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. Information Disclosure Statement The information disclosure statements (IDS) submitted on 10/04/2023 and 02/19/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. Election/Restrictions Applicant’s election of Group I in the reply filed on March 5 th , 202 6 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claim 34 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 5th, 2026 . Specification The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification. 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- 7 and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Redaelli et al. (US 2018/0105782 A1) (see PTO-892) in view of Fernandez-Alcon et al. (US 2016/0326477 A1) (see PTO-892) . Regarding claim 1, Redaelli et al. discloses a cell culture apparatus (abstract) comprising: one or more cell culture chambers (Fig. 1 a , cell culture chamber 4 – see figure below ) each comprising a flexible membrane (Fig. 1 a , membrane 3), the flexible membrane separating an upper chamber and a pneumatic chamber (Fig. 1, membrane 3 separates culture chamber 4 and actuation chamber 7) and being mechanically integrated with the pneumatic chamber (Fig. 1 a shows actuation chamber 7 and membrane 3 are attached), wherein the pneumatic chamber is fluidly connected to a pneumatic actuator comprising a source of one or more pressurized fluids (Fig. 3b , pressure line 1 3 ; [0076], [0087] , and [0257] teach means (i.e., pneumatic actuator) for introducing pressure and/or fluid, implying the actuation chamber (i.e., pneumatic chamber) is connected to the pneumatic actuator and comprises a source of one or more pressurized fluids ), the pneumatic actuator being configured to selectively adjust the pressure in the pneumatic chamber ( [0082]-[0083] and [0217]-[0218] teach pressure adjustment inside actuation chamber (i.e., pneumatic chamber), [ 0210 ] teaches pneumatic actuation ), thereby altering the shape of the flexible membrane through mechanical stimulation ( Fig. 1a-1b shows how the shape of the flexible membrane is altered; [0060] and [0217]-[0218] teach pressure is used to alter the shape (i.e., mechanical stimulation) ) . 2705100 647700 38100 0 Redaelli et al. fails to disclose wherein the cell culture apparatus is configured to generate and apply various mechanical stimuli comprising bending stress, shear stress, or a combination thereof to one or more cell types . However, Fernandez-Alcon et al. discloses a n organomimetic device including a membrane and microfluidic channels used to culture cells and apply mechanical forces to said cells (abstract). Fernandez-Alcon et al. teaches that a membrane can simulate mechanical stress or strain cells experience in their microenvironment. The mechanical strain generated by the membrane includes “stretching, bending, compressing, vibrating, contracting, waving, or any combinations thereof” ([0466], lines 1-3 and 11-1 3 ) induced by a pneumatic mechanism ([0466], lines 26-27). It would have been obvious to one of ordinary skill in the art to use the apparatus of Redaelli et al. to generate and apply various mechanical stimuli comprising bending stress, shear stress, or a combination thereof to one or more cell types, as taught by Fernandez-Alcon et al., to imitate the microenvironment cells experience. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Redaelli et al. and Fernandez-Alcon et al. to obtain the invention as specified in claim 1. Regarding claim 2, modified Redaelli et al. teaches the apparatus of claim 1. Redaelli et al. further teaches wherein the flexible membrane is comprised of a polymeric material comprising polycarbonate (PC), poly-methyl-meta-acrylate (PMMA), cyclic olefin copolymer (COC), polyimide, polydimethylsiloxane (PDMS), or combinations thereof ([0061] and [0204] teach PC, PMMA, PDMS as preferrable materials for the counter element (i.e., flexible membrane)) . Regarding claim 3, modified Redaelli et al. teaches the apparatus of claim 2. Redaelli et al. further teaches wherein the flexible membrane is comprised of PDMS ([0061] and [0204] teach PDMS is a preferrable material for the counter element (i.e., flexible membrane)) . Regarding claim 4, modified Redaelli et al. teaches the apparatus of claim 1. Redaelli et al. further teaches wherein the flexible membrane comprises a flat, concave, and/or convex shaped curvature upon mechanical stimulation (Fig. 1a-1b shows flexible membrane having a no curvat ure and