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 .
Applicant’s response filed 01/07/2026 has been received and entered into the case. Claims 1, 2, 6-9, 11, 15-27 are pending. Claims 15-27 are withdrawn. Claims 1, 2, 6-9, 11 have been considered on the merits. All arguments and amendments have been considered.
The following rejections are withdrawn in light of applicants claim amendments; Claim(s) 1, 2, 6 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Maoz et al. (Lab on Chip, 2017, vol. 17, p. 2294-2302), Claim(s) 1, 2, 6 rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Maoz et al. (WO2018157073 A1), Claim(s) 1, 2, 6-9 rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Wikswo et al. (US20180326417), and Claim(s) 1, 2, 6, 7, 9 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wang (Mol. Pharmaceutics, 2016, vol. 13, p. 895-906).
New rejections necessitated by amendment
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.
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, 2, 6-9, 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wang (Mol. Pharmaceutics, 2016, vol. 13, p. 895-906) in view of Lippman (IDS) and Jeong et al. (IEEE trans. on Biomed Eng., vol. 65, 2018, p. 431-439).
Wang teaches a microfluidic BBB device comprising layered microfluidic channels separated by a porous membrane having brain endothelial cells (b.End.3, i.e. brain microvascular endothelial cell line) cultured on the upper surface of the membrane and pericytes cultured on the opposite side of the membrane and astrocytes cultured on the bottom of the lower channel to better replicate the BBB neurovascular unit, organization and behaviors (abstract, introduction, Fig. 1, p. 897, whole page) according to claims 1, 2, 6, 7. Regarding claim 9, the device comprises embedded electrodes in the upper and lower microfluidic channels, wherein astrocytes, i.e. glial cells, are cultured in the lower channel on the electrode (Fig. 4A).
Wang does not teach the limitations of claims 8 and 11.
Regarding claim 8, Lippman teach using iBMEC’s which are from stem cells which can be differentiated into cells possessing both endothelial and BBB properties (p. 1, last parag.) Regarding claim 11, while the references do not teach the membrane to have an electrical resistance of at least 5000Ωxcm2, Lippman teaches a BBB device model comprising iBMEC’s, pericytes, astrocytes and neurons, wherein the iBMEC’s were treated with retinoic acid (RA) and then co-cultured with pericytes, astrocytes and neurons in Transwell inserts yielding a BBB model having TEER of approximately 5000 Ωxcm2 (abstract, intro. p. 1, last parag.-p. 2, p. 8, 1st col, last parag.). The RA is taught to enhance BBB properties in iBMEC’s including increase in tight junction protein expression (p. 2, Results section), increasing proliferation of BMEC’s and other cells culture (p. 3, 1st parag.), enhances barrier phenotype of iBMEC’s (p. 3, 1st full parag.). Lippman also finds that co-cultures demonstrate that iBMEC’s respond to cues from astrocytes, and pericytes and elevate TEER and enhance barrier characteristics (p. 3, last parag.-p. 5, p. 6, discussion section, Fig. 4A, B).
Before the effective filing date of the claimed invention, it would have been obvious to use iBMEC’s of Lippman in the device of Wang because one could have substituted one known BMEC for another in the device and the substitution would have been predictable.
Additionally, before the effective filing date of the claimed invention, Lippman teaches that there are methods to increase TEER in BBB model devices to at least 5000 Ωxcm2 , therefore one of ordinary skill in the art could have pursued known options within his or her technical grasp with a reasonable expectation of successfully making a model/device having TEER values comparable to in vivo BBB TEER levels.
Regarding applicants’ amendment to claim 1, drawn to the limitation of “wherein at least 90% of the cells on the surface of the microelectrode are neural cells from a single brain region; while the references teach using neural cell lines or IPSC’s as the cell source, it was known in the art to isolate and use primary cells in BBB chips (having MEA’s within). Jeong teaches that the use of cell lines instead of primary cells can result in large gaps in physiological cellular interactions in vitro compared to the in vivo environment (p. 432, 2nd col.). Jeong isolate and use primary astrocytes from the cortices of the forebrain (p. 434, section C primary cell preparation) and find that their BBB chip allows for the formation of realistic and brain-capillary interface, increased tight junction and barrier formation and thus increased TEER (p. 432, 2nd col., p. 436, section 3, Astrocyte-Endothelial cell interaction section).
