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/Amendments/Claims
Applicant’s response filed on 4/7/2026 has been considered. Claim 18 has been newly added. Claims 1-11 and 13-18 are pending. Claims 1-3, 6 and 8 have been amended. Claims 9-11 and 13-17 are currently withdrawn with traverse from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking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 and 18 are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office 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.
Claim Objections
Claim 1 is objected to for describing a fourth nucleic acid sequence encoding a “four peptide” rather than fourth peptide.
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.
Maintained 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 stand rejected in modified form 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, reference of record) 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, reference of record) in view of Fotin et al. US 2019/0241633, published 8/8/2019 (hereinafter Fotin, reference of record), Glasebrook et al. US 2004/0259780, published 12/23/2004 (hereinafter Glasebrook, reference of record) and Drucker. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell metabolism 27.4 (2018): 740-756 (hereinafter Drucker, reference of record). This rejection is repeated for the same reasons as outlined in the Office Action mailed on 1/8/2026. A reply to applicant’s arguments is found below.
Claims 1 and 8: 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 discloses preferred embodiments wherein the somatic tissue to be reprogrammed is a native non-pancreatic cell like an adult skin or fibroblast cell and wherein the delivery occurs in vivo (Perez, para 41, 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.
Claims 1 and 8: 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 claims 1-8 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant points to the amendments arguing that the prior art fails to teach that native non-pancreatic somatic tissue is reprogrammed in vivo to become insulinogenic and produce insulin. Applicant argues that Perez is directed to the differentiation of an isolated induced pluripotent cell type not reprogramming native cells in vivo. Applicant argues that the IPSCs taught by Perez are not native cells but cells that have been manipulated back into a pluripotent state allowing them to differentiate into almost any cell type and does not read on the amended claims. Thus, one of ordinary skill would not be motivated from the disclosure of Perez to modify native non-pancreatic cells of somatic tissue.
This argument has been fully considered, but was not found persuasive since Perez expressly teaches modifying native non-pancreatic cells of somatic tissue, with preferred embodiments towards adult skin or fibroblast cells and wherein the delivery occurs in vivo (Perez, para 41, 81). Perez states “As disclosed are methods of reprogramming skin cells into insulin-producing cells that involve delivering intracellularly into the skin cells a polynucleotide comprising nucleic acid sequences encoding Pdx1, Ngn3, Mafa and Tcf3” (Perez, para 81).
Applicant further argues that the secondary references fail to supplement the inadequacies of Perez in preprogramming post-natal skin tissue towards an insulinogenic phenotype. Applicant argues that Drucker does not support combining GLP-1 and FGF21 with PDX-1 and MafA in native non-insulin producing cells. Applicant points to example 1 to demonstrate the unique composition of amended claim 1 which is argued to be unexpected in view of the art.
This argument has been fully considered, but was not found persuasive since Perez expressly lists the primary transcription factors Pdx1, Ngn3, Mafa and Tcf3 which are collectively referred to as the PMN-T factors as being critical for the in vivo reprogramming of somatic tissue like adult skin or fibroblast cell (native non-pancreatic cells) into insulin-producing cells as a treatment for diabetes (Perez, para 3). 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. However, these are known in the art and 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.
New Claim Rejections - 35 USC § 103
Claims 1-8 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Perez (supra) as evidenced by Yosten (supra) in view of Fotin (supra), Glasebrook (supra) and Drucker (supra) as applied to claims 1-8 above in further view of Diaz-Starokozheva et al. "Early intervention in ischemic tissue with oxygen nanocarriers enables successful implementation of restorative cell therapies." Cellular and Molecular Bioengineering 13.5 (2020): 435 (hereinafter Diaz-Starokozheva). This is a new rejection necessitated by amendment of the claims in the responses filed 4/7/2026.
A description of Perez as evidenced by Yosten in view of Fotin, Glasebrook and Drucker can be found above with respect to claims 1-8. Although Perez expressly describes intracellular delivery by tissue nanotransfection, Perez does not provide the specific nanotransfection parameters described in claim 18 (Perez, para 86, 88 and claim 10).
Claim 18: Diaz-Starokozheva discloses tissue nanotransfection methods for the skin involving multiple electrical stimulations of 250 V in an amplitude and a duration of 10 ms (Diaz-Starokozheva, Methods-Tissue nanotransfection).
It would have been prima facie obvious to one of ordinary skill in the art to transfect Pdx1, Ngn3, Mafa and Tcf3 as described by Perez as evidenced by Yosten in view of Fotin, Glasebrook and Drucker using the nanotransfection protocols described by Diaz-Starokozheva.
It would have been a matter of combining prior art elements according to known methods to yield predictable results since Perez expressly describes intracellular delivery by tissue nanotransfection, yet falls short of providing the specific claimed parameters. Thus, one of ordinary skill would have been motivated to look to the prior art and the disclosure of Diaz-Starokozheva to investigate the commonly used nanotransfection protocols for skin tissue. One would have a reasonable expectation of success given that Diaz-Starokozheva observed robust expression of the transfected genes in native non-pancreatic cell tissue like skin. 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.
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 mailing date of this final action.
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Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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