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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5/15/2026 has been entered.
Status of Claims
Receipt of Remarks/Amendments filed on 5/15/2026 is acknowledged. Claims 1-2, 5-14, 17-29 and 31-42 are pending in this application. Claims 25-29, 31-36 and 41-42 are drawn to a non-elected group and are withdrawn. Claims 1-2, 5-14, 17-24, and 37-40 are currently under examination and the subject matter of the present Office Action.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Withdrawn Objections/Rejections
Applicant’s remarks/amendments with respect to the previous claim objections have been fully considered and are persuasive. The previous claim objections have been withdrawn due to the claim amendments.
Maintained Claim Objection(s) / Rejection(s)
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 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5-9, 13-14, 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Manaspon et al. (Annals of Biomedical Engineering, Vol. 45, No. 12, December 2017 (2017) pp. 2879–2887), hereinafter Manaspon, in view of Fabiilli et al. (Acta Biomater. 2013 July. 9(7): 7399-7409), hereinafter Fabiilli, and Suntornnond et al. (US 2020/0009298 A1), hereinafter Suntornnond.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Manaspon reports the use of low frequency, high intensity ultrasound to promote the spatial penetration of drug molecules away from the implant/injection site boundary upon release from injectable, phase inverting poly(lactic acid-co-glycolic acid) (PLGA) implants (Abstract). Manaspon teaches the preparation of the implants with the polymer solution in PBS placed at 37 °C and 80 rpm, and ultrasound at 2.2 W/cm2 applied daily, and the fluorescein released determined quantitatively (p. 2880, R. Col., bottom paragraph).
Manaspon described how an ultrasound unit (Omnisound 3000, Accelerated Care Plus Corp., Reno, NV) equipped with two collimating transducers was used to expose ultrasound wave to samples. 3 h after the implant was injected into the phantom, ultrasound was applied at either 0.7 or 2.2 W/cm2 intensity for 10 min, which reads on the d) claim feature in Claims 5 and 17 (p. 2880, R. Col., top paragraph).
Ascertainment of the difference between the prior art and the claims
(MPEP §2141.02)
Manaspon does not expressly teach the releasable additional component to be a drug. However, fluorescein was used as a mock drug (p. 2886, L. Col., 1st paragraph). Manaspon contemplates that coupled with increased local drug release, the acoustic radiation force interacting with the PLGA implants could result in increased drug release and penetration (p. 2886, conclusion paragraph)
Manaspon is silent on the cells in the acoustic-sensitive material. Fabiilli cures the deficiency of Manaspon. Fabiilli relays the use of biodegradable porous scaffolds in regenerative medicine as an adhesive substrate for the attachment of cells and/or the encapsulation of inductive proteins, e.g. growth factors, with applications in tissue regeneration etc. (Introduction, 1st paragraph; Discussion, 1st paragraph). Fabiilli teaches that non-invasive control of protein release from an implanted scaffold could improve the efficacy and safety of growth factor-based therapies, and how stimuli such as pH, proteases, electricity, light etc. is used to release the therapeutic agents. However, these external systems are unable to focus the triggering stimulus or interact with deep tissue implants (Introduction, 2nd paragraph). Fabiilli teaches that while most modifications to scaffold architecture are done prior to cell seeding and scaffold implantation, ultrasound is an externally applied stimulus capable of inducing “on-demand” release of growth factors and scaffold architecture modification. Fabiilli discloses the fabrication of fibrin gels and droplet-hydrogel composites using bovine fibrinogen (p. 4, Section 2.2). A calibrated single-element transducer was used to generate acoustic drop vaporization (ADV) within the gels; the scaffolds were exposed to ultrasound with the transducer moved to expose the entirety of each gel to ultrasound until vaporization was complete (p. 4, Section 2.3). The ultrastructural features of the fibrin scaffold were captured by imaging the fluorescence of AF647-tagged fibrinogen excited at 647 nm (p. 4, Section 2.3). After exposure, the hydrogel thickness, stiffness and viscoelastic properties were determined (p. 5, Section 2.5). Fabiilli teaches that ADV increased the stiffness of acoustic droplet–hydrogel composites; the complex shear modulus increased several fold following exposure to ultrasound (p. 10, 2nd paragraph). Fabiilli also teaches co-encapsulation of cells in the droplet-hydrogel composites, and cell-gel constructs were exposed to ultrasound treatment (p. 5, Section 2.7). Fabiilli contemplates that ADV-induced changes in hydrogel mechanical properties may have utility in directing the behavior of cells entrapped within, or migrating into, the composite materials, (p. 10, 2nd paragraph). Fabiilli also teaches that ultrasound in the range of 1-10 MHz can enhance the release of protein-based therapeutic (p. 9, 1st paragraph). Fabiilli concludes that its ADV hydrogel composite can function as drug delivery vehicle as well as modifier of scaffold architecture, and that encapsulated cells maintain viability (Conclusion).