Thus, before the effective filing date of the claimed invention, the use of primary cells isolated from a single brain region used in BBB devices was known and their use achieves a more in vivo like environment compared to in vitro devices which use cell lines, for example. Thus, a posita has good reason to pursue the known options within his or her technical grasp with a reasonable expectation of successfully making a BBB model which mimics the in vivo physiological conditions and function more accurately.
Claim(s) 1, 2, 6-9, 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wikswo et al. (US20180326417) in view of Lippman (IDS) and Jeong et al. (IEEE trans. on Biomed Eng., vol. 65, 2018, p. 431-439).
Wikswo teaches a microfluidic neurovascular(NVU)-BBB device (abstract, 0007, 0113) comprising a vascular chamber and a brain chamber separated from each other by a porous membrane, wherein one side of the membrane comprises astrocytes, pericytes, while the other side comprises brain microvascular endothelial cells as to replicate the BBB on stackable transwell inserts (0113, 0129-0132, 0134). All cells in the device are disclosed to be derived from iPSC’s (0113, 0114). The NVU-BBB device comprises microelectrode arrays (MEA) for measuring TEER (0118). Wikswo teaches that the transwell inserts can be stacked on electrodes to record electrical activity of the neurons, and one way to accomplish this is to pattern the substrate that supports the neurons with a MEA, thereby growing the neurons on the MEA (0161, Ex. 3, 0191, Ex. 4, 5, 9).
Wikswo does not teach the claimed TEER of claim 11.
Regarding claim 11, while the references do not teach the membrane to have an electrical resistance of at least 5000Ωxcm2, Lippman teaches a BBB device model comprising iBMEC’s, pericytes, astrocytes and neurons, wherein the iBMEC’s were treated with retinoic acid (RA) and then co-cultured with pericytes, astrocytes and neurons in Transwell inserts yielding a BBB model having TEER of approximately 5000 Ωxcm2 (abstract, intro. p. 1, last parag.-p. 2, p. 8, 1st col, last parag.). The RA is taught to enhance BBB properties in iBMEC’s including increase in tight junction protein expression (p. 2, Results section), increasing proliferation of BMEC’s and other cells culture (p. 3, 1st parag.), enhances barrier phenotype of iBMEC’s (p. 3, 1st full parag.). Lippman also finds that co-cultures demonstrate that iBMEC’s respond to cues from astrocytes, and pericytes and elevate TEER and enhance barrier characteristics (p. 3, last parag.-p. 5, p. 6, discussion section, Fig. 4A, B).
Before the effective filing date of the claimed invention, Lippman teaches that there are methods to increase TEER in BBB model devices to at least 5000 Ωxcm2 , therefore one of ordinary skill in the art could have pursued known options within his or her technical grasp with a reasonable expectation of successfully making a model/device having TEER values comparable to in vivo BBB TEER levels.
Regarding applicants’ amendment to claim 1, drawn to the limitation of “wherein at least 90% of the cells on the surface of the microelectrode are neural cells from a single brain region; while the references teach using neural cell lines or IPSC’s as the cell source, it was known in the art to isolate and use primary cells in BBB chips (having MEA’s within). Jeong teaches that the use of cell lines instead of primary cells can result in large gaps in physiological cellular interactions in vitro compared to the in vivo environment (p. 432, 2nd col.). Jeong isolate and use primary astrocytes from the cortices of the forebrain (p. 434, section C primary cell preparation) and find that their BBB chip allows for the formation of realistic and brain-capillary interface, increased tight junction and barrier formation and thus increased TEER (p. 432, 2nd col., p. 436, section 3, Astrocyte-Endothelial cell interaction section).
