DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/20/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Applicant's arguments filed 05/20/2026 have been fully considered but they are not persuasive.
Applicant has argued that it would have been nonobvious to modify the system disclosed by Cho et al. to be a vascularized tissue model, as required by the amendment to independent claim 4, as such modification would require significant structural modifications. The Examiner respectfully disagrees, as the type of modeling achieved by a microphysiological system is dictated by the biological processes conducted therein, and Cho et al. discloses that their device “can generally be applied to various cells” for biological experimentation (para. 16). The prior art device comprises channels that would be structurally capable of growing and experimenting with various cells, as discussed in the prior Office Action. Therefore, the prior art device would not require substantial modification to serve as a vascularized tissue model, as the skilled artisan would only need to use the device to culture cells representing a vascularized tissue microenvironment. Furthermore, the skilled artisan would have been motivated to modify the device disclosed by Cho et al. to be a vascularized tissue model based on the teachings of the prior art, as will be discussed in the new grounds of rejection below. In response to applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant has argued that a skilled person would not have expected an inclusion of an epithelial barrier, as required by the amendment to independent claim 4, would “allow for a consistent assessment of therapeutic agents, as described in the application as filed (see page 6, lines 5-12, as will as Example 1 of the application as filed)”. This argument is not entirely commensurate in scope with the current pending claims, as the claims require inclusion of an epithelial barrier arranged in the first opening between the first channel and the second channel, but the claims do not recite assessment of therapeutic agents. The Examiner asserts that it would have been obvious to one of ordinary skill in the art to modify the device disclosed by Cho et al. to include an epithelial barrier based on the teachings of the prior art, as will be discussed in the new grounds of rejection below.
The claim amendments have necessitated a new grounds of rejection.
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 22-23 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.
Claim 22 recites the limitation "the first cells" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 4, from which claim 22 depends, does not recite first cells.
Claim 23 recites the limitation "the first cells" in at least line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 4, from which claim 23 depends, does not recite first cells.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 4-5, 7, 12, 16, 19-20 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (US Patent Application Publication 2014/0273223) (already of record) in view of Chung et al. (US Patent Application Publication 2014/0302594) (already of record).
Regarding claim 4, Cho et al. discloses a microphysiological system (Abstract, para. 82), comprising a microfluidic chip (para. 14), comprising:
a planar surface (101) (para. 37) (Fig. 1, sheet 1 of 18);
a first channel (“low height” channel) (201) formed on the planar surface (Abstract, para. 37) (Fig. 2, sheet 2 of 18) and having a first volume defined by a first width, a first height, and a first length (Abstract, para. 61) (Figs. 1-2, sheets 1-2 of 18), the first channel extending in a first direction (Fig. 1, sheet 1 of 18); and
a second channel (high height channel, e.g., channel 200 in Fig. 1 and 10, sheets 1 and 12 of 18; channel 203 in Fig. 12, sheet 14 of 18) (Abstract, para. 40) formed on the planar surface adjacent to the first channel (para. 36-37) (e.g., Fig. 2, sheet 2 of 18), the second channel having a second volume defined by a second width, a second height, and a second length (Abstract) (Figs. 1-2, sheets 1-2 of 18), the second channel extending in the first direction (Fig. 1, sheet 1 of 18), the second height being greater than the first height (para. 36-40) (Fig. 2, sheet 2 of 18);
wherein the first channel is in fluid communication with the second channel through a first opening that extends along at least a portion of the first length wherein the first opening extends from the planar surface to the first height (para. 36, 43-50) (Figs. 2, 4, sheets 2, 4 of 28); and
wherein the first height and the second height are selected such that surface tension of a liquid added to either the first channel or the second channel provides a non-physical microfluidic barrier that selectively limits passage of the liquid through the first opening (para. 40, 53); and
an extracellular matrix (401) (called scaffold; reads on an extracellular matrix as it provides a 3-dimensional scaffold for cell growth therein and is made of extracellular matrix materials such as collagen) (para. 43-45) for use within the first channel (201) (para. 43), wherein a side wall of the extracellular matrix when added to the first channel and gelled extends across the first opening and forms a further barrier between the first channel and the second channel (para. 43) (Fig. 4, sheet 4 of 18),
wherein the microphysiological system further comprises cells arranged in the first opening between the first channel and the second channel (para. 43-48) (Fig. 4, sheet 4 of 4), and
wherein the microphysiological system is a model of a microenvironment within the body (para. 82).