Manaspon and Fabiilli are silent on the printing of the implant and the acoustic sensitive material comprising functional acrylate, diacrylate or methacrylate groups.
Suntornnond discloses a hydrogel composite comprising a Pluronic monocarboxylate poloxamer and a gelatin methacrylate peptide comprising crosslinkable moieties (Abstract; Claims 14 and 22). Suntornnond also teaches a bioshaping method using the hydrogel composite and a 3D network obtained by the method (Abstract). Suntornnond teaches that this 3D crosslinked network is implanted into a mammal’s body (Claim 46).
Suntornnond teaches bioprinting as a precision technology integrating living materials, motion control, computer- aided design (CAD) software and biomaterials with the aim to provide 3D tissue or organs for implantation, tissue models for drug-testing and cell-material interaction study [0005]. By using a 3D bioprinter, Suntornnond envisions that custom organs with patients' own cells would be used without immunologicalized issue.
Figs. 12A and 12D of Suntornnond shows the design of the tissue scaffold, the generation of support structure, creation of code files and models, and the printing process [0044]-[0047]. The hydrogel composite is shapeable at human body temperature, and able to support both cell proliferation and cell differentiation [0090]. Suntornnond understands the limitation of poloxamers, e.g. poor mechanical strength, coupled with their propensity to dissolve in aqueous environments, to be used as long - term structural support within a tissue scaffold [0095]. Suntornnond teaches modifying the poloxamer, which allows for an improved hydrogel composite, providing the advantages of the poloxamer described above while obliterating the shortcomings.
Suntornnond expressly teaches the synthesis of Pluronic-GelMA composite which utilizes modified Pluronic 127 and gelatin methacrylate to create the hydrogel composite for casting or printing (Examples 1-2). The printability of Plu-GelMA is dependent on Pluronic contents, i.e. the more Pluronic, the better the printability (Figs. 13A-13C; [00180]). This is because Pluronic is packed in micelles, which is easily flowable and structurally stable at a wide range of temperatures. Suntornnond teaches a Plu-GelMA with 2:1 ratio as model material for printing 3D. CAD was used for printing the vasculature-like structure (Example 4). Suntornnond teaches that printing may be performed as a single printing step where a three dimensional object may be obtained [0157].
L929 cells were seeded on the Plu-GelMA hydrogel composite, and Suntornnond shows that cells were able to attach and stay in the hydrogel (Example 7, Fig. 33). Plu – GelMA 2 : 1 achieved the highest cell number compared to other ratios; The L929 cells were able to attach onto the hydrogel composites and able to pack together when the cell hydrogel composite provides a good platform for cell attachment and proliferation [0181]. As such, Suntornnond teaches Pluronic - GelMA as the model material while Pluronic F127 is support material; with the Pluronic support material removed by using cold water [0180]-[0183].