Thus, before the effective filing date of the claimed invention, the use of primary cells isolated from a single brain region used in BBB devices was known and their use achieves a more in vivo like environment compared to in vitro devices which use cell lines, for example. Thus, a posita has good reason to pursue the known options within his or her technical grasp with a reasonable expectation of successfully making a BBB model which mimics the in vivo physiological conditions and function more accurately.
Claim(s) 1, 2, 6-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over each of Maoz et al. (Lab on Chip, 2017, vol. 17, p. 2294-2302) and Maoz et al. (WO2018157073 A1) in view of Wang (Mol. Pharmaceutics, 2016, vol. 13, p. 895-906), Wikswo et al. (US20180326417), WO2017070224 and Jeong et al. (IEEE trans. on Biomed Eng., vol. 65, 2018, p. 431-439).
Maoz teaches a device comprising a microelectrode (microelectrode array (MEA)) comprising cells cultured on the surface of the microelectrode and a porous membrane comprising an upper surface comprising cells cultured thereon (abstract, Fig. 1c). The porous membrane is positioned above the microelectrode and the cells cultured on the microelectrode are facing the lower surface of the membrane (Fig. 1c, p. 2295, Results and Discussion Device design, device fabrication). The device is designated a TEER-MEA organ chip and the reference teaches that TEER measurements are applied to Organ Chip models of blood-brain-barrier. The integration of electrodes into organ chips close to the cell monolayer combined with electric circuit modeling gives accurate TEER values compared to organ chip models wherein electrodes are placed in organ chip inlets and outlets far from the cell monolayer, which gives erroneous TEER values (p. 2295, 1st parag.). Maoz teaches that MEA is an invaluable tool for assessing function of excitable cells including neural cells and muscle cells (p. 2295, 2nd parag.) and the TEER-MEA chip allows for real time simultaneous assessment of cell barrier function and electrical activity and is applicable to any type of cultured electrically active cell (p. 2295, 3rd parag.). Regarding claim 6, the cells cultured on the membrane are at least 90% endothelial cells as only endothelial cells are cultured on the membrane (Fig. 1c).
Regarding claim 1, Maoz (WO’073) teaches a device comprising a microelectrode (microelectrode array (MEA)) comprising cells cultured on the surface of the microelectrode and a porous membrane comprising an upper surface comprising cells cultured thereon (abstract, Fig. 1c). The porous membrane is positioned above the microelectrode and the cells cultured on the microelectrode are facing the lower surface of the membrane (0012-0014, 0059-0061, Fig. 1C). The device is designated a TEER-MEA organ chip and the reference teaches that TEER measurements are applied to Organ Chip models of blood-brain-barrier (0008). The integration of electrodes into organ chips close to the cell monolayer combined with electric circuit modeling gives accurate TEER values compared to organ chip models wherein electrodes are placed in organ chip inlets and outlets far from the cell monolayer, which gives erroneous TEER values (0008). Maoz teaches that MEA is an invaluable tool for assessing function of excitable cells including neural cells and muscle cells (0009) and the TEER-MEA chip allows for real time simultaneous assessment of cell barrier function and electrical activity and is applicable to any type of cultured electrically active cell (0058).
Regarding claim 6, the cells cultured on the membrane are at least 90% endothelial cells as only endothelial cells are cultured on the membrane (Fig. 1c, 0012-0014, 0060, 0061).
While Maoz teaches that the organ-on chip devices can be applied to make BBB on-chip and that MEA’s is an invaluable tool for assessing function of excitable neural cells, Maoz does not teach the cells in the device to be brain endothelial cells (on the membrane) and the cells on the microelectrode to be neural cells, specifically glial cells according to claim 9.
