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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 14 February 2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group 1, claims 1-11 and 14-15 in the reply filed on 27 May 2025 was previously acknowledged.
Claims 12-13 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/27/2025.
New claims 17-20 were added in the response filed 14 February 2026 and depend from claim 1, therefore, have been included in Group 1.
Claim Status
Claims 2-3 and 10 were previously cancelled, claim 9 is newly canceled, claims 1, 5-8, 11, and 16 are currently amended, claims 17-20 are new, claims 12-13 have been withdrawn, and claims 1, 4-8, 11, and 14-20 have been considered on their merits.
Withdrawn Rejections/Objections
The rejection of claim 9 under 35 U.S.C. § 112(a) have been withdrawn as the claim has been canceled.
The claim rejections under 35 U.S.C. § 103 have been withdrawn due to Applicant’s amendments to the claims. However, a new rejection is set forth below.
Claim Interpretation
Regarding claim 1, the language “consist essentially of” is not defined by the specification. MPEP § 2111.03 (III) states, the transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976) (emphasis in original). Additionally, For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 ("PPG could have defined the scope of the phrase ‘consisting essentially of’ for purposes of its patent by making clear in its specification what it regarded as constituting a material change in the basic and novel characteristics of the invention."). If an applicant contends that additional steps or materials in the prior art are excluded by the recitation of "consisting essentially of," applicant has the burden of showing that the introduction of additional steps or components would materially change the characteristics of the claimed invention. In re De Lajarte, 337 F.2d 870, 143 USPQ 256 (CCPA 1964). See also Ex parte Hoffman, 12 USPQ2d 1061, 1063-64 (Bd. Pat. App. & Inter. 1989).
The histone deacetylase inhibitor 2-mercaptoethanol is known in art by other names to include β-Mercaptoethanol, 2-Hydroxyethylmercaptan, BME, and Thioethylene glycol.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 19 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 19 and 20 recites the limitation “D-MEM (Low Glucose) medium”, which renders the claim indefinite because it is unclear whether the limitation in parenthesis is part of the claimed invention. MPEP § 2173.05(d) states, description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. Therefore, it is unclear whether the information in parentheses is exemplary or a limitation of the claim. Additionally, the term “Low” in claims 19 and 20 is a relative term which renders the claim indefinite. The term “Low” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
As such, the limitations regarding the basal medium are interpreted as requiring any medium comprising DMEM which has a decreased level of glucose compared to a high glucose variant of DMEM.
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.
Claims 1, 4-5, 7-8, 11, and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over Pereyra-Bonnet et al. (PLoS One. 2014 Jun 25;9) in view of Lai et al. (Sci. Rep. 7, published 17 March 2017, IDS ref., of record) and He et al. (Scientific Reports, 7:16360, published 2017).
This is a new rejection necessitated by Applicant’s amendments to the claims. A response to applicant's traversal follows the reiterated rejection below.
Regarding claims 1, 5, 8, and 11, Pereyra-Bonnet teaches chemically transdifferentiated (reprogrammed) human skin fibroblasts (claim 11) without the use of transgenes (Abstract). Pereyra-Bonnet teaches fibroblasts were cultured in a transdifferentiation medium (TM) which consists of bFGF, xeno-free serum replacement, glutamine, nonessential amino acids and 0.1mM 2-mercaptoethanol (claim 5), antibiotics in DMEM/F12 Knockout (basal medium) (p. 2, Material and Methods). The TM of Pereyra-Bonnet reads as the first medium which consists essentially of a basal medium and 2-mercaptoehtanol. Pereyra-Bonnet teaches after 4 days the TM was changed and maintained for 3 more days (p. 2, Materials and Methods). Therefore, the fibroblasts were cultured in the medium consisting essentially of β-mercaptoethanol for 7 days. Pereyra-Bonnet appears to list all of the components of the TM which was absent of the OCT3/4 transcription stimulating factors LIF, CCL2, and IL-6 (claim 8). Pereyra-Bonnet teaches the fibroblasts utilized in this method showed plasticity even to the point of crossing the boundaries of distinct developmental germ layers (p. 9, Discussion). Pereyra-Bonnet focuses on reprogramming fibroblasts to insulin expressing cells; however, the purpose of this reference is to highlight the initial reprogramming step which relates to claim 1 step (a) and the first medium consisting essential of a basal medium and 2-mercaptoethanol. Pereyra-Bonnet teaches a second step wherein the medium is supplemented with specific factors in order to program these partially reprogrammed cells to cells of insulin-expressing clusters (p. 2, Materials and Methods). Pereyra-Bonnet teaches the goal of altering the expression of genes using only chemical molecules has been well-documented in skin fibroblasts, foreskin fibroblasts, and pancreatic endocrine cells (p. 9, Discussion). The two-stage process taught by Pereyra-Bonnet suggests the reprogramming potential of human fibroblast cells.
