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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/20/2026 has been entered.
Claims 1-5, 9, 10, 32-35 are pending and have been considered on the merits. All arguments and amendments have been considered.
Claim Objections
Claims 1, 5, 10 and 32, 33 objected to because of the following informalities: claim 1 starting at “an apical chamber”, line 2 of this section states “disposed on a top an apical…”. This is grammatically incorrect. Line 4 of claim 10 has duplicate recitations of “central chamber” and the last line of claim 32 recites “comprises comprise”. Claim 33 recites “…into the fluidic channel of the second interstitial chamber one or more additional chambers…”. Appropriate correction is required.
Regarding claim 5, the first 3 lines of the claim are redundant and grammatically incorrect. The claim has been amended to state that “wherein the second microfluidic channel of the apical chamber is in fluid communication with the fluidic channel of the central chamber is in fluid communication with the second microfluidic channel of the apical chamber…”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5, 9, 10, 32-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. When looking to applicants’ disclosure, the microfluidic device is taught to include a basal chamber, an apical chamber and a central interstitial chamber. The basal chamber includes a first microfluidic channel disposed thereon, the central interstitial chamber includes a second microfluidic channel disposed thereon, and the apical chamber includes a third microfluidic channel disposed thereon. The device also includes a first membrane disposed between the basal chamber and the interstitial chamber, a second membrane disposed between the interstitial chamber and the apical chamber, a three-dimensional, extracellular matrix hydrogel disposed in the interstitial chamber between the first and second membranes, and a base supporting the first, second and third microfluidic channels. The microfluidic device can contain multiple interstitial chambers stacked vertically to create layered structures reminiscent of stromal tissues in the lung (0008). (0012) In certain embodiments, the basal chamber(s) is in fluid and physical communication with the interstitial chamber(s) through the first membrane. In certain embodiments, the interstitial chamber(s) is in fluid and physical communication with the apical chamber(s) through the second membrane. In certain embodiments, the basal chamber(s), the interstitial chamber(s) and the apical chamber(s) can be in fluid and physical communication through the first membrane and the second membrane. In certain embodiments, the interstitial chamber(s) is continuous between the first and second membranes such that fluid and physical communication is permitted between the basal chamber(s) and the apical chamber(s) via the interstitial chamber(s). In certain embodiments, the first membrane has a first monolayer of epithelial cells disposed thereon, and the second membrane has a second monolayer of epithelial cells disposed thereon. In certain embodiments, the first membrane has a monolayer of epithelial cells disposed thereon, and the second membrane has a monolayer of endothelial cells disposed thereon. The specification teaches that the device may comprise more than one interstitial chamber and layered on top of each other (0008, 0017, 0019). Further, Fig. 2 and 9, teach the devices. (0072) With reference to FIG. 2 for the purpose of illustration and not limitation, there is provided a schematic of an exemplary microfluidic device. In certain embodiments, the microfluidic device 100 can include a base 10, an apical chamber 20 (also referred to herein as an epithelial chamber, epithelium or as the chamber containing an epithelial layer), an interstitial chamber 21 (also referred to herein as interstitium, an interstitial layer, a stromal layer, or a hydrogel layer), a basal chamber 22 (also referred to herein as an endothelial chamber, endothelium or as the chamber containing an endothelial layer), a first membrane 41 with a first monolayer of endothelial cells 32 disposed thereon, a second membrane 40 with a second monolayer of epithelial cells 30 disposed thereon, an interstitial extracellular matrix hydrogel with encapsulated human primary lung fibroblast cells encapsulated therein 31, and support pillars 50 to prevent membrane deflection. The layer of epithelial cells resides on the surface of the second membrane that is facing the apical chamber. The layer of endothelial cells resides on the surface of the first membrane that faces the basal chamber. [0100] With reference to FIG. 9D for the purpose of illustration and not limitation, there is provided a cross-sectional view of an exemplary 7-chamber microfluidic device 944 assembled by layered stacking or bonding of a basal chamber 943, a first membrane 942, a first interstitial chamber 941, a second membrane 940, a second interstitial chamber 939, a third membrane 938, a third interstitial chamber 937, a fourth membrane 936, a fourth interstitial chamber 935, a fifth membrane 934, a fifth interstitial chamber 933, a sixth membrane 932, and an apical chamber 931. (0079) In certain embodiments, the membrane 41 can be disposed between basal chamber 22 and interstitial chamber 21 such that the basal chamber 22 and the interstitial chamber 21 can be in fluid communication through the membrane 41. In certain embodiments, the membrane 40 can be disposed between interstitial chamber 21 and apical chamber 20 such that the interstitial chamber 21 and the apical chamber 20 can be in fluid communication through the membrane 40. In certain embodiments, the first membrane 41 can be disposed between basal chamber 22 and interstitial chamber 21 and the second membrane 40 can be disposed between interstitial chamber 21 and apical chamber 20, such that the basal chamber 22, the interstitial chamber 21, and the apical chamber 20 can be in fluid communication through the first membrane 41 and the second membrane 40. In the 5-chamber system, the specification discloses that a 5-chamber system that is separated at each chamber-to-chamber interface by a membrane can contain the first and fifth (topmost and bottommost, respectively) chambers as endothelial cell chambers (basal chambers), the second and fourth chambers as interstitial chambers containing different densities of hydrogels or fibroblast cells, and the third, center chamber as the apical chamber with epithelial cells seeded onto both facing membranes (0013).