Cho et al. is silent as to an epithelial barrier arranged in the first opening, and wherein the system is a vascularized tissue model.
However, Cho et al. discloses wherein the system is configured to mimic physiological processes such as growth, migration, and differentiation as related to cells in order to conduct accurate tests for pharmacology and biology studies (para. 82). Cho et al. further discloses wherein the device can be applied to “various cells” (para. 16).
Chung et al. discloses a microphysiological system (Abstract, para. 57) comprising a first channel in fluid communication with a second channel through a first opening that extends along at least a portion of a length of extension of the first channel (para. 36-37, 46) (Figs. 1-3, sheets 1-2 of 8), wherein a fluid in one channel is prevented from leaking into the other channel due to surface tension forces (para. 42). Chung et al. further discloses wherein the system comprises vascular endothelial cells arranged in the opening between the first channel and the second channel (para. 55) (Fig. 9, sheet 8 of 8); thus, the system comprises an epithelial barrier arranged in an opening between the first and second channel (consistent with Applicant’s specification, which states “In embodiments, the epithelial barrier comprises endothelial cells”, see p. 18 line 20 of the specification as-filed) and reads on a vascularized tissue model as it models physiology with vascular cells (para. 55-57). Chung et al. discloses that such a configuration can be used to evaluate “cell migration under various environmental conditions, and can be applied in various uses such as development of new drugs, construction of disease models such as cancers, Alzheimer's, etc., construction of tissues and organ models, simulation of biological environment, toxicity evaluation, drug evaluation, contamination evaluation, protein and other material evaluation, biocompatibility evaluation, stem cell studies, etc.” (para. 57).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the cells arranged in the first opening between the first and second channels disclosed by Cho et al. to comprise vascular endothelial cells, thereby arriving at an epithelial barrier and a vascularized tissue model as claimed, as Chung et al. discloses that it was known in the art to provide vascular endothelial cells at an opening between two channels to study migration for a wide variety of experimental and clinical purposes as discussed above, and the skilled artisan would have been motivated to adopt a configuration recognized in the art to be suitable for modeling cell migration to enhance the experimental and clinical utility of the device.
Regarding claim 5, Cho et al. discloses wherein the cells arranged in the first opening are continuous (para. 43-48) (Fig. 4, sheet 4 of 4), and Cho et al. in view of Chung et al. teaches wherein the cells form an epithelial barrier, as set forth above, with Chung et al. also disclosing continuous cells (para. 55) (Fig. 9). Therefore, the prior art combination arrives at the limitation of wherein the epithelial barrier is continuous.
Regarding claim 7, Cho et al. in view of Chung et al. teaches wherein the epithelial barrier comprises endothelial cells, as set forth above.
Regarding claim 12, Cho et al. discloses first cells in the extracellular matrix in the first channel (201) (para. 63-65, 84, 90).
Regarding claim 16, Cho et al. discloses wherein the extracellular matrix comprises a hydrogel (para. 86).
