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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/03/2025 has been entered.
Claim Interpretation
Regarding claim 2, the limitation “are formed via an additive manufacturing process” is a product-by-process limitation. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” MPEP § 2113.
Claim Rejections - 35 USC § 112
The previous 35 U.S.C. § 112(b) rejection is withdrawn in light of the amendments.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 5, 11, 22-23, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803).
Regarding claim 1, Chen discloses a system (annotated Fig. 4 and paragraph [0046]) comprising:
a multi-part assembly comprising (annotated Fig. 4 and paragraph [0046]):
at least one inlet flow line (annotated Fig. 4 and paragraph [0046]) configured to deliver a fluid to an interior volume of the multi-part assembly (annotated Fig. 4 and paragraph [0046]); and
at least one outlet flow line (annotated Fig. 4 and paragraph [0046]) configured to deliver the fluid from the interior volume of the multi-part assembly (annotated Fig. 4 and paragraph [0046]); and
a 3D-printed (paragraphs [0009]-[0011]) chip (abstract, “biochip”; annotated Fig. 4, element 10 “biochip”, and paragraph [0046];) housed within the interior volume of the multi-part assembly (annotated Fig. 4 and paragraph [0046]), the 3D-printed (paragraphs [0009]-[0011]) chip comprising:
at least one inlet flow passage disposed within the 3D-printed (paragraphs [0009]-[0011]) chip (annotated Fig. 4 and paragraph [0046]) and fluidly coupled to the at least one inlet flow line (annotated Fig. 4 and paragraph [0046]);
at least one outlet flow passage disposed within the 3D-printed (paragraphs [0009]-[0011]) chip (annotated Fig. 4 and paragraph [0046]) and fluidly coupled to the at least one outlet flow line (annotated Fig. 4 and paragraph [0046]), wherein the at least one inlet flow passage transitions to the at least one outlet flow passage within an interstitial space disposed within the 3D-printed (paragraphs [0009]-[0011]) chip (annotated Fig. 4 and paragraph [0046]),
wherein voids in the 3D-printed (paragraphs [0009]-[0011]) chip form each of the at least one inlet flow passage (annotated Fig. 4 and paragraph [0046]), the at least one outlet flow passage (annotated Fig. 4 and paragraph [0046]), and the interstitial space (annotated Fig. 4 and paragraph [0046]).
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Chen, annotated Fig. 4
Chen does not disclose:
wherein the interstitial space is accessible from a top of the 3D-printed hydrogel chip
via an access port disposed therein; and
an interstitial infill disposed within the interstitial space.
Regarding feature 1, Deutsch discloses the interstitial space being accessible from the top of the chip (paragraphs [0271]-[0272]; Fig. 10A, elements 1015 and 1015` “channels” are accessible when the top cover or lid is removed (paragraph [0239])).
In the analogous art of microfluidic chips, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of modified Chen with the open channels of Deutsch so that cells can be retrieved and further tested/processed (Deutsch, paragraph [0239]). Additionally, open channels in the art of microfluidic chips are a known entity, and it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of Chen with an open channel in order to observe cells growing the channel with optical microscopy; or to place reagents into the channel via an open port (Deutsch, paragraph [0265]).
Regarding feature 1, in addition, Chen discloses wherein the chip is composed of a material in a gel-like condition (paragraph [0049] “cells and its culture medium … in a gel-like condition”).
Chen does not disclose wherein the chip is composed of a hydrogel material.
However, it would have been obvious to one skilled in the art before the effective filing date to modify the material in a gel-like condition to be a hydrogel in order to effectively hold cells in a gel-like condition and to 3D bioprint the chip effectively.
Regarding feature 2, Adriani discloses via an access port disposed therein (paragraphs [0034] and [0036]-[0037] “opening”).
In the analogous art of vascularizing a cell aggregate, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the access port of Adriani in order for the cell aggregate to be seeded/introduced/inserted directly into the channels (e.g., microchannels) of the device without the need for the cell aggregate to be exposed to physico-mechanical changes that could potentially occur when cells flow through a fluidic channel (Adriani, paragraph [0034]).