Pereyra-Bonnet does not teach step (b), an OCT3/4 transcription stimulating factor and culturing the cells obtained in step (a) to create the reprogrammed cells, wherein the OCT3/4 transcription stimulating factor is any one or more selected from the group consisting of LIF, CCL2, and IL-6.
However, Lai teaches induced MSCs from skin fibroblasts with chemicals and growth factors (Abstract). Lai teaches one of these growth factors which can be utilized is LIF (p. 2, Results). Lai teaches the pluripotent transcription factor OCT4, has been indicated to contribute to the multipotency of MSCs (p. 2, Results). Lai teaches OCT4 was up-regulated in iMSCs to a level similar to BMMSCs as compared to fibroblasts (Fig. 1D), suggesting that iMSCs may be induced through the action of OCT4 (p. 2, Results). Lai teaches there is a lack of defined master regulator(s) in MSCs, several studies have indicated that pluripotency markers of ESCs, such as OCT4 and NANOG, might play critical roles in maintaining the potency and proliferative ability of MSCs (p. 7).
Additionally, He teaches embryonic stem cell pluripotency is governed by OCT4-centric transcriptional networks (Abstract). He teaches conventional ES cells can be derived and maintained in vitro with media containing the cytokine leukemia inhibitory factor (LIF), which propagates the pluripotent state by activating STAT3 signaling, and simultaneous inhibition of glycogen synthase kinase-3 (GSK3) and MAP kinase/ERK kinase signaling (Abstract). The teachings of He demonstrate LIF is an essential regulator of the OCT4 pathway, suggesting OCT4 is a pivotal factor in direct cell conversion.
Therefore, it would have been obvious to one of ordinary skill in the art to combine the initial reprogramming step of Pereyra-Bonnet with the disclosure of Lai and He with a reasonable expectation of success because both Pereyra-Bonnet and Lai teach methods to chemically reprogram fibroblasts and He teaches LIF stimulates the OCT4 pathway. One would be motivated to combine the initial reprogramming step of Pereyra-Bonnet with the disclosure of Lai and He because Lai teaches while there is a lack of defined master regulators in MSCs, several studies have indicated that pluripotency markers of ESCs, such as OCT4 and NANOG, may play critical roles in maintaining the potency and proliferative ability of MSCs which suggests the method of Lai may involve similar regulations through OCT4 to promote multipotency of fibroblasts (Lai et al., p. 7, 2nd full para. and Figure 1D). Additionally, He teaches LIF is a regulator of the OCT4 pathway which is essential to propagate the pluripotent state of cells and Pereyra-Bonnet teaches the goal of altering the expression of genes using only chemical molecules has been well-documented in skin fibroblasts. Thus, it would have been obvious to include LIF as the OCT3/4 transcription stimulating factor as suggested by Lia and He following the initial reprogramming step taught by Pereyra-Bonnet.
Regarding claim 4, the teachings of Pereyra-Bonnet in view of Lai and He render obvious the limitation directed to the OCT3/4 transcription stimulating factor is LIF.
Regarding claim 7, Lai teaches the growth factors included in the chemical reprogramming of human dermal fibroblasts to MSC-like cells include LIF and bFGF (p. 2, Results).
Regarding claims 14 and 15, Pereyra-Bonnet in view of Lai and He render obvious the method according to claim 1 (claims 14 and 15 step (i)). Pereyra-Bonnet teach the transdifferentiated human fibroblasts (somatic cells) can be differentiated into insulin-expressing clusters (Abstract) and Lai teach The induced MSCs have much higher clonogenicity than fibroblasts, and they can be maintained and expanded in regular MSC medium for at least 8 passages and further differentiated into osteoblasts, adipocytes, and chondrocytes. Therefore, the teachings of Pereyra-Bonnet and Lai read on the limitations of claims 14 and 15 step (ii). Regarding claim 15 step (iii), Pereyra-Bonnet teaches the transdifferentiated fibroblasts were microinjected with 50 µl of PBS into the splenic portion of the pancreas (p. 3, Engraftment of mice with transdifferentiated fibroblasts). Additionally, Lai teaches intratracheal administration of iMSCs into an acute lung injury mouse model, the iMSCs were combined with PBS for administration (p. 11, Endotoxin-induced acute lung injury in mice). The PBS in both references read as a pharmacologically acceptable carrier and the administration of said differentiation inducted cells would have necessarily included preparing a cell preparation.
Regarding claim 16, Lai suggests 2-mercaptoethanol may be a useful component for reprogramming somatic cells, however, the method taught by Lai comprises chemical inhibitors and growth factors which does not include 2-mercaptoethanol to generate functional iMSCs from human primary dermal fibroblasts (p. 4, last para. and Figure 6).
