DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office Action is in response to the paper filed 8 April 2026. Claims 3-10 and 19-22 have been amended. Claims 1 and 2 remain withdrawn. Claims 3-10 and 19-22 are currently pending and under examination.
This Application claims benefit of priority to Chinese patent document No. CN-2022101980285, filed March 1, 2022.
Withdrawal of Rejections:
The rejection of claims 3-10 and 19-22 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is withdrawn.
New/Modified Rejections Necessitated by Amendment:
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3-10 and 19-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 as amended recites “after obtaining the hollow supporting scaffold, pouring a cell-laden hydrogel matrix onto the hollow supporting scaffold, such that the hollow supporting scaffold is inserted into the cell-laden hydrogel matrix” (emphasis added). This claim is indefinite, because it initially appears that the matrix is poured onto the scaffold, but then the claim indicates that the scaffold is inserted into the matrix. These are different actions. As such, it is unclear if the matrix is poured onto the scaffold, the scaffold is inserted into the matrix, or the matrix is poured onto the scaffold and the scaffold is inserted into the matrix. For the purposes of examination, this limitation is deemed to require either pouring the matrix onto the scaffold or inserting the scaffold into the matrix.
Further regarding claim 3, as amended, this claim recites “after obtaining the hollow supporting scaffold, pouring a cell-laden hydrogel matrix onto the hollow supporting scaffold, such that the hollow supporting scaffold is inserted into the cell-laden hydrogel matrix, and curing the cell-laden hydrogel matrix.” As currently written, where the scaffold is inserted into the hydrogel matrix, it appears that not only the scaffold, but all the surrounding extraneous matrix is intended to be cured. This claim is indefinite, because it is unclear how a vascular structure is formed if both the scaffold and the matrix surrounding it are cured (i.e. into a solid block).
Claim 8 as amended recites soaking the scaffold “for 1-5, thereby…”; this limitation is indefinite, because it is unclear what unit “1-5” is intended to be modified by. For example, 1-5 hours or 1-5 days. For the purposes of examination, the unit is interpreted to be “days.”
Claim 4-7, 9, 10, and 19-22 are included in this rejection, as these claims depend from above rejected claims and fails to remedy the noted deficiencies.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 3-5, 7, 8, 10, 19, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Suzhou Yongqinquan Intelligent Equipment Co Ltd (CN 112917891, Published June 8, 2021- hereafter Suzhou, English translation provided and referred to hereafter – Previously presented).
With regard to claim 3, Suzhou teaches a method for constructing a vascularized, three-dimensional biological tissue structure (Abs.), the biological tissue having dimensions including about 20 mm x 18 mm (see Fig. 5A, butterfly structure), which is encompassed within 16mm x 16 mm to 40 mm x 40 mm. The method comprising coaxially printing a first mixed solution, which contains an inner material, and a second mixed solution, which contains an outer material, on a refrigeration platform, which is a receiving platform, to form a scaffold structure (Abs.; Fig. 2-3; claim 1, 8). The outer material is a composite material of a thermosensitive material and a crosslinking material, and the inner material is a thermosensitive material (Abs.; Fig. 7). The outer material is cured after printing (Fig. 1, 4, 7), thus obtaining a stable scaffold structure.
Suzhou further teaches immersing the stable scaffold structure into a culture medium to incubate at 37°C, which is a melting temperature, to melt and remove the thermosensitive material from the inner and cured outer materials to obtain a hollow supporting scaffold having a porous duct wall, thus obtaining a network structure with vascular cells (Abs.; Fig. 4, 5, 7; claim 1). It is taught that the steps of removing the thermosensitive material and inserting the scaffold into a cell culture medium occur simultaneously (p. 5, Para. 3, S50). However, the cells are in the thermosensitive material when it is immersed into the warm culture medium (Abs.), so as the thermosensitive material melts, the cells are released into the cell culture medium, where they are deposited and adhere to the now-hollow supporting scaffold to provide an endothelialized vascular network structure (p. 5, Para. 3, S50). As such, the process of Suzhou encompasses the steps of melting and removing the thermosensitive materials, as well as inserting the hollow support scaffold into a cell-laden hydrogel matrix.