Regarding feature 3, Roth discloses an interstitial infill disposed within the interstitial space (paragraphs [0006]-[0007] “sacrificial inks … gelatin microgels, or a poloxamer polymer”). In the analogous art of perfusable networks, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the interstitial infill of Roth in order to result in a support material that, when heated or cooled, can melt while encased in the crosslinked polymers, thereby generating 3D hollow (i.e. perfusable) networks (Roth, paragraph [0059]).
Regarding claim 2, Chen discloses wherein each of the multi-part assembly (Fig. 1, paragraphs [0014] and [0040]) and the chip are formed via an additive manufacturing process (Fig. 3, paragraphs [0014] and [0043]), and
wherein the multi-part assembly (see below obviousness argument) and the chip are composed of different materials (paragraph [0049] “cells and its culture medium … in a gel-like condition”).
Regarding the term “multi-part assembly” it would have been obvious to one skilled in the art before the effective filing date to modify the multi-part assembly to not be comprised of cells and its culture medium in a gel-like condition (like the biochip of Chen is), but rather a polymer or plastic that is commonly used in additive manufacturing in order to rigidly hold a gel-like substance without leakage of any fluid.
Regarding claim 5, Chen discloses one inlet flow passage and one outlet flow passage fluidly connected within the interstitial space (annotated Fig. 4).
Chen does not disclose wherein each of the at least one inlet flow passage and the at least one outlet flow passage comprises a single respective inlet or outlet portion which branches into a network of connected flow passages, comprising a network of inlet flow passages fluidly connected to a corresponding network of outlet flow passages within the interstitial space.
Roth discloses wherein each of the at least one inlet flow passage and the at least one outlet flow passage comprises a single respective inlet or outlet portion which branches into a network of connected flow passages, comprising a network of inlet flow passages fluidly connected to a corresponding network of outlet flow passages within the interstitial space (Figs. 1A and 12 and paragraphs [0018] and [0090]; claims 1 and 12-13).
In the analogous art of 3D printed vascular-like networks, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of Chen with the networks of Roth in order to have in vitro drug testing models include the presence of multi-scale, branched structures (e.g., bifurcations and trifurcations) as well as the increasing and decreasing diameters of vessels that are naturally found in vivo. These geometries are important for multiple tissues throughout the body, including (but not limited to) lymphatics, airways, and the gastrointestinal tract (Roth, paragraph [0003]).
Regarding claim 11, Chen discloses comprising at least one live cell (paragraph [0046], Fig. 5) disposed within the interstitial space (paragraph [0046], Fig. 5, right drawing) and/or attached to an interior surface of the at least one inlet flow passage and/or the at least one outlet flow passage (paragraph [0046], Fig. 5, right drawing).
Regarding claim 22, Chen does not disclose a removable top cover or lid enabling access to the interior volume,
wherein the interstitial space is accessible when the top cover or lid is removed.
Deutsch discloses a removable top cover or lid enabling access to the interior volume (paragraphs [0271]-[0272]),
wherein the interstitial space (paragraph [0271]; Fig. 10A, elements 1015 and 1015` “channels”) is accessible when the top cover or lid is removed (paragraph [0239]).
In the analogous art of microfluidic chips, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of modified Chen with the cover of Deutsch in order to both form a water-tight cell incubation or cytochemistry chamber (Deutsch, paragraph [0265]) and also to be able to remove the cover so that cells can be retrieved and further tested/processed (Deutsch, paragraph [0239]).
Regarding claim 23, Chen discloses wherein a gel-like condition (paragraph [0049] “cells and its culture medium … in a gel-like condition”).
Chen does not disclose wherein the interstitial infill comprises a hydrogel and a 3D-printed repeating lattice structure.
However, it would have been obvious to one skilled in the art before the effective filing date to modify the material in a gel-like condition to be a hydrogel in order to effectively hold cells in a gel-like condition and to 3D bioprint the chip effectively.
Nevertheless, Roth discloses wherein the interstitial infill (paragraphs [0006]-[0007] “sacrificial inks … gelatin microgels, or a poloxamer polymer”) comprises a hydrogel (paragraphs [0006]-[0007] “sacrificial inks … gelatin microgels, or a poloxamer polymer”) and a 3D-printed repeating lattice structure (Fig. 9B, paragraph [0029]).