Regarding claim 19, Cho et al. discloses wherein the system further comprises:
a first media within the second channel (200) (para. 84);
a third channel formed on the planar surface adjacent to the first channel (see “second lowest height” channel comprising cells 501, adjacent to “low height” channel comprising cells 500, Fig. 10, sheet 12 of 18), wherein the third channel has a third volume defined by a third width, a third height, and a third length (para. 84) (Fig. 10, sheet 12 of 18),
wherein the third channel extends in the first direction (Figs. 10-11, sheets 12-13 of 18), and wherein the third height is greater than the first height (para. 84) (Fig. 10, sheet 12 of 18),
wherein the third channel is in fluid communication with the first channel through a second opening that extends along at least a portion of the first length, wherein the second opening extends from the planar surface to the first height (para. 84, 87) (Fig. 10, sheet 12 of 18); and
wherein the first height and the third height are selected such that surface tension of a liquid added to the first channel or the third channel provides a non-physical microfluidic barrier that selectively limits passage of the liquid through the second opening (para. 40, 84, 87); and
a second media confined within the third channel (para. 84, 87) (Fig. 10, sheet 12 of 18).
Regarding claim 20, Cho et al. discloses wherein the third height (height of channel comprising cells 501) is less than the second height (height of channel 200) (para. 84, 87) (Fig. 10, sheet 12 of 18), and the system further comprises a second extracellular matrix confined within the third volume of the third channel (para. 84, 87).
Regarding claim 23, Cho et al. in view of Chung et al. teaches the vascularized tissue model, as set forth above, and Cho et al. further discloses wherein the system comprises first cells (para. 43-48, 82-84).
Cho et al. is silent as to wherein the first cells comprise cell types according to claim 23.
However, Chung et al. discloses that it was known in the art to culture liver cells alongside vascular endothelial cells to study interactions therebetween (para. 9).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the first cells disclosed by Cho et al. to comprise liver cells to thereby provide a liver model, based on the teachings of Chung et al., in order to enhance the experimental utility of the device in elucidating liver and endothelial cell interactions as is known in the art.
Regarding claim 24, Cho et al. discloses wherein the extracellular matrix is added to the first channel in liquid form and is then gelled (para. 87).
Claims 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (US Patent Application Publication 2014/0273223) (already of record) in view of Chung et al. (US Patent Application Publication 2014/0302594) (already of record) as applied to claim 7, above, and in further view of Uwamori et al. (Integration of neurogenesis and angiogenesis models for constructing a neurovascular tissue) (already of record).
Regarding claim 9, Cho et al. in view of Chung et al. teaches wherein the epithelial barrier comprises endothelial cells, as set forth above. Both Cho et al. and Chung et al. contemplate using their respective systems to culture various types of cells (see para. 16 of Cho et al. and para. 56-57 of Chung et al.).
The prior art combination is silent as to wherein the endothelial cells comprise brain microvascular endothelial cells (BMEC).
Uwamori et al. discloses a microfluidic chip (Abstract, Fig. 1) configured to mimic the brain microenvironment for the development of treatments for brain disorders (Abstract, p. 1 para. 1), the chip comprising a first channel, a second channel, and an opening between the first channel and the second channel (p. 10 para. 2-3) (Fig. 1, p. 2), wherein a gel is constrained within the first channel by surface tension forces (p. 10 para. 3). The chip further comprises a barrier formed by brain microvascular endothelial cells (BMEC) arranged in the opening between the first channel and the second channel (p. 1 para. 1, p. 9 para. 3-p. 10 para. 4) (Fig. 1, p. 2; Fig. 3, p. 4). Uwamori et al. discloses that this configuration provides a model of the blood brain barrier which is experimentally valuable for developing brain treatments (Abstract, p. 1 para. 1-p. 2 para. 2).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the endothelial cells taught by Cho et al. in view of Chung et al. to comprise BMECs, as Uwamori et al. discloses culturing such cells at an opening between first and second channels to mimic a blood brain barrier for the purpose of developing brain treatments, and the skilled artisan would have been motivated to enhance the experimental utility of the system for the development of brain treatments.
Regarding claim 11, Cho et al. discloses the microfluidic chip comprising the first channel having extracellular matrix therein and the second channel, as set forth above. Cho et al. further discloses wherein the second channel (high height channel) comprises cells therein (para. 89-90). Additionally, Cho et al. discloses wherein the chip is configured to mimic a cell environment within the body (para. 82), such as a disease microenvironment (para. 87). Cho et al. discloses wherein the device can be applied to “various cells” (para. 16).