a convex curvature upon mechanical stimulation ) . Regarding the limitation “flat, concave, and/or convex shaped curvature”, the limitation not addressed (e.g., concave shaped curvature) is claimed in the alternative. Therefore, the prior art meets the limitation absent clear evidence to the contrary and absent a showing of unexpected results. The limitation “to modulate bending stress on cells” is directed toward the intended manner of operating the claimed apparatus and does not differentiate the claimed apparatus from the prior art apparatus because all structural limitations are taught in the prior art apparatus (MPEP §2114 II). The apparatus taught by Redaelli et al. would be fully capable of achieving every claimed intended use because the prior art apparatus is taught to move the membrane in a bending motion (Figs. 1a-1b shows bending motion) and would be structurally capable of modulating bending stress on cells . Regarding claim 5, modified Redaelli et al. teaches the apparatus of claim 1, but fails to teach wherein the flexible membrane comprises a uniform thickness across its surface of about 25 µm to about 250 µm. However, Fernandez-Alcon et al. teaches that a membrane made of PDMS ([0277]) for an organomimetic device (abstract) can vary in thickness, so long as the thickness do es not significantly affect cell behavior and/or response ([0328]). Fernandez-Alcon et al. teaches membrane thicknesses between 10 micron and 100 micron (between 10 µm and 100 µm). It has been held that when ranges claimed ranges significantly overlap or lie inside ranges disclosed the prior art, a prima facie case of obviousness exists (MPEP § 2144.05). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the claimed range in view of the range disclosed in Fernandez-Alcon to obtain the invention as claimed in claim 5. Regarding claim 6, modified Redaelli et al. teaches the apparatus of claim 1. Redaelli et al. further teaches wherein each of the one or more cell culture chambers comprises an extracellular matrix layer comprising a hydrogel selected from the group consisting of collagen, elastin, alginate, and combinations thereof (Fig. 1b, cellular matrix 6; [0030], [0031]) , but fails to teach wherein the extracellular matrix layer is disposed on the flexible membrane . However, Fernandez-Alcon et al. teaches it is known in the art to coat a membrane for stimulating cells with an extracellular matrix ([0467]) and wherein the material of the extracellular matrix may be chosen from various collagen types, elastin, alginate, or any combinations thereof ([0278] teaches alginate, [0467] teaches collagen and elastin ) . Fernandez-Alcon et al. teaches that an extracellular matrix is used to facilitate cell adhesion and mimic a desired cellular environment ([0406] lines 6-14 and 22-24, [0467]). It would have been obvious to one of ordinary skill in the art to form the device of Redaelli et al. to incorporate an extracellular matrix made of collagen, elastin, alginate, or any combinations thereof, such that it is disposed on the flexible membrane, as taught by Fernandez-Alcon et al. to facilitate cell adhesion and mimic a desired cellular environment for cultured cells. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Redaelli et al. and Fernandez-Alcon et al. to obtain the invention as specified in claim 6. Regarding claim 7, modified Redaelli et al. teaches the apparatus of claim 6. Redaelli et al. further teaches one or more perfusion channels, perfusion channel inlets, and perfusion channel outlets each fluidly connected to the hydrogel and configured to deliver one or more liquid fluids to the hydrogel ([0187] discloses perfusion channels as microfluidic channels; [0243] teach inlet/outlet openings for cellular matrix (i.e., hydrogel) ; Fig. 3b shows inlet 10 and outlet 11 for cellular matrix). Regarding claim 12, modified Redaelli et al. teaches the apparatus of claim 1. Redaelli et al. further teaches wherein the one or more pressurized fluids of the pneumatic actuator comprise air, liquid, or a combination thereof ([0216] teaches a liquid (saline) in the actuation chamber (i.e., pneumatic chamber) , and that the actuation chamber receives pressurized fluid from a pneumatic actuator ([0210], [0257])) . Regarding claim 13, modified Redaelli et al. teaches the apparatus of claim 1. Redaelli et al. further teaches wherein the pneumatic actuator generates fluid pressures ranging from about 5 kPa to about 50 kPa through the pneumatic chamber. Redaelli