Finding of prima facie obviousness Rational and Motivation
(MPEP 2142-2143)
Both Fabiilli and Manaspon teach implants comprising polymer material that are responsive to ultrasound. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine the teachings of Fabiilli and Manaspon and incorporate a plurality of cells to the implant of Manaspon as Fabiilli has taught that the implant scaffolds are useful for regenerative medicine, wherein the cells are attached or encapsulated in the scaffold to regenerate tissue. One would also modify the fluorescein mock drug of Manaspon, and replace it with a therapeutic, e.g. protein therapeutic taught by Fabiilli, which can be controlled in its release for improved efficacy and safety. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to improve upon the teachings of Manaspon, adding a plurality of cells for regeneration, and also substituting the polymer with that of Fabiilli to obtain additional implants with different composite materials. Therefore, the claimed invention of the instant application would have been obvious to one skilled in the art at the time of the invention. The known work in the field would have prompted variations of it for use in the same field based on design incentives or other market forces where the variations are predictable to one of ordinary skill in the art.
The teachings of Suntornnond is compatible with Manaspon. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine the references, and design a scaffold, prepare a model using CAD, and print the implant using Pluronic - GelMA as the model material while Pluronic F127 is support material per the teaching of Suntornnond to create a composite that is shapeable at human body temperature, and able to support both cell proliferation and cell differentiation, while overcoming the shortcomings of other poloxamer composites. One skilled in the art would have substituted the PLGA of Manaspon with the methacrylate-containing peptide of Suntornnond arriving at the instant claims with functional acrylate or diacrylate or methacrylate groups. One would have been motivated to do so because Suntornnond teaches Pluronic-GelMA which is suitable for bioprinting which is efficient and creates materials that are structurally stable at a wide range of temperatures. The ordinary artisan would have been motivated to substitute one known element for another to obtain predictable results. The known work in the field of implants would have prompted variations of it for use in the same field based on design incentives or other market forces where the variations are predictable to one of ordinary skill in the art.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to also use the implant bioprinting technique taught by Suntornnond in the method of Manaspon and Fabiilli, as bioprinting is a precision technology, which could offer the use of patients’ own cell in creating 3D tissue or organs for implantation.
With respect to the instantly claimed limitation wherein said acoustic sensitive material hardens when exposed to ultrasound emissions, and the functional acrylate, diacrylate or methacrylate groups enable for acoustic sensitive material to harden, as discussed supra, the combination of Manaspon, Fabiilli and Suntornnond teach an acoustic sensitive material with functional methacrylate group. Therefore, the composition comprising acoustic sensitive material with functional methacrylate group would necessarily harden when exposed to ultrasound emission. Because the prior art composition is the same as the composition claimed, the composition must necessarily have the characteristics claimed in Claims 1 and 13. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter, which there is reason to believe inherently includes functions that are newly cited, or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter to be shown in the prior art does not possess the characteristic relied on” (205 USPQ 594).
Therefore, the claimed invention of the instant application would have been obvious to one skilled in the art at the time of the invention. The known work in the field would have prompted variations of it for use in the same field based on design incentives or other market forces where the variations are predictable to one of ordinary skill in the art.
Claims 10-12 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Manaspon et al. (Annals of Biomedical Engineering, Vol. 45, No. 12, December 2017 (2017) pp. 2879–2887), in view of Fabiilli et al. (Acta Biomater. 2013 July. 9(7): 7399-7409), and Suntornnond et al. (US 2020/0009298 A1) as applied to Claim 1-2, 5-9, 13-14, 17-21 above, and in view of Bao et al. (Biomacromolecules 14.6 (2013): 1971-1979.), hereinafter Bao, and Schillemans et al. (Macromolecules 2006, 39, 5885-5890), hereinafter Schillemans.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Manaspon, Fabiilli and Suntornnond have been set forth supra.
Manaspon teaches that different carriers and strategies capitalize on the mechanical forces of ultrasound for drug delivery to tumors including drug loaded nanoparticles or liposomes (p. 2885, L. Col., 1st paragraph). Manaspon teaches that ultrasound had been used to control release of insulin from a gel-like network system consisting of alginate-coated nanoparticles and chitosan coated nanoparticles (p. 2880, L. Col., 2nd paragraph).
Fabiilli also teaches that liposome-microbubble-hydrogel composites treated with low frequency (20 kHz) ultrasound release a model payload from the liposome and afford impressive control of release kinetics (p. 9, 1st paragraph).
Ascertainment of the difference between the prior art and the claims
(MPEP §2141.02)
The above cited references are silent on the solution of prepolymer and crosslinker-loaded microcapsules.
