predetermined trajectory (Kim, Para 0053; “3D printing may be performed by electrically controlling the 2-dimensional array unit.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Kim, in order to include an array of HIFU transducers and use a controller to cause the transducers to operate in an order. One of ordinary skill in the art would have been motivated to make the modification for the benefit of printing the implant with a higher speed (Kim, Para 0031; “… simultaneously focus ultrasound onto a plurality of target focal points using a plurality of ultrasound transducers, thereby producing an object at a higher speed than a deposition 3D printer …”).
With regard to Claim 16, Levenberg and Thanou disclose all the limitations of Claim 14 as discussed above, but do not clearly and explicitly disclose wherein:
the bioprinting device comprises a motor configured to position the one or more HIFU transducers in relation to the subcutaneous or deep tissue target location; and
the controller is configured to control the motor to position the one or more HIFU transducers to transmit, along the predetermined trajectory, the HIFU radiation to the subcutaneous or deep tissue target location.
Kim in the same field of endeavor discloses wherein:
the bioprinting device comprises a motor configured to position the one or more HIFU transducers in relation to the subcutaneous or deep tissue target location (Kim, Para 0053; “in a large movement, the controller may adjust the target focal point by mechanically moving the ultrasound transducer (the single device or the array) …”); and
the controller is configured to control the motor to position the one or more HIFU transducers to transmit, along the predetermined trajectory, the HIFU radiation to the subcutaneous or deep tissue target location (Kim, Para 0050; “The controller 10 is a combination of hardware and/or software for controlling the ultrasound transducer T, and serves to focus ultrasound onto the target focal point desired by the user by independently controlling each single integrated ultrasound device T1 to TN that constitutes the ultrasound transducer or controlling the ultrasound array unit.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Kim, in order to use a motor to change position of a transducer and use a controller to control the motor. One of ordinary skill in the art would have been motivated to make the modification for the benefit of printing the implant to be any pattern desired by a user (Kim, Para 0075; “the user may select the relief or intaglio printing method by controlling the focused intensity of the ultrasound transducer through the setting of the controller.”).
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Levenberg and Thanou, further in view of Martin and Tamayol.
With regard to Claim 18, Levenberg and Thanou disclose all the limitations of Claim 11 as discussed above. Levenberg further discloses wherein:
the prepolymer material is loaded with drugs (Levenberg, Abstract; “the at least one additional component is one or more of at least one releasable drug within said acoustic-sensitive material and/or a plurality of cells within said acoustic-sensitive material.”), and the gel formed from the prepolymer material is configured to provide a controlled release of the drugs in the subcutaneous or deep tissue target location (Levenberg, Para 0083; “the implant is configured for controlled release of drugs …, polymerization by general ultrasound induction … in deep tissues...”); or
the prepolymer material is loaded with cells, and the gel formed from the prepolymer material is configured to encapsulate the cells for tissue regeneration in the subcutaneous or deep tissue target location (Levenberg, Para 0080; “by combining tissue-specific and/or therapeutic cells with the injected material, the invention serves as a platform for cell-based therapies for tissue regeneration and augmentation.”).
Levenberg and Thanou do not explicitly and clearly disclose wherein:
the prepolymer material is electrically conductive, and the gel formed from the prepolymer material is electrically conductive; or
the prepolymer material is bioadhesive, and the gel formed from the prepolymer material is configured to seal an internal wound of the subject at the subcutaneous or deep tissue target location.
Martin in the same field of endeavor discloses wherein the prepolymer material is electrically conductive (Martin, Para 0183; “These applications involve modification of the hydrogel composition so as to contain a conductive species.”), and the gel formed from the prepolymer material is electrically conductive (Martin, Para 0183; “… to render the hydrogel compositions of the invention electrically conductive …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Martin, in order to use electrically conductive prepolymer material to form electrically conductive gel. One of ordinary skill in the art would have been motivated to make the modification for the benefit of enabling physiological measurements that rely on electrical signals such as ECG for heart and EMG for muscles (Martin, Para 0183; “… the hydrogel composition may be used to attach a transcutaneous nerve stimulation electrode, an electrosurgical return electrode, or an EKG electrode to a patient's skin or mucosal tissue.”).
