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 the Claims
Claims 1-27 responsive to communications on 09/25/2026 are pending.
Claims 7-8, 11-12, 15, and 17-19 are newly amended.
Claims 26 and 27 are newly added.
Claims 20-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 04/24/2026.
Claims 1-19 and 26-27 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of the claims under 35 USC 103 based on Deng et al. (US20160145581A1, on IDS 04/10/2025) are maintained but modified to address the claims as amended.
Claim Interpretation
Claim 1 recites “(Stage I condition)”, “(Stage II condition)”, “(Stage III condition)”, and “(Stage IV condition).” It is noted that a person of ordinary skill in the art would have recognized that the claim is establishing an abbreviation for the culture medium in that stage. Therefore, Stage I condition refers to a medium comprising (i) a glycogen kinase inhibitor, (ii) a TGFβ inhibitor, and (iii) a retinoic acid receptor (RAR) agonist, etc.
Claim Objection
Claim 12 is objected to for the following informalities: claim 12 recites “Valtalanib” which is a misspelling of “Vatalanib.”
Appropriate correction is required.
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 1-6, 8-10, 13-19, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (US20160145581A1, on IDS 04/10/2025) in view of Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019).
In regards to claims 1, 8-10, 13-16, and 19, Deng teaches methods for reprogramming human somatic cells to into human chemically induced pluripotent cells (hCiPSCs, or hereafter “PSCs” for simplicity) (Title, Abstract; paragraphs [0002-0005, 0062]; claims 1 and 13; Fig. 4C).
Deng teaches that this is a multi-stage method that uses differing chemical cocktails (Fig. 4C).
In regards to step (a) stage 1, Deng teaches that the somatic cells are cultured in a medium supplemented with the small molecules CHIR99021 (a glycogen kinase inhibitor) and 616452 (a TGFβ inhibitor) (Fig. 4C, claims 1-2, 26; referred to as “VC6TF”).
Deng also teaches that RAR agonists (including AM580) can be added in the media compositions to induced pluripotency (paragraph [0056]). A person of ordinary skill in the art would have been motivated to include a RAR agonist in the medium of step (a) stage 1 because Deng teaches that it improves pluripotency. They would be further motivated to add a RAR agonist such as AM580 because Zhao teaches that this improves formation of intermediates (p1681).
Furthermore, because Deng broadly teaches that compositions can be supplemented with a RAR agonist (such as AM580), because Zhao teaches that a RAR agonist can be added to the first stage of a multistage method for chemically reprogramming somatic cells to iPSCs (which also uses the same chemical cocktails as taught by Deng, see Graphical Abstract, first page), and because Deng and Zhao are the same research group, it could have been done with predictable results and a reasonable expectation of success.
Additionally, the resultant cells, appear to be monolayers of epithelial-like cells (Fig. 4C).
In regards to step (b) stage 2, as above, Deng teaches a medium comprising a chemical cocktail supplemented with CHIR99021 (a glycogen kinase inhibitor) and 616452 (RepSox, a TGFβ inhibitor) (Fig. 4C, claims 1-2, 26). As above, it would have been predictably obvious to supplement this chemical cocktail with a RAR agonist (such as AM580; see also stage 2 of Zhao, Graphical Abstract, first page).
Deng does not explicitly teach that the media was supplemented with a SMO agonist (which is well known in the art to activate Shh signaling). However, a person of ordinary skill in the art would have been motivated to add a SMO agonist (such as purmorphamine) because Moon teaches that activation of Shh by purmorphamine promotes reprogramming efficiency of fibroblasts (somatic cells) to iPSCs, and results in an intermediate cell type that expresses Sox2, Klf4, and N-Myc (Abstract, p1305; Fig. 5, p1313; which are noted are pluripotency related transcription factors). Furthermore, because Moon demonstrates that SHH (SMO) agonist purmorphamine, enhance reprogramming of fibroblasts with Oct4 (it is noted that the chemical cocktails of Deng or Zhao results in expression of Oct4 in intermediates (see Highlights, first page; Fig. 1, p1679), a person of ordinary skill in the art could have added a SMO/SHH agonist with predictable results and a reasonable expectation of success.
