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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 18, 2025 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on December 18, 2025. Claims 20 and 22-27 are currently pending. The requirement for restriction between Groups I-VI was previously made FINAL.
Therefore, claims 20 and 22-27 are currently under examination.
Priority
The present application filed July 22, 2021 is a CON of PCT/IL2020/050095, filed January 23, 2020, which claims benefit to provisional application 62/795,626, filed on January 23, 2019.
Thus, the earliest possible priority for the instant applications is January 23, 2019.
Modified & Maintained Claim Rejections - 35 USC § 102
Claims 20 and 22-27 remain rejected under 35 U.S.C. 102(a)(l) as being anticipated by Hanna et al. (US 2017/0275593 A1). This is a modified rejection necessitated by amendment of the claims in the response filed May 29, 2025.
Regarding claims 20, the claim is amended to recite the media does not contain more than 0.5 µM of an ERK inhibitor. Hence, the media can contain less than 0.5 µM of an ERK inhibitor. Hanna discloses the media component of ERK inhibitor, including species PD0325901, and specifically discloses the concentration range from .01 microM (μM) to about 50 μM ([0272]; [0307]).
Hanna discloses a method of generating naïve pluripotent stem cells (PSC) from non-naïve PSC by culturing the non- naïve PSC in a medium promoting the expansion of the naïve PSC, where the cell is a non-naïve primate cell ([0538-0539]; claim 26) (Abstract; [0033-0034]; [0068]). Hanna discloses the embodiments where the medium comprises the Axin stabilizer IWR-1, a PKC inhibitor, and the STAT3 activator Lif; the medium further comprise Notch inhibitors (Abstract; claims 1and 4; [0015]- [0016]; [0221]). Hanna discloses that IWR-1 is an inhibitor of the canonical Wnt pathway. The relevant inhibition of molecular pathways or structures like the AXIN destruction complex are disclosed along with the ability to differentially modulate or regulate the biological system towards greater stability and/or activity of the complex with inhibition of canonical Wnt signaling ([0312]; [0315). Hanna also teaches that the medium further comprises Notch inhibitors (claim 1 and 4; [0221]).
Regarding the limitation requiring that said medium does not contain more than .1 µM of a GSK3β inhibitor, Hanna explicitly teaches where GSK3β is absent (Fig. 8, example condition 41; [0013-0015]; [0601-0603]; [0607-0608]; [0610-0611]; [0148-1051]).
Moreover, where GSK3β is disclosed, it is disclosed as an alternative secondary optional signaling optimizing component ([0016]; Fig. 7; Fig. 18). Thus, Hanna discloses the claimed media for generating a naïve pluripotent stem cell (PSC), comprising culturing a non-naïve primate PSC cell in a culture medium comprising a WNT inhibitor, a Notch inhibitor and a protein kinase C (PKC) inhibitor, wherein said medium does not contain a GSK3β inhibitor, and does not contain more than 0.5 μM of an ERK inhibitor under conditions which allow generation of the naive PSC from said non-naive PSC, thereby generating the naive PSC (claims 1-5).
Regarding claims 22, dependent on claim 20, Hanna discloses where the media further contains STAT3 activator, ERK inhibitor, and comprises an SRC inhibitor (claims 1 and 3-4; Fig .7 & 18, Primary Signaling Regulatory components).
Regarding claims 23, dependent on claim 20, Hanna discloses where the media further contains YAP/TAZ inhibitor (claim 4; Fig. 7 & 18).
Regarding claims 24, dependent on claim 20, Hanna discloses where the media further contains Activin A (claim 5; Fig .7 & 18).
Regarding claims 25, dependent on claim 20, Hanna discloses where the medium is devoid of animal serum ([0143]).
Regarding claims 26, dependent on claim 20, Hanna discloses where the culture medium further comprises serum replacement ([0144]).