However, the amendments to claims 1, including “a fluidic channel through the thickness thereof”, and the claiming of the apical chamber as the top most chamber and having a second membrane arranged between the second interstitial central chamber having endothelial cells thereon facing the second microfluidic channel is not disclosed. At best parag. (0013) describes a 5-chamber device; however, the top most chamber is not an apical chamber as claimed. The amendments introduce new matter, which is not described in the specification as originally filed. Therefore, the amendments to claim 1 describing the currently claimed arrangement of the device changes the scope of the claims and applicants invention for which no support is provided. This is a new matter rejection.
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, 4, 5, 9 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.
Claims 1 and 9 recites the limitation "the first interstitial central chamber" (claim 1) as well as “the first interstitial chamber central chamber” and “the second interstitial central chamber” (claims 1 and 9). There is insufficient antecedent basis for this limitation in the claim. The claims include a central chamber and an interstitial chamber but not an interstitial central chamber or interstitial chamber central chamber.
Further, regarding current claim 1, it is not clear what the central chamber is, for example, does the central chamber comprise the interstitial, apical and basal chambers, and the membranes, or is the central chamber a chamber separate from the interstitial, apical and basal chambers. For examination purposes, the central chamber has been interpreted in light of the specification, which discloses that the microfluidic device comprises a basal chamber, an apical chamber and a central interstitial chamber.
Claim 4 recites the limitation "the fluidic second microfluidic" in the central chamber. There is insufficient antecedent basis for this limitation in the claim. First, there is no recitation of “a fluidic second microfluidic channel” or “the fluidic second microfluidic channel of the central chamber” in claim 1. Additionally, the term “fluidic” is redundant as it is a microfluidic channel.
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, 3-5, 9, 10, 32, 34, 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Grego et al. (US2014/0335496 A1, IDS) in view of Huh (US2018/0216058, IDS) supported by Kim et al. (Biomaterials, 2015, vol. 40, p.51-60).
Regarding claim 1, Grego teaches a microfluidic device airway model comprising a first chamber having an inlet and an outlet and containing airway/bronchial epithelial cells (0041); a second chamber having an inlet and an outlet and containing an extracellular matrix and fibroblasts embedded within (0044), wherein the second chamber is separated from the first chamber by a porous membrane; and a third chamber having an inlet and an outlet and containing endothelial cells, wherein the third chamber is separated from the second chamber by a porous membrane (abstract, 0009, 0012, 0030, 0031, 0041-0049). The system is configured to allow with separate fluidic pathways through each of the chambers allowing air and liquid flow therethrough (0009, 0012), thus corresponding the applicants claimed central chamber configured to permit airflow therethrough, having a microchannel therethrough, an apical chamber/channel (upper) disposed on the apical surface of the central chamber, an basal chamber/channel (lower) disposed on the basal surface of the central chamber, a first membrane between the basal chamber and the central chamber and a second membrane between the central chamber and the apical chamber.
Regarding claim 3, human primary lung fibroblasts are embedded within a three-dimensional extracellular matrix hydrogel within the interstitial chamber (0031, 0044).
Regarding claims 4, 5,10, the porous membranes allow for diffusion therethrough and thus allow for fluid communication between all of the channels (0010, 0012).
Regarding claim 9, each channel/chamber comprises tubing channels, a syringe pump, and an inlet and outlet port (0009, 0034, 0035).
