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 .
DETAILED ACTION
Amendments
In the reply filed on 06/15/2026, Applicant has amended claim 1 and canceled claims 2-6.
Claim Status
Claims 1 and 7-8 are pending.
Claim 8 has been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/08/2025.
Claims 1 and 7 are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/15/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
New 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 1 and 7 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 1 recites the phrase “a fibroblast line (MRC5)” in line 6. The use of parentheses renders the claim indefinite because it is unclear whether the limitation “MRC5” between the parentheses is part of the claimed invention. Since Applicant argues that the claimed invention utilizes bladder cancer cell lines “while simultaneously employing HUVEC and MRC5 cell lines” (Remarks, p. 11), it is recommended to remove the parentheses, so as to recite “a fibroblast line MRC5”. Claim 7 is rejected as being dependent from claim 1 but not resolving the ambiguity.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1-7 under 35 U.S.C. 103 as being unpatentable over Kim et al,. (PLoS ONE. 2019; 14(10): e0223689. p. 1-15. Cited in IDS 05/15/2023) in view of Datta et al., (npj Precision Oncology. 2020; 4:18, p. 1-13. Cited in IDS 05/15/2023) and Cho et al., (Adv. Healthcare Mater. 2019, 8, 1801019, p. 1-11) is withdrawn in light of Applicant’s cancellation of claims 2-6 and amendment to claim 1 to recite new limitations such as the layers being “separately within the structure” and the layers are composed of GelMA and a combination of the specified cell lines.
New 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.
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 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al,. (PLoS ONE. 2019; 14(10): e0223689. p. 1-15. Cited in IDS 05/15/2023) in view of Datta et al., (npj Precision Oncology. 2020; 4:18, p. 1-13. Cited in IDS 05/15/2023), Cho et al., (Adv. Healthcare Mater. 2019, 8, 1801019, p. 1-11. Prior art of record) and Lazzari et al., (Acta Biomaterialia. 2018; 78: 296-307).
With respect to claim 1, Kim teaches a three-dimensional (3D) cell culture printing model for bladder cancer, made by bioprinting bladder cancer cells such as the bladder cancer cell line 5637 cells in GelMA into a bladder cancer cell layer and stacking the bladder cancer cell layers into a 3D structure (see e.g., abstract and Fig 1 for the 3D bladder cancer cell construct made by layers of bladder cancer cells in GelMA), thus teaches a bladder cancer mimic comprising a 3D stacked structure including a bladder cancer cell layer, wherein the bladder cancer cell layer is composed of GelMA and the bladder cancer cell line 5637 cells.
However, Kim is silent on the 3D cancer mimic including endothelial cells and fibroblasts, nor teach the human umbilical vein endothelial cell (HUVEC) line or a fibroblast line MRC5.
Nevertheless, Kim teaches almost all cells in the in vivo environment are surrounded by extracellular matrix (ECM) and other cells, and 3D bioprinting techniques with scaffold bioink made up of cellular materials have been utilized to provide major ECM elements of the tumor microenvironment (p. 2, “Introduction”). Kim further teaches that this 3D printing technique can be used to create a cancer cell-like environment for a drug screening platform (e.g., abstract).
Datta summarizes 3D bioprinting in mimicking cancer microenvironment (e.g., abstract). Datta teaches, e.g., for reconstructing the tumor microenvironment, individual 3D bioprinted components can be assembled from droplets of tumor cells and microchannels comprising endothelial cells- and fibroblast-containing hydrogel acting as tumor stroma (e.g., p. 2, left col, last part, also see Table 1 for a list of 3D bioprinted cancer models comprising cancer cells, endothelial cells and fibroblasts), thus suggests endothelial cells and fibroblasts in hydrogel can be incorporated into the 3D bioprinted cancer models to mimic cancer microenvironment. In regard to the HUVEC line or a fibroblast line MRC5, Datta teaches the endothelial cell layer includes a HUVEC line (Datta, e.g., Fig 1 and Table 1) and the fibroblasts include MRC5 (Datta, e.g., Table 1 and p. 6, last para.).
