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 .
Response to Amendment
The amendment filed on 07/08/2026 has been entered. Claims 1, 4, 6-11, 13, 15-16 and 18-19 have been amended. Claims 2, 5, 12, 14, 17 and 20-21 have been cancelled. Claims 22-27 are newly added. Claims 1, 3-4, 6-11, 13, 15-16, 18-19 and 22-27 remain pending.
Response to Arguments
In Remarks, Pages 9-10, regarding Claims 1 and 11, Applicant argues that neither Levenberg nor Thanou discloses features of transmitting radiation at a predetermined transducer power and printing speed, and of forming a gel pattern having a predetermined line width at a subcutaneous or deep target location. Examiner respectfully disagrees. Levenberg discloses controlling polymerization levels by changing ultrasound exposure time and/or intensity (Levenberg, Para 0085, Para 0092), and discloses printing the injected mixture according to a CAD model (Levenberg, Para 0096). Such a disclosed CAD model predetermines all the geometry and dimensions of a mixture to be printed.
In Remarks, Page 10, regarding Claims 1 and 11, Applicant argues that neither Levenberg nor Thanou discloses the feature of causing thermosensitive carrier particles to increase in temperature, which further causes release of crosslinking agent. Examiner respectfully disagrees. Thanou discloses heating thermosensitive particles to cause release of drug or agent (Thanou, Para 0072). Applicant argues that Thanou is not directed to bioprinting techniques. However, all of Thanou, Levenberg and Application are directed to a same procedure of delivering drug or agent into body using carrier particles and then releasing the drug or agent at a target tissue site. Therefore, one of ordinary skill in the art would modify Levenberg with Thanou.
In Remarks, Page 10, regarding Claims 1 and 11, Applicant argues that neither Levenberg nor Thanou discloses the features of mixing a contrast agent into prepolymer material, and of capturing contrast enhanced images before and during gelation, and Basset discloses contrast agent in precursor solutions but does not disclose of the feature of capturing contrast enhanced images before and during gelation. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed in section of 35 USC 103 below, the combination of Levenberg, Thanou and Basset teaches the claimed feature.
In Remarks, Page 11, regarding Claim 19, Applicant argues that neither Levenberg nor Thanou discloses the features of using a thermosensitive carrier particle that encapsulates crosslinking agent, and of such particles being present in an amount of 32 wt.% to 63 wt.% in the mixture. As discussed above, Levenberg and Thanou are directed to a same technology of using carrier particles to deliver drug or agent into human body, and the two references combine to teach the feature of thermosensitive carrier particles encapsulating crosslinking agent. With regard to the newly added feature of the particles being present in an amount of 32 wt.% to 63 wt.% in the mixture, Examiner has identified a new reference Mumcuoglu (US 20210106726 A1) for disclosing the feature.
Claim Objections
Claim 22 is objected to because of the following informalities:
Claim 22, Line 2, “thermosensitive particles” should be changed to “thermosensitive carrier particles”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19 and 22-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 19 and 24-25 recite “the thermosensitive carrier particles … present in an amount of 32 wt.% to 63 wt.% in the biopolymer mixture”. Specification does not contain any detail of the claimed feature.
Claims 22-23 are also rejected under 35 U.S.C. 112(a) because they inherit the deficiencies of the claim(s) they respectively depend upon.
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, 10-11,13 and 26-27 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), further in view of Bassett et al (US 20220143276 A1; hereafter Bassett).