In the analogous art of perfusable networks, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the interstitial infill of Roth in order to result in a support material that, when heated or cooled, can melt while encased in the crosslinked polymers, thereby generating 3D hollow (i.e. perfusable) networks (Roth, paragraph [0059]).
Regarding claim 26, Chen discloses further comprising one or more sensors disposed within the at least one outlet flow passage (paragraph [0046] “sensor element 14 detecting or testing”),
wherein the one or more sensors comprise sensors for measuring metabolic activity (paragraph [0046] “metabolites of the cell … for the sensor element 14 detecting or testing”).
Regarding the limitations “luminescence, colorimetry, electrochemical activity, fluorescence, and/or metabolic activity” and “the at least one inlet flow passage, the at least one outlet flow passage, and/or the interstitial space”, these limitations are claimed in the alternative. No further rejections are required at this time.
Regarding claim 27, Chen discloses further comprising at least one endothelial cell (paragraph [0049]) attached to an interior surface of the at least one inlet flow passage (paragraph [0049]) and/or the at least one outlet flow passage (paragraph [0049]).
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Ingber (US 20190032021), Baker (US 10179896), and Ingber-997 (US 20170158997).
Regarding claim 4, Chen discloses one inlet flow passage and one outlet flow passage through the chip (annotated Fig. 4).
Chen does not disclose wherein each of the at least one inlet flow passage and the at least one outlet flow passage comprises at least two inlet or outlet flow passages, thereby forming at least two unconnected fluid flow passages through the chip,
wherein each of the at least two unconnected fluid flow passages contains a different fluid comprising at least one of blood and bile, and
wherein at least one of the at least two inlet or outlet flow passages is seeded with cholangiocytes.
Ingber discloses wherein each of the at least one inlet flow passage and the at least one outlet flow passage comprises at least two inlet or outlet flow passages, thereby forming at least two unconnected fluid flow passages through the chip (Figs. 2, 11B and 11E, the membrane can be “non-porous” according to paragraph [0056], if pores are deemed to be a connection), and
wherein each of the at least two unconnected fluid flow passages contains a different fluid (Figs. 2 and 8, paragraph [0120] “Chambers can each be independently fed by a separate culture medium stream” and “perfuse different media compositions through the Interstitial versus Microvascular channels”).
In the analogous art of organ chips, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of Chen with the two inlets and two outlets of Ingber in order to feed different cell culture media to the cells in the biochip, allowing the growth of different cell types and therefore simulating different organs and tissue types for pharmaceuticals to be tested upon.
Regarding the limitations, Baker discloses the following limitations:
comprising blood (abstract “blood through a fluid channel”).
In the analogous art of bioartificial organs, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the blood of Baker in order to use blood to transfer nutrients and/or to filter the blood of toxins (Baker, col. 4, lines 30-35).
Ingber-997 discloses wherein at least one of the at least two inlet or outlet flow passages is seeded with cholangiocytes (paragraphs [0009] and [0056], and Fig. 1A-1B).
In the analogous art of devices for simulating a function of a liver, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the cholangiocytes of Ingber-997 in order to simulate a function of a liver tissue (Ingber-997, paragraph [0009]).
Regarding the limitation “comprising at least one of blood and bile”, this limitation is phrased in the alternative. No further rejections are required at this time.
Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Ingber (US 20190032021).
Regarding claim 6, Chen discloses at least one of the at least one inlet flow passage and the at least one outlet flow passage within the interstitial space (annotated Fig. 4).
Chen does not disclose wherein at least one of the at least one inlet flow passage and the at least one outlet flow passage comprises at least one micropore disposed therein, in a portion of the passage disposed within the interstitial space.
Ingber discloses wherein at least one of the at least one inlet flow passage and the at least one outlet flow passage comprises at least one micropore disposed therein, in a portion of the passage disposed within the interstitial space (Fig. 11B, paragraph [0056] “or at least partially porous”).