It is not specifically taught that the cell-laden hydrogel matrix is then cured after application to the hollow support scaffold. However, it is taught that cells are mixed with a matrix material to obtain a mixed solution when preparing the initial structure, where the cell-containing structure is then cured (claim 1; Fig. 4, 7). As such, it would have been obvious to one of ordinary skill in the art that the supporting scaffold containing the cells may be subjected to an additional curing step without damage to the added cells, which would advantageously provide irreversible solidification of the matrix materials not solidified during the first round of curing.
It is noted that the limitation that “a porosity of the porous duct wall is adjustable by changing a concentration of the crosslinking material in the outer material” further defines a capability of the method, and does not provide for a required method step.
With regard to claim 4, Suzhou teaches that the inner and outer materials are prepared for coaxial printing by loading a liquid inner material and a liquid outer material into different syringes, and incubating them at 4°C to form a gel; loading the syringes into an extrusion 3D printer and connecting the nozzles, setting the process parameters for the printer, and setting a temperature of the receiving platform; and starting the printing software to enable the coaxial printing nozzle to start printing according to the preset path track and the organ file to be printed, and extruding the gel from the syringes onto the receiving platform to form the printed organ model, which is the scaffold structure, and processing the scaffold structure to cure the crosslinking material in the outer composite material to obtain the stable scaffold structure (p. 4, Ex. 1, para. 1 to p. 5, para. 2; Fig. 2-3).
With regard to claim 5, Suzhou teaches that the thermosensitive material, including the inner and/or outer material, includes F127 poloxamer, or gelatin (p. 4, Example 1).
With regard to claim 7, Suzhou teaches that the syringes are incubated at 4°C until the contents are in a gel state (Example 1; para. 7). While it is not specifically taught that incubation at 4°C occurs for 10-30 minutes, it would have been routine for one of ordinary skill in the art to determine the amount of time necessary for the contents of the syringes to become gel at 4°C. Additionally, please also note that "the discovery of an optimum value of a variable in a known process is usually obvious." Pfizer v. Apotex, 480 F.3d at 1368. The rationale for determining the optimal parameters for prior art result effective variables "flows from the 'normal desire of scientists or artisans to improve upon what is already generally known.'" Id. (quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). Accordingly, it would have been obvious to optimize the time the syringes are held at 4°C, including for 10-30 minutes, to result in the contents of syringes being in the desired gel state when practicing the taught method.
With regard to claim 8, Suzhou teaches that the printed scaffold structure is immersed into a culture medium with a second set temperature including 37°C, which is encompassed within 4-40°C, for a time sufficient to dissolve the sacrificial material of scaffold structure and obtain the hollow supporting scaffold, and culture the endothelial cells to form an endothelialized blood vessel network structure in the hollow supporting scaffold (Abs.; claim 1, s50; p. 3, para. 16, p. 5, s50). While it is not specifically taught that the printed scaffold is immersed for 1-5 days, it would have been routine for one of ordinary skill in the art to determine the amount of time necessary for the sacrificial material to fully dissolve and the endothelial cells to be cultured to a desired level. Additionally, please also note that "the discovery of an optimum value of a variable in a known process is usually obvious." Pfizer v. Apotex, 480 F.3d at 1368. The rationale for determining the optimal parameters for prior art result effective variables "flows from the 'normal desire of scientists or artisans to improve upon what is already generally known.'" Id. (quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). Accordingly, it would have been obvious to optimize the immersion time, including to 1-5 days, to result in the sacrificial material being fully dissolved, and the endothelial cells to be cultured to a desired level, when practicing the taught method.
Additionally, as PBS is utilized to prepare the liquid inner and outer materials, and to wash cell-containing vessels (p. 7, para. 5), it would have been obvious to one of ordinary skill in the art to include PBS as a liquid in the culture medium used for immersion.
With regard to claim 10, Suzhou teaches that the cell-laden hydrogel matrix comprises GelMA, which is gelatin methacrylate, at 5% (p. 6, Ex. 2, para. 9), which is fully encompassed within 5-15%.
With regard to claim 19, Suzhou teaches that the crosslinking material comprises GelMA, which is gelatin methacrylate (p. 6, Ex. 2, para. 9).
With regard to claim 20, Suzhou teaches that the diameter of the outer nozzle includes 0.6 mm, 1.21 mm, 1.6 mm, or 2.1 mm, which are fully encompassed within 14-21 G (about 0.8 mm to about 2.1 mm); and the diameter of the inner nozzle includes 0.15 mm or 0.18 mm, which are fully encompassed within 18-30G (about 0.2 mm to about 1.24 mm) (p. 5, para. 13).