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.”);
transmitting with one or more focused ultrasound transducers of a bioprinting device (Levenberg, Para 0113; “… focused ultrasound (FUS) for 3D printing/bioprinting”), via transcutaneous application, focused ultrasound radiation to the subcutaneous or deep tissue target location along a predefined trajectory at a predetermined transducer power and printing speed (Levenberg, Para 0085; “… 3D printing in the body is performed in deep locations in the body … polymerization levels are controlled by changing ultrasound exposure time and/or intensity …”. Para 0092 provides an example; “Applying ultrasound induction using low frequency transducers (from about 30 kHz to about 1000 kHz) for from about 5 seconds to about 30 seconds in order to reach polymerization with an intensity range of from about 0.5 Watt/cm to about 2.2 Watt/cm.”) to form a gel pattern having a predetermined line width at the subcutaneous or deep tissue target location (Levenberg, Para 0096; “… for in-situ noninvasive printing the acoustic-sensitive mixture is injected into the area of interest followed with local patterning by applying focused ultrasound induction according to the CAD model, layer by layer, until polymerizing the full model shape.” The disclosed CAD model defines all the predetermined dimensions of the printed gel), the focused ultrasound radiation configured to cause the carrier particles to release at least some of the crosslinking agent (calcium), the released crosslinking agent configured to cause gelation of the prepolymer material to form the gel pattern (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”); and
capturing, using an imaging device, one or more images of the biopolymer mixture before gelation and during gelation of the prepolymer material (Levenberg, Para 0101; “FIG. 1A shows a rapid polymerization of acoustic-sensitive PEG-DA based material—before induction (1Ai), during 1 MHz US induction (1Aii), and post polymerization (1Aiii and 1Aiv)”; Para 0102; “FIG. 2A (i-iii) shows bulk hydrogel formation under 5, 10 and 30 second of 1 MHz US exposure, respectively.” Both the disclosed Fig. 1A and Fig. 2A show serially acquired images for monitoring gelation process).
Levenberg does not explicitly and clearly disclose
the carrier particles being thermosensitive,
the focused ultrasound radiation configured to cause the thermosensitive carrier particles to increase in temperature, the increase in temperature configured to cause the thermosensitive carrier particles to release agent,
capturing images after the biopolymer mixture is delivered to the subcutaneous or deep tissue target location,
the captured images being enhanced with contrast agent, and
a contrast agent mixed into the prepolymer material.
Thanou in the same field of endeavor discloses
the carrier particles being thermosensitive (Thanou, Para 0235; “the lipid nanoparticle of the present invention is thermosensitive, i.e. undergoes a phase transition at a particular temperature.”),
the focused ultrasound radiation configured to cause the thermosensitive carrier particles to increase in temperature, the increase in temperature configured to cause the thermosensitive carrier 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),
capturing images after the biopolymer mixture is delivered to the subcutaneous or deep tissue target location (Thanou, Fig. 7 shows images acquired after TNP is delivered in deep tissue target location), and
the captured images being enhanced with contrast agent (Thanou, Para 0106; “FIG. 7: Changes in thermosensitive liposome (TNP) pharmacokinetics on FUS treatment to the tumour on the right haunch, 30 min after injection (200 μL; tail i.v.). Imaging was carried out as before for XL750 and by monitoring intrinsic topotecan fluorescence by excitation at 455 nm and emission collected in 10 nm steps over 500-720 nm.” Both the disclosed XL750 and intrinsic topotecan fluorescence can be regarded as contrast agents for imaging).
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 focused ultrasound to release agent from thermosensitive carrier particles and to monitor administered agent inside body with contrast-enhanced imaging. One of ordinary skill in the art would have been motivated to make the modification of using thermosensitive particles 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)”), and to make the modification of imaging administered agent for the benefit of ensuring proper distribution and uptake of administered agent and therefore therapeutic effect (Thanou, Para 0542; “NIRF imaging allows us to monitor the resulting changes in distribution and tumour uptake of a labelled material in real-time.”).
Levenberg and Thanou as discussed above do not clearly and explicitly disclose a contrast agent mixed into the prepolymer material.
Bassett in the same field of endeavor discloses 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.”).
With regard to Claim 3, Levenberg, Thanou and Bassett 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, Thanou and Bassett 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 focused ultrasound 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, Thanou and Bassett disclose the method of Claim 1, but as discussed above do not disclose wherein the focused ultrasound radiation is configured to heat the subcutaneous or deep tissue target location to between 39°C and 43°C.
