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 .
Drawings
The drawings were received on 6/1/2023. These drawings are acceptable.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim(s) 1, 3-8, 11-15 19-23, and 25-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yueh et al (US 2015/0291926 A1) (provided by applicant in IDS dated 7/14/2023) in view of Cho et al (US 2019/0390149 A1) (provided by applicant in IDS dated 7/14/2023).
With respect to claim 1 Yueh discloses a device for culturing cells (See Para. 0016 for discussion of how the cells to be cultivated comprise embryonic cell, organ, and tissue cell or stem cell), comprising:
an access port (culture medium infusion end 11) configured to receive a solution (See Para. 0039 and Figs. 1-2);
a loading chamber (dynamic culture flow module 10), wherein the access port is located in the loading chamber (See Fig. 1 and Para. 0039); and
a plurality of culture chambers (cell co-cultivation platforms 20), wherein the culture chambers are radiated from the loading chamber (See Paras. 0039-0040 and 0051) so that the solution injected into the loading chamber through the access port is distributed into the plurality of culture chambers, wherein the plurality of culture chambers comprises a protruding edge at an opening of the plurality of culture chambers (See Para. 0040 - "The cell co-cultivation platforms 20 are respectively passed through by the plurality of perfusion flow channels 13 to correspondingly form a plurality of cell trapping areas 35 in the cell co-cultivation platforms 20."; Figure 1 appears to depict trapping areas 34 as protruding from each of the plurality of culture platforms 20).
Yueh fails to disclose culturing organoids, wherein the plurality of culture chambers are open to an external environment.
Cho teaches a device for culturing organoids, where chambers are open to an external environment (See abstract - "The present invention provides an organoid culture device, comprising at least one first chamber for storing a culture medium; at least one second chamber for culturing an organoid; and a channel that interconnects adjacent chambers."; Paras. 0055-0057 discuss how "the culture device 100 includes a structure for efficiently culturing the organoid, and specifically may include at least one first chamber 101 for storing the culture medium, at least one second chamber 102 for culturing the organoid, and a channel 103 that interconnects adjacent chambers .... The chamber may provide a certain space for culturing an organoid, or a storage space for receiving the culture medium and may be preferably open at the top.").
It would have been obvious to one ordinary skill in the art before the effective filing date of the claimed invention to extend the device of Yueh to include culture or organoids, and to use a cell culture chamber open to an external environment, as taught Cho, since this would allow cultivation of an alternative complex mixture of cells using an open configuration, thereby increasing the applicability and value of the device of Yueh, as well as providing any improvement in cell cultivation my allowing, for instance, gas exchange with the surrounding environment (See Paras. 0055-0057 of Cho).
With respect to claim 3, Yueh fails to disclose that the device is optically transparent.
Cho teaches that the organoid culture device may be optically transparent (See Para. 0059 for discussion of how the chamber may be made of a transparent, semitransparent, or opaque material, and may have different characteristics in consideration of culture environment or utilization). Light sheet microscopy was used to analyze the three-dimensional brain tissue-like organoid with high-resolution (See para. 0148).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device, as disclosed by Yueh, to include or instead use materials resulting in an optically transparent device, as disclosed by Cho, since this would allow for observation of cells or organoids in culture, such as for monitoring growth or imaging (See Paras. 0059 and 0148 of Cho).
With respect to claim 4, Yueh fails to specifically disclose that the access port is located in a center of the loading chamber. However, Yueh does depict a device infusion end is in the center of the device (See Para. 0039; Figure 2 appears to depict the culture medium infusion end 11 as centralized) and distributing cells to the radial chambers via the infusion end (See Para. 0052 - "Please refer to FIG. 6 which is in vitro a schematic view of in vitro cell cultivation in accordance with the present disclosure ...infuses a culture medium 60 containing base cells 51 via the culture medium infusion end 11”; See Figure 6 - appears to depict roughly even dispersion of cells to all radial chambers).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device to specifically position the access or inlet port in the center of the loading chamber of the device of Yueh, since this would allow the uniform distribution of solutions and/or cells to each radial chamber, such as when seeding the chambers or introducing fresh culture media or a test solution, enabling equivalent treatment of cells in each chamber (See Para. 0039 of Yueh).
