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 .
Status of Application/Restriction/Claims
Firstly, the examiner would like to correct the record and clarify the recited groups in the restriction mailed 7/31/2025 as follows:
Group 1: Claims 1-8, drawn to a method for reprogramming cells of a somatic tissue to produce insulin and C-peptide, classified as A61K48/0016.
Group 2: Claim 9, drawn to a method of normalizing blood glucose levels in a subject with diabetes, classified as A61P3/10.
Group 3: Claims 10-15, drawn to a composition comprising a first nucleic acid sequence encoding PDX-1, second nucleic acid sequence encoding MafA, third nucleic acid sequence encoding GLP-1R and fourth nucleic acid sequence encoding FGF21, classified as C12N15/85.
Group 4: Claim 16-17, drawn to a kit for conducting in vivo transfection of post-natal skin tissue and inducing the skin tissue to be insulinogenic, classified as C12N2800/107.
Applicant’s election with traverse of Group I (Claims 1-8) in the reply filed on 10/30/2025 is acknowledged. Applicant’s traversal is on the grounds that the amended claims require the current subject matter to comprise 4 polynucleotide sequences that encode for PD-X, MaFA, GLP-1R and FGF21 which are shared across all groups. This is not found persuasive because the common technical feature was known in the art at the time of the invention, Briefly, Perez discloses a method for reprogramming somatic cells to produce insulin by transfecting DNA comprising SEQ ID Nos 2 and 4 (Perez, pg 9-15). Although Perez does not describe the third nucleic acid sequence encoding SEQ ID Nos 6, GLP1Rs are known in the art as demonstrated by Husain and could readily be substituted into the composition described by Perez as a combinatorial treatment for normalizing blood glucose levels (Husain, para 3-12). Furthermore, the search and examination of methods (Groups I and II) is not coextensive with the search for compositions (Group III and IV), since the methods have manipulative steps that the compositions don’t have, and are evaluated differently under certain statues (i.e. 35 U.S.C 101 and 112 in particular). Accordingly, unity of invention is lacking and the requirement is still deemed proper and is therefore made FINAL.
Claim 12 has been canceled. Claims 1-11 and 13-17 are pending. Claims 1, 9, 10, 11, 13 and 14 have been amended. Claims 9-11 and 13-17 are currently 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. Claims 1-8 are the subject of the present Official action.
Priority
Applicant’s claim for the benefit of a prior-filed application PRO 63/045,440 and PCT/US21/39083 filed on 6/29/2020 and 6/25/2021, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 6/29/2020
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/12/2022, 7/12/2024 and 7/22/2025 were received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement was considered by the examiner.
Claim Interpretation
The current claim language requires that all four peptides (SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 and SEQ ID NO: 8) are intracellularly delivered to somatic cells. Claim 1 is not necessarily limited to delivering all peptides simultaneously or with in the same expression vector.
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 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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Perez et al. US 2021/0340561, published 11/4/2021, priority date 8/1/2018 (hereinafter Perez) as evidenced by Yosten et al. "The physiology of proinsulin C-peptide: unanswered questions and a proposed model." Physiology 30.4 (2015): 327-332 (hereinafter Yosten) in view of Fotin et al. US 2019/0241633, published 8/8/2019 (hereinafter Fotin), Glasebrook et al. US 2004/0259780, published 12/23/2004 (hereinafter Glasebrook) and Drucker. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell metabolism 27.4 (2018): 740-756 (hereinafter Drucker).
Claim 1: Perez discloses a method for reprogramming somatic cells into insulin-producing cells by transfecting several transcription factors to change the identity of adult fibroblasts into functional beta-like pancreatic cells (Perez, para 3-4, 9, 43 and 81). Perez presents this as a method to replenish endogenous insulin-producing cells as a treatment for diabetes (Perez, para 3). Specifically, Perez lists the primary transcription factors as Pdx1, Ngn3, Mafa and Tcf3 which are collectively referred to as the PMN-T factors (Perez, para 4, 43). As shown in the sequence alignment below, Pdx1 and Mafa disclosed by Perez share 100% sequence similarity to instant SEQ ID Nos 2 and 4. Perez identifies Pdx1 and Mafa as critical transcription factors that bind to regulatory elements resulting in the transcription of insulin genes (Perez, para 4-7).