In the analogous art of organ chips, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of Chen with the porous passages of Ingber in order to feed different cell culture media to the cells in the biochip, allowing the growth of different cell types using nutrient and fluid molecules (Ingber, paragraph [0056]) and therefore simulating different organs and tissue types for pharmaceuticals to be tested upon.
Regarding claim 7, Chen discloses at least one live cell seeded within the biochip (Fig. 5, paragraph [0046]), the at least one inlet flow passage and the at least one outlet flow passage collectively form a vasculature (Figs. 4-5 and paragraph [0046]).
Chen does not disclose comprising at least one live cell seeded within the interstitial space, wherein the at least one micropore comprises an internal diameter in a range from about 40 µm to about 60 µm,
wherein the at least one micropore connects the vasculature to the interstitial space.
Ingber discloses comprising at least one live cell seeded within the interstitial space (Fig. 11B, “Gut epithelium”; paragraph [0138]),
wherein the at least one micropore (Fig. 11B, “Flexible, porous membrane” ; paragraph [0138]) connects the vasculature (Fig. 11B, “Blood side” ; paragraph [0138]) to the interstitial space (Fig. 11B, “Interstitial channel” ; paragraph [0138]).
In the analogous art of organ chips, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of Chen with the live cell in the interstitial space of Ingber and the micropore connecting the vasculature and the interstitial space in order to feed different cell culture media to the cells in the biochip, allowing the growth of different cell types using nutrient and fluid molecules (Ingber, paragraph [0056]) and therefore simulating different organs and tissue types for pharmaceuticals to be tested upon.
Regarding the limitation “wherein the at least one micropore comprises an internal diameter in a range from about 40 µm to about 60 µm”, the claim limitation is obvious under MPEP § 2144.04(IV)(A), which states that “where the only difference between the prior art and the claims was a recitation of relative dimensions … [and the claimed device] would not perform differently than the prior art device, the claimed device was not patentably distinct from the prior art device”. Ingber already discloses that these micropores can be made approximately large enough for cells to pass through the micropores, or down to small enough for only nutrient or fluid molecules to pass through it (Ingber, paragraph [0056]).
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Castaño (“Dynamic photopolymerization produces complex microstructures on hydrogels in a moldless approach to generate a 3D intestinal tissue model”) and Sung (“Poly(ethylene glycol) as a sensitive regulator of cell survival fate on polymeric biomaterials: the interplay of cell adhesion and pro-oxidant signaling mechanisms”).
Regarding claim 8, Chen discloses the chip (abstract).
Chen does not disclose acrylated-PEG1k-NHS disposed on the chip.
Castaño discloses acrylated-PEGDA-NHS disposed on a surface (pg. 2, right column, middle of page: “PEGDA” and “acrylic acid”; Fig. 4 and pg. 4, paragraph under “2.5. Functionalization of PEGDA-AA villi-like scaffolds with cell adhesive proteins”).
In the analogous art of hydrogels for live cells, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of Chen with the NHS-PEG-acrylate of Castaño in order to functionalize the hydrogel so as to further bind to unmodified extracellular matrix proteins as a substrate for cell culture (Castaño, pg. 2, second column, first paragraph, lower half of page, begins with “In our approach …”).
Regarding the phrase “PEG1k”, Castaño’s supplementary information discloses a molecular weight of 6000 g/mol for PEGDA (2.1 Materials).
However, Sung discloses PEG1k (abstract “PEG Mw 1000”).
In the analogous art of PEG 1k on glass coverslips, it would have been obvious to one skilled in the art before the effective filing date to modify the PEG to be PEG1k in order to promote cell adhesion, proliferation, spreading, and survival (Sung, abstract).
Regarding claim 9, Chen discloses photocuring three-dimensional printing (paragraph [0040]).
Chen does not disclose wherein the at least one precursor further comprises a photoinitiator.
Modified Chen discloses the at least one precursor (see rejection to claim 8).
Castaño discloses a photoinitiator (pg. 3, under 2.1. Materials and Fig. 1 caption “in the presence of the photoinitiator with UV radiation”).
