DETAILED ACTION
This office action is re-issued to respond to applicant’s argument.
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 20 November 2025 are acknowledged and have been entered. Claims 1-3, 5-6 and 10 are amended. Claims 7-9 and 11-14 have been cancelled. Claims 15-36 are newly added. Claims 1-6, 10, and 15-36 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 § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 10, and 15-36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. This is a new rejection necessitated by applicant’s claim amendments.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112a, as lacking adequate written description". According to MPEP § 2163.I.B, "While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure" and "The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
The newly amended claims recite “A method of detecting LINC00678 and/or PRDM14 in cells comprising measuring the expression level and/or the promoter activity of said at least LINC00678 and/or PRDM14 in cells”. Applicants’ remarks dated 11/20/2025 states that support for the amendments can be found throughout the original specification. No where in the specification can one find a method of detecting at least one gene from LINC00678 and/or PRDM14. Throughout the specification there are several recitations of ‘a method of detecting undifferentiated cells’ which requires measuring the expression levels or promoter activity of LINC00678 and/or PRDM14. The specification specifically teaches the technique for detecting residual undifferentiated cells in a mix population of differentiated and undifferentiated cells. Therefore, no basis for the limitation of detecting LINC00678 and/or PRDM14 was identified and the claims are rejected as incorporating new matter.
Claim Rejections - 35 USC § 102
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.
Claims 1-3, 5-6, and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by He (CN 114438219 A, published 5/6/2022). This is a new rejection necessitated by applicant’s claim amendments.
Regarding claims 1-2 and 5-6, He teaches using qPCR to measure lncRNA LINC00678 as RNA expression in a population of differentiated and undifferentiated human embryonic stem cells (hESCs) [Fig. 3; pg. 3, para 9].
Regarding claim 3, He teaches that the differentiated cell can be human embryonic stem cell differentiation of cells (such as ectoderm cells, mesoderm cells and/or endoderm cells) [pg. 2, para 7].
Regarding claim 24, He teaches that the differentiated cells have been differentiated from the undifferentiated cells by teaching that the 0 day represents undifferentiated cells and the 1-7 day represents different differentiation times [Fig. 3; pg. 3, para 9].
Claims 25-26 and 30-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tsuneyoshi (Tsuneyoshi et al., Biochemical and Biophysical Research Communications 367 (2008) 899–905; cited on the information disclosure statement filed 5/13/2022). This is a new rejection necessitated by applicant’s claim amendments.
Regarding claims 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].
Claims 25 and 30-32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Benvenisty (US 2013/0309769 A1). This is a new rejection necessitated by applicant’s claim amendments.
Benvenisty teaches a method comprising determining in a population of cells which comprises pancreatic progenitor cells, undifferentiated cells, at least one marker that is positively associated with the pancreatic differentiation, differentiated cells, where the marker is PRDM14 [0033]. Benvenisty teaches that the level of expression of the marker (gene) of the invention is determined using an RNA or a protein detection method to include RT-PCR, oligonucleotide microarray, RNA in situ hybridization, Fluorescence activated cell sorting (FACS), immunohistochemical analysis, or in situ activity assay [0130-0134]. Benvenisty teaches that an upregulation above a predetermined threshold of an expression level of the marker positively associated with the pancreatic differentiation as compared to the expression level of the marker in a reference cell, wherein said reference cell is a definite endodermal cell which expresses SOX17, is indicative of a pancreatic progenitor cell [0035].
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, 23-33, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Tang (Tang et al., Nature Biotechnology volume 29, pages829–834 (2011); cited on the information disclosure statement filed 5/13/2022) in view of He (CN 114438219 A1, published 5/6/2022), Chen (Chen et al. Protein Cell 2011, 2(3): 180–188), Murrell (WO 2015/086132 A1), Helmrath (WO 2022/072553 A1, published 4/7/2022) and Tsuneyoshi (Tsuneyoshi et al., Biochemical and Biophysical Research Communications 367 (2008) 899–905; cited on the information disclosure statement filed 5/13/2022). This is a new rejection necessitated by applicant’s claim amendments.
Regarding claims 1 and 25, Tang teaches that human pluripotent stem cells (hPSCs), including human embryonic and induced pluripotent stem cell (hESCs and hiPSCs)-based therapeutics carry the risk of teratoma formation by residual undifferentiated cells remaining among the differentiated products [abstract; pg. 823, col. 1, para 1]. Tang teaches that immunodepletion with antibodies against SSEA-5 and additional undifferentiated cell markers completely removed teratoma-formation potential from incompletely differentiated hESC cultures [abstract; pg. 829, col. 2, para 1].
Tang does not teach that the undifferentiated cells markers are LINC00678 and PRDM14 and can be measured by qPCR or immunostaining. Tang does not teach that the differentiated cells are selected from differentiated endodermal, mesodermal and ectodermal cells. Tang does not teach that the differentiated endodermal cells are hepatic endoderm cells. Tang do not teach measuring the expression level of PRDM14 by isothermal amplification.