Bao describes the ultrasound-modulated shape memory and payload release effects in a biodegradable cylindrical rod made of chitosan-functionalized PLGA microspheres (Title). Bao recognizes that minimally invasive implants and/or scaffold integrated with multiple functionalities are of interest in the clinical settings, and teaches the preparation of chitosan (CTS) functionalized poly(lactic-co-glycolic acid) (PLGA) microspheres containing lysozyme (Lyz) payload by sintering the composite microspheres in a mold; High-intensity focused ultrasound (HIFU) was used to enable shape memory effect and release the encapsulated Lyz (Abstract). Bao teaches manipulation of the acoustic power and insonation duration. Bao teaches CTS anchored to the microsphere surface by adsorption forming physical cross-linking between CTS and PLGA macromolecular chains.
Schillemans teaches the synthesis of bilayer-coated nanogels by crosslinking acrylamide (AA) and bisacrylamide (BA) monomers inside liposomes, stating that their convenient and versatile method of nanogel synthesis allow incorporation of membrane proteins in the bilayer and the use of monomers that readily pass the lipid membrane (Abstract). Schillemans cites an alternative, less commonly used approach for hydrogel particle synthesis, comprising the used of the internal compartment of lipid vesicles (liposomes) for the preparation of hydrogel particles, which allows good control over particle size and size distribution, and is compatible with biological macromolecules (p. 5885, L. Col.). Schillemans relays that liposomes formed in AA/BA solution contain monomer both in the inner compartment and in the outer liquid, and that in order to produce nanoparticles within the liposomal reactor, it is important to restrict the hydrogel formation of the monomers to the inner compartment of the liposomes by (1) dilution of the monomers to a concentration too low for hydrogel formation and more preferably, by (2) inhibition of free radical polymerization to prevent leaking of the monomer and the cross-linker out of the liposomes (p. 5887, R. Col., last paragraph).
Finding of prima facie obviousness Rational and Motivation
(MPEP 2142-2143)
Manaspon comprehends that there are different strategies to capitalize on the mechanical forces of ultrasound for drug delivery, and contemplate drug loaded nanoparticles or liposomes. Fabiilli has also taught release a model payload from the liposome by low frequency (20 kHz) ultrasound. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to incorporate the teachings of Bao and create a composite that has ultrasound-modulated shape memory and payload release effects comprising microsphere to release the cargo by ultrasound. This is a situation where elements of references are combined in a predictable manner so that the elements retain their function. As such, the artisan would enjoy a reasonable expectation of success. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine the teachings of Schillemans and create the microsphere, which the Examiner interprets to be the same as microcapsules, by crosslinking monomers inside liposomes which allows good control over particle size and size distribution, wherein there are monomers in solution externally and internally together with the crosslinker. Hence, one with ordinary skill in the art would have applied the known technique taught by Schillemans and apply it to the teachings of Manaspon, Fabiilli and Bao, to obtain an acoustic sensitive material comprising the monomer (prepolymer) and crosslinker inside the liposome, which would be released to start the polymerization process upon exposure to ultrasound. Applying a known technique to a known method ready for improvement to yield predictable results is the rationale supporting obviousness. See MPEP § 2143 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007).
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 37-40 are rejected under 35 U.S.C. 103 as being unpatentable over Manaspon et al. (Annals of Biomedical Engineering, Vol. 45, No. 12, December 2017 (2017) pp. 2879–2887), in view of Fabiilli et al. (Acta Biomater. 2013 July. 9(7): 7399-7409), and Suntornnond et al. (US 2020/0009298 A1) as applied to Claim 1-2, 5-9, 13-14, 17-21 above, and in view of Lang et al. (US 7799077 B2), hereinafter Lang, and Lipsa et al. (Revue Roumaine de Chimie, 2008, 53(5), 405–413), hereinafter Lipsa.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Manaspon, Fabiilli and Suntornnond have been set forth supra.