In the analogous art of generating porous hydrogels using microfluidics, it would have been obvious to one skilled in the art before the effective filing date to modify the precursor of modified Chen with the photoinitiator of Castaño in order to polymerize the substrate in the presence of ultraviolet light (Castaño, Fig. 1 caption).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, in view of Swami (US 20220118446).
Regarding claim 10, Chen discloses a surface of the at least one inlet flow passage (annotated Fig. 4) and/or the at least one outlet flow passage (annotated Fig. 4).
Chen does not disclose comprising at least one bioactive coating comprising at least one of gelatin methacrylate (GelMA) and collagen methacrylate (ColMA),
wherein the at least one bioactive coating is disposed on at least a surface of the at least one inlet flow passage and/or the at least one outlet flow passage.
Swami discloses at least one bioactive coating comprising gelatin methacrylate (GelMA) (paragraph [0056] and [0104]),
wherein the at least one bioactive coating is disposed on at least a surface of the at least one passage (paragraph [0056]).
Regarding the limitation “wherein the at least one bioactive coating is disposed on a surface of the at least one inlet flow passage and/or the at least one outlet flow passage”, Fig. 5A of Swami provides that the perfusable hydrogel (made of gelatin methacrylate), element 502, has a channel running through it, element 501 (paragraph [0068]), which comprises an inlet and an outlet flow passage.
In the analogous art of a perfusable hydrogel microchannel shell, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the hydrogel gelatin methacrylate of Swami in order to integrate 3D cell culture models into a vessel that facilitates nutrient delivery and waste removal, as well as provide mechanical cues (Swami, paragraph [0051]).
Regarding the limitation “at least one of gelatin methacrylate (GelMA) and collagen methacrylate (ColMA)”, the limitations are claimed in the alternative. Because the limitation has already been rejected under gelatin methacrylate (GelMA), no further rejections are required at this time.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, in view of Le Berre (US 20190388887).
Regarding claim 13, arguably, Chen discloses further comprising a fluid reservoir fluidly coupled upstream of the at least one inlet flow passage (Fig. 4, the pump’s fluid reservoir is upstream of the inlet flow passage).
Chen does not disclose:
a fluid reservoir fluidly coupled downstream of the at least one inlet flow line; and
a pump disposed downstream of the fluid reservoir and upstream of the at least one inlet flow passage.
Le Berre discloses a fluid reservoir (Fig. 6, elements 110 or 111 “tanks” and paragraph [0163]) fluidly coupled downstream of the at least one inlet flow line (Fig. 6, elements 119 and 120 “recirculation channels” and paragraphs [0164] and [0166]) and upstream of the at least one inlet flow passage (Fig. 6, ports 2 and 3 “input ports”; paragraphs [0162] and [0132]); and
a pump (Fig. 6, elements 116 or 117 “pumps”) disposed downstream of the fluid reservoir (Fig. 6, elements 110 or 111 “tanks” and paragraph [0163]) and upstream of the at least one inlet flow passage (Fig. 6, ports 2 and 3 “input ports”; paragraphs [0162] and [0132]).
In the analogous art of microfluidic chips, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of modified Chen with the fluid reservoir and its arrangement with the at least one inlet flow line and inlet flow passage in order to provide a heated or cooled liquid to the microfluidic chip via a pump, in order to observe live cells and their respective physical, chemical, or biological phenomena, such as polymerization dynamics for the microtubules within living cells (Le Berre, paragraphs [0159] and [0162]).
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Castaño (“Dynamic photopolymerization produces complex microstructures on hydrogels in a moldless approach to generate a 3D intestinal tissue model”).
Regarding claim 15, Chen does not disclose a covalent linker attached to the hydrogel material; and collagen attached to the covalent linker.
Castaño discloses a covalent linker (NHS, pg. 4, under “2.5. Functionalization of PEGDA-AA villi-like scaffolds with cell adhesion proteins”) attached to the hydrogel material (PEGDA-AA, pg. 2, right column, middle of page: “PEGDA” and “acrylic acid”; Fig. 4 and pg. 4, paragraph under “2.5. Functionalization of PEGDA-AA villi-like scaffolds with cell adhesive proteins”); and collagen attached to the covalent linker (pg. 9, Fig. 4, caption: “spectra acquired after each step of the functionalization process… EDC/NHS activated hydrogel in blue, and collagen-functionalized hydrogel in green”; pg. 8, second column, last paragraph “incorporation of NHS molecules through amide bonds …. incubation with collagen”; pg. 9 under “3.3. Caco-2 cells form a polarized monolayer covering the villi-like microstructures fabricated in PEGDA-AA upon collagen functionalization”).