Deng also does not explicitly teach that the media was supplemented with a c-Jun inhibitor. However, a person of ordinary skill in the art would have been motivated to supplement the media with a c-Jun inhibitor (a JNK inhibitor such as SP600125) in order to promote a naïve pluripotency during reprogramming of cells as taught by Fang (Conversion Condition Optimization for Rhesus Monkey Naive iPSCs, p490; Fig. 1, p489). Furthermore, because Fang teaches that a JNK inhibitor such as SP600125 can be supplemented in media to promote naïve pluripotency during reprogramming, and since Deng and Fang are the same research group, it could have been done with predictable results and a reasonable expectation of success.
In regards to the difference between a Stage I and Stage II, Deng teaches that the media can be changed every 4 days (paragraphs [0127]). Therefore, the VC6TF media as taught by Deng, can refer to both Stage I or Stage II conditions.
In regards to step (c) stage III, Deng teaches a step comprising reprogramming cells with another medium comprising an HDAC inhibitor, a TGFβ inhibitor, and a SAH inhibitor (DZNep) (claim 21; paragraphs [0006-0007]; Fig. 4C; referred to as “VC6TFZ”).
In another step, Deng teaches that cells are reprogrammed with MAPK inhibitor PD0325901 (paragraph [0073]; Fig. 4C; as part of a “dual inhibitor” medium and referred to as “2i-medium”).
However, Applicant should note that according to MPEP § 2144.04, In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); in re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any mixing ingredients is prima facie obvious).
Indeed, since the claims and the method of Deng produce identical cells, the ordering does not appear critical.
It would have been predicably obvious to add a MAPK inhibitor because Deng teaches that this is suitable for maturation to chemically induced pluripotent stem cells (paragraph [0073]; Fig. 4C).
Additionally, as taught by Deng, these cocktails promote for expression of Oct4 (paragraphs [0152-0159]) and therefore, appear to have the same property of establishment of an initial pluripotency network as measured by Oct4 expression. It is noted that this clause has been interpreted as a property of cells if Oct4 is measured, not a specific step of measuring Oct4 expression.
In regards to (d) stage IV, as above, Deng teaches a final maturation step comprising reprogramming with MAPK inhibitor PD0325901 (paragraph [0073]; Fig. 4C; as part of a “dual inhibitor” medium).
While Deng does not explicitly teach that the medium comprises a B-RAF inhibitor, a person of ordinary skill in the art would have been motivated to add a B-RAF inhibitor (such as SB590885) because Lee teaches that it supports maintenance of a naïve pluripotent state, and therefore, allows for obtaining a global gene expression profile that most closely resembles the cells of human preimplantation embryos (Kinase inhibitors and the Naïve Primed Pluripotent State Transition, p4; Fig. 2, p5). Furthermore, because Lee teaches that a B-RAF inhibitor (such as SB590885) can be added to chemical cocktails for reprogramming somatic cells comprising MAPK inhibitor PD0325901 and CHIR99021 (the second dual inhibitor molecule as taught by Deng) (Kinase inhibitors and the Naïve Primed Pluripotent State Transition, p4; Fig. 2, p5), it could have been done with predictable results and a reasonable expectation of success.
Additionally, as taught by Deng, these cocktails promote for expression of Oct4, SOX2, and Nanog (paragraphs [0013, 0025, 0152-0159]) and therefore, appear to have the same property of establishment of a fully established pluripotency network as measured by Oct4, SOX2, and Nanog co-expression. It is noted that this clause has been interpreted as a property of cells if Oct4, SOX2, and Nanog were measured, not a specific step of measure these markers.
