This office action is intended to supersede the previous office action to change if from a final rejection to a non-final rejection.
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 .
Application Status
The Amendments and Remarks filed 25 June 2026 are acknowledged and have been entered. Claims 1-2, 10 and 25 are amended. Claims 7-9, 11-14 and 34 have been cancelled. Claims 1-6, 10, 15-33 and 35-36 are pending and being examined on the merits.
Any rejection or objection not reiterated herein has been overcome by applicant’s claim amendments.
Priority
The priority date of the current application is 05/13/2022.
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 1-6, 21-33 and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Kuroda (Kuroda et al. PLoS ONE 7(5): e37342) in view of Tsuneyoshi (Tsuneyoshi et al., Biochemical and Biophysical Research Communications 367 (2008) 899–905; cited on the information disclosure statement filed 5/13/2022), Liu (Liu et al. Nucleic Acids Research, 2016, Vol. 44, No. 1 75–94), Chen (Chen et al. Protein Cell 2011, 2(3): 180–188) and Murrell (WO 2015/086132 A1).
Regarding claim 1-2, 5-6, 22-27, and 30-31, Kuroda teaches methods for detecting residual undifferentiated pluripotent stem cells within differentiated cell preparations because residual pluripotent cells present a tumorigenic risk. Kuroda explains that highly sensitive assays are required for quality control of differentiated cell products and teaches detecting residual undifferentiated cells by quantitative RT-PCR, flow cytometry, and other assays using expression of pluripotency-associated markers. Specifically, Kuroda teaches mixtures containing differentiated retinal pigment epithelial cells (RPE; i.e., neuroectodermal lineage (regarding claim 28)) together with residual undifferentiated iPSCs and determining expression of pluripotency markers to detect those residual cells. Kuroda further teaches that qRT-PCR provides extremely sensitive detection of residual undifferentiated cells within differentiated cell populations. Kuroda teaches that qRT-PCR analysis for Lin28 detects 0.002% of residual undifferentiated hiPSCs in hiPSC-induced RPE cells, namely, that a single hiPSC in 5.06104 RPE cells is detectable. [Abstract; Introduction, pp. 1–2; pg. 4, col. 1, para 1 - col. 2].
Kuroda, however, does not expressly disclose using LINC00678 or PRDM14 as the measured marker where the differentiated cells can comprise endodermal, ectodermal, or mesodermal cells. Kuroda does not teach wherein the differentiated cells comprise cells
selected from the group consisting of differentiated hepatic endodermal, mesodermal and ectodermal cells. Kuroda does not teach isothermal amplification of nucleic acids.
Regarding claim 25-26 and 30-31, Tsuneyoshi teaches that expression of PRDM14 was expressed in undifferentiated human ES cells and that this expression was reduced during differentiation [Fig. 2; pg. 902, col. 1, para 1]. Tsuneyoshi teaches detecting PRDM14 expression levels by RT-PCR analysis using undifferentiated human ES cells and cells differentiated from human ES cells [pg. 900, col. 2, last paragraph; Fig. 1].
Regarding claim 32, Tsuneyoshi teaches measuring the expression of PRDM14 by immunostaining [Fig. 2; pg. 902, col. 1, para 1; Fig. 2].
Liu teaches that LINC00678 is specifically associated with human embryonic stem cells. Liu identifies hESC-specific SuperHypoMarks associated with only 71 genes, including POU5F1, NANOG and LINC00678. Liu further teaches that long noncoding RNAs including LINC00678 “might be potential novel markers for stem cells.” (Figure 5E, Figure S28; p. 87, col. 2, para 2)
Chen further demonstrates that LINC00678 expression is abundant in induced pluripotent stem cells but dramatically decreases after differentiation into neural progenitor cells. Chen identifies LINC00678 as one of the transcripts exhibiting approximately an 11.6 log2-fold reduction following differentiation, with expression decreasing from approximately 184.49 FPKM to 0.05 FPKM in one clone and from 111.91 FPKM to 0.04 FPKM in another [Table 1].
Regarding claims 3-4, 25 and 29, Chen teaches that embryonic stem cells and induced pluripotent stem (iPS) cells can differentiate into hepatocytes (i.e., differentiated hepatic endoderm cells).
