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
This action is written in response to applicant’s correspondence received 4 April 2025. Claims 1-4 and 6-18 are pending. Claims 6-18 remain withdrawn from consideration as being drawn to a non-elected invention. Accordingly, claims 1-4 are currently under examination.
Applicant’s arguments, filed 4 April 2025, and the arguments presented during the interview conducted 27 March 2025 have been fully considered and are deemed persuasive. Therefore, the previously pending 35 USC § 103 rejections of record, filed 6 December 2024, have been withdrawn. Because no new limitations have been introduced into the independent claims present in the application, THIS ACTION IS NON-FINAL.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 21 April 2025 has been considered.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Karch (Stem cell reports 13.5 (2019): 939-955) in view of Lee (Stem cell research 40 (2019): 101554) in view of Lee (Stem cell research 40 (2019): 101554), Boulin (WormBook: The Online Review of C. elegans Biology [Internet] (2006)), and Samsonov (Journal of cell science 117.25 (2004): 6129-6141).
Regarding claim 1, Karch is drawn to a study concerned with the expression patterns and detection of tau proteins that are expressed from a MAPT gene (i.e., an endogenous tau gene) (Abstract). Karch teaches that 29 induced pluripotent stem cell lines carrying MAPT mutations were collected from human patients (pg. 949). Karch teaches that the induced pluripotent stem cells can be differentiated into the neuronal and glial subtypes that are affected in primary tauopathies, giving a tool toward understanding the biology of tau in a human cell model that may more faithfully reflect the endogenous condition (pg. 943). Karch teaches that tau proteins are important to detect because they are responsible for frontotemporal lobar degeneration (pg. 939).
Regarding claims 2-3, Karch teaches the use of human induced pluripotent stem cells (pg. 945; see Table 3).
However, Karch does not teach expressing tau as a fusion protein with a reporter molecule, wherein the DNA encoding the reporter molecule is located upstream of an endogenous tau gene (Claim 1). In addition, although Karch studies iPSCs having tau mutations and detects pluripotency marker expression in the iPSCs (pg. 946; see Figure 2), Karch does not specifically teach the detection of tau protein in the iPSCs themselves (Claim 1). Karch does not teach or suggest that the reporter molecule is a fluorescent protein (Claim 4).
However, one of ordinary skill in the art would have considered the teachings of Lee, Boulin, and Samsonov as the references are common fields of endeavor pertaining to the study of pluripotent stem cells and detecting proteins of interest.
Regarding the detection of endogenous proteins in iPSCs, Lee is drawn to a study concerned with the generation of a Nestin-EGFP reporter in human iPSCs (Abstract). Lee teaches that Nestin is a neuroectodermal marker involved in induced pluripotent stem cell differentiation toward neural lineages (Abstract). Lee teaches that reporter human iPSCs can be created by adding an EGFP fusion tag (i.e., a fluorescent reporter protein), via a CRISPR/Cas9-mediated knock-in system, to the C-terminus of an endogenous Nestin gene in KSCBi005-A cells (i.e., a human iPSC line originating from bone marrow blood cells) (pg. 1-2; see Figure 1A). Lee teaches that vectors encoding Cas9 and an sgRNA targeting the stop codon region of the Nestin gene were co-transfected together with a donor construct containing EGFP (i.e., a DNA encoding the fluorescent reporter molecule), a Puro marker, and two homologous sequences to upstream and downstream of the NESTIN targeting site (pg. 1-2; see Figure 1A). Lee teaches that the endogenous Nestin gene and downstream EGFP were in frame and could be expressed as a fusion protein (pg. 1-2; see Fig. 1A, 1C). Lee teaches that the NESTIN-GFP reporter was able to be visualized in neural cells following differentiation of the iPSCs (pg. 3; see Figure 1J).
Regarding the DNA encoding the reporter protein being located upstream of the endogenous gene, Boulin is drawn towards a study concerned with reporter gene fusions (pg. 1; Introduction). Boulin teaches that it is known in the art how to generate an N-terminal GFP translational reporter (pg. 7, section 2.3.3; see reproduced Figure 4 on pg. 14). Boulin teaches that the GFP protein is located upstream of a genomic gene of interest (i.e., an endogenous gene) and is able to be expressed as a fusion protein when translated (pg. 7, section 2.3.3; see reproduced Figure 4 on pg. 14).
Regarding the generation of a GFP-tau fusion protein, Samsonov is drawn towards a study concerned with investigating the interaction of tau proteins with microtubules in cultured embryo neurons (Abstract). Samsonov teaches that the embryo neurons were injected with a plasmid encoding either GFP-tau23 of GFP-tau24 (pg. 6130). Samsonov teaches that the GFP-tau fusion constructs were able to be visualized in the embryo cell cultures and their interactions with microtubules studied (pg. 6131; see Fig. 1). Samsonov teaches that a fusion of GFP to either the N-terminal or C-terminal of tau does not significantly affect the functional properties of tau (pg. 6132). Samsonov teaches that tau is implicated in microtubule stabilization and the use of the GFP-tau reporter construct allowed for reliable information concerning tau-microtubule interactions in living cells (pg. 6136-6137).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the iPSCs comprising the MAPT mutations described by Karch via a CRISPR/Cas9-mediated knock in of an EGFP reporter protein at the endogenous MAPT gene, as described by Lee, in order to generate a fusion construct comprising the EGFP located upstream of the endogenous tau protein, as described by Boulin and Samsonov. A person of ordinary skill in the art would have been motivated to do so in order to study the interaction of the endogenous tau protein with microtubules following differentiation of the iPSCs. A person of ordinary skill in the art would have had a reasonable expectation of success because Lee teaches that knocking-in an EGFP reporter protein at an endogenous gene of interest in iPSCs was known, Boulin teaches that utilizing a GFP protein located upstream of an endogenous gene of interest was known, and Samsonov teaches that a GFP reporter protein fused to the N-terminus of a tau protein did not affect the functional properties of tau. Therefore, modifying the iPSCs comprising the MAPT mutations described by Karch via a CRISPR/Cas9-mediated knock in of an EGFP reporter protein at the endogenous MAPT gene, as described by Lee, in order to generate a fusion construct comprising the EGFP located upstream of the endogenous tau protein, as described by Boulin and Samsonov, would have resulted in the predicable outcome of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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