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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-19) in the reply filed on 10/08/2025 is acknowledged.
Claim 21 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as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. Election was
made without traverse in the reply filed on 10/08/2025.
Accordingly, claims 1-19 and 21 are pending and claims 1-19 have been examined herein.
Priority
The instant claims herein are examined utilizing the accepted effective filing date of 2/18/2020 for the basis of any prior art rejections.
Claim Rejections - 35 USC § 112(b)
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 2-3 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 2-3 recites the limitation "non-spheroid-forming cells". It is unclear what kind of cell Applicant intends to encompass and the specification does not define what cells are part of the genus of “non-spheroid-forming cells.” Where applicant acts as his or her own lexicographer to specifically define a term of a claim, the written description must clearly redefine the claim term and set forth the definition so as to put one reasonably skilled in the art on notice that the applicant intended to define that claim term as such. Thus, the term is indefinite because the specification does not clearly define the term. Claim 3 is also included in this rejection for being dependent on indefinite claim 2. For the purpose of compact prosecution, he examiner is interpreting that any cancer cell is a “non-spheroid-forming cell” absent evidence to the contrary.
Claim 3 recites the limitation "the . . . iPSC-derived mesenchymal stem cells". There is insufficient antecedent basis for this limitation in the claim because there is no previous recitation of any iPSC-derived mesenchymal stem cells in the claims from which this claim depends. Thus, the claim is indefinite.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to rejections made based on said interpretations. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-5, 13 and 18-19 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Frenguelli et al (WO 2019122351 A1, 21 Dec 2018; Published 27 June 2019).
Frenguelli teaches 3D bioprinting and culturing of human or animal tissue (abstract). The reference teaches a method of culturing wherein at least two types of cells are co-cultured at different ratios for in vitro culture (see claims 25-27 of Frenguelli). The reference teaches that the cells can be a combination of healthy and diseased cells, iPSCs or cells derived from patient-specific iPSCs, and that the cancer cells such as pancreatic, colon, breast, liver, lung, hepatocellular carcinoma cells, etc. (p. 6, lines 5-31) (“obtaining cancer cells isolated from a subject and co-culturing the cancer cells with induced pluripotent stem cells or induced pluripotent stem cell-derived cells to form a spheroid-shaped culture” as in instant claim 1; “wherein the cancer cells comprise non-spheroid-forming cells” as in instant claim 2; “wherein the cancer is a cancer consisting of breast cancer, . . ., lung cancer, . . . , pancreatic cancer, . . . liver cancer” as in instant claim 13; “a fibrosis-encapsulated tumoroid produced by the method of any one of claims 1 to 18” as in instant claim 19). The ratio for cels in co-culture are chosen between 1:1, 1:5, 1:10, 1:25, 1:50, 1:100, and any range in between (i.e., ratio of iPSCs and cancer cells can be 1:1 or 1:100) (“wherein the co-culture in step (b) is performed by mixing and culturing the cancer cells and the induced pluripotent stem cells or induced pluripotent stem cell-derived cells at a cell number ratio of 0.01:1 to 100:1” as in instant claim 4; “cell number ratio of 1.5:1 to 2.5:1” as in instant claim 5). Culturing occurred for up to 13 days (“wherein the co-culture is performed for 2 days to 14 days” as in instant claim 18). Instant claim 3 recites, inter alia, “wherein the non-spheroid-forming cells are formed into the spheroid-shaped culture by the induced pluripotent stem cells or iPSC-derived mesenchymal stem cells,” which raises questions are to its limiting effects. MPEP 2111.04 states "‘whereby/wherein clauses in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.
Accordingly, absent evidence to the contrary, Frenguelli anticipates instant claims 1-5, 13 and 18-19.
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.
Claim(s) 6 and 8-9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frenguelli et al (WO 2019122351 A1, 21 Dec 2018; Published 27 June 2019) as applied to claims 1-5, 13 and 18-19 above, and further in view of Noel et al (J Vis Exp. 2017 Aug 23;(126):56081).
The teachings of Frenguelli were recited in the above 35 U.S.C. 102 rejection as applied to claim 1 of which claim 6 and 8-9 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach inducing a fibrotic layer on the culture.