In the analogous art of photopolymerization of hydrogels, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of modified Chen with the covalent linker, hydrogel, and collagen of Castaño in order to produce a material that can be used for a cell culture substrate that can achieve long-term cell culture experiments without degradation of the substrate over time that would normally occur with soft collagen hydrogel scaffolds (Castaño, pg. 12, right column, middle-to-end of page).
Claims 12 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claims 11 and 27 respectively, further in view of Ingber-997 (US 20170158997).
Regarding claim 12, Chen does not disclose a biliary endothelial cell, a cholangiocyte, a heptic stellate cell (HSCs), a mucous cell, a parietal cell, a cardiac fibroblast (CF), a Paneth cell, a Merkel cell, a seminiferous tubule, a tubule epithelial cell, a macula densa cell, a glomerular endothelial cell, a podocyte, a mesangial cell, a parietal epithelial cell, an immortalized cell, a T cell, and/or a peripheral blood mononuclear cell (PBMC).
Ingber-997 discloses cholangiocytes (paragraphs [0009] and [0056], and Fig. 1A-1B).
In the analogous art of devices for simulating a function of a liver, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the cholangiocytes of Ingber-997 in order to simulate a function of a liver tissue (Ingber-997, paragraph [0009]).
Regarding the limitations, “a biliary endothelial cell, a cholangiocyte, a hepatic stellate cell (HSCs), a mucous cell, a parietal cell, a cardiac fibroblast (CF), a Paneth cell, a Merkel cell, a seminiferous tubule, a tubule epithelial cell, a macula densa cell, a glomerular endothelial cell, a podocyte, a mesangial cell, a parietal epithelial cell, an immortalized cell, a T cell, and/or a peripheral blood mononuclear cell (PBMC)” the limitations are claimed in the alternative. Because the limitation has already been rejected under a cholangiocyte, no further rejections are required at this time.
Regarding claim 28, modified Chen teaches the interstitial space and interstitial infill (see rejection to claim 1).
Chen does not disclose further comprising at least one of a human umbilical vein endothelial cell (HUVEC), an induced pluripotent stem cell (iPSC), a primary liver sinusoidal (LSEC), and a cholangiocyte seeded in the interstitial space and supported by the interstitial infill.
Ingber-997 discloses wherein a space is seeded with cholangiocytes (paragraphs [0009] and [0056], and Fig. 1A-1B).
In the analogous art of devices for simulating a function of a liver, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the cholangiocytes of Ingber-997 in order to simulate a function of a liver tissue (Ingber-997, paragraph [0009]).
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), Roth (US 20230398803), and Ingber-997 (US 20170158997) as applied to claim 12, further in view of Castaño (“Dynamic photopolymerization produces complex microstructures on hydrogels in a moldless approach to generate a 3D intestinal tissue model”).
Regarding claim 21, Chen does not disclose at least one precursor covalently tethered to the hydrogel material; and
at least one bioactive coating covalently bonded to the at least one precursor;
at least one live cell attached to the bioactive coating.
Castaño discloses at least one precursor (NHS, pg. 4, under “2.5. Functionalization of PEGDA-AA villi-like scaffolds with cell adhesion proteins”) covalently tethered to the hydrogel material (pg. 2, right column, middle of page: “PEGDA” and “acrylic acid”; Fig. 4 and pg. 4, paragraph under “2.5. Functionalization of PEGDA-AA villi-like scaffolds with cell adhesive proteins”); and
at least one bioactive coating covalently bonded to the at least one precursor (pg. 8, second column, last paragraph “incorporation of NHS molecules through amide bonds …. incubation with collagen”);
at least one live cell attached to the bioactive coating (pg. 9 under “3.3. Caco-2 cells form a polarized monolayer covering the villi-like microstructures fabricated in PEGDA-AA upon collagen functionalization”).