Regarding claims 27, dependent on claim 20, Hanna discloses wherein said primate PSC is a human PSC ([0538-0539]; [0541]; claim 52).
Modified & Maintained Claim Rejections - 35 USC § 103
Claims 20 and 22-27 are rejected under 35 U.S.C. 103 as being unpatentable over Hanna et al. (US 11,920,164 B2, citations to prior publication US 2017/0275593 A1), in view of, Theunissen et al. (Cell Stem Cell. 2014 Oct 2;15(4):471-487. Epub 2014 Jul 24; hereinafter ‘Theunissen’; see IDS), and further in view of Theunissen et al. (US 12,123,019 B2, citations to prior publication US 2017/0114323 A1; hereinafter ‘Whitehead’) and Hanna et al. (US 10,920,192 B2, citations to prior publication US 2014/0315301 A1; hereinafter ‘Yeda’). This is a new rejection necessitated by amendment of the claims in the response filed May 29, 2025.
Regarding claim 20, the claim is amended to recite the media does not contain more than 0.5 µM of an ERK inhibitor. Hence, the media can contain less than 0.5 µM of an ERK inhibitor. Hanna discloses the component of ERK1 inhibitor, such as species PD0325901, and specifically discloses the concentration range from .01 microM (μM) to about 50 μM ([0272]; [0307]).
Hanna discloses a method of generating naïve pluripotent stem cells (PSC) from non-naïve PSC by culturing the non- naïve PSC in a medium promoting the expansion of the naïve PSC, where the cell is a non-naïve primate cell ([0538-0539]; claim 26) (Abstract; [0033-0034]; [0068]). Hanna discloses the embodiments where the medium comprises the Axin stabilizer IWR-1, a PKC inhibitor, and the STAT3 activator Lif; the medium further comprise Notch inhibitors (see Abstract; [0015]- [0016]; [0221]). Hanna discloses that IWR-1 is an inhibitor of the canonical Wnt pathway. The relevant inhibition of molecular pathways or structures like the AXIN destruction complex are disclosed and ability to differentially modulate or regulate the biological system towards greater stability and/or activity of the complex with inhibition of canonical Wnt signaling (see [0312]; [0315). Hanna also teaches that the medium further comprise Notch inhibitors (see [0221]).
Regarding the limitation requiring that said medium does not contain more than .01 µM of a GSK3β inhibitor, Hanna explicitly teaches where GSK3β is absent (Fig. 8, example condition 41; [0013-0015]; [0601-0603]; [0607-0608]; [0610-0611]; [0148-1051]). Moreover, where GSK3β is disclosed, it is disclosed as an alternative secondary optional signaling
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optimizing component ([0016]; Fig. 7; Fig. 18). Thus, Hanna clearly discloses where the claimed media, see claims 1-5.
Regarding the utility of the combination of a WNTi, Notchi, and a protein kinas C (PKC inhibitor) to generate naïve PSCs, Hanna teaches the impact of each component and various mythologies to optimize the generation of a naive pluripotent stem cell (PSC), comprising culturing a non-naive primate PSC cell, see Fig. 7.
Hanna teaches the generation of naïve PSCs media comprising various combinations of different pathway inhibitors (column 5-14), including embodiments where GSK3β is absent). Hanna teaches the relevant and specific pathway inhibition (column 31, lines 43-column 32), highlighting the relevance of certain pathways or structures like the AXIN destruction complex and ability to differentially modulate or regulate the pathway towards greater stability and/or activity of the complex with inhibition of canonical Wnt signaling (column 31, last para.). Likewise, Hanna exemplifies the inclusion of a Notch inhibitor among the range of various medium combinations and configurations taught throughout the reference. Hanna teaches to the relevance and specificity of Notch signaling and Notch 1 inhibitors (column 38, last para. - column 39, lines 1-27). Additionally, Hanna teaches the culture media composition can additionally comprise signaling optimizing components, including Notch inhibitors (column 48, lines 45-51). Hanna teaches the composition can optionally comprise a PKC inhibitor (abstract and column 32, lines 62-67) for possibly inhibiting the Mbd3 expression (column 14, lines 40-42), along with examples of non-limiting species (column 33, lines 1-16).
