DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 5/15/2026 to claims 1, 4, 14, 15, 17, 19, and 21 have been entered. Claims 5, 7-11, 13, 16, 18, 20, and 25-31 are canceled. Claims 1-4, 6, 12, 14, 15, 17, 19, 21-24, and 32 remain pending, of which claims 1-4, 6, 12, 14, 15, 17, 19, 21, 22, and 32 are being considered on their merits. Claims 23 and 24 remain withdrawn from consideration. References not included with this Office action can be found in a prior action.
The instant amendments to claim 1 have overcome the 35 U.S.C. § 112(b) and 35 U.S.C. § 103 rejections of record, which are withdrawn.
Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
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 1-4, 12, 14, 15, 17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Olova et al. (Aging Cell (epub Nov. 2018), 18(1), e12877; Reference U) in view of Sommer et al. (STEM CELLS 2009;27:543–549).
Olova teaches a method of generating induced pluripotent stem cells from subjects of varying age, the method comprising transfecting/transducing human dermal fibroblasts (HDFs, e.g. somatic cells) with to express OSKM (i.e. Oct4, Sox2, Klf4, and c-Myc, e.g. the Yamanaka factors), wherein the IPSCs are taught as “partially reprogrammed” after 7- to 11-days of culturing and express the pluripotency marker TRA-1-60, and wherein the eAge as calculated by Horvath’s multitissue age predict peaks 3-days post-transduction and linearly decreases until about 20 days post-transduction (Fig. 1; the paragraph starting “To understand the dynamics of eAge…” in the right column of page 2), and wherein the cells express a combination of pluripotency and fibroblast marker reading in-part on claim 1 and reading on claims 2-4, 12, 14, the embodiment of mRNA made in the cells from the vector of Olova for claim 17, and the embodiment of proteins expressed from mRNA made in the cells from the vector of Olova for claim 19.
Regarding claim 1, Olova does not teach culturing the human dermal fibroblasts in the absence of one or more of Oct4. Klf4, Sox2, and/or c-Myc. Regarding that embodiment of claim 1 and claim 15, Olova does not teach any inducible expression cassette.
Sommer teaches a tetracycline-inducible lentiviral expression cassette comprising Oct4, Klf4, Sox2, and cMyc, which is used to induce pluripotent stem cell generation from fibroblasts (Abstract; Fig. 1, and termed “pHAGE-STEMCCA” or “Tet-STEMCCA”; “Cell culture” on p544), reading on the embodiment of an inducible expression cassette for the generic removal (e.g. removal of the inducer) of claim 1 and on claim 15, Sommer teaches that the inducible lentiviral expression cassette is advantageous to assess the kinetics of reprogramming (the fibroblasts to induced pluripotent stem cells) in MEFs derived from a single iPS clone (p547, subheading “Secondary iPS Generation by Reactivation of STEMCCA” and Fig. 5A).
Regarding claims 1 and 15, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the Oct4, Klf4, Sox2, and cMyc of Olova with the tetracycline-inducible lentiviral expression cassette comprising Oct4, Klf4, Sox2, and cMyc of Sommer in Olova’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Olova and Sommer are directed towards methods of introducing Oct4, Klf4, Sox2, and cMyc into fibroblasts to generate induced pluripotent stem cells. The skilled artisan would have been motivated to do so because Sommer teaches that the substitution would be predictably advantageous to assess the kinetics of reprogramming fibroblasts to induced pluripotent stem cells.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Olova and Sommer as applied to claim 1 above, and further in view of Wen et al. (STEM CELLS TRANSLATIONAL MEDICINE 2013;2:118–128; provided in the IDS dated 4/20/2022).
The teachings of Olova and Sommer are relied upon as set forth above.
Regarding claim 6, Olova and Sommer do not teach SSEA4 as a pluripotency marker.
Wen teaches a method of reprogramming human fibroblasts into pluripotent stem cells, the method comprising 1) obtaining and culturing human fibroblasts (p119, subheading “Tissue Collection”), 2) singly transfecting the human fibroblasts with a lentiviral vector encoding for Oct4, Klf4, Sox2, and cMyc to generate induced pluripotent stem cells (p119, subheading “Lentivirus Production and Infection”), 3) differentiating the induced pluripotent stem cells to embryoid bodies and then fibroblast-like cells and such as to positively express the pluripotency markers NANOG, OCT4, SOX2, hTERT, SSEA-3, SSEA-4, Tra-1–60, and Tra-1–80 (p120, paragraph starting “For embryoid body (EB) formation…” through paragraph ending “…were determined by immunocytochemistry; Fig. 2A for pluripotency marker expression and discussion of this figure at p121, paragraph starting “To generate iPSCs…”), reading on claim 6.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to further detect SSEA4 in the methods of Olova in view Wen. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Wen and Olova are directed towards methods of introducing Oct4, Klf4, Sox2, and cMyc into fibroblasts to generate induced pluripotent stem cells and Wen teaches detailed methods of detecting SSEA4.. The skilled artisan would have been motivated to do so because Wen teaches that SSEA4 is a predictable marker of pluripotency in induced pluripotent stem cells, and so the further detection of SSEA4 would predictably improve Olova’s methods as another marker to discriminate between pluripotency and fibroblast fate.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 19 is alternatively rejected and claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Olova and Sommer as applied to claim 1 above, and further in view of Tammam et. al. (Oncotarget (2016), 7(25), 37728-37739;) and Li et al. (Cell Research (2011), 21:196-204).
The teachings of Olova and Sommer are relied upon as set forth above, and read in part on claim 19. Regarding claims 19 and 32, Olova and Sommer do not optionally teach wherein the targeted delivery system comprises a nanoparticle delivery system.