In the analogous art of photopolymerization of hydrogels, it would have been obvious to one skilled in the art before the effective filing date to modify the biochip of modified Chen with the precursor, hydrogel, bioactive coating, and cells of Castaño in order to produce a material that can be used for a cell culture substrate that can achieve long-term cell culture experiments without degradation of the substrate over time that would normally occur with soft collagen hydrogel scaffolds (Castaño, pg. 12, right column, middle-to-end of page).
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Ling (US 20200157483).
Regarding claim 24, Chen does not disclose wherein the interstitial infill comprises a plurality of spherical pores, wherein the spherical pores are connected via a plurality of interconnects.
Ling discloses wherein the interstitial infill (paragraph [0047], Fig. 1) comprises a plurality of spherical pores (paragraph [0047], Fig. 1), wherein the spherical pores are connected via a plurality of interconnects (paragraph [0047], Fig. 1).
In the analogous art of three-dimensional bioreactors, it would have been obvious to one skilled in the art before the effective filing date to modify the interstitial infill of modified Chen with the interstitial infill of Ling in order to maximize the surface to volume ratio for the cells to bind to a plurality of interconnected non-random voids (Ling, paragraphs [0047] and [0074]).
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Asnaghi (US 20110033918).
Regarding claim 25, Chen does not disclose wherein the interstitial infill comprises one or more integral handles.
Asnaghi discloses wherein the interstitial infill (paragraph [0075]) comprises one or more integral handles (paragraph [0033] “handle”).
In the analogous art of bioreactors with scaffolds, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen’s interstitial infill with one or more integral handles of Asnaghi in order to facilitate handling of the scaffold by the user (Asnaghi, paragraph [0033]).
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Grigoryan (US 20210348104).
Regarding claim 29, modified Chen teaches the 3D-printed hydrogel chip (see rejection to claim 1).
Chen does not disclose wherein the 3D-printed hydrogel chip comprises at least one of PEGMA (Polyethylene glycol methyl ether methacrylate), thiolated gelatin, thiolated
collagen, methacrylated chitosan, thiolated chitosan, methacrylated heparin, thiolated heparin,
thiolated hyaluronic acid, multi-arm PEG-maleimide, multi-arm PEG-thiol, multi-arm PEG-
DBCO, multi-arm PEG-N3, and multi-arm PEG-biotin with streptavidin.
Grigoryan discloses thiolated gelatin, methacrylated chitosan, thiolated chitosan, and methacrylated heparin (paragraph [0035]).
In the analogous art of bio-scaffolds, it would have been obvious to one skilled in the art before the effective filing date to modify the 3D-printed hydrogel chip of Chen with the chemical species of Grigoryan in order to have a 3D printable or moldable material that can form a pattern for cellular growth in a 3D environment.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Miller (US 20180002658).
Regarding claim 30, modified Chen teaches the 3D-printed hydrogel chip (see rejection to claim 1).
Chen does not disclose wherein the 3D-printed hydrogel chip comprises a photo-absorber comprising Irgacure 2959 and a photo-initiator comprising tartrazine.
Miller discloses wherein a 3D-printed hydrogel comprises a photo-absorber comprising Irgacure 2959 (paragraph [0070]) and a photo-initiator comprising tartrazine (paragraph [0071]).
In the analogous art of 3D bioprinting of tissues with perfusable vasculature, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the Irgacure 2959 and tartrazine of Miller in order to have a photoinitiator that upon light absorption, releases free radicals and catalyzes hydrogel polymerization (Miller, paragraph [0070]). In addition, a photo-absorber has the ability to absorb light wavelengths associated with the photoinitiator to result in reduced overcuring (Miller, paragraph [0071]).
Allowable Subject Matter
Claim 31 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claim 31, the closest prior art is Chen (US 20230011168) in view of Deutsch (US 20110034348), Adriani (US 20240018483), and Roth (US 20230398803) as applied to claim 1, further in view of Ingber (US 20190032021) and Le Berre (US 20190388887).