Regarding claim 34, Grego teaches extracellular matrix hydrogels which are chemically crosslinked (00440). Matrigel® is a known crosslinked ECM hydrogel as are poly(ethylene glycol dimethacrylate) (PEDGMA) hydrogels.
Grego does not teach the newly added limitations directed to a second interstitial chamber, a third and fourth membrane and the one or more additional chambers of clam 1. Additionally Grego does not teach the limitations of claims 32-35.
Huh teaches a microfluidic device comprising a first and second microchannel in fluid communication with each other through a membrane disposed between the microchannels, wherein the membrane has airway epithelial cells thereon (abstract, 0005-0008, 0049) and endothelial cells adhered to the second side of the membrane (0052) and a central cell-laden gel layer comprising extracellular matrix proteins with cells (fibroblasts) embedded therein on the second side of the membrane allowing the embedded cells to communicate with the cells on the membranes (0008, 0053). Additional cells may be embedded within the gel layer including stromal cells, airway and/or vascular cells, connective tissue or cells, and macrophages (0051-0053).
Regarding claim 1, Huh teaches that the device/base can include additional channels (four, six, eight or more, total channels) in pairs of two (or larger than two) disposed thereon, each having a membrane disposed between . The number of channels and layouts of the channels, including size and dimensions, can vary based on the design of the device (0047).
Regarding claims 4, 5, 10, and 35, the channels are in fluid communication with each other through the membranes (0048, 0055, 0056), and thus, each of the channels are confined by a membrane, which allow the channels to all be in fluid communication with each other.
Regarding claim 34, the gel is disclosed to be chemically crosslinked via sulpho-sanpah treatment (0016, 0057).
Therefore, before the effective filing date of the claimed invention, it would have been within the purview of one of ordinary skill in the art to modify the device of Grego to include additional channels as a matter of design choice in view of Huh.
While the specific arrangement currently claimed is not taught per se, the art teaches microfluidic devices which recreate the aveolar-capillary interface/3D microarchitecture (tissue-tissue-interface) of the lung, wherein the devices comprise a top apical channel (comprising epithelial cells), a membrane, a middle cell-laden gel layer comprising fibroblasts, a membrane, and a bottom basal layer (comprising endothelial cells), wherein the channels are in fluid communication with each other through the membranes. The art suggests that the device may comprise eight or more channels each having a membrane between.
Regarding claims 1, 3, 32, directed to a first and second interstitial chamber comprising fibroblast-laden hydrogels and a third and fourth membrane having a monolayer of epithelial cells thereon, when adding additional chambers/channels adjacent to the central chambers as taught by Huh, it would be obvious to include additional central 3D ECM hydrogel in the channels mimicking the lung interstitium which in vivo is sandwiched between opposing monolayers of aveolar epithelial cells facilitating gas exchange, and thus when layering as claimed, having two interstitial chambers in the central section of the device, it would be obvious to surround the central chambers (mimicking the interstitium, each containing a fibroblast-laden ECM hydrogel therein) with epithelial cells, separate these central interstitial chambers by a membrane and line the other sides of the membranes with microvascular endothelial cells to mimic the air-blood barrier of the lung thereby mimicking the aveolar-capillary interface.
The combination of prior art references of record teach biomimetic microfluidic devices comprising multiple chambers in a microfluidic device separated by membranes having cells thereon. Huh teaches a central layer having cells embedded within, which communicate with the cells on the membranes in the other channels to mimic the natural in vivo environments, and suggests adding additional chambers/channels adjacent to the central chambers.
Regarding claim 32, when adding additional chambers/channels adjacent to the central chambers as taught by Huh (to Grego), it would have been obvious to add a 3D ECM hydrogel to the one or more channels (in communication with the cells in adjacent channels) and for the hydrogel to comprise the same or different density to provide an ECM environment which mimics that of the native tissue/organ environments. It is well-known that the native ECM influences cell behaviors including cell migration, proliferation, differentiation and varies widely. Varying stiffness, for example, allows a posita to study cell-matrix interactions influencing cell behavior (for support see Kim, p. 51-52, Introduction.) and thus, it would have been obvious before the effective filing date of the claimed invention to vary ECM densities in biomimetic devices to allow one to study cell behavior.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Grego et al. (US2014/0335496 A1, IDS) in view of Huh (US2018/0216058, IDS) supported by Kim et al. (Biomaterials, 2015, vol. 40, p.51-60) as applied to claims 1, 3-5, 9, 10, 32, 34, 35 above, and further in view of Vulto et al. (WO2017/155399 A1, IDS).