Regarding claims 1-2 and 5-6, He teaches using qPCR to measure lncRNA LINC00678 as RNA expression in a population of differentiated and undifferentiated human embryonic stem cells (hESCs) [Fig. 3; pg. 3, para 9].
Regarding claim 3, He teaches that the differentiated cell can be human embryonic stem cell differentiation of cells (such as ectoderm cells, mesoderm cells and/or endoderm cells) [pg. 2, para 7].
Regarding claim 23, He teaches detecting undifferentiated cells in at a detection sensitivity of 0.0025% or more [Fig. 3].
Regarding claim 24, He teaches that the differentiated cells have been differentiated from the undifferentiated cells by teaching that the 0 day represents undifferentiated cells and the 1-7 day represents different differentiation times [Fig. 3; pg. 3, para 9].
Regarding claims 21 and 33, Murrell teaches using qCPR, sequencing, microarrays, or isothermal amplification to measure nucleic acid expression levels of cell differentiation markers [claim 1-10, and 17-18]
Regarding claim 4 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 25-28 and 35-36, Helmrath teaches that PRDM14 is a gene expressed in induced iPSCs [0142]. Helmrath teaches that the iPSCs can differentiate into endoderm, mesoderm and ectoderm cells [0141].
Regarding claims 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].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to detect the expression levels of LINC00678 and PRDM14 in hESC or iPSCs, respectively, by qPCR, immunostaining, or isothermal amplification as a measure of detecting undifferentiated cells in a differentiated cell population selected from the group consisting of endodermal, mesodermal, ectodermal or hepatic endodermal cells. One of ordinary skill would be motivated to use the expression levels of LINC00678 and PRDM14 as an undifferentiated cells marker for the advantage of labeling and removing teratoma-forming cells from a heterogeneously differentiated population. 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 Tang, He, Murrell, Chen, Helmrath, and Tsuneyoshi all teach measuring undifferentiation cell markers from a mixed differentiation population.
Claims 10, 15-20, 25-28, 30-33, and 35-36 are rejected under 35 U.S.C. 103 as being unpatentable over Tsuneyoshi (Tsuneyoshi et al., Biochemical and Biophysical Research Communications 367 (2008) 899–905; cited on the information disclosure statement filed 5/13/2022), in view of Nguyen (Nguyen et al. Adv Drug Deliv Rev. 2010 September 30; 62(12): 1175–1186), Helmrath (WO 2022/072553 A1, published 4/7/2022), Chen (Chen et al. Protein Cell 2011, 2(3): 180–188) and Murrell (WO 2015/086132 A1). This is a new rejection necessitated by applicant’s claim amendments.
Regarding claims 10, 15, 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].
Tsuneyoshi do not teach measuring the expression of PRDM14 in a tissue formed by transplanting differentiated cells into a model animal and that the differentiated cells comprise at least one selected from the group consisting of endodermal, mesodermal, ectodermal cells, and hepatic endoderm cells. Tsuneyoshi do not teach measuring the expression level of PRDM14 by isothermal amplification.
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 claims 10, 15-18, 20, 25-28 and 35-36, Helmrath teaches that PRDM14 is a gene expressed in induced iPSCs [0142]. Helmrath teaches that the iPSCs can differentiate into endoderm, mesoderm and ectoderm cells [0141]. Helmrath teaches that differentiation of PSCs into DE culture and subsequently into various intermediate mature cell types can be determined by the presence of stage specific cell markers [0162]. Helmrath teaches that pluripotent stem cells can be cultured and induced to differentiate into definitive endoderm cells which, subsequently, can be differentiated into organoids and transplanted into mice tissue [0222-0231]. Helmrath teaches accessing the expression of mature cell markers after transplantation [0231, 0104, 0215; Fig. 4].
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 qCPR, 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 Tsuneyoshi, Ngyuen, Helmrath, and Murrell all teach measuring undifferentiation cell markers.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: The closest prior art to the claimed inventions are discussed above. Neither reference nor the prior art teaches methods that detects the undifferentiated cells in the differentiated cells at a detection sensitivity between 0.0025% to 0.1%.
Response to Arguments
Applicant's arguments filed see pg. 6, filed 11/20/2025, with respect to the rejection(s) of claim(s) 1-6 under 35 USC 102(a)(1) as being anticipated by Benvenisty have been fully considered but they are not persuasive. Applicant’s independent claim is now directed to a method of detecting PRDM14 in cells and are no longer directed to detecting undifferentiated cells. Benvenisty teaches the claimed invention as discussed above.
Applicant’s arguments, see pgs. 6-7, filed 11/20/2025, with respect to the rejection(s) of the claim(s) 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 in view of He and Chen, Murrell, Helmrath, and Nguyen.
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637