Ascertainment of the difference between the prior art and the claims
(MPEP §2141.02)
Manaspon, Fabiilli and Suntornnond do not teach the combination of functional acrylate, diacrylate or methacrylate groups with the other components recited in Claims 37-40.
Lang discloses an invention directed to orthopedic implants and systems; relating to methods of implant design, manufacture, modeling and implantation as well as to surgical tools and kits (Abstract). Lang teaches that its repair systems and prosthesis can comprise a polymeric material or liquid metal; the polymeric material can be attached to a metal or metal alloy. The polymeric material can be injected and be self-hardening, or harden when exposed to a chemical, energy beam, light source, ultrasound and others (Col. 7, lines 43-49). Suitable synthetic polymers include, polyacrylates, vinyl polymers, polymethyl methacrylates etc.; Bioresorbable synthetic polymers can also be used including polyvinyl alcohol (PVA), polylactic acid etc. and similar copolymers (Col. 33, lines 30-44). Lang teaches that more than one polymer can be used in combination with each other (Col. 33, lines 56-58).
Lipsa supports Lang in teaching PVA/PLA polymer blends. Lipsa relates that biodegradable materials are used and studied in an increasingly number of applications inclusive of biomedical applications such as in implants, citing how poly(lactic acid), poly(caprolactone) (PCL) and poly(glycolic acid) (PGA) are biodegradable (p. 405, Introduction, 1st paragraph). Lipsa teaches how PVA is of great interest for being biodegradable, biocompatible and non-toxic, and being useful for graft and crosslinking reactions, as well as modification to obtain materials having new properties (p. 405, Introduction, 2nd paragraph). Furthermore, PVA blends with other polymers such as poly(methyl methacrylate), poly(acrylic acid) etc. (p. 405, Introduction, 3rd paragraph). Meanwhile, PLA is attracting much attention for its excellent mechanical properties and for being non-toxic to the human body (p. 405, Introduction, 4th paragraph).
Finding of prima facie obviousness Rational and Motivation
(MPEP 2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to combine the teachings of Lang with that of Manaspon, and replace the PLGA of the implant of Manaspon with PVA or PVA/PLA blend per the teaching of Lang and Lipsa, and/or add polylactic acid to the composition comprising acrylate in the implant taught by Manaspon, Fabiilli and Suntornnond because Lang has taught the use of copolymers, and the advantages of PVA and PLA. The ordinary artisan would have been motivated to substitute one known element for another to obtain predictable results. The known work in the field of implants would have prompted variations of it for use in the same field based on design incentives or other market forces where the variations are predictable to one of ordinary skill in the art.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant argued that the claimed term “hardens” is structurally and functionally linked in the claim to the requirement that the acoustic sensitive material comprises functional acrylate, diacrylate, or methacrylate groups which enable the hardening. The specification expressly and consistently describes hardening as a process of crosslinking or polymerization of the reactive functional groups. (page 10-13 of remarks).
In response, the examiner argues that no where in the specification is there a clear definition or clear reference that the term “hardens” refers to a process of crosslinking or polymerization of the reactive functional groups. The applicant in the remarks also do not state where in the specification there is a clear reference or definition that the term “hardens” refers to a process of crosslinking or polymerization of the reactive functional groups. While the claims are read in light of the specification, the limitations of the specification cannot be incorporated into the claims. While the specification may disclose process of crosslinking or polymerization of the reactive functional groups, the claims do not recite this and there is no clear definition or reference in the specification that the term “hardens” refers to crosslinking or polymerization of the reactive functional groups.
Applicant argued that Manaspon teaches passive hardening of PLGA through solvent exchange, prior to ultrasound application, and contains no acrylate, diacrylate or methacrylate functional groups. Manaspon’s frequency of 3 MHz (3,000 kHz) is three times higher than claimed upper limite of 1,000 kHz. It was argued that Manaspon does not teach material that hardens in response to ultrasound.