In regard to simultaneously employing HUVEC and MRC5 cell lines in a cancer model, Lazzari teaches a multicellular cancer spheroid to mimic pancreatic tumor complexity (see e.g., title), which consists of pancreatic cancer cells PANC-1, endothelial cells HUVEC, and fibroblasts MRC5 to form a hetero-type multicellular tumor spheroid (e.g., abstract). Lazzari teaches the integration of the three cell types enabled to reproduce in vitro with fidelity the influence of the surrounding environment on the sensitivity of cancer cells to chemotherapy (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3D bioprinted bladder cancer mimic disclosed by Kim, by combining endothelial cells HUVEC line and fibroblasts MRC5 line in the cancer mimic as suggested by Datta and Lazzari with a reasonable expectation of success. Since Kim aims to use 3D bioprinting technique with scaffold bioink made up of cellular materials to create a cancer cell-like environment for a drug screening platform (e.g., abstract and p. 2, “Introduction”), since Datta suggests individual 3D bioprinted components comprising tumor cells, endothelial cells and fibroblasts can be assembled for reconstructing the tumor microenvironment and suggests a HUVEC line and MRC5 fibroblast line (e.g., p. 2, left col, last part, and p. 6, last para., also see Table 1 and Fig 1), and since Lazzari reduces to practice simultaneously employing HUVEC and MRC5 cell lines together with a cancer cell line in a 3D cancer model and teaches the integration of the three cell types enabled to reproduce in vitro with fidelity the influence of the surrounding environment on the sensitivity of cancer cells to chemotherapy (e.g., abstract), one of ordinary skill in the art would have had a reason to simultaneously combine endothelial cells HUVEC and fibroblasts MRC5 cell lines in Kim’s 3D bioprinted bladder cancer mimic as suggested by Datta and Lazzari in order to create a cancer cell-like environment for drug screening (Kim, abstract).
However, Kim, Datta and Lazzari are silent on the 3D bioprinted cancer mimic comprising a stacked structure including layers of each cell type separately within the structure, nor teach the endothelial cell layer and the fibroblast layer comprising GelMA.
Nevertheless, Kim reduces to practice a method for bioprinting a bladder cancer cell layer comprising bladder cancer cells in GelMA and stacking the cancer cell layers to form a 3D model (see e.g., Fig 1 for bioprinting and stacking bladder cancer cell layers) and contemplates “stacking layers with many cells into 3D structure” (see p. 5, para 1).
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As stated supra, Datta teaches for reconstructing the tumor microenvironment, individual 3D bioprinted components can be assembled (e.g., p. 2, left col, last part, also see Fig 1B, attached, for assembling individually bioprinted cancer cell layer and endothelial cell layer to form a 3D stacked structure including separately within the structure a cancer cell layer and an endothelial cell layer).