With respect to claim 5, Yueh and Cho, in combination, make obvious the device of claim 4, and Yueh further discloses wherein the plurality of culture chambers are symmetrical with respect to rotations about the access port (See Figure 6 - each chamber appears to be equivalent and symmetrical about a center point).
With respect to claim 6, the combination of Yueh and Cho fails to specifically teach wherein the solution injected into the loading chamber through the access port is evenly distributed into the plurality of culture chambers. However, Yueh does disclose distributing cells via a solution to the radial chambers via the infusion end (See Para. 0052 and Figure 6, which appears to depict roughly even dispersion of cells to all radial chambers).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined device of Yueh and Cho, as taught by Yueh, to specifically allow even distribution of a solution to each of the radial chambers, such as by positioning an access port in the center of the loading chamber, since this would allow the uniform distribution of solutions and/or cells to each radial chamber, such as when seeding the chambers or introducing fresh culture media or a test solution, enabling equivalent treatment of cells in each chamber (See Para. 0052 and Fig. 6 of Yueh).
With respect to claim 7, applicant should note that the recitation “where the device is configured to contact a culture media from the external environment through the opening of the plurality of culture chambers” is directed to the function of the apparatus and/or the manner of operating the apparatus. All the structural limitations of the claim have been taught by the combination of Yueh and Cho and the apparatus of the combination of Yueh and Cho is capable of the recitation of claim 7. As such, it is deemed that the claimed apparatus is not differentiated from the apparatus of Yueh and Cho (see MPEP §2114)."
With respect to claim 8, Yueh and Cho, in combination, make obvious the device of claim 1, and teach culturing organoids (See rejection 1 above), but Yueh does not specifically disclose wherein the solution is a hydrogel solution.
Cho discloses a hydrogel solution for culturing cells (See Para. 0075 - "Meanwhile, the organoid can be efficiently cultured through three dimensional cultures, and can be effectively cultured through a hydrogel, such as Matrigel, which is widely utilized in the art"; Para. 0102 recites "An induced hepatocyte (H) or an induced hepatocyte and a human umbilical vein endothelial cell (HUVEC) {HE) were encapsulated in a 3-dimensional hydrogel and cultured statically (S) or with a flow (F) in the device.").
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device, as disclosed by NTHU, to include or instead use a hydrogel solution, as disclosed by Cho, since this would allow the introduction and encapsulation of cells In a hydrogel, such as for 3D organoid culture, thereby increasing the applicability and therefore value of the device of Yueh (See Paras. 0075 and 0102 of Cho).
With respect to claim 11, the combination of Yueh and Cho fails to teach wherein each of the culture chambers has a width or a height ranging from about 100 um to about 5 cm. However, it would have been obvious to one of ordinary skill in the art to modify the combined device of Yueh and Cho to include, or instead use, a particular width or height, such as from about 100 um to about 5 cm, as determined through routine experimentation/testing of device chamber size, in order to optimize available culturing space for a given application.
With respect to claim 12, the combination of Yueh and Cho fails to teach wherein each of the culture chambers has a width or a height of about 1cm. However, it would have been obvious to one of ordinary skill in the art to modify the combined device of Yueh and Cho to include, or instead use, a particular width or height, such as from about 1cm, as determined through routine experimentation/testing of device chamber size, in order to optimize available culturing space for a given application.
With respect to claim 13, Yueh fails to disclose wherein at least about 80% of the organoids in the culture chamber are viable at day 21 of culturing.
Cho teaches where a microfluidic organoid culturing device increases viability, and organoids may be cultured for several weeks (See Para. 0025 - ''The culture system of the present invention enhances differentiation capability, viability, and functionality of an organoid, and enables mass production, thereby contributing to the development of a source technology that can lead the field of next-generation cell therapy."; Paras. 0126-0127 discuss how- ''The brain organoid cultured in the device of the present invention and the brain organoid cultured in the existing culture system were incubated for 30 days, and then the degree of apoptosis was comparatively analyzed. Referring to FIG. 10A, the immunostaining and image-based quantitative analysis showed that decreased expression of the stained caspase-3 (casp3), an
apoptosis marker, is exhibited in the brain organoid cultured in the device as compared with the existing culture system."; Para. 0129 discusses how "The results suggest that the dynamic culture platform of the present invention can sufficiently supply oxygen into the organoid, and thus provide an environment in which apoptosis can be decreased.").