Regarding claim 17, Pereyra-Bonnet appears to list all of the components of the TM which was absent of any DNA methyltransferase inhibitors and embryonic stem cell extracts.
Regarding claim 18, Pereyra-Bonnet appears to list all of the components of the TM which were absent of cytokines or hormones.
Regarding claims 19 and 20, Pereyra-Bonnet teaches the basal medium is DMEM/F12, which is a combination of the DMEM and F12 medium. The reference does not specify whether the DMEM is of high or low glucose. Since this initial reprogramming step of Pereyra-Bonnet is not considered a high‑density, fast‑proliferating cell culture, such as a viral infection or proliferation assay. These types of culture conditions would require the high glucose variant; it is believed this medium comprises a low glucose level. Additionally, even if the DMEM was of the high glucose variation, the combination of both DMEM and Ham’s F12 would result in a reduced glucose level compared to DMEM alone, therefore, the DMEM/F12 medium of Pereyra-Bonnet reads on a low glucose DMEM medium.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments filed 14 February 2026 have been fully considered but they are not persuasive.
Regarding the arguments on page 8, section I of the remarks, directed to Lai not teaching or suggesting the claimed sequential method, this is not persuasive because the claimed method was rendered obvious using more than just Lai as a reference. The teachings of Lai, to include the utilization of LIF, rely not only on the disclosure of Lai but also the disclosure of He. Additionally, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the combination of Pereyra-Bonnet in view of Lai and He provided the necessary teachings, suggestions, and motivation to render obvious the claimed method.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant’s arguments, see page 9 section II of the remarks, filed 14 February 2026, with respect to Han have been fully considered and are persuasive. The new rejections do not rely on Han, therefore, the arguments directed to this reference are considered moot.
In response to applicant’s argument found on page 13 section IV of the remarks, that there is no motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Applicant is highlighting the Lai reference does not attribute special importance to LIF, however, while Lai does disclose the use of LIF in the reprogramming medium as not critical to the efficacy of the reprogramming, the disclosure set forth in the Lai and He references highlight the importance of the OCT3/4 pathway and how LIF relates to said pathway.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Pereyra-Bonnet et al. (PLoS One. 2014 Jun 25;9) in view of Lai et al. (Sci. Rep. 7, published 17 March 2017, IDS ref., of record) and He et al. (Scientific Reports, 7:16360, published 2017) as applied to claims 1, 4-5, 7-8, 11, and 14-20 above, and further in view of Hasegawa et al. (Sci. Rep. 4, published 24 June 2014, IDS ref., of record).
This is a new rejection necessitated by Applicant’s amendments to the claims. A response to applicant's traversal follows the reiterated rejection below.
Regarding claim 6, Pereyra-Bonnet in view of Lai and He do not teach wherein the second medium further contains CCL2.
However, Hasegawa teaches chemokine (C-C motif) ligand 2 (CCL2) enhances the expression of pluripotent marker genes through phosphorylation of the signal transducer and activator of transcription 3 (STAT3) protein (Abstract). Hasegawa teaches hiPSCs cultured with CCL2 can differentiate at a higher efficiency than culturing with just bFGF (Abstract). Hasegawa teaches expression levels of key transcription factors of human iPSCs showed higher expression of NANOG, KLF4, ZFP42, and DPPA3 in CCL2 treated hiPSCs compared to those cultured with bFGF (p. 2, Results and Figure 1b).
Therefore, it would have been obvious to one of ordinary skill in the art to include CCL2 of Hasegawa in the method rendered obvious by Pereyra-Bonnet in view of Lai and He with a reasonable expectation of success because Hasegawa teaches hiPSCs cultured with CCL2 have enhanced differentiation ability and are more competent to differentiate into different lineages (pp. 5-6, Human iPSCs cultured with CCL2 enhance differentiation ability). One would be motivated to include CCL2 of Hasegawa in the method rendered obvious by Pereyra-Bonnet in view of Lai and He because Hasegawa teaches cells cultured with CCL2 possess enhanced differentiation ability.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant's arguments directed to the rejection of claim 6, found on page 14 of the remarks, filed 14 February 2026, have been fully considered but they are not persuasive. The response does not set forth any arguments directed to the merits of the rejection. Since claim 1 is prima facie obvious over Pereyra-Bonnet in view of Lai and He, therefore, the assertion that claim 6 is patentable because it depends from claim 1 is not persuasive.
Relevant prior art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Wang et al. (Cellular Reprogramming, Vol. 20, No. 1, 2018)
Wang teaches transdifferentiation of fibroblasts into cardiac myocytes (Abstract). Wang teaches Oct 4 alone, combined with small molecules, could induce cardiac differentiation of fibroblasts. Wang suggests Oct4 expression promotes transdifferentiation efficiency.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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