Thanou further discloses wherein the focused ultrasound 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, Thanou and Bassett, 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, Thanou and Bassett 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 pattern is configured 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, Thanou and Bassett disclose the method of Claim 1. Levenberg further discloses wherein transmitting with the bioprinting device, via transcutaneous application, the focused ultrasound 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 focused ultrasound 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.”);
a bioprinting device comprising a controller (Levenberg, Page 7; “Example 189. The system according to any one of examples 169-188, wherein said implant comprises a dedicated form when focused ultrasound is applied to said implant according to a predetermined CAD model layer.” The disclosed system has the function of applying focused ultrasound according to a predetermined CAD layer, so necessarily corresponds to or comprises the claimed controller) and one or more focused ultrasound transducers (Levenberg, Para 0113; “… focused ultrasound (FUS) for 3D printing/bioprinting”), the controller configured to cause the one or more transducers configured to transmit, via transcutaneous application, focused ultrasound radiation to a subcutaneous or deep tissue target location of a subject along a predefined trajectory at a predetermined transducer power and printing speed (Levenberg, Para 0085; “… 3D printing in the body is performed in deep locations in the body … polymerization levels are controlled by changing ultrasound exposure time and/or intensity …”. Para 0092 provides an example; “Applying ultrasound induction using low frequency transducers (from about 30 kHz to about 1000 kHz) for from about 5 seconds to about 30 seconds in order to reach polymerization with an intensity range of from about 0.5 Watt/cm to about 2.2 Watt/cm.”) to form a gel pattern having a predetermined line width at the subcutaneous or deep tissue target location (Levenberg, Para 0096; “… for in-situ noninvasive printing the acoustic-sensitive mixture is injected into the area of interest followed with local patterning by applying focused ultrasound induction according to the CAD model, layer by layer, until polymerizing the full model shape.” The disclosed CAD model defines all the predetermined dimensions of the printed gel), and the focused ultrasound radiation configured to cause the carrier particles to release at least some of the crosslinking agent (calcium), the released crosslinking agent configured to cause gelation of the prepolymer material to form the gel pattern (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”), and
an imaging device configured to capture one or more images of the biopolymer mixture before gelation and during gelation of the prepolymer material (Levenberg, Para 0101; “FIG. 1A shows a rapid polymerization of acoustic-sensitive PEG-DA based material—before induction (1Ai), during 1 MHz US induction (1Aii), and post polymerization (1Aiii and 1Aiv)”; Para 0102; “FIG. 2A (i-iii) shows bulk hydrogel formation under 5, 10 and 30 second of 1 MHz US exposure, respectively.” Both the disclosed Fig. 1A and Fig. 2A show serially acquired images for monitoring gelation process).
Levenberg does not explicitly and clearly disclose
the carrier particles being thermosensitive,
the focused ultrasound radiation configured to cause the thermosensitive carrier particles to increase in temperature, the increase in temperature configured to cause the thermosensitive carrier particles to release agent,
capturing images after the biopolymer mixture is delivered to the subcutaneous or deep tissue target location,
the captured images being enhanced with contrast agent, and
a contrast agent mixed into the prepolymer material.
Thanou in the same field of endeavor discloses
the carrier particles being thermosensitive (Thanou, Para 0235; “the lipid nanoparticle of the present invention is thermosensitive, i.e. undergoes a phase transition at a particular temperature.”),
the focused ultrasound radiation configured to cause the thermosensitive carrier particles to increase in temperature, the increase in temperature configured to cause the thermosensitive carrier 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),
capturing images after the biopolymer mixture is delivered to the subcutaneous or deep tissue target location (Thanou, Fig. 7 shows images acquired after TNP is delivered in deep tissue target location), and
the captured images being enhanced with contrast agent (Thanou, Para 0106; “FIG. 7: Changes in thermosensitive liposome (TNP) pharmacokinetics on FUS treatment to the tumour on the right haunch, 30 min after injection (200 μL; tail i.v.). Imaging was carried out as before for XL750 and by monitoring intrinsic topotecan fluorescence by excitation at 455 nm and emission collected in 10 nm steps over 500-720 nm.” Both the disclosed XL750 and intrinsic topotecan fluorescence can be regarded as contrast agents for imaging).