The teachings of Grego in view of Huh are found above.
The references do not teach support pillars of claim 2.
WO’399 teach a microfluidic device having a microfluidic channel network comprising a channel having an extracellular matrix gel with fibroblast cells therein (p. 8, lines 29-p. 9, lines 1-20, p. 12, lines 8-10), which contains pillars to support gel formation within the channel network and prevent spreading (p. 14, lines 30-p. 15, lines 1-11).
Therefore, before the effective filing date of the claimed invention, it would have been obvious to include support pillars in the microfluidic device of Grego taken with Huh, as WO’399 teaches the pillars to support the network when a gel is in the central channel.
Claim(s) 1, 3-5, 9, 10, 32-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ingber et al. (WO2010/009307A2, IDS) in view of Grego et al. (US2014/0335496 A1, IDS) and Huh (US2018/0216058, IDS) supported by Kim et al. (Biomaterials, 2015, vol. 40, p.51-60).
Regarding claim 1, WO’307 teaches a microfluidic device which is an organ mimic device comprising a central chamber separated by two or more porous membranes to divide the central channel into two or more parallel central microchannels, thus creating three or more parallel microchannels, wherein fluids are applied through the microchannels (abstract, 0019, 0021, 0066, 0092, 00165, 0166, 00168). The three or more microchannels are each separated by a porous membrane. The membranes are lined by a common tissue type in the central channel and two different tissue types on the opposite sides of the membrane in the two outer channels (0021), i.e., corresponding the applicants claimed central chamber having a microchannel therethrough, an apical chamber/channel (upper) disposed on the central chamber, a basal chamber/channel (lower) disposed on the below the central chamber, a first membrane between the apical chamber (upper) and the central chamber and a second membrane between the central chamber and the basal chamber (lower). Fluids are applied through the microchannels (0019). The reference teaches that the device may have more than two operating channels and/or more than two central microchannels (0088, 0092, 00108).
Regarding, claims 4, 5, 10, 35, Paragraph (0019) teaches that “The one or more porous membranes are configured to divide the central microchannel into a two or more closely apposed parallel central microchannels, wherein one or more first fluids are applied through the first central microchannel and one or more second fluids are applied through the second or more central microchannels. The surfaces of each porous membrane can be coated with cell adhesive molecules to support the attachment of cells and promote their organization into tissues on the upper and lower surface of each membrane, thereby creating one or more tissue-tissue interfaces separated by porous membranes between the adjacent parallel fluid channels. The membrane may be porous, flexible, elastic, or a combination thereof with pores large enough to only permit exchange of gases and small chemicals, or large enough to permit migration and transchannel passage of large proteins, as well as whole living cells.” Thus , allowing fluid communication between all of the channels (see also 0066, 0087, 0094, 00103).
The membranes are taught to comprise lung epithelial cells on the upper side of the membrane, stromal cells, and endothelial cells on the bottom side of the membrane thereon (0067, 00112, 00120, 00145-0155, 00168).
Regarding claim 9, each microchannel is disclosed to comprise and inlet and outlet port (0072, 0080, 0081) and the device comprises a fluid pump (0071) and injector (0073).
Regarding claim 33, while the reference does not teach the claimed additional cells in the one or more additional chamber and wherein vessels form over a period of 4 hours to 4 months, the organ mimic device is designed to utilize multi-cell type cellular microarrays and allows different growth factors, chemicals, nutrients, for example to be added to different cell types according to the need of the cells in vivo, and said controlling of the location of said growth factors, chemicals, nutrients may create more physiologically correct organs and tissues, direct specific cell modeling and functioning (0053-0055, 0057). The reference teaches that many types of cells can be used in the device including blood vessel and vascular cells (0136, 0154, also see 0132-0145, 0152). Therefore, depending on the specific function and/or structure to be studied, it would be well within the purview of one of ordinary skill in the art to add the desired cell types and combinations thereof, i.e. vasculogenic combinations of cells, to a biomimetic microfluidic device, and the vessel formation would be inherent to their combination within the said device. Ingber teaches that in the lung “(0016)” The blood-gas barrier or tissue-tissue interface between the pulmonary capillaries and the alveolar lumen is composed of a single layer of alveolar epithelium closely juxtaposed to a single layer of capillary endothelium separated by a thin extracellular matrix (ECM), which forms through cellular and molecular self-assembly in the embryo. Virtually all analysis of the function of the alveolar-capillary unit has been carried out in whole animal studies because it has not been possible to regenerate this organ-level structure in vitro.