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Sequence Search Results for SEQ ID NO: 2 encoding Pdx1
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Sequence Search Results for SEQ ID NO: 4 encoding Mafa
With respect to C-peptide, it is argued that C-peptide is intrinsically produced by these functional beta-like pancreatic cells, since C-peptide is a component of proinsulin which is cleaved to produce mature insulin as evidenced by Yosten. Specifically, Yosten teaches that C-peptide is produced, processed and secreted with insulin by pancreatic beta- cells (Yosten, para 1).
Claims 2-5: Perez discloses the simultaneous or sequential delivery of transcription factors Pdx1, Ngn3, Mafa and Tcf3 into the cytosol of somatic tissue including skin cells (Perez, para 7). Perez provides alternative embodiments wherein the transcription factors are located on one or more expression factors and combinations thereof operably linked by promoters, enhancers and other signal sequences (Perez, para 7-10 and 35).
Claim 6: Perez discloses preferred embodiments wherein the somatic cell is a skin cell (Perez, para 41, 81).
Claim 7: Perez describes intracellular delivery via nanotransfection and transfection in vivo (Perez, para 86, 93).
Although Perez discloses the intracellular delivery of Pdx1 and Mafa for reprogramming somatic cells into insulin producing cells, Perez does not disclose the intracellular delivery of SEQ ID NO: 6 and SEQ ID NO: 8 which encode for GLP-1R and FGF21, respectively.
Claim 1: However, nucleic acid sequences encoding a peptide with at least 95% sequence identity to SEQ ID NO: 6 and SEQ ID NO: 8 which encode for GLP-1R and FGF21, respectively, are known in the art as shown by Fotin and Glasebrook. Fotin discloses a GLP-1R sequence which shares 99.8% sequence similarity to SEQ ID NO: 6. Glasebrook discloses a FGF21 sequence which shares 100% sequence similarity to SEQ ID NO: 8 (sequence search results shown below). The relative importance of GLP-1 and FGF21 in the augmentation of insulin production is known in the art as shown by Drucker. Briefly, Drucker describes how GLP-1 is critical for beta-cell proliferation and insulin gene transcription (Drucker, pg 743 col 1 and Fig 2). Drucker describes how FGF21 is an important metabolic regulator that improves insulin sensitivity in peripheral tissues (Drucker, pg 746 col 1).
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Sequence Search Results for SEQ ID NO: 6 encoding GLP-1R
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Sequence Search Results for SEQ ID NO: 8 encoding FGF21
It would have been prima facie obvious to one of ordinary skill in the art to deliver SEQ ID NO: 6 and SEQ ID NO: 8, which encode for GLP-1R and FGF21, in the methods for reprogramming somatic cells into insulin-producing cells as described by Perez in addition to Pdx1 and Mafa. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Perez establishes Pdx1 and Mafa as key transcription factors that induce the initial reprogramming of somatic cells into beta-like pancreatic cells, while GLP-1R and FGF21 are known to be important in enhancing the overall metabolic environment necessary to support and maintain the beta-like pancreatic cells as shown by Drucker. Thus, one of ordinary skill would have been motivated to make this combination given that Pdx1 and Mafa are critical for initiating the reprogramming process, while GLP-1R and FGF21 provide the vital extrinsic metabolic cues that complement the actions of Pdx1 and Mafa leading to a more robust and functional therapy to replenish endogenous insulin-producing cells as a treatment for diabetes. One would have a reasonable expectation of success given that the sequence of all four peptides known in the art and there exist predictable means for substituting known transcription factor genes into a single or multiple polycistronic vector. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634