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 focused ultrasound to release agent from thermosensitive carrier particles and to monitor administered agent inside body with contrast-enhanced imaging. One of ordinary skill in the art would have been motivated to make the modification of using thermosensitive particles 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)”), and to make the modification of imaging administered agent for the benefit of ensuring proper distribution and uptake of administered agent and therefore therapeutic effect (Thanou, Para 0542; “NIRF imaging allows us to monitor the resulting changes in distribution and tumour uptake of a labelled material in real-time.”).
Levenberg and Thanou as discussed above do not clearly and explicitly disclose a contrast agent mixed into the prepolymer material.
Bassett in the same field of endeavor discloses 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.”).
With regard to Claim 13, Levenberg, Thanou and Bassett disclose the system of Claim 11, but as discussed above do not explicitly and clearly disclose wherein the imaging device comprises an ultrasound imaging device.
Thanou further discloses wherein the imaging device comprises an ultrasound imaging device (Thanou, Para 0078; “Imaging may be based on ultrasound …”). 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, Thanou and Bassett, as further suggested by Thanou, in order to use ultrasound to guide the procedure. 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.
With regard to Claim 26, Levenberg, Thanou and Bassett disclose the system of Claim 11, but as discussed above do not explicitly and clearly disclose wherein the contrast agent comprises gas vesicles.
Bassett further discloses wherein the contrast agent comprises gas vesicles (Bassett, Para 0113; “… it is possible to add visualization agents, such as microbubbles to enable visualization under ultrasound …”). 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, Thanou and Bassett, as further suggested by Bassett, in order to use gas vesicles as contrast agent. One of ordinary skill in the art would have been motivated to make the modification for the benefit of gas vesicles or microbubbles being the most reliable contrast agent for contrast-enhanced ultrasound imaging.
With regard to Claim 27, Levenberg, Thanou and Bassett disclose the system of Claim 11, but as discussed above do not explicitly and clearly disclose wherein the one or more images captured by the imaging device are used to guide the bioprinting device when transmitting the focused ultrasound radiation.
Bassett further discloses wherein the one or more images captured by the imaging device are used to guide the bioprinting device in the gelation procedure (Bassett, Para 0106; “The completeness of the hydrogel delivery can be confirmed using ultrasound.”; Para 0201; “FIG. 19 shows ultrasound images for one patient prior to the ablation procedure (left image) and after installation of the hydrogel (right image). … The previously empty uterine cavity can be seen to have been filled by 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, Thanou and Bassett, as further suggested by Bassett, in order to use images to guide or confirm the gelation process. One of ordinary skill in the art would have been motivated to make the modification for the benefit of achieving expected treatment outcome by visually ensuring an implant of a desired shape/size to be formed at desired location.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Levenberg, Thanou and Bassett, in view of Martin et al (US 20190060516 A1; hereafter Martin).
With regard to Claim 8, Levenberg, Thanou and Bassett disclose the method of Claim 1, but do not explicitly and clearly disclose wherein:
the prepolymer material is electrically conductive; and
the gel pattern 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 pattern 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, Thanou and Bassett, 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.”).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Levenberg, Thanou and Bassett, in view of Tamayol et al (US 20200123485 A1; hereafter Tamayol).
With regard to Claim 9, Levenberg, Thanou and Bassett disclose the method of Claim 1, but do not clearly and explicitly disclose wherein:
the prepolymer material is bioadhesive; and
the gel pattern 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 pattern 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, Thanou and Bassett, 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.
Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Levenberg, Thanou and Bassett, in view of Kim et al (US 20200061904 A1; hereafter Kim).
With regard to Claim 15, Levenberg, Thanou and Bassett disclose the system of Claim 14, but do not clearly and explicitly disclose wherein:
the bioprinting device comprises an array of focused ultrasound transducers including the one or more focused ultrasound transducers; and
the controller is configured to cause the focused ultrasound transducers of the array of focused ultrasound 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 focused ultrasound transducers including the one or more focused ultrasound 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 focused ultrasound transducers of the array of focused ultrasound 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, Thanou and Bassett, as suggested by Kim, in order to include an array of focused ultrasound 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, Thanou and Bassett disclose the system of Claim 11, but do not clearly and explicitly disclose wherein:
the bioprinting device comprises a motor configured to position the one or more focused ultrasound 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 focused ultrasound transducers to transmit, along the predetermined trajectory, the focused ultrasound 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 focused ultrasound 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 focused ultrasound transducers to transmit, along the predetermined trajectory, the focused ultrasound 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, Thanou and Bassett, 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, Thanou and Bassett, further in view of Martin and Tamayol.