Cho et al. is silent as to the system comprising pericytes in the second channel.
Uwamori et al. discloses a microfluidic chip (Abstract, Fig. 1) configured to mimic the brain microenvironment for the development of treatments for brain disorders (Abstract, p. 1 para. 1), the chip comprising a first channel, a second channel, and an opening between the first channel and the second channel (p. 10 para. 2-3) (Fig. 1, p. 2), wherein an extracellular matrix gel is constrained within the first channel by surface tension forces (p. 9 para. 4-p. 10 para. 3). Pericytes are provided within the second channel (p. 2 para. 2, p. 9 para. 6-p. 10 para. 3) (Fig. 3, p. 4) to accurately model the brain microenvironment (p. 1 para. 1).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the microfluidic chip disclosed by Cho et al. to comprise pericytes in the second channel, as taught by Uwamori et al., in order to enhance the experimental utility of the system by enabling it to model the blood brain barrier for the development of brain treatments.
Claims 13-15 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (US Patent Application Publication 2014/0273223) (already of record) in view of Chung et al. (US Patent Application Publication 2014/0302594) (already of record) as applied to claims 12 and 16, respectively, above, and in further view of Kim et al. (US Patent Application Publication 2021/0171889) (already of record).
Regarding claim 13, Cho et al. discloses the first cells in the extracellular matrix, as set forth above. Cho et al. further discloses wherein the chip is configured to mimic a cell environment within the body (para. 82). Cho et al. discloses wherein the device can be applied to “various cells” (para. 16).
Cho et al. is silent as to the first cells being neural cells.
Kim et al. discloses a microfluidic chip for modeling a cell environment within the body (para. 9), the chip comprising a gel channel configured to confine a gel therein owing to a height difference between the gel channel and channels adjacent thereto (para. 124, 139). The gel channel comprises an extracellular matrix gel having astrocytes (neural cells) provided therein (para. 120-123, 142); thus, the chip provides an accurate model of the brain microenvironment for the evaluation of new drug efficacy and toxicity (Abstract, para. 4, 14).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the system disclosed by Cho et al. such that the first cells are astrocytes (neural cells), based on the teachings of Kim et al., as the skilled artisan would have been motivated to configured the system so as to model a brain microenvironment for new drug development in order to enhance the experimental utility of the device.
Regarding claim 14, Cho et al. in view of Kim et al. teaches wherein the neural cells comprise astrocytes, as set forth above.
Regarding claim 15, Cho et al. discloses the first cells in the extracellular matrix, as set forth above. Cho et al. further discloses wherein the chip is configured to mimic a cell environment within the body (para. 82). Cho et al. discloses wherein the device can be applied to “various cells” (para. 16).
Cho et al. is silent as to wherein the first cells are cardiac cells, skeletal muscle cells, hepatic cells, renal cells, bone cells, skin cells, esophageal cells, intestinal cells, gastric cells, colon cells, lung cells, or pancreatic cells.
Kim et al. discloses a microfluidic chip for modeling a cell environment within the body (para. 9), the chip comprising a gel channel configured to confine a gel therein owing to a height difference between the gel channel and channels adjacent thereto (para. 124, 139). The gel channel comprises an extracellular matrix gel having cardiac cells provided therein (para. 120-121, 142); thus, the chip provides an accurate model of the heart microenvironment for the development of new drugs (Abstract, para. 132).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the system disclosed by Cho et al. such that the first cells are cardiac cells, based on the teachings of Kim et al., as the skilled artisan would have been motivated to configured the system so as to model a heart microenvironment for new drug development in order to enhance the experimental utility of the device.
Regarding claim 17, Cho et al. discloses wherein the extracellular matrix comprises a hydrogel, as set forth above. Cho et al. further discloses wherein the chip is configured to mimic a cell environment within the body (para. 82). Cho et al. discloses wherein the device can be applied to “various cells” (para. 16).
Cho et al. is silent as to the hydrogel comprising basement membrane extract.
