DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election of Group I, claims 1-12, drawn to a tumor-on-a-chip, and the species of the capture probes of proteins, and the species of brain and spinal cord tumors in the reply filed on 02 September 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
3. Claims 1-19 are pending.
Claims 13-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-12 read on the elected invention and have been examined herein. Claim 8 has been examined herein to the extent that it reads on the elected species of capture molecules or probes that are proteins; and claim 10 has been examined to the extent that it reads on the elected species of brain or spinal cord tumors. Claims 8 and 10 encompass the non-elected species of the additionally recited types of capture molecules or probes (claim 8) and the additionally recited types of cancers (claim 10). Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Objection to Drawings
4. The drawings are objected to under 37 CFR 1.83(a). A set of drawings filed on 29 July 2022 includes figures presented in color.
MPEP 608.02, part VIII states:
Color drawings and color photographs are not accepted in utility applications filed under 35 U.S.C. 111 unless a petition filed under 37 CFR 1.84(a)(2) or (b)(2) is granted. Color drawings and color photographs are not permitted in international applications (see PCT Rule 11.13 ).
Unless a petition is filed and granted, color drawings or color photographs will not be accepted in a utility patent application filed under 35 U.S.C. 111. The examiner must object to the color drawings or color photographs as being improper and require applicant either to cancel the drawings or to provide substitute black and white drawings.
Herein, a petition for color drawings or color photographs has not been filed and the conditions for color drawings have not been met. Note that color drawings are only accepted on rare occasions when they are the only practical medium by which to disclose the subject matter to be patented. See MPEP 608.02(VIII).
If the drawings are intended to be in color, a petition for color drawings must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Alternatively, corrected drawing sheets in black and white in compliance with 37 CFR 1.121(d) are required.
Note that if black and white drawings are filed, the specification must be amended so that the description of the drawings are no longer in color. See, for example, para [0018] (note that paragraph numbering herein is with respect to the published application) which recites “Red stars denote brain microvessel” and para [0020] wherein Figure 5C is described as follows “Representative confocal immunofluorescence images showing a 3D brain microvessel lumen (yellow) in contact with CD8+ T-cells (green) and GBM (PN, GBML20) tumor cells (red).”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
5. 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 1-12 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 1-12 are indefinite over the recitation of “a first plurality of evenly spaced micropillars arranged in a substantially circular shape within the central chamber and a second plurality of evenly spaced micropillars arranged in a substantially circular shape within the first plurality evenly spaced of micropillars.” First, it is unclear as to what is meant by “a first plurality of evenly spaced micropillars arranged in a substantially circular shape within the central chamber and a second plurality of evenly spaced micropillars arranged in a substantially circular shape within the first plurality evenly spaced of micropillars.” Secondly, it is unclear as to how the arrangement of the second plurality of micropillars “within the first plurality” of micropillars results in partitioning the central chamber into an inner, middle and outer region.
Claim 6 is indefinite over the recitation of ““the first and the second plurality of evenly spaced micropillars are evenly spaced by a distance between about 50 µm and 200 µm” because it is not clear as to whether the stated distance is between each micropillar or between the first plurality of micropillars and the second plurality of micropillars.
Claims 11 and 12 are indefinite over the recitation of “wherein a device configured to replicate or mimic a brain tumor comprises tumor cells that are glioblastoma cells” because it is not clear as to how the “a device” of claims 11 and 12 relate back to the tumor-on-a-chip device of claim 1. For instance, it is not clear as to whether “a device” is intended to be limited to the tumor-on-a-chip device or includes a different device that is present in addition to the tumor-on-a-chip device. In the latter instance, it is unclear as to whether the device of claims 11 and 12 is required by the claims or if the claims are merely defining what would be encompassed by a device configured to replicate or mimic a brain tumor. This rejection may be obviated by amendment of claim 11 to recite, “The device of claim 10, wherein the device is configured to replicate or mimic a brain tumor, the tumor cells are glioblastoma cells and the middle region further comprises tumor-associated macrophages.
Priority
6. The present claims are entitled to priority to provisional application 62/227,704, filed 03 July 2021.
Claim Rejections - 35 USC § 102
7. 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2, 4-5 and 10-12 are is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cui et al (eLife. 10 September 2020;9:e52253, p. 1-21 and “Figure 2- figure supplement 2”).