With regard to claim 22, Suzhou teaches that the temperature of the receiving platform includes 5-37°C (claim 1, s50; claim 5), and is therefore a high-temperature platform and a low-temperature platform.
Claims 3, 6, 9 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Suzhou, as applied to claim 3 above, and further in view of Murphy et al. (US 2014/0093932, Published 2014 – Previously presented).
The teachings of Suzhou as applied to claim 3 have been set forth above.
With regard to claim 6, Suzhou teaches that construction of the inner and outer materials includes 4-30% Pluronic® F127 (F127 poloxamer), which fully encompasses 10-30% (p. 3, Para. 11), wherein it would have been obvious to one of ordinary skill in the art to utilize an amount of Pluronic® F127 within the expressly taught range, which includes 10-30%.
It is not specifically taught that the Pluronic® F127 is dissolved in a phosphate solution for the inner and outer materials, or that the outer material is formulated by dissolving a photoinitiator and polyethylene glycol diacrylate (PEG-DA) at 4-30% in phosphate solution prior to additional of the Pluronic® F127 solution.
Murphy et al. teach constructing a vascular structure containing biological tissue utilizing bioprinting (Abs.; Ex. 4, Para. 240). The method including preparing bioink by dissolving 30% Pluronic® F-127 in PBS (Para. 139). The bioink may further comprise a photoinitiator to assist in curing of scaffold material (Para. 131-133). UV cross-linkable hydrogel materials usable in the method in addition to gelatin, include PEG-DA, where 10% PEG-DA is dissolved in water with a photoinitiator (Para. 129-130, 149, Ex. 4). Wherein, as both water and PBS are utilized to mix UV cross-linkable hydrogel materials, it would have been obvious to an ordinary artisan to utilize either water or PBS to dissolve the PEG-DA.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Suzhou and Murphy et al., because both teach constructing a vascular structure containing biological tissue utilizing bioprinting, the methods including preparing bioinks. The use of PBS to dissolve Pluronic® F-127 and PEG-DA, and the use of 10% PEG-DA with a photoinitiator in a solution is known in the art as taught by Murphy et al. The use of PBS with the 10-30% Pluronic® F-127 would have been expected to predictably and successfully provide a 10-30% solution of Pluronic® F-127 as desired by Suzhou. Additionally, the use of 10% PEG-DA with a photoinitiator in a solution including PBS as taught by Suzhou in the method of Suzhou to provide the outer material, amounts to the simple substitution of one known UV cross-linkable hydrogel material for another, and would have been expected to predictably and successfully provide UV cross-linkable hydrogel material as desired for the method of Suzhou.
With regard to claim 9, Suzhou teaches that the scaffold structure is immersed in culture media for a time sufficient to melt the sacrificial materials, and at a temperature from 5-37°C (Abs.; p. 3, S50). While it is not specifically taught that immersion is in water, it is further taught that PBS is used for washing steps (p. 7, para. 7). As such, it would have been obvious to one of ordinary skill in the art to utilize PBS, which includes water, for immersion. Additionally, as it is taught that the scaffold structure is immersed for an amount of time sufficient to melt the sacrificial materials, it would have been routine for an ordinary artisan to determine the necessary amount of time required based on the exact materials utilized. Likewise, it would have been routine for an ordinary artisan to determine the optimal temperature to melt the sacrificial materials based on the exact materials utilized, and the desired time period. Additionally, please also note that "the discovery of an optimum value of a variable in a known process is usually obvious." Pfizer v. Apotex, 480 F.3d at 1368. The rationale for determining the optimal parameters for prior art result effective variables "flows from the 'normal desire of scientists or artisans to improve upon what is already generally known.'" Id. (quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). Accordingly, it would have been obvious to optimize the immersion time, including to 1-3 days, and the immersion temperature, including to 4°C, to result in the sacrificial material being fully dissolved as desired when practicing the taught method.
Suzhou do not specifically teach that after obtaining the hollow supporting scaffold, a sterilization step is performed by soaking the hollow supporting scaffold in a 75% ethanol solution for 1-5 hours.