Kim et al. discloses a microfluidic chip for modeling a cell environment within the body (para. 9), the chip comprising a gel channel configured to confine a gel therein owing to a height difference between the gel channel and channels adjacent thereto (para. 124, 139). The gel channel comprises an extracellular matrix gel having cells provided therein (para. 120-121, 142), wherein the extracellular matrix comprises a hydrogel “preferably” comprising basement membrane extract gel (para. 123).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the hydrogel disclosed by Cho et al. to comprise basement membrane extract, based on the teachings of Kim et al., as the skilled artisan would have been motivated to select a material recognized to be preferable for modeling a cell microenvironment of the body.
Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Cho et al. (US Patent Application Publication 2014/0273223) (already of record) in view of Chung et al. (US Patent Application Publication 2014/0302594) (already of record) as applied to claim 4, above, and in further view of Cho et al. (US Patent Application Publication 2021/0348098) (hereinafter “Cho et al. ‘098”).
Regarding claim 21, Cho et al. discloses the gelled extracellular matrix in the first channel comprising first cells (para. 43-48), and the second channel, and Cho et al. in view of Chung et al. teaches the epithelial barrier comprising endothelial cells provided between the first and second channels, as set forth above. Cho et al. further discloses wherein the chip is configured to mimic a cell environment within the body (para. 82) and wherein the device can be applied to “various cells” (para. 16).
The prior art combination is silent as to wherein the gelled extracellular matrix comprises first cells and the second channel contains endothelial cells and pericyte cells in a liquid medium.
Cho et al. ‘098 discloses a microfluidic chip (Abstract) (Figs. 1a-1b, sheet 1 of 33) comprising a first channel (central channel) comprising a gelled matrix including first cells (para. 95, 119, 158, 174), and a second channel containing endothelial cells and pericyte cells in a liquid medium wherein the endothelial cells and pericyte cells are provided so as to form an endothelial barrier at an interface between the first and second channels (para. 115-117, 148, 158, 174). Providing the pericytes alongside the endothelial cells improves the accuracy of the chip as a microphysiological model (para. 115-117).
It would have been obvious to one of ordinary skill in the art to modify the second channel disclosed by Cho et al. to contain endothelial cells and pericyte cells in a liquid medium, as Cho et al. ‘098 discloses that it was known in the art to provide cells in such a manner so as to form a physiologically accurate endothelial barrier, and the skilled artisan would have been motivated to adopt a technique recognized in the art to be effective for forming an accurate barrier comprising endothelial cells.
Regarding claim 22, Cho et al. in view of Chung et al. Teaches wherein the system provides a vascular tissue model, as set forth above, and Cho et al. discloses wherein the system comprises first cells (para. 43-48, 82-84).
The prior art combination is silent as to wherein the model is a blood brain barrier model, wherein the first cells are neural cells including astrocytes.
Cho et al. ‘098 discloses a microfluidic chip (Abstract) (Figs. 1a-1b, sheet 1 of 33) comprising a first channel (central channel) comprising a gelled matrix including first cells including astrocytes (para. 95, 110, 119, 158, 174), and a second channel communicating with the first channel (para. 115, 148, 158, 174). Cho et al. ‘098 discloses that astrocytes play an important role in modeling the blood brain barrier (para. 9) and thus the microfluidic chip can accurately model brain physiology for the development of brain disease treatment (Abstract, para. 98).
It would have been obvious to one of ordinary skill in the art at the time before the effective filing date of the claimed invention to modify the system taught by Cho et al. in view of Chung et al. to be a blood brain barrier wherein first cells are neural cells including astrocytes, based on the teachings of Cho et al. ‘098, as the skilled artisan would have been motivated to configured the system so as to model the brain microenvironment for brain treatment development in order to enhance the experimental utility of the device.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOLLY KIPOUROS whose telephone number is (571)272-0658. The examiner can normally be reached M-F 8.30-5PM.
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/HOLLY KIPOUROS/Primary Examiner, Art Unit 1799
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