Cui et al teaches a tumor-on-a-chip device - i.e., a GBM- or glioblastoma-on-a-chip device which comprises: a cartridge housing; a central chamber embedded in the cartridge housing; and a first plurality of evenly spaced micropillars arranged in a substantially circular shape within the central chamber and a second plurality of evenly spaced micropillars arranged in a substantially circular shape, wherein the first plurality of micropillars and second plurality of micropillars are arranged concentrically to one another, such that the central chamber is partitioned into at least an outer region, a middle region, and an inner region; wherein each of the outer region, middle region, and inner region is fluidly connected to at least one aperture; and wherein the outer region comprises endothelial cells configured to mimic a microvasculature, and the middle region comprises tumor cells configured to mimic a tumor (see p. 3-4 “Modeling the GBM tumor niche in an ex vivo ‘GBM-on-a-Chip’
microphysiological system” and Figure 2A and Figure 2 supplement 1)
Regarding claim 2, Cui (p. 4 and p. 13 “Generation of ex vivo tumor microenvironment”) teaches that the GBM-on-a-Chip includes a core, inner region that is configured to introduce media and flush out media. At p. 4, Cui states that the GBM-on-a-Chip includes “a core media region (center region) for long-term media supply (Figure 2A and Figure 2—figure supplement 1).” Accordingly, Cui teaches that the device includes an inner region configured for media perfusion and waste removal.
Regarding claim 4, as shown in Figure 2A and Figure 2 - figure supplement 1, the first plurality of evenly spaced micropillars and the second plurality of evenly spaced micropillars are concentric.
Regarding claim 5, the illustrations of Cui show that the first and the second plurality of evenly spaced micropillars have a circular cross-sectional shape (Figure 2A and Figure 2 - figure supplement 1).
Regarding claims 10-12, the GBM-on-a-chip device of Cui is configured to mimic a glioblastoma and comprises glioblastoma cells and tumor-associated macrophages, as well as circulating CD8+T-cells (e.g., p. 3 and Figure 2 and Figure 2 - supplement figure 1). For instance, Cui (p. 3) states:
“Modeling the GBM tumor niche in an ex vivo ‘GBM-on-a-Chip’
microphysiological system
To dissect the heterogeneity of anti-PD-1 immunotherapy responses in molecularly distinct GBM cohort of PN, CL, and MES subtypes, we developed a microfluidics-based 3D ‘GBM-on-a-Chip’ microphysiological system (Figure 2 and Figure 2—figure supplement 1) mimicking the subtype specific in vivo GBM tumor niche. In this organotypic system, we housed a 3D brain microvessel (Figure 2A–C, yellow) derived from human brain microvascular endothelial cells (hBMVECs), TAMs
derived from human macrophages (Figure 2—figure supplement 2A and B), patient-derived and molecularly-distinct GBM cells (Figure 2A–C, red), and sorted allogeneic human CD8+ T-cells (Figure 2A–C, green) from primary peripheral blood mononuclear cells (PBMCs) within a 3D brain mimicking hyaluronan (HA)-rich Matrigel extracellular matrix (ECM) (Figure 2—figure supplement 2; Wang et al., 2019) (details see Materials and methods).”
Claim Rejections - 35 USC § 103
8. 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) 3 and 6-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cui et al (eLife. 10 September 2020;9:e52253, p. 1-21 and “Figure 2- figure supplement 2”).
The teachings of Cui are presented above.
Regarding claim 3, Cui (p. 3 and Figure 2-figure supplement 1) teaches that the glioma cells are patient-derived cells and thereby are autologous cells. Cui does not teach that the endothelial cells are also patient-derived cells.
However, Cui (final para at p. 11 states:
“The current model might be further improved to replicate a truly patient-specific ex vivo GBM model. First, the allogeneic immune and stromal cells used in the current proof-of-concept GBM model may limit the clinical significance of the findings for patient-specific immunotherapy screening. An autologous model constructed with all patient-derived cells will envision a truly personalized GBM-on-a-Chip to further improve the predictive value of the system.”
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the GBM-on-a-Chip device of Cui so as to have used autologous, patient-derived endothelial cells together with the patient-derived glioma cells in order to have further achieved the advantage set forth by Cui of improving the patient-specific ex vivo GBM model.
Regarding claim 6, Cui does not teach that “the first and the second plurality of evenly spaced micropillars are evenly spaced by a distance between about 50 µm and 200 µm.”
However, Cui (e.g., p. 13) does provide the guidance for the microfabrication of the microfluidics-based GBM-on-a-Chip and in Figure 2 - figure supplement 1B provides a scale bar with an image of the device. See also Figure 2.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention and well in the skill of the ordinary artisan to have selected the optimum distance between the micropillars, including a distance of between 50 µm and 200 µm in order to have achieved the result set forth by Cui that the evenly / regularly spaced micropillars “confine cell-embedded hydrogels
to mimic the native in vivo pathological architecture of GBM tumors” (p. 4 final para).
Regarding claims 7-9, Cui does not specifically teach that the GBM-on-a-Chip device further comprises capture molecules, particularly capture molecules that are proteins, and particularly capture molecules that are positioned between each of the micropillars.