Noel teaches the preparation of 3-dimensional spheroid co-cultures of pancreatic cancer cells and fibroblasts (title). The reference teaches that many cancer types, including pancreatic cancer, have dense fibrotic stroma that plays a role in tumor progression and invasion (abstract). Activated cancer associated fibroblasts are a key component of the tumor stroma that interact with cancer cells and support their growth and survival (same para). Models that recapitulate the interaction of cancer cells and activated fibroblasts are important tools for studying the stromal biology and for development of antitumor agents (same para) (“inducing a fibrotic layer on the culture” as in instant claim 6; “wherein step (c) comprises encapsulating the fibrotic layer by at least one cell type selected from the group consisting of fibroblasts, . . . cancer-associated fibroblasts” as in instant claim 9). The reference teaches that once the spheroids are formed, they can be transferred for use for metabolic assays (“Washing and transfer of spheroids” para 1) (“further comprising step (d) of selecting a fibrosis encapsulated tumoroid on which the fibrotic layer has been induced” as in instant claim 8).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a tumoroid as taught by Frenguelli, where the tumoroid has a fibrotic layer as taught by Noel, to arrive at the instantly claimed invention. As Noel shows that multi-cellular tumor spheroid containing fibroblasts can be used for metabolic assays and drug efficacy testing, one of ordinary skill would have been motivated to modify the method of Frenguelli to include a fibroblast layer as taught by Noel with a reasonable expectation of advantageously recapitulate the interaction of cancer cells and activated fibroblasts as taught by the prior art.
Claim(s) 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frenguelli et al (WO 2019122351 A1, 21 Dec 2018; Published 27 June 2019) in view of Noel et al (J Vis Exp. 2017 Aug 23;(126):56081) as applied to claims 6 and 8-9 above, and further in view of Leung et al (Biomater Sci. 2015 Feb; 3(2):336-44. Epub 2014 Nov 13).
The teachings of Frenguelli and Noel in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 6 of which claim 7 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach compacting the induced fibrotic layer.
Leung teaches media additives to promote spheroid circularity and compactness (title). The reference teaches that comparing drug efficacy across different cell types in spheroid culture can be difficult due to variations in spheroid morphologies and transport characteristics (abstract). Improving the reproducibility of compact, circular spheroids contributes to standardizing and increasing the fidelity of the desired gradient profiles in these drug screening three-dimensional tissue cultures (same para). Multicellular spheroid models have been generated through various methods and has been applied to fabricate 3-D tissues such as cancer tumor models (Introduction para 2). Spheroids generally become more circular and compact when supplemented with low concentration of collagen compared to unsupplemented control conditions (“Effect of additives on spheroid morphology” para 3). Whereas high collagen concentrations had varied responses, primarily a negative impact on spheroid circularity and compactness and in some cell types (A549 and HeLa) completely abrogating single spheroid formation, similar to previously reported formation of small multi-spheroids within cultures containing higher concentrations of Matrigel (same para). In contrast, cells behave in a much more uniform fashion in the presence of MethoCel. For most cells tested (DU145, A549, HeLa, MDA-MB-231, MCF-7), the presence of MethoCel improved circularity and compactness of spheroids in a dose dependent manner with varying degrees of effectiveness (same para). MethoCel demonstrated its ability in enhancing spheroid morphology in the acute phase of spheroid culture (2 days), but it was unclear whether such enhancement would be sustained over a long culture period (“Effect of additives on spheroid morphology” para 4). To test this we chose three tumor cell lines (MDA-MB-231, DU145 and PC3) to further examine the effects of MethoCel on monoculture spheroid formation over a period of 4 days. Spheroids consisting of either MDA-MB-231 or DU145 became more circular and compact from day 1 to 4 post seeding (Fig. 3; same para). The addition of 0.24 mg mL−1 of MethoCel led to further enhancement over time when compared to cultures with no additives and spheroid morphology was minimally affected by culture time (same para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a tumoroid as taught by Frenguelli and Noel in combination, where the tumoroid is compacted as taught by Leung, to arrive at the instantly claimed invention. As Leung shows that spheroid morphologies and transport characteristics are effected by compactness and circularness, one of ordinary skill would have been motivated to combine the method of Frenguelli and Noel in combination with compacting via addition of medium supplements as taught by Leung according to known methods to yield the predictable result of advantageously improving the reproducibility of compact, circular spheroids and increase their fidelity as taught by the prior art.
Claim(s) 10-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frenguelli et al (WO 2019122351 A1, 21 Dec 2018; Published 27 June 2019) in view of Noel et al (J Vis Exp. 2017 Aug 23;(126):56081) as applied to claims 6 and 8-9 above, and further in view of Ho et al (Theranostics. 2012;2(1):66-75. doi: 10.7150/thno.3568. Epub 2012 Jan 1).
The teachings of Frenguelli and Noel in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 6 of which claims 10-12 ultimately depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach inducing a vascular cell layer on the fibrotic layer (claim 10), or that the vascular cell layer is induced by endothelial cells or vascular endothelial cells (claim 11).