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Cho teaches 3D cell printing of a human skin equivalent that better reflects the actual complexity of native human skin (e.g., abstract). Cho teaches the skin model is made by 3D cell printing of individual layers of bioinks each comprising a different cell type in gelatin hydrogel (see Fig 1 for the step-by-step process, especially the bottom-right panel of Fig 1(A), attached, for the diagram of the final 3D stacked structure including, separately within the structure, an endothelial cell HUVEC layer, a fibroblast HDF layer and a keratinocyte HEK layer). Cho teaches the compartments (i.e., layers) provide a more realistic microenvironment and the model offers better predictive and reliable in vitro platform for investigation of mechanisms of pathological research and skin disease modeling (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3D bioprinted bladder cancer mimic comprising bladder cancer cell line 5637 cells, endothelial cells HUVEC and fibroblasts MRC5 as suggested by Kim in view of Datta and Lazzari, by combining bioprinting and assembling individual layers of each cell type in hydrogel so as to prepare a 3D stacked structure comprising separate cell layers as suggested by Datta and Cho with a reasonable expectation of success. Since Kim contemplates stacking layers with many cells (cell types) into 3D structure and reduces to practice a method for bioprinting a bladder cancer cell layer comprising bladder cancer cells in GelMA hydrogel (see p. 5, para 1 and Fig 1), since Datta teaches individual 3D bioprinted components of cancer cells, endothelial cells and fibroblasts can be assembled for reconstructing the tumor microenvironment (e.g., p. 2, left col, last part, and Fig 1B attached), and since Cho teaches 3D cell printing of individual separate layers of endothelial cells, fibroblasts and keratinocytes to form a 3D stacked structure (see Fig 1A attached) that provides a more realistic microenvironment and offers better predictive and reliable in vitro platform for disease modeling (e.g., abstract), one of ordinary skill in the art would have had a reason to combine bioprinting and assembling individual layers of endothelial cells, fibroblasts and bladder cancer cells in hydrogel as suggested by Datta and Cho to obtain a 3D stacked structure including, separately within the structure, an endothelial HUVEC layer, a fibroblast MRC5 layer and a bladder cancer cell 5637 cell layer in the bladder cancer mimic of Kim in view of Datta and Lazzari in order to better mimic the bladder cancer microenvironment for a drug screening platform (Kim, abstract).
Furthermore, in regard to the GelMA hydrogel, since Kim reduces to practice bioprinting a bladder cancer cell layer in GelMA hydrogel (see p. 5, para 1 and Fig 1), since Datta teaches HUVEC line is compatible with GelMA (see e.g., Table 1, last row) and human dermal fibroblasts are also compatible with GelMA (see e.g., Table 1, last row), one of ordinary skill in the art would have chosen GelMA hydrogel to mix with bladder cancer cell line 5637, HUVEC line as well as MRC5 line (a human lung fibroblast line) in bioprinting the individual cell layers with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since Kim reduces to practice bioprinting a bladder cancer cell layer in GelMA hydrogel to prepare a 3D bladder cancer mimic, and since Datta teaches GelMA hydrogel is compatible with HUVEC line and human dermal fibroblasts thus would likely be compatible with human lung fibroblast line MRC5.
In regard to the bladder cancer mimic having a cylindrical shape, Kim teaches user-created constructs design is loaded into the computer and is controlled by a computer program design model (p. 3, para 2). Datta summarizes multiple 3D bioprinted cancer models including models that have a cylindrical shape (see e.g., Fig 1 a GBM model and Fig 5 an ovarian cancer model that have a cylindrical shape).
Accordingly, it would have been obvious for one of ordinary skill in the art to have chosen the 3D bladder cancer mimic having a cylindrical shape as suggested by Datta with a reasonable expectation of success. Since Kim teaches the shape of the constructs can be designed and controlled by a computer program design model (p. 3, para 2), and since Datta summarizes and thus reduces to practice 3D bioprinted cancer models that have a cylindrical shape (see e.g., Fig 1 and Fig 5), one of ordinary skill in the art would have had a reason to choose to design and make the bladder cancer mimic having a cylindrical shape.
In regard to the bladder cancer mimic being co-cultured in a microfluidic environment having a permeate flow rate of 15-25 µl/min, it is noted that the limitation “being co-cultured…" is interpreted as intended use. MPEP 2111.02 II states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Accordingly, since the limitation merely states the intended use of the bladder cancer mimic, i.e., to be co-cultured in a microfluidic environment having a permeate flow rate of 15-25 µl/min, rather than any distinct definition of any of the claimed invention's limitations, then this limitation is of no significance to claim construction and does not provide any patentable weight in determining patentability of the claimed product.
