DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/20/2026 has been entered.
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 Claims 15-27 are withdrawn.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.
New 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 1, 7 and dependent claims 2, 6, 8, 9, 11 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.
Applicants’ amendment to claim 1 requires a microelectrode having neural cells cultured on the surface and a porous membrane comprising BMEC’s cultured on the upper surface of the membrane, yet the claim further states that, “wherein: said porous membrane is positioned above said microelectrode, said BMEC’s cultured on said microelectrode are facing said lower surface of said porous membrane and said lower surface is devoid of BMEM’s. The claim is confusing in that the BMEM’s are claimed in (ii) to be on the upper surface of the porous membrane, positioned above the microelectrode having neural cells cultured thereon, yet has been amended to state that the BMEM’s are cultured on the microelectrode which is facing the lower surface of the porous membrane.
For examination purposes, the claimed device is interpreted in light of the teachings of the specification, which discloses a microelectrode having neural cells cultured on the surface and a porous membrane comprising BMEC’s cultured on the upper surface of the membrane.
Claim 7 recites the limitation "said fluid" in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 7 should depend on claim 2.
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 Brown et al. (Biomicrofluidics, 2015, p. 1-15), 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 claims 2 and 7, membrane and microelectrode are inside a chamber, i.e. the microfluidic device itself, which contains a fluid, i.e. coculture medium (p. 185, System construction, p. 186, Fig. 1, p. 187, BBBoC assembly section). Regarding claim 6, the porous membrane is in the cell insert layer, while the microelectodes are each in the bottom perfusion layer and the top layer covering the neuronal chamber, each in fluid communication (p. 186, Fig. 1). 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 or the inclusion of neurons in the device.
Brown teaches that many BBB model devices fail to support all the cell types involved in the BBB formation and lack the shear forces for mature tight junction formation. More accurate in vitro BBB devices are needed to better understand the formation and function of the BBB and for studying therapeutics and toxicity across the BBB. Brown teach an in vitro BBB device comprising a microfluidic device having a vascular chamber (containing endothelial cells on a membrane) and a brain chamber (comprising neurons, astrocytes and pericytes) which is separated by a porous membrane, allowing cell-to-cell communication between the cells, as well as perfusion of both chambers (abstract). Brown teaches that their NeuroVascular Unit, i.e. BBB model, comprises and supports the growth and development of all cells involved in the proper formation of the BBB, which includes neurons, astrocytes, pericytes and microvascular endothelial cells (p. 2, 2nd to last parag., Fig. 1A), each necessary to recapitulate the BBB’s complexity and for evaluating neuronal response to BBB permeability, and allowing a microenvironment supporting all cell types for long term culture without loss of viability (p. 5, section D.).
Lippman teaches that BBB models have been difficult to construct which possess optimal BBB phenotypes, which are scalable and useable to investigate BBB function and brain-penetrating therapeutics. Lippman developed a human in vitro BBB device comprising BMEC’s, pericytes, astrocytes and neurons (abstract), wherein the combination of cells upregulates BBB properties, enhances TEER and barrier maturation (p. 5, co-culture enhances section). Lippman teaches that iBMEC’s cultured with pericytes, astrocytes, and neurons achieve physiological TEER values, forming a scalable, fully human BBB model (p. 2, 1st parag.).
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. Further, Brown and Lippman teach that neurons are important in BBB models to yield fully functioning BBB models which recapitulate the complexity of the BBB and allowing barrier maturation and the studying of BBB permeability. Therefore, one of ordinary skill in the art would have been motivated by the teachings of the art to include neurons in BBB models with BMEC’s, and glial cells including astrocytes.
Additionally, before the effective filing date of the claimed invention, Lippman teaches that there are methods to increase TEER in BBB model devices (comprising BMEC’s, neurons and glial cells) 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 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). While neurons are not disclosed as being one of the primary cells isolated, neurons and astrocytes are found together, mix together and touch each other directly within the brain and spinal cord, for example.
Thus, before the effective filing date of the claimed invention, the isolation of primary cells from a brain region was known in the art, and the use of primary cells isolated from a single brain region 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. The art collectively teaches the use of primary cells isolated from a brain region, and includes the use of neurons and glial cells, therefore, not only would the combination of cells be obvious, but one would have a reasonable expectation of successfully isolated cells which exist together in a single brain region. 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 neurons, astrocytes, pericytes, while the other side comprises brain microvascular endothelial cells as to replicate the BBB on stackable transwell inserts (0113, 114, 0129-0132, 0134, 0158, 0161). 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 claims 2 and 6, the device comprises first chamber assembly comprising stacked or multiple layers. The microelectrode array is taught to be on the bottom surface of the first chamber or lower chamber (0121, 0122, 0161) and the membrane is disposed on the bottom surface of a second base layer (0129), separating the upper assembly from the bottom assembly (0132). The membrane and electrodes are taken to be in a chamber, i.e., the device itself and the electrodes and membranes are in separate chambers (See Fig. 1E-2B, 0131-0134) and the chambers are in fluid communication with each other through the membrane (0023). Regarding claim 7, the chambers are disclosed to comprise culture media (0029, 0146, 0147).
Wikswo does not teach the limitation of claim 1 drawn to “wherein at least 90% of the cells on the surface of the microelectrode are neural cells (neurons and glia cells) from a single brain region, or the claimed TEER of claim 11.