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device, as disclosed by NTHU, to include or instead consider culturing organoids for several weeks in a device designed to increase viability, as disclosed by Cho, such as one capable of producing -80% organoid viability at day 21, determined through routine testing of device parameters and viability on particular days of
culturing, since this would simply afford the ability to optimize for a given endpoint and evaluate organoid viability on a specific day of culturing (See Paras. 0025, 0126-0127, and 0129 of Cho).
With respect to claim 14, applicant should note that the recitation “where in the protruding edge is configured to pin a meniscus of the solution at the opening of the culture chambers, allowing filling of the culture chamber without spillage of the solution through the opening” is directed to the function of the apparatus and/or the manner of operating the apparatus. All the structural limitations of the claim have been taught by the combination of Yueh and Cho and the apparatus of the combination of Yueh and Cho is capable of the recitation of claim 14. As such, it is deemed that the claimed apparatus is not differentiated from the apparatus of Yueh and Cho (see MPEP §2114)."
With respect to claim 15, the combination of Yueh and Cho teaches wherein each
culture chamber comprises a different type of cells or organoids for co-culturing (See Para. 0008 of Yueh for discussion of how "... one of objectives of the present disclosure is to provide a platform system for in vitro cell co-cultivation ... "; See Para. 0013 - ''The plurality of cell co-cultivation platforms are for co-cultivation of a plurality of base cells and a plurality of cell to be cultivated. The plurality of cell co-cultivation platforms are arranged around the culture medium infusion end").
With respect to claim 19, Yueh discloses a method for culturing cells (See Para. 0016 for discussion of how the cells to be cultivated comprise embryonic cell, organ, and tissue cell or stem cell) comprising:
injecting a solution including cells or organoids into a loading chamber through an access port (See Para. 0015 for discussion of how cell to be cultivated are infused into the cell infusion end 11);
filling a plurality of culture chambers with the solution including cells or organoids, wherein the culture chambers are radiated from the loading chamber so that the solution injected into the loading chamber is distributed into the plurality of culture chambers (See Para. 0040 - "The cell co-cultivation platforms 20 are respectively passed through by the plurality of perfusion flow channels 13 to correspondingly form a plurality of cell trapping areas 35 in the cell co-cultivation platforms 20."), wherein the plurality of culture chambers comprises a protruding edge at an opening of the culture chambers for preventing spillage of the solution through the opening (Figure 1 appears to depict trapping areas 34 as protruding from each of the plurality of culture platforms 20); and
providing a culture media to the device through the opening of the plurality of culture chambers (See Paras. 0015 and 0049 for discussion of how, after the cells to be cultivated are respectively trapped at the cell trapping areas, the culture medium infusion end and the culture medium recovery end are opened and infused with the culture medium via the culture medium infusion end to perform a dynamic perfusion culture process for co-cultivation of the cells).
Yueh fails to disclose culturing organoids, wherein the plurality of culture chambers are open to an external environment.
Cho teaches a device for culturing organoids, where chambers are open to an external environment (See abstract - "The present invention provides an organoid culture device, comprising at least one first chamber for storing a culture medium; at least one second chamber for culturing an organoid; and a channel that interconnects adjacent chambers."; Paras. 0055-0057 discuss how "the culture device 100 includes a structure for efficiently culturing the organoid, and specifically may include at least one first chamber 101 for storing the culture medium, at least one second chamber 102 for culturing the organoid, and a channel 103 that interconnects adjacent chambers .... The chamber may provide a certain space for culturing an organoid, or a storage space for receiving the culture medium and may be preferably open at the top.").
It would have been obvious to one ordinary skill in the art before the effective filing date of the claimed invention to extend the device of Yueh to include culture or organoids, and to use a cell culture chamber open to an external environment, as taught Cho, since this would allow cultivation of an alternative complex mixture of cells using an open configuration, thereby increasing the applicability and value of the device of Yueh, as well as providing any improvement in cell cultivation my allowing, for instance, gas exchange with the surrounding environment (See Paras. 0055-0057 of Cho).