In regard to the layers being provided at a filling rate of 10 to 20%, it is noted that the specification defines the term “filling rate” as being referring to the area percentage of the bioprinting ink corresponding to one layer relative to the bottom area of the 3D structure made by stacking 10 layers (see specification, [0031]). Kim teaches the bladder cancer cell layers have a porous platform of the scaffold (see e.g., Fig 1 and legend, also see microscopic view of the porous structure in Fig 2E, attached). From the microscopic view in Fig 2E attached herein,
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the cell layers likely have a filling rate of 10% to 20% (e.g., the area percentage of the bioprinting ink of vertical lines in layer 1 or horizontal lines in layer 2 relative to the bottom area of the 3D structure). Accordingly, it would have been obvious for one of ordinary skill in the art to have chosen the claimed filling rate as suggested by Kim with a reasonable expectation of success. Since Kim has reduced to practice bladder cancer cell layers that likely have a filling rate of 10% to 20% in the bladder cancer mimic, one of ordinary skill in the art would have had a reason to choose the claimed filling rate in bioprinting the cell layers of the endothelial cell layer, the fibroblast layer and the bladder cancer cell layer. Furthermore, since one of ordinary skill in the art would have immediately expected that the filling rate of the cell layers (i.e., the porosity) would affect the circulation of culture medium in the cancer mimic, and thus is a result effective variable, it would have been obvious to one having ordinary skill in the art to choose the claimed filling rate, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
With respect to claim 7 directed to a lab-on-a-chip comprising the mimic, Kim suggests that further research on organs-on-chips systems would improve the treatment of cancer and other diseases (p. 13, para 2). Datta teaches cancer-on-a-chip devices have allowed more physiologically relevant three-dimensional (3D) in vitro cancer models (e.g., abstract, and see Fig 1 and Fig 7 for integration of microfluidic devices with 3D bioprinted organ-on-a-chip models). Cho teaches combined with a microfluidic device, in vitro 3D skin models, termed as a skin-on-a-chip or skin integrated vascular channel-on-a-chip, could improve tissue-tissue interfaces (p. 2, para 1).
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined a microfluidic device with the bladder cancer mimic so as to make a lab-on-a-chip as suggested by Kim, Datta and Cho with a reasonable expectation of success. Since Kim, Datta and Cho all suggest a lab-on-a-chip device comprising the 3D bioprinted organ model, one of ordinary skill in the art would have had a reason to make a lab-on-a-chip device comprising the bladder cancer mimic in order to build more physiologically relevant 3D in vitro cancer models to improve the treatment of cancer (Datta, abstract and Kim, p. 13, para 2).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 06/15/2026 are acknowledged.
Applicant argues that (1) the claimed invention is directed not merely to a simple combination of cells, but to a structure of a superior bladder cancer mimic using specific cell lines (T24, 5637, HUVEC, MRC5, etc.) together with a GelMA-based bio-ink composition optimized therefor, while Datta teaches in Table 1 that different types of bio-inks are used depending on the cell line employed and “For example, even in lung cancer models, different bio-inks are used depending on the specific cell line employed”. Datta therefore instructs PHOSITAs that when different cell lines are used, the types of suitable bio-inks are also entirely different (Remarks, p. 10-11).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, as stated supra, the prior 103 rejection over Kim in view of Datta and Cho is withdrawn in light of Applicant’s amendment to claim 1 to recite new limitations such as the layers being “separately within the structure” and the layers are composed of GelMA and the combination of the specified cell lines. However, as necessitated by amendments, a new ground of rejection is made over Kim in view of Datta, Cho and Lazzari as discussed above.
Specifically, in regard to the combination of specified cell lines (T24 or 5637, HUVEC, MRC5), Kim teaches both the bladder cancer cell lines T24 and 5637 and reduces to practice the 5637 line in bioprinting a 3D cancer mimic, Datta teaches the endothelial cell HUVEC line and the fibroblast MRC5 line (e.g., Fig 1, Table 1 and p. 6, last para.) in 3D cancer models, and Lazzari teaches simultaneously employing HUVEC and MRC5 cell lines together with a pancreatic cancer line in a cancer model. Thus, one of ordinary skill in the art would have had a reason to simultaneously combine HUVEC and MRC5 cell lines together with the bladder cancer line 5637 to make a bladder cancer mimic with a reasonable expectation of success.