In regards to claim 2, Deng teaches that media can be supplemented with a Dot1L inhibitor such as EPZ004777 to induce pluripotency (paragraph 0056], claim 9). Thus, a person of ordinary skill in the art would have been motivated to include a Dot1L inhibitor in the Stage 1 condition in order to induce pluripotency. Furthermore, because Zhao demonstrates that EPZ004777 can be added to a first condition medium to boost reprogramming to intermediates (Graphical Abstract, first page; p1681), it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 3-6, in regards to the timings of the stages, Deng teaches that cells may initially be reprogrammed “VC6TF” medium for about 16-20 days (claim 24, Fig. 4C). As discussed above, this medium can refer to both stage I and stage 2 media (see paragraph [0127], media is changed every 4 days). Together this overlaps with a timing of 4-12 days in stage I conditions and 8-20 days in stage II conditions.
In regards to stage III conditions, Deng teaches that cells can be cultured in “VC6TFZ” (i.e., stage III) for the remaining time (claim 24, Fig. 4C), but that the medium should be switched to “2i-medium” (i.e., stage IV) between day 28 and day 48 (paragraph [0072; Fig. 4C). Therefore, taken together, the stage III of Deng may be performed for at least 8 days which overlaps with the claimed range.
In regards to stage IV conditions, Deng teaches that cells may be cultured in “2i-medium” (i.e., stage IV) from 4-20 days (paragraph [0011]) which overlaps with the claimed range.
In regards to claims 17-18, Deng teaches that the somatic cells can be skin fibroblasts (paragraph [0062]).
In regards to claim 26, Deng teaches that the cells can be derived from adipose-derived stem cells (paragraph [0010]), which are the same as adipose-derived mesenchymal stromal cells.
Therefore, the combined teachings of Deng, Zhao, Moon, Fang, and Lee renders the invention unpatentable as claimed.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (US20160145581A1, on IDS 04/10/2025) in view of Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019), as applied to claim 1 above, and further in view of Matthieu et al. (Cell Stem Cell, 2014).
In regards to claim 7, Deng does not teach that the cells were reprogrammed under 5% O2 hypoxic conditions. However, a person of ordinary skill in the art would have been motivated to reprogram cells under 5% hypoxic conditions because Matthieu teaches that 5% O2 enhances iPSCs generation (Introduction, p592-593; Fig. 2, p596).
Furthermore, because Matthieu teaches that cells can be effectively reprogrammed to iPSCs in 5% O2 (Cell Culture and Reprogramming, p602) and Deng and Matthieu are in the same technical field of generating iPSCs from somatic cells, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Deng, Zhao, Moon, Fang, Lee, and Matthieu renders the invention unpatentable as claimed.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (US20160145581A1, on IDS 04/10/2025) in view of Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019) as applied to claim 1 above, and further in view of Ihry et al. (US20210123016A1, priority to 05/01/2019).
In regards to claim 11, Deng does not explicitly teach a step of adding a ROCK inhibitor in the first step. However, a person of ordinary skill in the art would have been motivated to use a ROCK inhibitor (such as Y27632) because Ihry teaches that ROCK inhibitors (including Y27632) can be useful for preventing disassociation-induced death in iPSCs cultures and is beneficial for maintaining their viability (claims 1 and 17-18; paragraphs [0002, 0174, 0277]). Furthermore, because Ihry teaches that ROCK inhibitors including Y27632 can be added to cell media for preventing stem cell death (claims 1 and 17-18; paragraph [0002, 0174, 0277]), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Deng, Zhao, Moon, Fang, Lee, and Ihry renders the invention unpatentable as claimed.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (US20160145581A1, on IDS 04/10/2025) in view of Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019) as applied to claim 1 above, and further in view of Ichida et al. (US20120021519A1)
In regards to claim 12, Deng does not explicitly teach a step of adding an RTK inhibitor in the first step. However, a person of ordinary skill in the art would have been motivated to add an RTK inhibitor, because Ichida teaches that RTK inhibitors such as tyrphostin-derived inhibitors (of which AG1296, is a type) or PTK787 (Vatalanib) can be added to reprogramming methods in order to replace exogenous SOX or KLF4 (by inhibiting EGF signaling) requirements (paragraphs [0126, 1105, and 1188-1198]). Furthermore, because Ichida teaches that RTK inhibitors can be used for the reprogramming of cells and teaches examples of tyrphostin-derived inhibitors (of which AG1296 is a type) and PTK787 (Vatalanib), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Deng, Zhao, Moon, Fang, Lee and Ichida renders the invention unpatentable as claimed.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Deng et al. (US20160145581A1, on IDS 04/10/2025) in view of Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019) as applied to claims 1 and 2 above, and further in view of Wang et al. (Biology Open, 2019).