Lippman teaches that BBB models have been difficult to construct which possess optimal BBB phenotypes, which are scalable and useable to investigate BBB function and brain-penetrating therapeutics. Lippman developed a human in vitro BBB device comprising BMEC’s, pericytes, astrocytes and neurons (abstract), wherein the combination of cells upregulates BBB properties, enhances TEER and barrier maturation (p. 5, co-culture enhances section). Lippman teaches that iBMEC’s cultured with pericytes, astrocytes, and neurons achieve physiological TEER values, forming a scalable, fully human BBB model (p. 2, 1st 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, 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 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). While neurons are not disclosed as being one of the primary cells isolated, neurons and astrocytes are found together, mix together and touch each other directly within the brain and spinal cord, for example.
Thus, before the effective filing date of the claimed invention, the isolation of primary cells from a brain region was known in the art, and the use of primary cells isolated from a single brain region 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. The art collectively teaches the use of primary cells isolated from a brain region, and includes the use of neurons and glial cells, therefore, not only would the combination of cells be obvious, but one would have a reasonable expectation of successfully isolated cells which exist together in a single brain region. 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 claims 2, 6, 7, the device is a dual channel, microfluidic organ chip culture device comprising two parallel microchannels separated by a porous membrane. The channels are in fluid communication with each other (p. 2295, Device design, p. 2296, Fig. 1) and the channels comprise cell culture medium, i.e. endothelial and cardiac media (p. 2300, Cell culture section).
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 claims 2, 6, 7, the device is a dual channel, microfluidic organ chip culture device comprising two parallel microchannels separated by a porous membrane (0012, 0013). The channels are in fluid communication with each other, and the channels (0060) comprise cell culture medium, i.e. endothelial and cardiac media (0086).
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.
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 neurons, astrocytes, pericytes, while the other side comprises brain microvascular endothelial cells as to replicate the BBB on stackable transwell inserts (0113, 114, 0129-0132, 0134, 0158, 0161). 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 claims 2 and 6, the device comprises first chamber assembly comprising stacked or multiple layers. The microelectrode array is taught to be on the bottom surface of the first chamber or lower chamber (0121, 0122, 0161) and the membrane is disposed on the bottom surface of a second base layer (0129), separating the upper assembly from the bottom assembly (0132). The membrane and electrodes are taken to be in a chamber, i.e., the device itself and the electrodes and membranes are in separate chambers (See Fig. 1E-2B, 0131-0134) and the chambers are in fluid communication with each other through the membrane (0023). Regarding claim 7, the chambers are disclosed to comprise culture media (0029, 0146, 0147).
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 neurons, 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 combination of cells mimic structural and functional features of the BBB and the use of neurons in the device allows for a more mature electrophysiology, indicating advanced and accelerated maturation (p. 1, last parag.-p. 2, 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, neurons, and glial cells. The art teaches that BMEC’s (iBMEC’s), neurons, 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.
The above references do not teach the limitation of claim 1 drawn to “wherein at least 90% of the cells on the surface of the microelectrode are neural cells (neurons and glia cells) from a single brain region.
Regarding 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). While neurons are not disclosed as being one of the primary cells isolated, neurons and astrocytes are found together, mix together and touch each other directly within the brain and spinal cord, for example.
Thus, before the effective filing date of the claimed invention, the isolation of primary cells from a brain region was known in the art, and the use of primary cells isolated from a single brain region 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. The art collectively teaches the use of primary cells isolated from a brain region, and includes the use of neurons and glial cells, therefore, not only would the combination of cells be obvious, but one would have a reasonable expectation of successfully isolated cells which exist together in a single brain region. 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 teachings 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. are found above.
The 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
Applicants’ arguments filed 7/20/2026 have been fully considered but they are not persuasive.
Applicants’ arguments directed to the claim amendment which now requires the presence of both neurons and glial cells have been addressed in the rejections above.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicants argue Wang teaches pericytes cultured on the opposite side of the membrane from endothelial cells, which does not satisfy the claimed configuration of wherein the lower surface of the membrane is “devoid of BMEC’s”, but rather contradicts it. The claim requires BMEC’s on the upper surface only.
It is important to point out that the claim requires the lower surface (of the membrane) to be devoid of BMEC’s. The pericytes of Wang are not BMEC’s, and thus applicants argument is not persuasive or commensurate in scope with the claimed invention.
Regarding Lippman applicants argue that Lippman does not teach the claimed structural arrangement and does not teach at least 90% neurons and glia cells from a single brain region cultured on the microelectrode.
Lippman is relied upon for teaching a human in vitro BBB device comprising BMEC’s, pericytes, astrocytes and neurons, wherein the combination of cells upregulates BBB properties, enhances TEER and barrier maturation. Additionally, Lippman teaches their BBB model having TEER of approximately 5000 Ωxcm2 .
Regarding Maoz and Jeong, applicants argue that the reference teaches using primary astrocytes from the forebrain, however they do not teach both neurons and glia cells according to the amended claims.
It is the Examiners position that 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. Jeong isolate and use primary astrocytes from the cortices of the forebrain 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. While neurons are not disclosed as being one of the primary cells isolated, neurons and astrocytes are found together and touch each other directly within the brain and spinal cord, for example.
Thus, before the effective filing date of the claimed invention, the isolation of primary cells from a brain region was known in the art, and the use of primary cells isolated from a single brain region 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. The art collectively teaches the use of primary cells isolated from a brain region, and includes the use of neurons and glial cells, therefore, not only would the combination of cells be obvious, but one would have a reasonable expectation of successfully isolated cells which exist together in a single brain region. 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.
Conclusion
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melenie Gordon can be reached at 571-272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TIFFANY M GOUGH/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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