In regard to using GelMA-based bio-ink, since Kim reduces to practice bioprinting a bladder cancer cell 5637 line layer in GelMA bio-ink (see p. 5, para 1 and Fig 1), since Datta teaches HUVEC line is compatible with GelMA (see e.g., Table 1, last row) and human dermal fibroblasts are also compatible with GelMA (see e.g., Table 1, last row), one of ordinary skill in the art would have chosen GelMA bio-ink to mix with bladder cancer cell line 5637, HUVEC line as well as MRC5 line (a human lung fibroblast line) in bioprinting the individual cell layers with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since Kim reduces to practice bioprinting a bladder cancer cell layer of the 5637 line in GelMA bio-ink to prepare a 3D bladder cancer mimic, and since Datta teaches GelMA bio-ink is suitable for HUVEC line and human dermal fibroblasts thus would likely be suitable for human lung fibroblast line MRC5.
It is further noted that Applicant’s argument regarding Datta teaches “For example, even in lung cancer models, different bio-inks are used depending on the specific cell line employed” (Remarks, p. 10) is not supported by Datta. The only teaching on lung cancer model by Datta is “3D bioprinting has also been combined with low-temperature molding using A549/95-D cell and gelatin-sodium alginate based bioink to develop a model for exploring lung cancer invasion, where bioprinted cells showed increased migration potential compared to cells in 2D as determined from histochemical, scratch test and genetic assays 70” (p. 10, para 1). Nowhere in Datta teaches in lung cancer models, different bio-inks are used depending on the specific cell line employed.
Applicant argues that (2) the claimed invention is not directed to merely stacking cells as allegedly disclosed in Cho, but rather, a bladder cancer mimic comprises "a three-dimensionally (3D) stacked structure including, separately within the structure, an endothelial cell layer, a fibroblast layer, and a bladder cancer cell layer" specifically designed such that the mimic exhibits properties and characteristics similar to those of actual cancer tissue (Remarks, p. 11-12).
Applicant’s arguments have been fully considered but they are not persuasive.
As stated supra, Kim reduces to practice a method for bioprinting a bladder cancer cell layer comprising bladder cancer cells in GelMA and stacking the cancer cell layers to form a 3D model (see e.g., Figs. 1-2) and contemplates “stacking layers with many cells into 3D structure” (see p. 5, para 1). Kim acknowledges that 3D bioprinting techniques with scaffold bioink made up of cellular materials have been utilized to provide major ECM elements of the tumor microenvironment (p. 2, “Introduction”) and specifically teaches that the 3D printing technique of Kim can be used to create a cancer cell-like environment for a drug screening platform (e.g., abstract).
Datta teaches for reconstructing the tumor microenvironment, individual 3D bioprinted components can be assembled (e.g., p. 2, left col, last part, also see Fig 1B, attached above, for assembling individually bioprinted cancer cell layer and endothelial cell layer to form a 3D stacked structure including separately within the structure a cancer cell layer and an endothelial cell layer).
Cho teaches 3D cell printing of a human skin equivalent that better reflects the actual complexity of native human skin (e.g., abstract), that is made by 3D cell printing of individual layers of bioinks each comprising a different cell type in gelatin hydrogel (see Fig 1, especially the bottom-right panel of Fig 1(A), attached above, for the diagram of the final 3D stacked structure including, separately within the structure, an endothelial cell HUVEC layer, a fibroblast HDF layer and a keratinocyte HEK layer). Cho teaches the compartments (i.e., layers) provide a more realistic microenvironment and the model offers better predictive and reliable in vitro platform for investigation of mechanisms of pathological research and skin disease modeling (e.g., abstract).
Therefore, one of ordinary skill in the art would have had a reason to combine bioprinting and assembling individual layers of each cell type as suggested by Datta and Cho with a reasonable expectation of success, in order to obtain a bladder cancer mimic comprising a 3D stacked structure including, separately within the structure, an endothelial HUVEC layer, a fibroblast MRC5 layer and a bladder cancer cell 5637 cell layer, as instantly claimed, to better mimic the bladder cancer microenvironment for a drug screening platform (Kim, abstract).