With respect to claim 20, Yueh fails to specifically disclose that the access port is located in a center of the loading chamber. However, Yueh does depict a device infusion end is in the center of the device (See Para. 0039; Figure 2 appears to depict the culture medium infusion end 11 as centralized) and distributing cells to the radial chambers via the infusion end (See Para. 0052 - "Please refer to FIG. 6 which is in vitro a schematic view of in vitro cell cultivation in accordance with the present disclosure ...infuses a culture medium 60 containing base cells 51 via the culture medium infusion end 11”; See Figure 6 - appears to depict roughly even dispersion of cells to all radial chambers).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device to specifically position the access or inlet port in the center of the loading chamber of the device of Yueh, since this would allow the uniform distribution of solutions and/or cells to each radial chamber, such as when seeding the chambers or introducing fresh culture media or a test solution, enabling equivalent treatment of cells in each chamber (See Para. 0039 of Yueh).
With respect to claim 21, Yueh and Cho, in combination, make obvious the device of claim 4, and Yueh further discloses wherein the plurality of culture chambers are symmetrical with respect to rotations about the access port (See Figure 6 - each chamber appears to be equivalent and symmetrical about a center point).
With respect to claim 22, the combination of Yueh and Cho does not specifically teach wherein the solution injected into the loading chamber through the access port is evenly distributed into the plurality of culture chambers., However, Yueh does teach distributing cells via a solution to the radial chambers via the infusion end (See Para. 0052 and Figure 6, which appears to depict roughly even dispersion of cells to all radial chambers).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined device of Yueh and Cho device, as disclosed by Yueh, to specifically allow even distribution of a solution to each of the radial chambers, such as by positioning an access port in the center of the loading chamber, since this would allow the uniform distribution of solutions and/or cells to each radial chamber, such as when seeding the chambers or introducing fresh culture media or a test solution, enabling equivalent treatment of cells in each chamber (See Para. 0052 and Fig. 6 of Yueh).
With respect to claim 23, Yuel fails to disclose wherein that the solution is a hydrogel solution.
Cho discloses a hydrogel solution for culturing cells (See Para. 0075 - "Meanwhile, the organoid can be efficiently cultured through three dimensional cultures, and can be effectively cultured through a hydrogel, such as Matrigel, which is widely utilized in the art"; Para. 0102 recites "An induced hepatocyte (H) or an induced hepatocyte and a human umbilical vein endothelial cell (HUVEC) {HE) were encapsulated in a 3-dimensional hydrogel and cultured statically (S) or with a flow (F) in the device.").
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device, as disclosed by NTHU, to include or instead use a hydrogel solution, as disclosed by Cho, since this would allow the introduction and encapsulation of cells In a hydrogel, such as for 3D organoid culture, thereby increasing the applicability and therefore value of the device of Yueh (See Paras. 0075 and 0102 of Cho).
With respect to claim 25, the combination of Yueh and Cho teaches that the hydrogel solution is solidified to form a hydrogel in the plurality of culture chambers after being injected into the loading chamber and distributed into the plurality of culture chambers (See Paras. 0078-0079 for discussion of how the hydrogel is a material in which a liquid that contains water as a dispersion medium is hardened, through the sol-gel phase transition, to lose fluidity and to form a porous structure. The hydrogel can be formed by causing a hydrophilic polymer that has a three-dimensional network structure and a microcrystalline structure to contain water and to be expanded; also see Para. 0102).
With respect to claim 26, Yueh fails to disclose wherein at least about 80% of the organoids in the culture chamber are viable at day 21 of culturing.
Cho teaches where a microfluidic organoid culturing device increases viability, and organoids may be cultured for several weeks (See Para. 0025 - ''The culture system of the present invention enhances differentiation capability, viability, and functionality of an organoid, and enables mass production, thereby contributing to the development of a source technology that can lead the field of next-generation cell therapy."; Paras. 0126-0127 discuss how- ''The brain organoid cultured in the device of the present invention and the brain organoid cultured in the existing culture system were incubated for 30 days, and then the degree of apoptosis was comparatively analyzed. Referring to FIG. 10A, the immunostaining and image-based quantitative analysis showed that decreased expression of the stained caspase-3 (casp3), an
apoptosis marker, is exhibited in the brain organoid cultured in the device as compared with the existing culture system."; Para. 0129 discusses how "The results suggest that the dynamic culture platform of the present invention can sufficiently supply oxygen into the organoid, and thus provide an environment in which apoptosis can be decreased.").