However, Cui (p. 11-12) does teach:
“our GBM-on-a-Chip allows for a multidimensional readout of
patient-specific responses to different immunotherapy regimens ex vivo on the basis of cellular (immune cell infiltrate composition, phenotypes, and dynamics), epigenetic, transcriptomic, and secretomic signatures to examine the prognostic relationship between patient response and the GBM subtypes (PN, MES, and CL) and genetic mutations (IDH)…
we demonstrated the feasibility of a patient-specific screening for immunotherapy
responses ex vivo with our GBM-on-a-Chip platform to dissect the heterogeneous tumor immune microenvironments, rationalize and screen effective therapeutic combinations and facilitate precision immuno-oncology. We envision that a truly personalized GBM-on-a-Chip system can significantly accelerate the pace for identifying novel therapeutic biomarkers, developing patient-specific immunotherapeutic strategies, and optimizing therapeutic effect and long-term management for a broader GBM patient population.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the GBM-on-a-Chip device of Cui so as to have included capture molecules that are proteins, such as antibodies to detected secreted proteins, which could be used to monitor patient-specific responses to immunotherapies. Further, regarding claim 9, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have included such capture molecules between the micropillars so that the capture molecules were evenly spaced on the GBM-on-a-Chip device and/or did not interfere with the growth of the glioma and endothelial cells.
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Yi et al (Nature Biomedical Engineering. July 2019. 3: 509-519; cited in the IDS) teaches a GBM-on-a-Chip device comprising GBM cells isolated from a patient present in an inner region of the device and surrounded by endothelial cells / BdECM (see, e.g., Figure 1 and p. 510). Yi et al (p. 510) states:
“The GBM-on-a-chip was therefore composed of innermost cancer cells, surrounding vascular endothelial cells and an outermost chamber filled with culture medium. Using an in-house 3D-printing system30, the chip was fabricated as follows: (1) the chamber wall was printed with gas permeable silicone ink on a non-permeable glass substrate; (2) to construct the GBM-mimetic structure, BdECM bioink laden with
HUVECs was first printed in a ring shape; (3) BdECM bioink laden with GBM cells was then printed to fill the inside of the BdECM–HUVEC ring structure and (4) the whole printed construct was solidified in a humidified cell culture incubator and the top of the
chamber was then covered with a glass cover slip (Fig. 3b,c and Supplementary Video 1). The culture medium was fed through an inlet hole in the silicone chamber (containing a second hole to balance the pressure).”
However, Yi et al does not teach the presently claimed tumor-on-a-chip device, comprising (in part) a central chamber embedded in a cartridge housing; and having a first plurality of evenly spaced micropillars arranged in a substantially circular shape within the central chamber and a second plurality of evenly spaced micropillars arranged in a substantially circular shape within the first plurality evenly spaced of micropillars, such that the central chamber is partitioned into at least an outer region, a middle region, and an inner region; wherein each of the outer region, middle region, and inner region is fluidly connected to at least one aperture; and wherein the outer region comprises endothelial cells configured to mimic a microvasculature, and the middle region comprises tumor cells configured to mimic a tumor.
Ma et al (Sci. Adv. 30 Oct 2020. 6: eaba5536, p. 1-14 and Supplementary Materials, p. 1-13) teaches a 3-dimensiaonl microfluidics-based leukemia-on-a-chip device characterized as “composed of three distinct functional regions (fig. S1A):a central sinus region vascularized by ECs, an inner ring region serving as an interface of leukemia blasts (B-ALL cells) and niche cells (ECs and MSCs) interactions, and the outer ring channels(which is used to create the endosteal region by encapsulating osteoblasts and B-ALL cells within hydrogel), connected with four medium reservoirs, for cell culture medium supplies and waste removal. All the cell types were embedded in a fibrin hydrogel to maintain 3D cell culture” (p. 11, col. 1). As shown and described in Supplementary Fig. S1, the innermost “central area” comprises endothelial cells (ECs); the “central area” is surrounded by the “ring area” which comprises ECs, mesenchymal stromal cells (MSCs) and B-cell acute lymphoblastic leukemia (B-ALL) cells; which is surrounded by the “outer area” which comprises osteoblast and B-ALL cells. Ma further teaches that “(t)hese three functional regions were partitioned by regularly spaced trapezoid micropillars that confine cell-embedded hydrogels, by balancing surface tension and capillary forces, to overall mimic the native in vivo BM tissue architecture of leukemia” (p. 2, col. 1). Ma et al does not teach or suggest the presently claimed tumor-on-a-chip device particularly wherein the outer region comprises endothelial cells configured to mimic a microvasculature.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682