Applicant further argues (3) that the claimed invention is directed to a novel and non-obvious structure of a superior bladder cancer mimic (Remarks, p. 10) and a reconstruction of an actual bladder cancer-like environment (Remarks, p. 12). Using this structure, subsequent drug compatibility tests or anticancer efficacy evaluations can provide results that are much closer to actual in vivo drug efficacy. Accordingly, the claimed mimic constitutes a highly important technical feature (Remarks, p. 12).
Applicant’s arguments have been fully considered but they are not persuasive.
As stated supra, Kim contemplates “stacking layers with many cells into 3D structure” (see p. 5, para 1) and specifically teaches that “the 3D scaffolds were similar to bladder cancer tissue. This technique can be used to create a cancer cell-like environment for a drug screening platform” (abstract, “Conclusions”).
Datta teaches individual 3D bioprinted components can be assembled for reconstructing the tumor microenvironment and teaches “3D organotypic models comprising the vascular structures are one of the most realistic models for studying cancer metastasis and anticancer drug screening” (p. 10, right col).
Cho teaches 3D cell printing of a human skin equivalent that better reflects the actual complexity of native human skin (e.g., abstract). Cho teaches the compartments (i.e., layers) provide a more realistic microenvironment and the model offers better predictive and reliable in vitro platform for investigation of mechanisms of pathological research and skin disease modeling (e.g., abstract).
Therefore, one of ordinary skill in the art would have immediately expected that the bladder cancer mimic suggested by Kim in view of Datta, Cho and Lazzari would have reconstructed an actual bladder cancer-like environment and can be used for subsequent drug screening to provide predictive and reliable results that are close to actual in vivo drug efficacy as suggested by Kim, Datta and Cho. Thus, the purported superior and highly important technical features argued by Applicant would have been expected by prior art.
Applicant further argues (4) that in regard to the claimed filling rate, Kim does not disclose any specific description. The percentage inferred by the Office from its finding related to Figure 2E of Kim is merely an estimation and cannot be regarded as a disclosure of actual filling rate. The post-filing art Li et al. use a filling rate of 20% to 40% in 3D bioprinting and the prior art Luo et al. use a filling rate of 40% in performing 3D bioprinting. Thus, a filling rate of approximately 20% to 40% corresponds to conventional filling rates. The instant invention finds that when a filling rate of 15% was used, stable results were obtained (Remarks, p. 13-15).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, as Applicant acknowledges, Kim clearly presents a microscopic view of the bioprinted 3D bladder cancer mimic in Fig 2E (attached above). One of ordinary skill in the art would have immediately expected that figures in a research publication would be considered as description of the results. As seen in the attached Fig 2E above, the actual filling rate can be precisely calculated by dividing the bio-ink area of the vertical lines in layer 1 (or horizontal lines in layer 2) by the bottom area of the 3D structure, thus is not merely an estimation. Even though examiner does not have access to an image-analysis software thus has to reasonably “estimate” that the cell layers likely have the claimed filling rate of 10% to 20%, Applicant is reminded that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant' s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304. Furthermore, since one of ordinary skill in the art would have immediately expected that the filling rate of the cell layers would affect the structure of the 3D mimic and the circulation of culture medium within the cancer mimic, and thus is a result effective variable, it would have been obvious to one having ordinary skill in the art to choose the claimed filling rate, since it has been held that discovering an optimum value of a result effective variable involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
Since Kim suggests a filling rate likely to be 10% to 20% as claimed, the bladder cancer mimic suggested by Kim in view of Datta, Cho and Lazzari would have been expected to obtain the same results as argued.