Wang teaches a microfluidic BBB device comprising layered microfluidic channels separated by a porous membrane having brain endothelial cells (b.End.3, i.e. brain microvascular endothelial cell line) cultured on the upper surface of the membrane and pericytes cultured on the opposite side of the membrane and astrocytes cultured on the bottom of the lower channel to better replicate the BBB neurovascular unit, organization and behaviors (abstract, introduction, Fig. 1, p. 897, whole page) according to claims 1, 2, 6-8. Regarding claim 9, the device comprises embedded electrodes in the upper and lower microfluidic channels, wherein astrocytes are cultured in the lower channel on the electrode to better mimic the in vivo BBB (Fig. 4A).
Wikswo teaches a microfluidic neurovascular(NVU)-BBB device (abstract, 0007, 0113) comprising a vascular chamber and a brain chamber separated from each other by a porous membrane, wherein one side of the membrane comprises astrocytes, pericytes, while the other side comprises brain microvascular endothelial cells as to replicate the BBB on stackable transwell inserts (0113, 0129-0132, 0134). All cells in the device are disclosed to be derived from iPSC’s (0113, 0114). The NVU-BBB device comprises microelectrode arrays (MEA) for measuring TEER (0118). Wikswo teaches that the transwell inserts can be stacked on electrodes to record electrical activity of the neurons, and one way to accomplish this is to pattern the substrate that supports the neurons with a MEA, thereby growing the neurons on the MEA (0161, Ex. 3, 0191, Ex. 4, 5, 9).
Regarding clam 8, WO2017070224 teaches a microfluidic BBB-on-chip device comprising a porous membrane having cells culture thereon. The cells may be cultured on the top and/or bottom of the membrane. The cells include glial cells including astrocytes and endothelial cells, specifically iBMEC’s (p. 1-3, 17, 1st parag.,). WO’224 teaches that microelectrode arrays can be integrated on the membrane and can be applied to astrocytes which are known to be excitable (p. 22, last parag., last sentence -p. 23, 1st parag.).
The art teaches cells for use in organ-on-chip devices depending on the specific organ to be studied. The instant invention is taken to be a BBB device comprising BMEC’s and glial cells. The art teaches that BMEC’s (iBMEC’s) and glial cells (cells of the neurovascular unit) are used to generate BBB models to study interactions between BMEC’s and other cells of the neurovascular unit. Therefore, before the effective filing date of the claimed invention, it would have been obvious to use BBB specific cells in the device of Maoz, given the teachings of the secondary references. One could have pursued known cell options within his or her technical grasp with a reasonable expectation of successfully making a BBB device.
Regarding applicants’ amendment to claim 1, drawn to the limitation of “wherein at least 90% of the cells on the surface of the microelectrode are neural cells from a single brain region; while the references teach using cell lines or IPSC’s as the cell source, it was known in the art to isolate and use primary cells in BBB chips (having MEA’s within). Jeong teaches that the use of cell lines instead of primary cells can result in large gaps in physiological cellular interactions in vitro compared to the in vivo environment (p. 432, 2nd col.). Jeong isolate and use primary astrocytes from the cortices of the forebrain (p. 434, section C primary cell preparation) and find that their BBB chip allows for the formation of realistic and brain-capillary interface, increased tight junction and barrier formation and thus increased TEER (p. 432, 2nd col., p. 436, section 3, Astrocyte-Endothelial cell interaction section).
Thus, before the effective filing date of the claimed invention, the use of primary cells isolated from a single brain region used in BBB devices was known and their use achieves a more in vivo like environment compared to in vitro devices which use cell lines, for example. Thus, a posita has good reason to pursue the known options within his or her technical grasp with a reasonable expectation of successfully making a BBB model which mimics the in vivo physiological conditions and function more accurately.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over each of Maoz et al. (Lab on Chip, 2017, vol. 17, p. 2294-2302) Maoz et al. (WO2018157073 A1) in view of Wang (Mol. Pharmaceutics, 2016, vol. 13, p. 895-906), Wikswo et al. (US20180326417), WO2017070224 and Jeong et al. (IEEE trans. on Biomed Eng., vol. 65, 2018, p. 431-439) as applied to claims 1, 2, 6-9 above, and further in view of Lippman (IDS)
The above references do not teach the TEER value of claim 11.