In regards to claim 27, it is noted that a Wnt inhibitor is optional in Stage IV in claim 2. Since claim 27 identifies that the Wnt inhibitor is selected from the group consisting of IWP-2, IWR-1 etc. and then optionally identifies other possible reagents, it is considered requires in claim 27.
Deng does not explicitly teach a Wnt inhibitor in Step IV.
However, a person of ordinary skill in the art would have been motivated to include a WNT inhibitor, such as IWR-1 because Wang teaches that inhibiting WNT (with IWR-1) enhances a substantial increase in more mature, homogeneous TRA-1-60+ colony formation at the middle to late reprogramming stage (Abstract; p1; Fig. 7, p9) and because the addition of IWR1 produced flat-shaped iPSC colonies that more morphologically resemble human ESCs than the other conditions (p5, left column)/ Furthermore, because Wang demonstrates that cells can be reprogrammed with WNT inhibitor IWR-1 (Human somatic cell reprogramming, p9-10), a person of ordinary skill in the art could have incorporated a WNT inhibitor, such as IWR1 into Step IV with predicable results and a reasonable expectation of success.
Therefore, the combined teachings of Deng, Zhao, Moon, Fang, Lee, and Wang renders the invention unpatentable as claimed.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8-10, and 13-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,982,237B2 in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019).
Claim 7 is rejected is on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,982,237B2 in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019) as applied to claim 1 above, and further in view of Matthieu et al. (Cell Stem Cell, 2014).
Claim 11 is rejected is on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,982,237B2 in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019) as applied to claim 1 above, and further in view of Ihry et al. (US20210123016A1, priority to 05/01/2019).
Claim 12 is rejected is on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,982,237B2 in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019) as applied to claim 1 above, and further in view of Ichida et al. (US20120021519A1).
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,982,237B2 in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019) as applied to claims 1 and 2 above and further in view of Wang et al. (Biology Open, 2019).
While the instant claims and the claims of the patent are not identical, they are not patentable distinct because they are both drawn to methods for chemically reprogramming somatic cells, which can be skin fibroblasts or mesenchymal adipose cells to induced pluripotent stem cells with chemical cocktails, including GSK inhibitors, TGFβ receptor inhibitors, SAH inhibitors, HDAC inhibitors, etc. over multiple stages.
In regards to the specifics of the stages, these are all embodiments as taught by Deng. As discussed above, Deng teaches methods for reprogramming human somatic cells to into human chemically induced pluripotent cells (hCiPSCs, or hereafter “PSCs” for simplicity) (Title, Abstract; paragraphs [0002-0005, 0062]; claims 1 and 13; Fig. 4C).
Deng teaches that this is a multi-stage method that uses differing chemical cocktails (Fig. 4C).
In regards to step (a) stage 1, Deng teaches that the somatic cells are cultured in a medium supplemented with the small molecules CHIR99021 (a glycogen kinase inhibitor) and 616452 (a TGFβ inhibitor) (Fig. 4C, claims 1-2, 26; referred to as “VC6TF”).
Deng also teaches that RAR agonists (including AM580) can be added in the media compositions to induced pluripotency (paragraph [0056]). A person of ordinary skill in the art would have been motivated to include a RAR agonist in the medium of step (a) stage 1 because Deng teaches that it improves pluripotency. They would be further motivated to add a RAR agonist such as AM580 because Zhao teaches that this improves formation of intermediates (p1681).