While Ingber does not teach the central channel to comprise a 3D ECM hydrogel, they do suggest the natural microenvironment of the lung comprising an ECM between epithelial and endothelial cells. Ingber does not teach claims 1 and 3, drawn to a 3D ECM in the central channel comprising human lung fibroblasts and does not teach the newly added limitations directed to a second interstitial chamber, a third and fourth membrane and the one or more additional chambers of clam 1. Ingber does not teach the limitations of claims 32, 34, 35.
Grego teaches a microfluidic device airway model comprising a first chamber having an inlet and an outlet and containing airway/bronchial epithelial cells (0041); a second chamber having an inlet and an outlet and containing an extracellular matrix and fibroblasts embedded within (0044), wherein the second chamber is separated from the first chamber by a porous membrane; and a third chamber having an inlet and an outlet and containing endothelial cells, wherein the third chamber is separated from the second chamber by a porous membrane (abstract, 0009, 0012, 0030, 0031, 0041-0049). The system is configured to allow with separate fluidic pathways through each of the chambers allowing air and liquid flow therethrough (0009, 0012), thus corresponding the applicants claimed central chamber configured to permit airflow therethrough, having a microchannel therethrough, an apical chamber/channel (upper) disposed on the apical surface of the central chamber, an basal chamber/channel (lower) disposed on the basal surface of the central chamber, a first membrane between the basal chamber and the central chamber and a second membrane between the central chamber and the apical chamber.
Regarding claim 3, human primary lung fibroblasts are embedded within a three-dimensional extracellular matrix hydrogel within the interstitial chamber (0031, 0044).
Regarding claim 34, Grego teaches extracellular matrix hydrogels which are chemically crosslinked (00440). Matrigel® is a known crosslinked ECM hydrogel as are poly(ethylene glycol dimethacrylate) (PEDGMA) hydrogels.
Grego does not teach the newly added limitations directed to a second interstitial chamber, a third and fourth membrane and the one or more additional chambers of clam 1.
Huh teaches a microfluidic device comprising a first and second microchannel in fluid communication with each other through a membrane disposed between the microchannels, wherein the membrane has airway epithelial cells thereon (abstract, 0005-0008, 0049) and endothelial cells adhered to the second side of the membrane (0052) and a central cell-laden gel layer comprising extracellular matrix proteins with cells (fibroblasts) embedded therein on the second side of the membrane allowing the embedded cells to communicate with the cells on the membranes (0008, 0053). Additional cells may be embedded within the gel layer including stromal cells, airway and/or vascular cells, connective tissue or cells, and macrophages (0051-0053).
Regarding claim 1, Huh teaches that the device/base can include additional channels (four, six, eight or more, total channels) in pairs of two (or larger than two) disposed thereon, each having a membrane disposed between . The number of channels and layouts of the channels, including size and dimensions, can vary based on the design of the device (0047).
Regarding claims 4, 5, 10, and 35, the channels are in fluid communication with each other through the membranes (0048, 0055, 0056), and thus, each of the channels are confined by a membrane, which allow the channels to all be in fluid communication with each other.
Regarding claim 34, the gel is disclosed to be chemically crosslinked via sulpho-sanpah treatment (0016, 0057).
Therefore, before the effective filing date of the claimed invention, it would have been within the purview of one of ordinary skill in the art to modify the device of Ingber with Grego to include additional channels as a matter of design choice in view of Huh.
While the specific arrangement currently claimed is not taught per se, the art teaches microfluidic devices which recreate the aveolar-capillary interface/3D microarchitecture (tissue-tissue-interface) of the lung, wherein the devices comprise a top apical channel (comprising epithelial cells), a membrane, a middle cell-laden gel layer comprising fibroblasts, a membrane, and a bottom basal layer (comprising endothelial cells), wherein the channels are in fluid communication with each other through the membranes. The art suggests that the device may comprise eight or more channels each having a membrane between.