With regard to Claim 18, Levenberg, Thanou and Bassett disclose the system of Claim 11. 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 pattern 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 pattern 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, Thanou and Bassett as discussed above do not explicitly and clearly disclose wherein:
the prepolymer material is electrically conductive, and the gel pattern is electrically conductive; or
the prepolymer material is bioadhesive, and the gel pattern 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 pattern 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, Thanou and Bassett, 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 pattern 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, Thanou and Bassett, 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 Mumcuoglu et al (US 20210106726 A1; hereafter Mumcuoglu), in view of Thanou, further in view of Bassett.
With regard to Claim 19, Mumcuoglu discloses a biopolymer mixture for in vivo bioprinting (Mumcuoglu, Para 0001; “… a hydrogel which may be used particularly for bone repair …”; Para 0003; “a hydrogel comprising: … an alginate … microparticles comprising an inorganic calcium compound …”. The disclosed hydrogel corresponds to the claimed biopolymer mixture), the biopolymer mixture comprising:
a prepolymer material (alginate) configured to form into a gel in the presence of a crosslinking agent (calcium) (Mumcuoglu, Para 0037; “Preferably at least a part of the calcium crosslinks the carboxy groups present in the alginate.”); and
carrier particles encapsulating the crosslinking agent, the carrier particles present in an amount of 32 wt.% to 63 wt.% in the biopolymer mixture (Mumucuoglu, Para 0028; “The hydrogel preferably comprises the microparticles in an amount of 1 to 20 w/v % …”; Para 0019; “The hydrogels of the present invention preferably comprise alginate in an amount of 0.5 to 5 w/v % …”. With the disclosed weight/volume percent of microparticles and of alginate, the weight percentage of microparticles in the mixture of microparticles and alginate has a range that covers the claimed 32 wt.% - 63 wt.%).
Mumcuoglu does not clearly and explicitly disclose:
the carrier particles being thermosensitive, and configured to release agent in response to a temperature increase; and
a contrast agent mixed into the prepolymer material, the contrast agent configured to enhance an image of the biopolymer mixture.
Thanou in the same field of endeavor discloses the carrier particles being thermosensitive (Thanou, Abstract; “controlled release of the drug, previously encapsulated in thermo-sensitive (lipid nano)particles”), and configured to release 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 Mumucuoglu, as suggested by Thanou, in order 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 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.”).
Mumucuoglu and Thanou as discussed above do not clearly and explicitly disclose a contrast agent mixed into the prepolymer material, the contrast agent configured to enhance an image of the biopolymer mixture.
Bassett in the same field of endeavor discloses 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.”), the contrast agent configured to enhance an image of the biopolymer mixture (Bassett, Para 0113-0116 discloses a plurality of contrast agents for image enhancement). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Mumucuoglu 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 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Mumcuoglu, Thanou and Bassett, in view of Levenberg.
With regard to Claim 22, Mumcuoglu, Thanou and Bassett disclose the biopolymer mixture of Claim 19, but as discussed above do not explicitly and clearly disclose wherein:
the thermosensitive particles comprise thermosensitive liposomes; and
the crosslinking agent comprises calcium ions encapsulated by the thermosensitive liposomes, the calcium ions configured to enable ionic gelation of the prepolymer material.
Thanou further discloses the thermosensitive particles comprise thermosensitive liposomes (Thanou, Para 0090; “the liposome is thermosensitive”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Mumcuoglu, Thanou and Bassett, as further suggested by Thanou, in order to use thermosensitive carrier particles. One of ordinary skill in the art would have been motivated to make the modification for the benefit of 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.”).