Furthermore, the ordinary artisan would have recognized methods of screening for and optimizing the media with the claimed components for generating a naive pluripotent stem cell (PSC), comprising culturing a non-naive primate PSC cell were established in the prior art, further in view of Theunissen, Whitehead and Yuda.
Theunissen teaches the systematic identification of culture conditions for induction and maintenance of naive human pluripotency (pg. 471, Section: Summary), such as generating secondary naive human iPSCs from secondary derived fibroblasts (Fig. 3F, 4f, and pg. 477, column 2, lines 1-3). Principally, regarding the absence of GSK3β in the media, or said medium being devoid of an amount of GSK3β inhibitor that increases β-catenin translocation, Theunissen expressly teaches reporter activity and pluripotency gene expression were unaffected by the removal of GSK3 inhibition (pg. 477, column 2, lines 36-39; Fig. 4 and S4E). Theunissen teaches the role of individual components of the 5i/L/FA medium, where single kinase inhibitors were removed, and the effect on a clonal line of OCT4- ΔPE-GFP+ hESCs was analyzed (pg. 477, Section: Generation of Transgene-free Naive Human ESCs in 5i/L). In this manner, iterative chemical screening was taught to identify combinations of kinase inhibitors to generate human pluripotent cells by characterization of a pluripotent state identified by sustained OCT4- ΔPE-GFP activity (pg. 471, Summary and pg. 473, para. 1) and transcriptional profiling (Fig. 6). Moreover, the POSITA would have expected to have obtained a method of efficiently generating naïve PSCs by utilizing a media effective for changing the pluripotency state of a vertebrate cell to a naïve state, where GSK3 inhibition is removed, further in view of Whitehead.
Whitehead teaches the generation and proliferation of naïve human embryonic stem cells is enhanced by the removal of GSK3 inhibition (Fig 15A-15C, column 139, lines 41-44, and column 143, lines 3-5).
Moreover, a person of ordinary skill in the art would have reasonably expected additional assemblages or configurations of relevant inhibitory constituents to have generated naïve PSCS, further in view of Yeda. Yeda teaches additional constitutes able to sufficient modulate the relevant pathways towards generating the required cell type (abstract and claims 1-31), as well as concept and utility of optimized reprogramming recipes (column 1, lines 59-61), optimizing conditions (Fig. 71, Example 3 & 5, column 119 and column 44, para. 2).
Taken together, it would have been obvious to the ordinary artisan, before the effective filing date, to have applied the known technique of generating naïve PSCs by culturing non-naïve PSCs in a culture media containing relevant pathway inhibitors sufficient to produce or generate such cells through employing the distinct inhibitory agents and appropriately modulating the relevant biological pathways, as taught by Hanna, along with a manner of inhibitor screening without the inclusion of GSK3, as taught by Theunissen and further in view of Whitehead.
In doing so, the ordinary artisan would have yielded the predictable result of efficiently producing or generating naïve PSCs from non-naïve PSCs. Furthermore, as Theunissen teaches their technique of iterative chemical screening was effective at successfully identifying such a combination of inhibitors for generating naïve PSCs, it would have been obvious for the ordinary artisan to try selecting from various combinations of relevant pathway inhibitor constituents in the culture media, as the teachings specifically disclose screening processes for media optimization towards promoting the generation of naïve PSCs, with a reasonable expectation of success. Furthermore, as Hanna and Yeda teach these compositional components act in a modulatory threshold fashion, able to be tuned according to presence and concentration, optimized or, in other words, result effective variables, the POSITA would have recognized the variable nature of the taught inhibitors for generating naïve PSCs.