In response, as discussed in the rejections above, one skilled in the art would have substituted the PLGA of Manaspon with the methacrylate-containing peptide of Suntornnond arriving at the instant claims with functional acrylate or diacrylate or methacrylate groups because Suntornnond teaches Pluronic-GelMA which is suitable for bioprinting which is efficient and creates materials that are structurally stable at a wide range of temperatures. The ordinary artisan would have been motivated to substitute one known element for another to obtain predictable results. The known work in the field of implants would have prompted variations of it for use in the same field based on design incentives or other market forces where the variations are predictable to one of ordinary skill in the art. Further, as discussed supra and acknowledged by the applicant, Manaspon teaches the preparation of the implants with the polymer solution in PBS placed at 37 °C and 80 rpm, and ultrasound at 2.2 W/cm2 applied daily. The instant claims recite the ultrasound emissions are characterized by at least one selected from the group consisting of, wherein frequency from about 30-1000 kHz is recited in the alternative and not required. As recited in the claim and acknowledged by applicant, acoustic sensitive material comprising functional acrylate, diacrylate, or methacrylate groups enable the hardening and as such, substituting the PLGA of Manaspon with the methacrylate-containing peptide of Suntornnond would lead to hardening in response to ultrasound.
Applicant argued that Fabiilli teaches purely mechanical stiffening of a pre-formed fibrin scaffold through bubble induced strain stiffening, with no relationship to chemical polymerization, and discloses operating conditions that are incompatible with free radical polymerization of acrylate or methacrylate groups.
In response, as discussed supra, Fabiilli is utilized because while Manaspon discloses a releasable mock drug (e.g., fluorescein), Manaspon does not teach a plurality of cells within said acoustic-sensitive material. As mentioned above, both Fabiilli and Manaspon teach implants comprising polymer material that are responsive to ultrasound and it would have been obvious to one of ordinary skill in the art to combine the teachings of Fabiilli and Manaspon and incorporate a plurality of cells to the implant of Manaspon as Fabiilli has taught that the implant scaffolds are useful for regenerative medicine, wherein the cells are attached or encapsulated in the scaffold to regenerate tissue. Thus, one skilled in the art would not have been taught away from incorporating a plurality of cells to the implant of Manaspon even if Fabiilli does not teach chemical polymerization or discloses operating conditions incompatible with polymerization of acrylate or methacrylate.
Applicant argued Suntornnond teaches photopolymerization of GelMA using light and a photoinitiator, a crosslinking mechanism that is incompatible with ultrasound triggered hardening.
In response, as discussed supra, Suntornnond is utilized because Manaspon and Fabiilli are silent on the acoustic sensitive material comprising acrylate or methacrylate groups. One skilled in the art would have substituted the PLGA of Manaspon with the methacrylate-containing peptide of Suntornnond arriving at the instant claims with functional acrylate or diacrylate or methacrylate groups. One would have been motivated to do so because Suntornnond teaches Pluronic-GelMA which is suitable for bioprinting which is efficient and creates materials that are structurally stable at a wide range of temperatures. The ordinary artisan would have been motivated to substitute one known element for another to obtain predictable results. The known work in the field of implants would have prompted variations of it for use in the same field based on design incentives or other market forces where the variations are predictable to one of ordinary skill in the art. It is unclear to the examiner how Suntornnond teaching photopolymerization of GelMA would teach one skilled in the art away from substitute PLGA of Manaspon with the methacrylate-containing peptide of Suntornnond. As mentioned above, Manaspon teaches the ultrasound emissions recited in the claims (e.g. ultrasound at 2.2 W/cm2 applied daily) and substitute PLGA of Manaspon with the methacrylate-containing peptide of Suntornnond would necessarily result in hardening when exposed to the ultrasound emission.
Applicant argued that examiner’s inherency argument that a composition with methacrylate necessarily hardens upon ultrasound exposure is unsupported and directly contradicted by the well established chemistry of free radical polymerization which requires a dedicated initiator, proceeds through inertial cavitations at energy levels incompatible with the cited references.