Regarding claims 21 and 33, Murrell teaches using qPCR, sequencing, microarrays, or isothermal amplification to measure nucleic acid expression levels of cell differentiation markers [claim 1-10, and 17-18].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to substitute LINC00678 or PRDM14 for one of Kuroda’s known pluripotency markers because Liu expressly identifies LINC00678 as a potential stem-cell marker associated with pluripotent hESC identity, while Chen experimentally demonstrates that LINC00678 expression is characteristic of undifferentiated pluripotent cells and is substantially lost upon differentiation; and Tsuneyoshi teaches detecting PRDM14 expression levels by RT-PCR analysis using undifferentiated human ES cells and cells differentiated from human ES cells. A skilled artisan would therefore reasonably have expected that measuring LINC00678 or PRDM14 expression using Kuroda’s established qRT-PCR detection methods, or Murrell’s isothermal amplification assay (as this would amount to a simple substitution of one known assay for detecting differentiation markers for another) would provide an alternative sensitive assay for detecting residual undifferentiated cells within differentiated cell preparations.
One of ordinary skill would also have expected that the RT-PCR analysis of Kuroda would similarly be able to detect LINC00678 or PRDM14 detection sensitivity of 0.1% or less given Kudora’s teaching that qRT-PCR analysis for detects 0.002% of residual undifferentiated hiPSCs in hiPSC-induced retinal pigment epithelial cells.
It would have been further been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that the iPSCs population of Kuroda would comprise both iPSCs and iPSCs that have differentiated into hepatic endotherm cells as taught by Chen. The combination of prior art elements according to known methods to yield predictable results supports can support a conclusion of obviousness. See MPEP 2143(I). One of ordinary skill in the art would have a reasonable expectation of success since both Kuroda and Chen teach measuring differentiation of iPSCs using differentiation markers.
Regarding claim 35, the undifferentiated cells are hiPSCs rather than ES cells, therefore Kuroda teaches the limitation that the undifferentiated cells exclude ES cells.
Regarding claim 36, the RPE cells of Kuroda are cells of the neuroectodermal lineage and are not endothermal cells. Accordingly, Kuroda teaches a differentiated cell population that excludes endodermal cells.
Claims 10, 15-20, 25-28, 30-33, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Kuroda (Kuroda et al. PLoS ONE 7(5): e37342) in view Tsuneyoshi (Tsuneyoshi et al., Biochemical and Biophysical Research Communications 367 (2008) 899–905; cited on the information disclosure statement filed 5/13/2022), Nguyen (Nguyen et al. Adv Drug Deliv Rev. 2010 September 30; 62(12): 1175–1186), Chen (Chen et al. Protein Cell 2011, 2(3): 180–188) and Murrell (WO 2015/086132 A1).
Regarding claims 10, 15-16, 18, 25-28 and 30-31, Kuroda teaches methods for detecting residual undifferentiated pluripotent stem cells within differentiated cell preparations because residual pluripotent cells present a tumorigenic risk. Kuroda explains that highly sensitive assays are required for quality control of differentiated cell products and teaches detecting residual undifferentiated cells by quantitative RT-PCR, flow cytometry, and other assays using expression of pluripotency-associated markers. Specifically, Kuroda teaches mixtures containing differentiated retinal pigment epithelial cells (RPE; i.e., neuroectodermal lineage (regarding claims 18 and 28)) together with residual undifferentiated iPSCs and determining expression of pluripotency markers to detect those residual cells. Kuroda further teaches that qRT-PCR provides extremely sensitive detection of residual undifferentiated cells within differentiated cell populations. Kuroda teaches that qRT-PCR analysis for Lin28 detects 0.002% of residual undifferentiated hiPSCs in hiPSC-induced RPE cells, namely, that a single hiPSC in 5.06104 RPE cells is detectable. [Abstract; Introduction, pp. 1–2; pg. 4, col. 1, para 1 - col. 2].