Furthermore, in regard to the post-filing art Li et al. and the prior art Luo et al. use a filling rate of 20% to 40% in performing 3D bioprinting, it is noted that post-filing art Li uses a different bio-ink (waterborne polyurethane acrylate) embedded with different cells (nitrifying bacteria that are prokaryotic cells) for different purpose (sewage treatment), and similarly prior art Luo uses a different bio-ink (gelatin-alginate modified with cellulose nanofiber) embedded with different cells (fibrochondrocytes) for different purpose (in vivo implant), compared to the GelMA embedded with specific bladder cancer cell 5637 line, HUVEC line and MRC5 line for in vitro drug screening as instantly claimed and suggested by Kim in view of Datta, Cho and Lazzari. As Applicant has previously argued that when different cell lines are used, the types of suitable bio-inks are also entirely different (Remarks, p. 10-11), thus, the teaching of Li and Luo on the filling rate in the context of different bio-inks or cells, would not dissuade one of ordinary skill in the art from choosing a filling rate of 10%-20% as suggested by Kim.
Applicant further argues (5) that regarding the "permeate flow rate" limitation, Claim 1, as now presented, employs a permeate flow rate significantly lower than those generally known to PHOSITAs, as prior art Xin uses 12 mL/h for electrospraying to produce microgels and post art Costa teaches a flow rate of 5 mL/h is used for electrostatic extrusion to produce alginate microbeads. Thus, both teach a flow rate higher than that is claimed (Remarks, p. 15-17).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, as stated supra, the limitation that the bladder cancer mimic is co-cultured in a microfluidic environment having a permeate flow rate of 15-25 µl/min, is directed to intended use. MPEP 2111.02 II states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations, then the preamble is not considered a limitation and is of no significance to claim construction”. Accordingly, since the limitation merely states the intended use of the bladder cancer mimic, i.e., to be co-cultured in a microfluidic environment having a permeate flow rate of 15-25 µl/min, rather than any distinct definition of any of the claimed invention's limitations, this limitation is of no significance to claim construction and does not provide any patentable weight in determining patentability of the claimed product.
Applicant is further reminded that neither the prior rejection nor the outstanding rejection is based on the claimed range of the permeate flow rate falls within a range selectable by PHOSITAs as Applicant argues (Remarks, p. 15).
Furthermore, in regard to the prior art Xin and post art Costa teach a flow rate higher than that is claimed, Applicant is reminded that both Xin and Costa teach a flow rate of ejecting bio-ink (electrospraying in Xin and electrostatic extrusion in Costa) in producing 3D structures (microgels or microbeads). This “flow rate” is completely different from that is claimed (i.e., the 3D bladder cancer mimic being co-cultured in a microfluidic environment having a permeate flow rate of 15-25 µl/min, of culture medium perfusion, see instant Fig 4 and e.g., specification, [0063]). Thus, the cited prior art Xin and post art Costa would not negate the bladder cancer mimic suggested by Kim in view of Datta, Cho and Lazzari.
Applicant finally argues (6) that the only manner in which the Office could find motivation to combine or modify the disclosures of prior art is by impermissible hindsight (Remarks, p. 19-20).
Applicant’s arguments have been fully considered but they are not persuasive.
As a first matter, although Applicant argues that “the Office ignores the full teachings of each cited reference” (remarks, p. 19), Applicant does not specifically point out how examiner ignores the full teachings of each cited reference.
Furthermore, 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). In the instant case, as stated supra, Kim teaches a bladder cancer mimic comprising a 3D stacked structure including a bladder cancer cell layer, and contemplate stacking many cells (cell types) to make a 3D structure, and teaches “the 3D scaffolds were similar to bladder cancer tissue. This technique can be used to create a cancer cell-like environment for a drug screening platform” (e.g., abstract). Datta and Lazzari are cited to make obvious the claimed cell types of endothelial cells and fibroblasts, and Datta and Cho make obvious the 3D stacked structure including individual cell layers separately within the structure. Thus, one of ordinary skill in the art would have had a reason to combine the teaching of Datta, Cho and Lazzari with Kim in order to obtain a bladder cancer mimic that is obvious from the one in the instant claims.
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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