Ho teaches penetration of endothelial cell coated multicellular tumor spheroids (title). The reference teaches the investigation of the use of iron oxide nanoparticles that target tumor vasculature, via the tumstatin peptide, in a novel three-dimensional tissue culture model (abstract). The developed tissue culture model more closely mimics the in vivo environment with a leaky endothelium coating around a glioma tumor mass (same para). The novel endothelial cell-coated tumor model provides an in vitro microtissue environment to evaluate effects of drug therapy on neo-vascularization inhibition (same para). The reference teaches that Multicellular tumor spheroid (MTS), a three-dimensional cluster of cancer cells grown in vitro, mimics the early avascular stage of tumor growth such as the presence of ECM and diffusion gradients of nutrients and wastes (Introduction, para 2). As a result, MTS can contain heterogeneous regions of tumor cell growth including a necrotic center with proliferating cells restricted to the outer rim of the MTS (same para). A uniform in vitro tumor model comprising of both tumor spheroids and a vascular endothelium is highly desired to study the extravasation and penetration (Introduction para 4). They used micromolded non-adhesive agarose gels to construct a uniform MTS coated with endothelial cells (para 5). Utilizing the micromold and self-assembly techniques, cell-cell sorting interactions formed a model for a tumor core that must be accessed through a leaky vasculature (same para) (“further comprising step (e) of inducing a vascular cell layer on the fibrotic layer” as in instant claim 10; “wherein the vascular cell layer is induced by endothelial cells” as in instant claim 11). Rat RG2 cells, a glioblastoma model cell line, formed a MTS core similar to that of a solid tumor, while bovine-pulmonary arterial endothelial (BPAE) cells assembled on the surface of the MTS. The layer of endothelial cells restricted access to the tumor core and acted as the vascular endothelium (same para). This technique formed hundreds of uniform replicates for the endothelium-coated tumor (same para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a tumor spheroid as taught by Frenguelli and Noel in combination, where a vascular layer is formed on the surface of the spheroid as taught by Ho, to arrive at the instantly claimed invention. Ho shows endothelial cells can be utilized to create a vascular endothelial cell layer over a tumor spheroid. One of ordinary skill would have been motivated to modify the tumor spheroid of Frenguelli and Noel in combination to include an endothelial cell layer as taught by Ho with a reasonable expectation of advantageously creating a developed tissue culture model more closely mimics the in vivo environment with a leaky endothelium coating as taught by the prior art.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frenguelli et al (WO 2019122351 A1, 21 Dec 2018; Published 27 June 2019) in view of Noel et al (J Vis Exp. 2017 Aug 23;(126):56081) and Ho et al (Theranostics. 2012;2(1):66-75. doi: 10.7150/thno.3568. Epub 2012 Jan 1) as applied to claims 10-11 above, and further in view of Wang et al ().
The teachings of Frenguelli, Noel, and Ho in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 11 of which claims 12 ultimately depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the endothelial cells or vascular endothelial cells are induced from induced pluripotent stem cells (claim 12).
Wang teaches that endothelial cells (ECs) have great potential in vascular diseases research and regenerative medicine (abstract). Autologous human ECs are difficult to acquire in sufficient numbers in vitro, and human induced pluripotent stem cells (iPSCs) offer unique opportunity to generate ECs for these purposes (same para). Differentiated ECs exhibited strong expression of cells-specific markers (CD31 and von Willebrand factor antibody), similar to that present in human umbilical vein endothelial cells (same para). In addition, the hiPSC derived ECs were able to form tubular structure and respond to vascular-like flow generated on a microdevice. Furthermore, the human induced pluripotent stem cell-endothelial cells (hiPSC-ECs) pretreated with tumor necrosis factor (TNF-α) were susceptible to adhesion to human monocyte line U937 under flow condition, indicating the feasibility of this hiPSCs derived microsystem for mimicking the inflammatory response of endothelial cells under physiological and pathological process (same para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a tumor spheroid as taught by Frenguelli, Noel and Ho in combination, where the endothelial cells are derived from iPSCs as taught by Wang, to arrive at the instantly claimed invention. Wang shows endothelial cells can successfully be induced from induced pluripotent stem cells. One of ordinary skill would have been motivated to simply substitute one known element (endothelial cells of Frenguelli, Noel, and Ho) for another (iPSC-derived endothelial cells of Wang) to obtain the predictable result of advantageously having cells that can mimic the response of endothelial cells under physiological and pathological process without getting autologous ECs as taught by the prior art.
Claim(s) 14 and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frenguelli et al (WO 2019122351 A1, 21 Dec 2018; Published 27 June 2019) as applied to claim 1-5, 13 and 18-19 above, and further in view of Mohapatra et al (WO2015179393A1, 19 May 2015; Published 26 Nov 2015).