Kuroda does not teach measuring the expression level and/or the promoter activity of the at least one gene selected from the group consisting of LINC00678 and PRDM14 in undifferentiated cells in a tissue formed by transplanting differentiated cells into a model animal. Kuroda do not teach measuring the expression level of PRDM14 by isothermal amplification.
Tsuneyoshi teaches that expression of PRDM14 was expressed in undifferentiated human ES cells and that this expression was reduced during differentiation [Fig. 2; pg. 902, col. 1, para 1]. Tsuneyoshi teaches detecting PRDM14 expression levels by RT-PCR analysis using undifferentiated human ES cells and cells differentiated from human ES cells [pg. 900, col. 2, last paragraph; Fig. 1].
Regarding claim 32, Tsuneyoshi teaches measuring the expression of PRDM14 by immunostaining [Fig. 2; pg. 902, col. 1, para 1; Fig. 2].
Regarding claim 10, Nguyen teaches that stem cell therapy has the potential to regenerate injured tissue and discusses methods for evaluating the function of transplanted cells for restoring the heart, nervous system, and pancreas [abstract]. Nguyen teaches that although the use of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) as alternative sources for cell therapy can bypass the problem that some adult cells often fail to transdifferentiate into target tissue, hESCs and iPSCs have a low efficiency of directed in vitro differentiation into therapeutic cell types, presenting an additional obstacle for clinical implementation [pg. 1, para 2-3]. Nguyen teaches a schematic of the key steps in evaluating the lineage, fate and function of transplanted hESCs and/or iPSCs where human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) undergo differentiation in vitro prior to injection into an animal tissue [Fig. 1; pg. 11, para 4]. Nguyen teaches that whether stem cells differentiate in vivo after transplantation (e.g., adult progenitor cells) or in vitro prior to transplantation (e.g., ESCs and iPSCs), it is important to confirm cell specific differentiation and lineage commitment [pg. 2, para 2]. Nguyen teaches that if not performed adequately, cells incapable of providing the appropriate function will be given to patients [pg. 2, para 2]. Nguyen teaches that differentiation gene expression analysis can be used for the confirmation of stem cell differentiation into the target cell type and can be detected by reporter genes, quantitative real time polymerase chain reaction (RT-PCR), and microarray analysis [pg. 2, para 2; section 2.3].
Regarding claim 19, Chen teaches that embryonic stem cells and induced pluripotent stem (iPS) cells can differentiate into hepatocytes (i.e., differentiated hepatic endoderm cells).
Regarding claim 33, Murrell teaches using qPCR, sequencing, microarrays, or isothermal amplification to measure nucleic acid expression levels of cell differentiation markers [claim 1-10, and 17-18]
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to measure the expression of PRDM14, by qPCR, immunostaining, or isothermal amplification, in a tissue formed by transplanting iPSC cells that has differentiated into mesodermal, ectodermal, or hepatic endoderm cells capable of being used as stem cell therapy for the regeneration of injured tissue. One of ordinary skill would be motivated to measure the expression of PRDM14 to confirm cell specific differentiation and lineage commitment so that cells incapable of providing the appropriate function will not be given to patients. One of ordinary skill would be motivated with an expectation of success since Kuroda, Tsuneyoshi, Nguyen, and Murrell all teach measuring undifferentiation cell markers.
One of ordinary skill would also have expected that the RT-PCR analysis of Kuroda would similarly be able to detect LINC00678 or PRDM14 detection sensitivity of 0.1% or less given Kudora’s teaching that qRT-PCR analysis for detects 0.002% of residual undifferentiated hiPSCs in hiPSC-induced retinal pigment epithelial cells.
Regarding claim 35, the undifferentiated cells are hiPSCs rather than ES cells, therefore Kuroda teaches the limitation that the undifferentiated cells exclude ES cells.
Regarding claims 20 and 36, the RPE cells of Kuroda are cells of the neuroectodermal lineage and are not endothermal cells. Accordingly, Kuroda teaches a differentiated cell population that excludes endodermal cells.
Response to Arguments
Applicant's arguments filed see pgs. 6-8, filed 06/25/2026, with respect to the rejections of claims under 35 USC 102(a)(1) and under 35 USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made over Kuroda and Liu and of previously cited references.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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