Regarding claims 1, 3, 32, directed to a first and second interstitial chamber comprising fibroblast-laden hydrogels and a third and fourth membrane having a monolayer of epithelial cells thereon, when adding additional chambers/channels adjacent to the central chambers as taught by Huh, it would be obvious to include additional central 3D ECM hydrogel in the channels mimicking the lung interstitium which in vivo is sandwiched between opposing monolayers of epithelial cells facilitating gas exchange, and thus when layering as claimed, having two interstitial chambers in the central section of the device, it would be obvious to surround the central chambers (mimicking the interstitium, each containing a fibroblast-laden ECM hydrogel therein) with epithelial cells, and separate these central interstitial chambers by a membrane lining the other sides of the membranes with endothelial cells to mimic the air-blood barrier of the lung thereby mimicking the aveolar-capillary interface.
The combination of prior art references of record teach biomimetic microfluidic devices comprising multiple chambers in a microfluidic device separated by membranes having cells thereon. Huh teaches a central layer having cells embedded within, which communicate with the cells on the membranes in the other channels to mimic the natural in vivo environments, and suggests adding additional chambers/channels adjacent to the central chambers.
Regarding claim 32, when adding additional chambers/channels adjacent to the central chambers as taught by Huh (to Inger with Grego), it would have been obvious to add a 3D ECM hydrogel to the one or more channels (in communication with the cells in adjacent channels) and for the hydrogel to comprise the same or different density to provide an ECM environment which mimics that of the native tissue/organ environments. It is well-known that the native ECM influences cell behaviors including cell migration, proliferation, differentiation and varies widely. Varying stiffness, for example, allows a posita to study cell-matrix interactions influencing cell behavior (for support see Kim, p. 51-52, Introduction.) and thus, it would have been obvious before the effective filing date of the claimed invention to vary ECM densities in biomimetic devices to allow one to study cell behavior.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ingber et al. (WO2010/009307A2, IDS) in view of Grego et al. (US2014/0335496 A1, IDS) and Huh (US2018/0216058, IDS) supported by Kim et al. (Biomaterials, 2015, vol. 40, p.51-60), as applied to claims 1, 3-5, 9, 10, 32-35, and further in view of Vulto et al. (WO2017/155399 A1, IDS).
The teachings of Ingber et al. (WO2010/009307A2, IDS) in view of Grego et al. (US2014/0335496 A1, IDS) and Huh (US2018/0216058, IDS) are found above.
The references do not teach support pillars of claim 2.
WO’399 teach a microfluidic device having a microfluidic channel network comprising a channel having an extracellular matrix gel with fibroblast cells therein (p. 8, lines 29-p. 9, lines 1-20, p. 12, lines 8-10), which contains pillars to support gel formation within the channel network and prevent spreading (p. 14, lines 30-p. 15, lines 1-11).
Therefore, before the effective filing date of the claimed invention, it would have been obvious to include support pillars in the microfluidic device of Ingber with Grego as WO’399 teaches the pillars to support the network when a gel is in the central channel.
Response to Arguments
Applicant's arguments filed 1/20/2026 have been fully considered but they are not persuasive.
Applicants argue that Grego (and Ingber taken with Grego) describes a multi-layer device with 3 chambers and that even if a skilled artisan might have found it obvious to duplicate the chambers of Grego in light of the teachings of Huh who suggest devices to include multiple channels, the specific combinations and arrangement of cells and membranes as claimed would not have been obvious.
The biomimetic microfluidic devices of the prior art are made to enable the studying of complex tissue properties and functionalities and are designed to mimic in vivo airway mucosal microarchitecture, which include airway epithelial cells cultured at an air-liquid interface, fibroblasts within a hydrogel and microvascular endothelial cells vertically stacked. Grego, for example, teach an airway mucosa model comprising an apical chamber having epithelial cells on a membrane which separates the apical chamber from a central interstitial chamber comprising a fibroblast-laden hydrogel layer, and a second membrane separating the interstitial chamber from an endothelial chamber, mimicking the airway epithelium, interstitium and vasculature. When adding additional chambers/channels as suggested by Huh, it would have been obvious to one of ordinary skill in the art to arrange the chambers as claimed, specifically with multiple interstitial chambers in the center having an ECM hydrogel in the channels, mimicking the lung interstitium, which in vivo is sandwiched between opposing monolayers of epithelial cells facilitating gas exchange, and thus when layering as claimed, having two interstitial chambers in the central section of the device, it would be obvious to surround the central chambers (mimicking the interstitium, each containing a fibroblast-laden ECM hydrogel therein) with epithelial cells, and separate these central interstitial chambers by a membrane lining the other sides of the membranes with endothelial cells to mimic the air-blood barrier of the lung thereby mimicking the aveolar-capillary interface.
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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/TIFFANY M GOUGH/ Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651