Tamayol in the same field of endeavor discloses wherein the prepolymer material is bioadhesive (Tamayol, Para 0080; “GelMA also adheres to various tissues if directly crosslinked on their surface.”), and the gel formed from the prepolymer material is configured to seal an internal wound of the subject at the subcutaneous or deep tissue target location (Tamayol, Para 0015; “The hydrogel formulation has a composition effective to generate, upon the curing, a scaffold structure in the situs to facilitate muscle hypertrophy and/or new muscle fibers in the situs.”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Levenberg and Thanou, as suggested by Tamayol, in order to form bio-adhesive gel to seal an internal wound. One of ordinary skill in the art would have been motivated to make the modification for the benefit of using the method for sealing internal wound or tissue repair in a non-invasive way.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Martin, in view of Thanou.
With regard to Claim 19, Martin discloses a biopolymer mixture for in vivo bioprinting (Martin, Para 0129; “Provided herein are scaffold complexes suitable for use medical devices that are incorporated into a tissue of a human subject to whom the complexes are administered, e.g., by injection or implantation.”), the biopolymer mixture comprising:
a thermal crosslinking agent (Martin, Para 0185; “For thermal crosslinking, a free radical polymerization initiator is used, and can be any of the known free radical-generating initiators conventionally used in vinyl polymerization.”); and
a prepolymer material configured to form into a gel when exposed to heat and the thermal crosslinking agent (Martin, Para 0184; “the polymers of the gel/hydrogels of the invention may be covalently crosslinked.”; Para 0185; “The temperature for thermally crosslinking will depend on the actual components …”).
Martin does not clearly and explicitly disclose the mixture comprising:
a contrast agent configured to enhance an image of the mixture; and
thermosensitive carrier particles configured to encapsulate agent and release the agent in response to a temperature increase.
Thanou in the same field of endeavor discloses disclose the mixture comprising:
a contrast agent configured to enhance an image (Thanou, Para 0082; “the API and/or the delivery system (particles) thus preferably comprise a label, or an imaging and/or contrast agent.”) of the mixture; and
thermosensitive carrier particles configured to encapsulate agent (Thanou, Abstract; “controlled release of the drug, previously encapsulated in thermo-sensitive (lipid nano)particles”) and release the agent in response to a temperature increase (Thanou, Para 0237; “The lipid nanoparticles may also show an improved release, for example in terms of reduced time taken for content to be released and/or increased amount of content released, at the critical temperatures described above, i.e. from 39.0°C. to 45.0°C …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Martin, as suggested by Thanou, in order to include an imaging contrast agent in the mixture and to include thermosensitive carrier particles to carry crosslinking agent and to release the agent when heated. One of ordinary skill in the art would have been motivated to make the modification for the benefit of ensuring the mixture to be delivered to the target location precisely thus achieving the desired therapeutic effect (Thanou, Para 0400; “Lipid nanoparticles (LNPs) of the present invention designed for heat triggered local controlled drug release in target tumours, that are also equipped with imaging probes for the real time/diagnostic imaging of drug delivery from point of administration to target …”), and achieving precisely-controlled release of agent at a temperature level that can be efficiently achieved and is safe for human body (Thanou, Para 0037; “The (application of the) ultrasound may cause (preferably controlled or sustained) release of the API, preferably from the drug delivery system (e.g. liposome or particles), in the body e.g. at or near a target site.”; Para 0040; “Preferably, the temperature of the tissue or desired body part is raised or increased to 39° C. to 42°C.”).
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Martin and Thanou, in view of Bassett.
With regard to Claim 20, Martin and Thanou disclose all the limitations of Claim 19 as discussed above, but do not explicitly and clearly disclose wherein the contrast agent is mixed into the prepolymer material.
Bassett in the same field of endeavor discloses wherein the contrast agent is mixed into the prepolymer material (Bassett, Para 0046; “one or both crosslinkable precursor solutions may contain contrast agents or other means for visualizing the hydrogel implant.”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Martin and Thanou, as suggested by Bassett, in order to mix a contrast agent into the prepolymer material. One of ordinary skill in the art would have been motivated to make the modification for the benefit of ensuring the prepolymer material to be injected to the correct target location and with the correct amount prior to the polymerization process (Bassett, Para 0137; “The presence of the visualization agent in application may enable the user to detect when the cavity has been sufficiently filled with material through the presence of excess exiting the target cavity.”).
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant’s disclosure. Mammadov (AU 2018201765 A1) teaches 3D bioprinting process using HIFU technology.
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/L.Z./Examiner, Art Unit 3798
/PASCAL M BUI PHO/Supervisory Patent Examiner, Art Unit 3798