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device, as disclosed by NTHU, to include or instead consider culturing organoids for several weeks in a device designed to increase viability, as disclosed by Cho, such as one capable of producing -80% organoid viability at day 21, determined through routine testing of device parameters and viability on particular days of
culturing, since this would simply afford the ability to optimize for a given endpoint and evaluate organoid viability on a specific day of culturing (See Paras. 0025, 0126-0127, and 0129 of Cho).
With respect to claim 27, the combination of Yueh and Cho teaches wherein each
culture chamber comprises a different type of cells or organoids for co-culturing (See Para. 0008 of Yueh for discussion of how "... one of objectives of the present disclosure is to provide a platform system for in vitro cell co-cultivation ... "; See Para. 0013 - ''The plurality of cell co-cultivation platforms are for co-cultivation of a plurality of base cells and a plurality of cell to be cultivated. The plurality of cell co-cultivation platforms are arranged around the culture medium infusion end").
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yueh et al (US 2015/0291926 A1) and Cho et al (US 2019/0390149 A1) in view of Cruz-Acuna (Cruz-Acuña, R., Quirós, M., Huang, S. et al. PEG-4MAL hydrogels for human organoid generation, culture, and in vivo delivery. Nat Protoc 13, 2102–2119 (2018). https://doi.org/10.1038/s41596-018-0036-3) (provided by applicant in IDS dated 7/14/2023).
Refer above for the combined teachings of Yueh and Cho.
With respect to claim 7, the combination of Yueh and Cho fails to teach that the device is configured to contact a culture media from the external environment through the opening of the plurality of culture chambers.
Cruz-Acuna discloses where culture media may be added to an open-top culture chamber comprising hydrogel encapsulated cells for organoid generation (Fig. 2 - "Synthesis of the PEG-4MAL hydrogel and organoid generation .... b, PEG-4MAL hydrogel is cast by pipetting the mixture of functionalized PEG-4MAL and spheroids into the cross-linker solution. Encapsulated spheroids expand and develop into human organoids").
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, to modify the device, as taught by the combination of Yueh and Cho, to include contacting a culture media from an external source, as taught by Cruz-Acuna, since this would simply allow the introduction of fresh media on top of hydrogel-encapsulated cells for 3D organoid culture, thereby providing any improved or altered cell growth or organoid formation (See description in Fig. 2 of Cruz-Acuna).
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yueh et al (US 2015/0291926 A1) and Cho et al (US 2019/0390149 A1) in view of Griffith (US 2018/02723A1) (provided by applicant in IDS dated 7/14/2023).
Refer above for the combined teachings of Yueh and Cho.
With respect to claim 14 the combination of Yueh and Cho fails to teach that the protruding edge is configured to pin a meniscus of the solution at the opening of the culture chambers, allowing filling of the culture chambers without spillage of the solution through the opening.
Griffith teaches that an organoid culturing device may comprise a structure to pin a meniscus (See Para. 0016 - "The system combines one or more of the following features to improve the operability and performance of modeled organs on a chip ... Some embodiments provide entry geometry that eliminates a step or V-cut to minimize fluid film disruption; and includes a radial meniscus pinning groove around the source well, the groove being able to "pin" the fluid meniscus, making a specified fluid height energetically favorable."; Para. 0102 further discusses "For nonwetting liquid, meniscus pinning occurs at the base edge and the top edge of the side face of a vertical well ... "; Para. 0124 - "These one or more geometric features in fluid containers for the organs-on-chips apparatus allow for pinning of fluid in a radial fashion to limit the meniscus effect created by surface tension").
It would have been obvious to one of ordinary skill in the art to modify the cell culturing device of combined Yueh and Cho to include or instead use an opening in an organoid culture device comprising meniscus pinning edge geometry, as disclosed by Griffith, since this would afford improved fluid handing control, thereby reducing spillage, enabling directed spillage to a specific runoff channel, and/or ensuring a flat liquid surface by removing a meniscus, such as when a flat surface is desired for cell/organoid imaging (See Paras. 0016 and 0124 of Griffith).
Conclusion
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/BRITTANY I FISHER/Examiner, Art Unit 1796 December 13, 2025