Regarding claims 22, the combined teachings of Hanna, Theunissen, Whitehead and Yuda render claim 20 obvious. Additionally, Hanna teaches where the media contains STAT3 activator and comprises an SRC inhibitor (claims 1 and 3-4; Fig .7 & 18, Primary Signaling Regulatory components). Theunissen further teaches the utility of the SRC inhibitor (Fig. 1a; pg. 475, column 2, para. 2; pg. 477, column 1, para. 1)
Regarding claims 23, the combined teachings of Hanna, Theunissen, Whitehead and Yuda render claim 20 obvious. Additionally, Hanna teaches where the media further contains YAP/TAZ inhibitor (claim 4; Fig. 7 & 18).
Regarding claims 24, the combined teachings of Hanna, Theunissen, Whitehead and Yuda render claim 20 obvious. Additionally, Hanna discloses where the media further contains Activin A (claim 5; Fig .7 & 18). Theunissen further teaches the utility of Activin A as an optimized component in the media (Fig. 4; pg. 477, column 2, para. 3).
Regarding claims 25, the combined teachings of Hanna, Theunissen, Whitehead and Yuda render claim 20 obvious. Additionally, Hanna discloses where the medium is devoid of animal serum ([0143]). Theunissen further teaches where the media is serum-free (Fig. 5; pg. 475, column 1, para. 1; pg. 485, column 2, para. 2).
Regarding claims 26, the combined teachings of Hanna, Theunissen, Whitehead and Yuda render claim 20 obvious. Additionally, Hanna teaches where the culture medium further comprises serum replacement ([0144]). Theunissen further teaches where the media comprises serum replacement (pg. 479, column 2, para. 1).
Regarding claims 27, the combined teachings of Hanna, Theunissen, Whitehead and Yuda render claim 20 obvious. Additionally, Hanna teaches wherein said primate PSC is a human PSC ([0538-0539]; [0541]; claim 52). Theunissen further teaches where the cells are human PSC (Title; Abstract).
Response to Applicants’ arguments as they apply to the rejection of Claims 20 and 22-27 under 35 USC § 102 and 35 USC § 103
Applicant's arguments filed December 18, 2025, have been fully considered but they are not persuasive.
At pages 3-5 of the remarks filed on December 18, 2025, Applicants essentially argue the following:
Applicant argues Hanna does not disclose where the media contains a Notch inhibitor and lacks more than 0.1 μM GSK3β inhibitor. Applicant argues to supply the missing Notch inhibitor, the rejection necessarily draws from unelated, list-based disclosures elsewhere in Hanna et al., and the examiner is “picking and choosing”.
This argument is not persuasive because Hanna discloses the claimed media in the specific combination, as well as alternatives, concentrations, and specifically discloses the same components for the same purposes. For instance, looking to Fig. 7 and claims 1-2, and 3, of Hanna’s disclosure the ordinary artisan would understand the medium can comprise the NOTCH inhibitor with no requirement that the media comprises a GSK3β inhibitor. This contrasts with the media of claim 1 and 6, where the media is limited by further comprising the GSK3β inhibitor. This is not picking and choosing but pointing to the media alternatives taught by Hanna for the same method of generating a naive pluripotent stem cell (PSC), comprising culturing a non-naive primate PSC cell in a culture medium.
The Examiner respectfully submits that patents are relevant as prior art for all they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). With that, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, even nonpreferred embodiments. See MPEP § 2123: Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989); Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005).
Applicant argues the claimed method is founded on the unexpected discovery that combined inhibition of WNT, PKC, and Notch, while explicitly excluding more than 0.1 μM GSK3f3 inhibitor, suffices to generate and maintain naïve primate PSCs.
This argument is not persuasive because the closest prior art already disclosed the generation of naïve primate PSCs with the claimed media. Furthermore, this argument is not persuasive because the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence, and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
Claims 20 and 22-27 are rejected. No claims are allowed.
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/J.D.L./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633