Regarding claim 11, while the references do not teach the membrane to have an electrical resistance of at least 5000Ωxcm2, Lippman teaches a BBB device model comprising iBMEC’s, pericytes, astrocytes and neurons, wherein the iBMEC’s were treated with retinoic acid (RA) and then co-cultured with pericytes, astrocytes and neurons in Transwell inserts yielding a BBB model having TEER of approximately 5000 Ωxcm2 (abstract, intro. p. 1, last parag.-p. 2, p. 8, 1st col, last parag.). The RA is taught to enhance BBB properties in iBMEC’s including increase in tight junction protein expression (p. 2, Results section), increasing proliferation of BMEC’s and other cells culture (p. 3, 1st parag.), enhances barrier phenotype of iBMEC’s (p. 3, 1st full parag.). Lippman also finds that co-cultures demonstrate that iBMEC’s respond to cues from astrocytes, and pericytes and elevate TEER and enhance barrier characteristics (p. 3, last parag.-p. 5, p. 6, discussion section, Fig. 4A, B).
Before the effective filing date of the claimed invention, Lippman teaches that there are methods to increase TEER in BBB model devices to at least 5000 Ωxcm2 , therefore one of ordinary skill in the art could have pursued known options within his or her technical grasp with a reasonable expectation of successfully making a model/device having TEER values comparable to in vivo BBB TEER levels.
Response to Arguments
Applicant's arguments filed 1/7/2026 have been fully considered but they are not persuasive. Applicant argues that the references fail to teach the structural arrangement wherein at least 90% of cells cultured on the surface of the microelectrode are neural cells from a single brain region. Applicants also argue that claim 2 requires the lower surface of the membrane to be devoid of the cultured cells of the upper surface and that the cited references teach cells culture on both surfaces of the membrane. For example, Wang teaches pericytes cultured on the opposite side of the membrane from endothelial cells, which does not satisfy the requirement of the neurons on one side of the membrane and brain endothelial cells on the other side, thus failing to disclose a lower surface devoid of culture cells. Applicants argue that Wikswo teaches astrocytes and pericytes, which are not neurons, on one side of the membrane and endothelial cells on the other side of the membrane, failing to disclose a lower surface devoid of cultured cells. Additionally, regarding the 103 rejection, applicants further argue that Claim 1 recites a device comprising a microelectrode comprising neuron cells culture on the microelectrode, a porous membrane comprising an upper surface comprising cultured cells and a lower surface, wherein the membrane is positioned above the microelectrode and the neuron cells are cultured on the microelectrode facing the lower surface of the membrane, further claim 2 requires that the lower surface is devoid of the cultured neuron cells of the upper surface.
Applicants’ arguments are not commensurate in scope with the claimed invention.
It is important to point out that claim 2 is drawn to the lower surface (of the membrane) being devoid of said cultured cells of said upper surface (of the membrane). This is interpreted by the Examiner to mean that the same cells cultured on said upper surface are not on the lower surface, meaning that a different cell type can/may be present on the lower surface so long as it is not the same cultured cell from the upper surface. The claim is not drawn to being devoid of any cells but rather devoid of the cells (endothelial) cultured on the upper surface. Additionally, applicants argue the “neuron cells” of the upper surface; however the claims are drawn to neural cells not neurons (see below) and the neural cells are not cultured on the upper surface but rather below the membrane on the microelectrode.
Regarding applicants’ argument that the cells of Wang and Wikswo do not satisfy the requirement of neurons of claim 1, applicants arguments are not commensurate in scope with the claimed invention because the claims are not drawn to neurons, but rather neural cells, and claim 9 is drawn to glial cells. Astrocytes are neural and glial cells.
Thus, applicants arguments are not commensurate in scope with the claimed invention, and are not found persuasive at this time.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY MAUREEN GOUGH whose telephone number is (571)272-0697. The examiner can normally be reached M-Thu 8-5.
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/TIFFANY M GOUGH/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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