Mumcuoglu, Thanou and Bassett as discussed above do not explicitly and clearly disclose wherein the crosslinking agent comprises calcium ions encapsulated by the liposomes, the calcium ions configured to enable ionic gelation of the prepolymer material.
Levenberg in the same field of endeavor discloses wherein the crosslinking agent comprises calcium ions encapsulated by the liposomes, the calcium ions configured to enable ionic gelation of the prepolymer material (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”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Mumcuoglu, Thanou and Bassett, as suggested by Levenberg, in order to use calcium to enable ionic gelation. One of ordinary skill in the art would have been motivated to make the modification for the benefit of proven capability of crosslinking negative-charged prepolymer materials.
With regard to Claim 23, Mumcuoglu, Thanou, Bassett and Levenberg disclose the biopolymer mixture of Claim 22, but as discussed above do not explicitly and clearly disclose wherein the contrast agent comprises gas vesicles.
Bassett further discloses wherein the contrast agent comprises gas vesicles (Bassett, Para 0113; “… it is possible to add visualization agents, such as microbubbles to enable visualization under ultrasound …”). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Mumcuoglu, Thanou, Bassett and Levenberg, as further suggested by Bassett, in order to use gas vesicles as contrast agent. One of ordinary skill in the art would have been motivated to make the modification for the benefit of gas vesicles or microbubbles being the most reliable contrast agent for contrast-enhanced ultrasound imaging.
With regard to Claim 24, Levenberg, Thanou and Bassett disclose the method of Claim 1, but do not explicitly and clearly disclose wherein the thermosensitive carrier particles are present in an amount of 32 wt.% to 63 wt.% in the biopolymer mixture.
Mumcuoglu in the same field of endeavor discloses wherein the thermosensitive carrier particles are present in an amount of 32 wt.% to 63 wt.% in the biopolymer mixture (Mumcuoglu, Para 0028; “The hydrogel preferably comprises the microparticles in an amount of 1 to 20 w/v % …”; Para 0019; “The hydrogels of the present invention preferably comprise alginate in an amount of 0.5 to 5 w/v % …”. With the disclosed weight/volume percentage of microparticles and of alginate, the weight percentage of microparticles in the mixture of microparticles and alginate has a range that covers the claimed 32 wt.% - 63 wt.%). 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, Thanou and Bassett, as suggested by Mumcuoglu, in order to include relatively comparable amounts of calcium-based cross-linker and pre-polymer. One of ordinary skill in the art would have been motivated to make the modification for the benefit of forming a stable gel without significant residue of either of the ingredients that could potentially affect normal characteristics of the formed gel.
With regard to Claim 25, Levenberg, Thanou and Bassett disclose the system of Claim 11, but do not explicitly and clearly disclose wherein the thermosensitive carrier particles are present in an amount of 32 wt.% to 63 wt.% in the biopolymer mixture.
Mumcuoglu in the same field of endeavor discloses wherein the thermosensitive carrier particles are present in an amount of 32 wt.% to 63 wt.% in the biopolymer mixture (Mumcuoglu, Para 0028; “The hydrogel preferably comprises the microparticles in an amount of 1 to 20 w/v % …”; Para 0019; “The hydrogels of the present invention preferably comprise alginate in an amount of 0.5 to 5 w/v % …”. With the disclosed weight/volume percentage of microparticles and of alginate, the weight percentage of microparticles in the mixture of microparticles and alginate has a range that covers the claimed 32 wt.% - 63 wt.%). 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, Thanou and Bassett, as suggested by Mumcuoglu, in order to include relatively comparable amounts of calcium-based cross-linker and pre-polymer. One of ordinary skill in the art would have been motivated to make the modification for the benefit of forming a stable gel without significant residue of either of the ingredients that could potentially affect normal characteristics of the formed gel.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEI ZHANG whose telephone number is (571)272-7172. The examiner can normally be reached Monday-Friday 8am-5pm E.T..
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Pascal Bui-Pho can be reached at (571) 272-2714. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/L.Z./ Examiner, Art Unit 3798
/PASCAL M BUI PHO/ Supervisory Patent Examiner, Art Unit 3798
Prosecution Insights