et al. teaches in [0083] the pressure within the actuation chamber (i.e., pneumatic chamber) during pressurization caused by an actuator (e.g., pneumatic, [ 0210 ]) is between 0.01 atm and 10 atm, most preferably 0.5 atm, which is equivalent to between 1.01325 kPa and 1013.25 kPa, most preferably 50.6 kPa. Therefore, the range disclosed by Redaelli et al. anticipates the range as claimed (MPEP § 2131.03). Regarding claim 14, modified Redaelli et al. teaches the apparatus of claim 1. Redaelli et al. further teaches wherein the pneumatic actuator generates fluid pressures at frequencies ranging from about 0.05 Hz to about 5 Hz through the pneumatic chamber . Redaelli et al. teaches in [0 241 ] that the compression step , caused by pressurized fluid sent from the pneumatic actuator ([ 0210 ], [0218]), occurs with a frequency between 0.05 and 50 Hz, and preferably between 0.5 and 5 Hz. Therefore, the range disclosed by Redaelli et al. anticipates the range as claimed (MPEP § 2131.03). Regarding claim 15, modified Redaelli et al. teaches the apparatus of claim 1. Redaelli et al. further teaches wherein the pneumatic chamber is fluidly connected to the pneumatic actuator through an interface component ( Fig. 3b shows the interface component – see annotated figure below; [0076], [0087], and [0257] teach means for introducing pressure and/or fluid, implying the actuation chamber (i.e., pneumatic chamber) is connected to the pneumatic actuator) comprising: one or more interface inlets (Fig. 3b, pressure line 13) configured to receive the one or more pressurized fluids from the pneumatic actuator ([0076], [0087], and [0257] teach means (i.e., pneumatic actuator) for introducing pressure and/or fluid, implying the actuation chamber (i.e., pneumatic chamber) is connected to the pneumatic actuator and comprises a source of one or more pressurized fluids); one or more interface channels (Fig. 3b, interface channels shown); one or more interface outlets ( Fig. 3b, interface outlets shown ); and one or more chamber portion outlets ( Fig. 3b, cellular matrix outlet 11 ). center 0 0 0 The limitation “configured to apply the one or more pressurized fluids to the pneumatic chamber” is directed toward the intended manner of operating the claimed apparatus and does not differentiate the claimed apparatus from the prior art apparatus because all structural limitations are taught in the prior art apparatus (MPEP §2114 II). The apparatus taught by Redaelli et al. would be fully capable of achieving every claimed intended use because the prior art apparatus is taught to receive and release fluid ( [0242]-[0243] ) and would be structurally capable of applying the one or more pressurized fluids to the pneumatic chamber . Claims 8- 10 are rejected under 35 U.S.C. 103 as being unpatentable over Redaelli et al. (US 2018/0105782 A1) and Fernandez-Alcon et al. (US 2016/0326477 A1) as applied to claim 1 above, and further in view of Hansen et al. (US 2018/0163166 A1) (see PTO-892) . Regarding claim 8, modified Redaelli et al. teaches the apparatus of claim 1 , but fails to teach wherein the flexible membrane is comprised of one or more microfluidic layers each independently comprising one or more microfluidic chambers, microfluidic inlets, and microfluidic outlets disposed therein, each of the microfluidic chambers being fluidly connected through one or more porous membranes. center 979805 0 0 However, Hansen et al. discloses a microfluidic device for culturing cells (abstract) comprising microfluidic chambers, a microfluidic inlet, and a microfluidic outlet (Fig. 1 , array inlet 22, array outlet 24 – see annotated figure below). Hansen et al. teaches that forming these structures from PDMS is known in the art ([0114 ]) . Hansen et al. further teaches that the microfluidic chambers retains cells. It would have been obvious to one of ordinary skill in the art to form the flexible membrane of modified Redaelli et al. with microfluidic chambers, microfluidic inlets, and microfluidic outlets because the microfluidic chambers would retain cells , as taught by Hansen et al., and the microfluidic inlets and outlets would permit media flux through the apparatus. Additionally, Fernandez-Alcon et al. teaches that porous membranes enhance fluid/molecule transport ([0322]) . It would have been obvious to one of ordinary skill in the art to modify the apparatus of modified Redaelli et al. to include a porous membrane to enhance fluid/molecule transport, as taught by Fernandez-Alcon et al., through the apparatus to assist with culturing the cells. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Redaelli et al., Fernandez-Alcon et al., and Hansen et al. to obtain the invention as specified in claim 8. Regarding claim 9, modified Redaelli et al. teaches the apparatus of claim 8. Redaelli et al. further teaches wherein one or more microfluidic chambers further comprises an extracellular matrix layer (Fig. 1a, shows microfluidic chambers with cellular matrix ) comprising a hydrogel selected from the group consisting of collagen, elastin, alginate, and combinations thereof ( [0030], [0032] ). Regarding claim 10, modified Redaelli et al. teaches the apparatus of claim 8. Modified Redaelli et al. further teaches the microfluidic inlet and the microfluidic outlet (see claim 8 rejection). Redaelli et al. fails to teach a syringe pump fluidly connected to at least one of the one or more microfluidic inlets or microfluidic outlets, the syringe pump comprising a source of one or more pressurized liquid fluids and configured to modulate shear stress on cells through the microfluidic chambers. However, Hansen et al. teaches that syringe pumps can be used to control flow rates of microfluidic devices ([0285] , lines 37-41 ) and that syringe pumps comprise a source of one or more pressurized liquid fluids ([0282], lines 52-56 discloses that the syringe contains liquid medium and acts as pump ; Fig. 5, syringe 19 comprises a fluid which is pressurized upon use ). It would have been obvious to one of ordinary skill in the art to modify the apparatus of modified Redaelli et al. to incorporate a syringe pump fluidly connected to at least one of the one or more microfluidic inlet or microfluidic outlets to control the flow rate as taught by Hansen et al. Additionally, it would have been obvious to one of ordinary skill in the art to a source of one or more pressurized liquid fluids to provide media, to the apparatus. The limitation “configured to modulate shear stress on cells through the microfluidic chambers” is directed toward the intended manner of operating the claimed apparatus and does not differentiate the claimed apparatus from the prior art apparatus because all structural limitations are taught in the prior art apparatus (MPEP §2114 II). The apparatus taught by Hansen et al. would be fully capable of achieving every claimed intended use because the prior art apparatus is taught to provide a range of shear stresses on cells ([0285]-[0286], [0289]) based on and would be structurally capable of modulating the shear stress on cells through the microfluidic chambers. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Redaelli et al., Fernandez-Alcon et al., and Hansen et al. to obtain the invention as specified in claim 10. Claims 11 is rejected under 35 U.S.C. 103 as being unpatentable over Redaelli et al. (US 2018/0105782 A1) , Fernandez-Alcon et al. (US 2016/0326477 A1) , and Hansen et al. (US 2018/0163166 A1) as applied to claim 10 above, and further in view of Lauschke et al. (US 2023/0158490 A1 ) (see PTO-892). Regarding claim 11, modified Redaelli et al. teaches the apparatus of claim 10, but fails to teach wherein the syringe pump generates liquid fluid rates ranging from about 50 µL/sec to about 150 µL/sec through the microfluidic chambers. However, Lauschke et al. teaches that a syringe pump used for a microfluidic device (abstract) configured to pump at flowrates ranging from about 1 mL/min ( about 16.7 µL/sec) to about 10 mL/min (about 166.7 µL/sec) ([0049]). It would have been obvious to one of ordinary skill in the art to use the flow rate ranges as claimed because it has been held that claimed ranges that overlap or lie inside ranges disclosed by the prior art, a prima facie case of obviousness exists (MPEP § 2144.05). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Redaelli et al., Fernandez-Alcon et al., Hansen et al., and Lauschke et al. to obtain the invention as specified in claim 11. Claims 16 -18 are rejected under 35 U.S.C. 103 as being unpatentable over Redaelli et al. (US 2018/0105782 A1) and Fernandez-Alcon et al. (US 2016/0326477 A1) as applied to claim 15 above, and further in view of Hung et al. (US 2012/0003732 A1) (see PTO-892). Regarding claim 16, modified Redaelli et al. teaches the apparatus of claim 15. Redaelli et al. fails to teach wherein the interface component further comprises one or more apertures defining the one or more cell culture chambers. -238125 1646555 However, Hung et al. teaches an interface component comprising one or more apertures defining the one or more cell cultures chambers (Fig. 5, well layer 503 defines one or more upper reservoir s 505 and one or more lower reservoirs 504; [0127] teaches the reservoirs are for culturing cells – see annotated figure below) . It would have been obvious to one of ordinary skill in the art to modify the apparatus of Redaelli et al. to incorporate the multiple apertures of Hung et al. to improve efficiency by increasing holding capacity. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Redaelli et al., Fernandez-Alcon et al., and Hung et al. to obtain the invention as specified in claim 16. Regarding claim 1 7 , modified Redaelli et al. teaches the apparatus of claim 15. Redaelli et al. fails to teach a base component connecting one or more cell culture chambers to the interface component. center 819150 However, Hung et al. teaches a base component connecting one or more cell culture chambers to the interface component (Fig. 4b, glass slide – see figure below) . It would have been obvious to one of ordinary skill in the art to modify the apparatus of Redaelli et al. to include the base component of Hung et al. because it would support the overall device and connect one or more cell culture chambers to fluidic ports. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Redaelli et al., Fernandez-Alcon et al., and Hung et al. to obtain the invention as specified in claim 1 7 . Regarding claim 1 8 , modified Redaelli et al. teaches the apparatus of claim 1. Redaelli et al. fails to teaches one or more pluralities of cell culture chambers each comprising multiple pneumatic chambers fluidly connected through one or more channels independent from other pluralities of cell culture chambers, and each comprising selectively adjusted pressures generated from the pneumatic actuator independent from other pluralities of cell culture chambers. center 6600825 0 0 center 3600450 0 0 However, Hung et al. teaches one or more pluralities of cell culture chambers (Fig. 11A shows one or more pluralities of cell culture chambers – see figure below ) each comprising multiple pneumatic chambers (Fig. 11B shows a flow inlet and flow outlet (i.e., multiple pneumatic chambers) for each cell culture chamber – see figure below ) fluidly connected through one or more channels independent from other pluralities of cell culture chambers (Fig. 11A shows channels independent from other pluralities), and each comprising selectively adjusted pressures generated from the pneumatic actuator ([0100], [0145] pressure generated from pneumatic manifold) independent from other pluralities of cell culture chambers ( [0106] teaches that each unit can be used as an independent biomimetic cell, implying pressure applied can be independent from other pluralities of cell cultures ). It would have been obvious to one of ordinary skill in the art to form the apparatus of Redaelli et al. with one or more pluralities of cell culture chambers each comprising multiple pneumatic chambers fluidly connected through one or more channels independent from other pluralities of cell culture chambers, and each comprising selectively adjusted pressures generated from the pneumatic actuator independent from other pluralities of cell culture chambers , as taught by Hung et al., because it would allow the user to study different cell lines simultaneously . Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Redaelli et al., Fernandez-Alcon et al., and Hung et al. to obtain the invention as specified in claim 18. Conclusion The prior art made of record and not relied upon is considered pertinent to applicant's disclosure : Ingber et al. (U.S. Patent 10,472,612 B2) discloses a system for culturing cells, the system mimicking natural intestinal epithelial structures using a membrane. Voronov et al. (US 2021/0115368 A1) discloses microfluidic systems for culturing cells. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT ADRIAN J CARREON whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-6818 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday - Friday 8:30 AM - 5 PM . 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, FILLIN "SPE Name?" \* MERGEFORMAT Michael Marcheschi can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-272-1374 . 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. /A.J.C./ Examiner, Art Unit 1799 /William H. Beisner/ Primary Examiner, Art Unit 1799