Tammam teaches a method of introducing recombinant OCT4 protein into human fibroblasts, the method comprising loading chitosan nanoparticles with recombinant OCT4 protein and contacting the human fibroblasts with the OCT4-loaded chitosan nanoparticles sufficient to deliver the recombinant OCT4 protein to the nucleus of the cells (p37737, paragraph starting “Human fibroblasts were seeded…” and Fig. 6; also p37730 for recombinant expression of OCT4 protein in Sf9 insect cells), reading on claims 19 and 32. Tammam teaches that the chitosan nanoparticles are advantageous to stabilize the DNA-binding activity of recombinant OCT4 protein (p37729, paragraph starting “In this study…”; subheading “Chitosan S-NPs stabilize OCT4 DNA-binding activity” on p37730-31). Tammam teaches that there is a need in this art to improve upon methods of generating induced pluripotent stem cells, and the most commonly used method is retroviral transduction but which bears the risk of insertional mutagenesis of the genome-integrating viruses (1st paragraph of the Introduction), reading on claims 19 and 32.
Li teaches a method of reprogramming mouse fibroblasts into pluripotent stem cells, the method comprising infecting the cells with a virus carrying a gene encoding for OCT4 and treating the cells with a combination of 0.5 mM VPA, 5 µM tranylcypromine, 3 µM CHIR99021 and 1 µM 616452 (i.e. VC6T) such as to generate induced pluripotent stem cells (p202, subheading “Lentivirus infection and iPS cell generation”; 1st paragraph of the Discussion on p201; Fig. 1 for GFP+ stem cell generation and Fig. 2 for expression of pluripotency markers), reading on claims 19 and 32.
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the transduction methods comprising OCT4, KLF4, SOX2, Myc of Olova with chitosan nanoparticle and recombinant OCT4 protein composition and methods of loading of fibroblasts with said composition of Tammam and the small molecule treatment methods of Li in Olova’s methods of making induced pluripotent stem cells A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Olova and Li are directed towards methods of generating induced pluripotent stem cells from fibroblasts, and Li shows that the combination of OCT4 and treatment with the combination of 0.5 mM VPA, 5 µM tranylcypromine, 3 µM CHIR99021 and 1 µM 616452 is sufficient to generate induced pluripotent stem cells. The skilled artisan would have been motivated to do so because ). Tammam teaches that there is a need in this art to improve upon methods of generating induced pluripotent stem cells, and the most commonly used method is retroviral transduction but which bears the risk of insertional mutagenesis of the genome-integrating viruses, and so the substitution would likely improve upon the methods of Olova by removing the lentivirus vector and so remove any possibility mutagenizing the fibroblasts of Olova.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Olova and Sommer as applied to claim 1 above, and further in view of Weltner et al. (Nature Communications (July 6th, 2018), 9:2463).
The teachings of Olova and Sommer are relied upon as set forth above.
Regarding claim 21, Olova and Sommer do not teach wherein the Oct4, Klf4, Sox2, and/or cMyc are introduced into the somatic cell by CRISPR/Cas-9.
Weltner teaches methods reprogramming skin fibroblasts into induced pluripotent stem cells, the method comprising by targeting the endogenous OCT4, KLF4, SOX2, Myc, and LIN28A promoters utilizing CRISPRa (Abstract; subheading “Fibroblast reprogramming with CRISPRa” on page 3 and continuing on page 6), reading on claim 21. Weltner teaches the reprogramming methods are advantageous due to a high multiplexing capacity and ability to target endogenous loci (Abstract), reading on claim 21
It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the transduction methods comprising OCT4, KLF4, SOX2, Myc of Olova with the CRISPRa/Cas9 system targeting expression of endogenous OCT4, KLF4, SOX2, Myc, and LIN28A promoters of Weltner in Olova’s induced pluripotent stem cells. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Olova and Weltner are directed towards methods of reprogramming fibroblasts into induced pluripotent stem cells. The skilled artisan would have been motivated to do so because Weltner teaches the reprogramming methods comprising CRIPSR are advantageous due to a high multiplexing capacity and ability to target endogenous loci, thus improving upon the methods and cells of Olova.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Olova and Sommer as applied to claim 1 above, and further in view of Prieur et al. (WO 2012/136841; provided in the IDS dated 4/20/2022).
The teachings of Olova and Sommer are relied upon as set forth above.
Regarding claim 22, Olova and Sommer do not teach further culturing the cells in the presence of LIN28 and/or NANOG.
Prieur teaches a method for reprogramming cells from aged donors or senescent cells to pluripotent cells that have lost marks of senescence (Abstract). Prieur teaches reprogramming said cells into iPSCs (i.e. induced pluripotent stem cells) with reprogramming factors comprising Oct4, Klf4, Sox2, cMyc, Lin28 and, optionally Nanog (Abstract), reading on claim 22.
Regarding claim 22, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). See M.P.E.P. § 2144.06. In this case, It would have been obvious to a person of ordinary skill in the art before the invention was filed to add the LIN28 and/or NANOG or Prieur to the composition and methods of Olova because Oct4, Klf4, Sox2, cMyc, Lin28 and Nanog are all taught as useful for the same purpose as reprogramming factors to generate induced pluripotent stem cells from a starting somatic cell type.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 5-14 of the reply have been fully considered, but not found persuasive of error over the new grounds of rejection above and necessitated by the instant claim amendments. Briefly restated, the instant amendments to claim 1 necessitated the replacement of Wen with Olova as the primary reference in the 35 U.S.C. § 103 rejections above, and Wen is now only applied to dependent claim 6.
In so much that the case is not in condition for allowance, Applicant’s remarks requesting rejoinder on pages 13 and 14 of the reply are not persuasive.
Conclusion
No claims are allowed. No claims are free of the art.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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