In response, applicant appear to argue that the hardening of the composition with methacrylate requires certain conditions under which the hardening (or polymerization) can occur. However, the claims do not recite or require these conditions and the claims are merely directed to an implant or implant system which comprise an ultrasound transducer (in the case of implant system), acoustic sensitive material and at least on component within said acoustic sensitive material, wherein said acoustic sensitive material comprise one or more of materials with acrylate or diacrylate or methacrylate groups. The combination of cited references renders obvious the acoustic sensitive material, at least one component in the acoustic sensitive material and an ultrasound transducer. The hardening or polymerization/crosslinking of the acoustic sensitive material appears to be an intended use or effect that would necessarily occur when the acoustic materials is exposed to ultrasound emissions. As mentioned previously, Manaspon teaches the ultrasound emissions recited in the claims (e.g. ultrasound at 2.2 W/cm2 applied daily) and applicant have not clearly explained as to why the hardening or polymerization of the acoustic material would not occur when exposed to ultrasound emission of Manaspon.
Applicant argued that the proposed combination requires multiple modifications to each reference, abandonment of each reference’s operative mechanism and a chain of unsupported technical assumption.
In response, as discussed in 103 rejection above, both Fabiilli and Manaspon teach implants comprising polymer material that are responsive to ultrasound and it would have been obvious to one of ordinary skill in the art to combine the teachings of Fabiilli and Manaspon and incorporate a plurality of cells to the implant of Manaspon as Fabiilli has taught that the implant scaffolds are useful for regenerative medicine, wherein the cells are attached or encapsulated in the scaffold to regenerate tissue. One would also modify the fluorescein mock drug of Manaspon, and replace it with a therapeutic, e.g. protein therapeutic taught by Fabiilli, which can be controlled in its release for improved efficacy and safety. It would have been obvious to improve upon the teachings of Manaspon, adding a plurality of cells for regeneration, and also substituting the polymer with that of Fabiilli to obtain additional implants with different composite materials.
Further, as discussed in the examiner’s response above, one skilled in the art would have substituted the PLGA of Manaspon with the methacrylate-containing peptide of Suntornnond arriving at the instant claims with functional acrylate or diacrylate or methacrylate groups because Suntornnond teaches Pluronic-GelMA which is suitable for bioprinting which is efficient and creates materials that are structurally stable at a wide range of temperatures. The ordinary artisan would have been motivated to substitute one known element for another to obtain predictable results. The known work in the field of implants would have prompted variations of it for use in the same field based on design incentives or other market forces where the variations are predictable to one of ordinary skill in the art. Also, it would have been obvious to one of ordinary skill in the art to also use the implant bioprinting technique taught by Suntornnond in the method of Manaspon and Fabiilli, as bioprinting is a precision technology, which could offer the use of patients’ own cell in creating 3D tissue or organs for implantation.
Thus, Applicant’s argument that proposed combination requires multiple modifications to each reference, abandonment of each reference’s operative mechanism and a chain of unsupported technical assumption is not found persuasive to overcome the rejections above.
Applicant argued that Schillemans does not teach acoustic sensitive microcapsules and its liposomes release contents through chemical means, not ultrasound.
In response, Schillemans is utilized for its teaching of microsphere, which the Examiner interprets to be the same as microcapsules, by crosslinking monomers inside liposomes which allows good control over particle size and size distribution, wherein there are monomers in solution externally and internally together with the crosslinker. Hence, one with ordinary skill in the art would have applied the known technique taught by Schillemans and apply it to the teachings of Manaspon, Fabiilli and Bao, to obtain an acoustic sensitive material comprising the monomer (prepolymer) and crosslinker inside the liposome, which would be released to start the polymerization process upon exposure to ultrasound. Applying a known technique to a known method ready for improvement to yield predictable results is the rationale supporting obviousness. See MPEP § 2143 and KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385, 1395-97 (2007). Thus, even if Schillemans does not teach acoustic sensitive microcapsule and ultrasound release, the rejection is a 103 rejection and Schillemans provides the motivation to utilize its microsphere.
Applicant also argued that Lang addresses hard tissue orthopedic bone cement and does not teach the specific PEG-DA, PVA-MA or HAMA in the context of soft tissue implants.
In response, Lang teaches that the implant can be adapted to soft tissue damage (e.g. col. 29, line 45-55). Thus, applicant’s argument is not persuasive.
Conclusion
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/ALI S SAEED/Examiner, Art Unit 1616
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