Murphy et al. teach that a wetting agent, hydrogel, and bioink include water (para. 73, 128, 139) the fabricated mold, which is a scaffold, was pre-sterilized using a 70% ethanol solution and UV light for 45 minutes (Par. 201), wherein it would have been routine for an ordinary artisan to adjust the concentration of ethanol, and the amount of time required to sterilize the scaffold based on the exact materials utilized. Additionally, please also note that "the discovery of an optimum value of a variable in a known process is usually obvious." Pfizer v. Apotex, 480 F.3d at 1368. The rationale for determining the optimal parameters for prior art result effective variables "flows from the 'normal desire of scientists or artisans to improve upon what is already generally known.'" Id. (quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). Accordingly, it would have been obvious to optimize the ethanol concentration, including to 75%, and the sterilization time, including to 1-5 hours, to result in the scaffold being fully sterilized and ready for the end use when practicing the taught method.
The rationale for the combination of of Suzhou and Murphy et al. has been set forth previously. The sterilization of a bioprinted scaffold using ethanol is known in the art as taught by Murphy et al. The use of a sterilization step would have been expected to predictably and successfully improve the method of Suzhou, by providing a scaffold free of contaminants and ready for the desired end use.
With regard to claim 21, while Suzhou teaches the use of coaxial printing using an inner and outer jet (claim 3), it is not specifically taught that the moving speed of the nozzle for the coaxial printing is 400-800 mm/min, and an inner-to-outer extrusion speed ratio is 1:4-1:1.
Murphy et al. teach a bioprinter head speed including 3mm/sec, which is 180 mm/min, where the bioprinting involves optimizing and/or balancing parameters such as print height, pump speed, robot speed, or combinations thereof independently or relative to each other (Para. 62). Additionally, favorable pump speeds may depend on the ratio between the cross-sectional areas of the reservoir and dispense needle with larger ratios requiring lower pump speeds (Para. 62). As Murphy et al. teach that the head speed and speed ratio are based on a combination of factors, it would have been routine for an ordinary artisan to adjust the speed of the nozzle and extrusion speed ratio based on the exact materials utilized and the other bioprinter factors. Additionally, please also note that "the discovery of an optimum value of a variable in a known process is usually obvious." Pfizer v. Apotex, 480 F.3d at 1368. The rationale for determining the optimal parameters for prior art result effective variables "flows from the 'normal desire of scientists or artisans to improve upon what is already generally known.'" Id. (quoting In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003)). Accordingly, it would have been obvious to optimize the speed of the nozzle, including to 400-800 mm/min, and the inner-to-outer extrusion speed ratio to 1:4 to 1:1, to result in a scaffold, and resulting vascular structure, having the desired characteristics when practicing the taught method.
The rationale for the combination of Suzhou and Murphy et al. has been set forth previously. As Suzhou teaches extrusion bioprinting, the nozzle necessarily has a speed and the process necessarily has an inner-to-outer extrusion speed ratio, and Murphy et al. provides guidance to determine appropriate nozzle speed and extrusion speed ratio for bioprinting.
Response to Arguments
Applicant urges that Suzhou does not disclose claim 3 as amended, including removing the thermosensitive material from the inner material and from the cured outer material; and after obtaining the hollow supporting scaffold, pouring a cell-laden hydrogel matrix onto the hollow supporting scaffold, such that the hollow supporting scaffold is inserted into the cell-laden hydrogel matrix. Instead, Suzhou teaches that the solution contains cells before printing. Murphy fails to cure the noted deficiencies.
Applicant’s arguments have been fully considered, but have not been found persuasive.
With regard to Applicant’s arguments regarding amended claim 3; as noted in the modified rejection above, Suzhou teaches immersing the stable scaffold structure into a culture medium to incubate at 37°C, which is a melting temperature, to melt and remove the thermosensitive material from the inner and cured outer materials to obtain a hollow supporting scaffold having a porous duct wall, thus obtaining a network structure with vascular cells (Abs.; Fig. 4, 5, 7; claim 1). It is taught that the steps of removing the thermosensitive material and inserting the scaffold into a cell culture medium occur simultaneously (p. 5, Para. 3, S50). However, the cells are in the thermosensitive material when it is immersed into the warm culture medium (Abs.), so as the thermosensitive material melts, the cells are released into the cell culture medium, where they are deposited and adhere to the now-hollow supporting scaffold to provide an endothelialized vascular network structure (p. 5, Para. 3, S50). As such, the process of Suzhou encompasses the steps of melting and removing the thermosensitive materials, as well as inserting the hollow support scaffold into a cell-laden hydrogel matrix.
With regard to Murphy, the noted deficiencies have been addressed above.
Conclusion
No claims are allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653