Regarding claim 31, Chen discloses further comprising:
at least one live cell (paragraph [0038]), the interstitial space (annotated Fig. 4 and paragraph [0046]);
a fluid reservoir fluidly coupled upstream of the at least one inlet flow passage (Fig. 4, the pump’s fluid reservoir is upstream of the inlet flow passage);
a fluid reservoir fluidly coupled downstream of the at least one inlet flow line (annotated Fig. 4, collection tube on the right side of the figure);
a pump disposed upstream of the at least one inlet flow passage (annotated Fig. 4, syringe pump on the left side of the figure); and
the at least one inlet flow passage and the at least one outlet flow passage collectively form a vasculature (Figs. 4-5 and paragraph [0046]).
Chen does not disclose:
at least one live cell seeded within the interstitial space
a fluid reservoir fluidly coupled downstream of the at least one inlet flow line and upstream of the at least one inlet flow passage;
a pump disposed downstream of the fluid reservoir and upstream of the at least one inlet flow passage; and
at least one sampling port and/or fluid sampling line fluidly coupled to at least one of the reservoir, the outlet flow line, the outlet flow passage, the interstitial space and/or another system flow passage;
wherein the multi-part assembly and the chip are composed of different materials;
wherein at least one of the at least one inlet flow passage and the at least one outlet flow passage comprises at least one micropore disposed therein, in a portion of the passage disposed within the interstitial space;
wherein the at least one micropore connects the vasculature to the interstitial space.
However, the prior art does not provide a teaching or suggestion that would have led a person of ordinary skill in the art to arrive at the claimed invention within the claim environment. Regarding claim 31, the claim is considered allowable subject matter due to the numerous and disparate prior art citations among the combinability of the four parent references, including those additional references further in view of Ingber and De Berre.
Additional Prior Art References
The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure.
Ranek (US 20250250521) – This invention is a microphysiological organoid model.
Pant (US 20150377861) – This invention is a cell culture device with an array of microfluidic networks.
Response to Arguments
Applicant’s arguments filed 10/03/2025 have been fully considered but they are not persuasive.
Regarding pg. 9 of Applicant remarks, the claim objections and claim rejection under 35 U.S.C. § 112(b) have been withdrawn in light of the amendments.
Regarding pg. 10 of Applicant remarks, the Applicant presents arguments about the combinability of Chen in view of Deutsch, Adriani, and Roth.
Deutsch discloses prior art on the ability to access its channels from above, as described in, for instance, Fig. 4A, where a pipetting device is capable of accessing the channels of Deutsch’s microfluidic chip. Arguments about the nature of the two waste reservoir channels are not relevant as they are both channels which can be covered or uncovered with a top cover (Fig. 10A, element 1016 “cover”) with access from above, showing that these top-accessible channels are known in the prior art. Additionally, input channels of Deutsch have the same ability to be covered or uncovered (see Deutsch, Fig. 10A and paragraphs [0270]-[0272]). These open channels can be combined with Chen for top accessibility for the motivation given above.
Regarding Applicant arguments to Adriani, Adriani discloses an access port, which does not teach away from combinability with the Chen invention. To cite the entire motivation statement above:
In the analogous art of vascularizing a cell aggregate, it would have been obvious to one skilled in the art before the effective filing date to modify modified Chen with the access port of Adriani in order for the cell aggregate to be seeded/introduced/inserted directly into the channels (e.g., microchannels) of the device without the need for the cell aggregate to be exposed to physico-mechanical changes that could potentially occur when cells flow through a fluidic channel (Adriani, paragraph [0034]).
This access port structure presents an alternative method of seeding the cells in the channel of Chen.
Regarding Applicant remarks, pg. 12, Roth discloses gelatin microgels, such as those in a sacrificial ink, providing a disclosure for an interstitial infill.
Regarding the dependent claims, these claims, except claim 31, are rejected for the previous reasons given.
Regarding claim 31, the claim is considered allowable subject matter due to the numerous and disparate prior art citations among the combinability of the references, including those additional references further in view of Ingber and De Berre.
Conclusion
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/N.G.E./Examiner, Art Unit 1799
/MICHAEL A MARCHESCHI/Supervisory Patent Examiner, Art Unit 1799