The teachings of Frenguelli were recited in the above 35 U.S.C. 102 rejection as applied to claim 1 of which claims 14 and 16-17 depends. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach wherein the co-culture is performed in at least one culture medium selected from the group consisting of DMEM, IMDM, a-MEM, TI-free OGM, F12, RPMI 1640, Williams' s medium E, McCoy's 5A, essential 8 medium, SFM medium, N2B2 medium, OBM medium, growth medium-5, growth medium-10, and DMEM/F12 (instant claim 14), the medium contains cancer- associated fibroblasts, endothelial cells, mesenchymal stem cells (iMSCs) differentiated from induced pluripotent stem cells (iPSCs), or a growth factor (instant claim 16) or wherein the growth factor is at least one selected from the group consisting of vascular endothelial growth factor (VEGF), vascular endothelial growth factor A (VEGFA), transforming growth factor beta (TGF-3), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and insulin-like growth factor-1(IGF-1) (instant claim 17).
Mohapatra teaches a method of forming multi-cellular tumoroids, the method comprising: co-culturing tumor cells (TCs), cancer associated fibroblast cells (CAFs), and epithelial cells (ECs) in a cell culture media (claim 1 of Mohapatra). The reference teaches that the medium is mesenchymal stem cell conditioned and contains at least about 800 pg/mL VEGF and at least about 1200 pg/mL of TGF-B1 (see claim 6 and 8 of Mohapatra) (“wherein the culture medium further contains cancer-associated fibroblasts . . . a growth factor” as in instant claim 16; “wherein the growth factor is at least one selected from the group consisting of vascular endothelial growth factor (VEGF) . . . transforming growth factor beta (TGF-B)” as in instant claim 17). The culture medium can be a suitable standard base medium including DMEM, DME, RMPI-1640, and MEM (Co-culture of cells, para 11) (“DMEM, . . ., RPMI 1640” as in instant claim 14). Cancer cells can induce and maintain the fibroblasts active phenotype, which in turn, produce a series of growth factors (including VEGF) and cytokines that sustain tumor progression by promoting extracellular matrix (ECM) remodeling, cell proliferation, angiogenesis, maintenance of stemness, regulating inflammation, regulating immune response, promoting a hospitable metabolic environment and epithelial-mesenchymal transition (“Co-culture of cells” para 4). Indirectly, CAFs can promote and maintain tumor progression by secreting proteases and other molecules involved in proteolysis and degradation of the ECM, such as plasminogen activators and matrix metalloproteinases (same para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a tumor spheroid as taught by Frenguelli, where the medium contains cancer-associated fibroblasts, VEGF, and TGF-B1 as taught by Mohapatra, to arrive at the instantly claimed invention. Mohapatra shows cancer-associated fibroblasts, VEGF and TGF-B1 can successfully be added to a culture medium. One of ordinary skill would have been motivated to combine the prior art elements [tumor spheroid culture of Frenguelli with the medium components of Mohapatra] according to known methods with a reasonable expectation of advantageously sustain tumor progression by promoting extracellular matrix (ECM) remodeling, cell proliferation, angiogenesis, maintenance of stemness as taught by the prior art. One of ordinary skill in the art would recognize that the improvements caused by the addition of VEGF, TGF-B1, and cancer-associated fibroblasts would improve similar cultures in the same way.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Frenguelli et al (WO 2019122351 A1, 21 Dec 2018; Published 27 June 2019) in view of Mohapatra et al (WO2015179393A1, 19 May 2015; Published 26 Nov 2015) as applied to claims 14 and 16-17 above, and further in view of Johnson et al (Sci Rep 5 Feb 2019; 9(1):1407).
The teachings of Frenguelli and Mohapatra in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 14 of which claim 15 depends. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach wherein the culture medium further contains B27, N2, G2, or forskolin (instant claim 15).
Johnson teaches that a tumorsphere is a solid, spherical formation developed from the proliferation of one cancer stem/progenitor cell (abstract). The reference teaches that part of the protocol to culture tumorspheres into solid, round structure includes the addition of B27 supplement (50x) to tumorsphere medium (Procedure, step 1). The reference teaches that the addition of B27 increases tumorsphere formation and sustains several passages of sphere cultures (same para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a tumor spheroid as taught by Frenguelli, where the medium contains B27 as taught by Johnson, to arrive at the instantly claimed invention. Chen shows B27 can successfully be added to a tumorsphere culture medium. One of ordinary skill would have been motivated to combine the prior art elements [tumor spheroid culture of Frenguelli and Mohapatra in combination with B27 as taught by Johnson] according to known methods with a reasonable expectation of advantageously increasing tumorsphere formation and sustaining the tumorspheres for several passages as taught by the prior art. One of ordinary skill in the art would recognize that the improvements caused by the addition of B27 would improve similar cultures in the same way.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 7-3.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras Jr can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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