Furthermore, because Deng broadly teaches that compositions can be supplemented with a RAR agonist (such as AM580), because Zhao teaches that a RAR agonist can be added to the first stage of a multistage method for chemically reprogramming somatic cells to iPSCs (which also uses the same chemical cocktails as taught by Deng, see Graphical Abstract, first page), and because Deng and Zhao are the same research group, it could have been done with predictable results and a reasonable expectation of success.
Additionally, the resultant cells, appear to be monolayers of epithelial-like cells (Fig. 4C).
In regards to step (b) stage 2, as above, Deng teaches a medium comprising a chemical cocktail supplemented with CHIR99021 (a glycogen kinase inhibitor) and 616452 (RepSox, a TGFβ inhibitor) (Fig. 4C, claims 1-2, 26). As above, it would have been predictably obvious to supplement this chemical cocktail with a RAR agonist (such as AM580; see also stage 2 of Zhao, Graphical Abstract, first page).
Deng does not explicitly teach that the media was supplemented with a SMO agonist (which is well known in the art to activate Shh signaling). However, a person of ordinary skill in the art would have been motivated to add a SMO agonist (such as purmorphamine) because Moon teaches that activation of Shh by purmorphamine promotes reprogramming efficiency of fibroblasts (somatic cells) to iPSCs, and results in an intermediate cell type that expresses Sox2, Klf4, and N-Myc (Abstract, p1305; Fig. 5, p1313; which are noted are pluripotency related transcription factors). Furthermore, because Moon demonstrates that SHH (SMO) agonist purmorphamine, enhance reprogramming of fibroblasts with Oct4 (it is noted that the chemical cocktails of Deng or Zhao results in expression of Oct4 in intermediates (see Highlights, first page; Fig. 1, p1679), a person of ordinary skill in the art could have added a SMO/SHH agonist with predictable results and a reasonable expectation of success.
Deng also does not explicitly teach that the media was supplemented with a c-Jun inhibitor. However, a person of ordinary skill in the art would have been motivated to supplement the media with a c-Jun inhibitor (a JNK inhibitor such as SP600125) in order to promote a naïve pluripotency during reprogramming of cells as taught by Fang (Conversion Condition Optimization for Rhesus Monkey Naive iPSCs, p490; Fig. 1, p489). Furthermore, because Fang teaches that a JNK inhibitor such as SP600125 can be supplemented in media to promote naïve pluripotency during reprogramming, and since Deng and Fang are the same research group, it could have been done with predictable results and a reasonable expectation of success.
In regards to the difference between a Stage I and Stage II, Deng teaches that the media can be changed every 4 days (paragraphs [0127]). Therefore, the VC6TF media as taught by Deng, can refer to both Stage I and Stage II conditions.
In regards to step (c) stage III, Deng teaches a step comprising reprogramming cells with another medium comprising an HDAC inhibitor, a TGFβ inhibitor, and a SAH inhibitor (DZNep) (claim 21; paragraphs [0006-0007]; Fig. 4C; referred to as “VC6TFZ”).
In another step, Deng teaches that cells are reprogrammed with MAPK inhibitor PD0325901 (paragraph [0073]; Fig. 4C; as part of a “dual inhibitor” medium and referred to as “2i-medium”).
However, Applicant should note that according to MPEP § 2144.04, In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); in re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any mixing ingredients is prima facie obvious).
Indeed, since the claims and the method of Deng produce identical cells, the ordering does not appear critical.
It would have been predicably obvious to add a MAPK inhibitor because Deng teaches that this is suitable for maturation to chemically induced pluripotent stem cells (paragraph [0073]; Fig. 4C).
Additionally, as taught by Deng, these cocktails promote for expression of Oct4 (paragraphs [0152-0159]) and therefore, appear to have the same property of establishment of an initial pluripotency network as measured by Oct4 expression. It is noted that this clause has been interpreted as a property of cells if Oct4 is measured, not a specific step of measuring Oct4 expression.
In regards to (d) stage IV, as above, Deng teaches a final maturation step comprising reprogramming with MAPK inhibitor PD0325901 (paragraph [0073]; Fig. 4C; as part of a “dual inhibitor” medium).
While Deng does not explicitly teach that the medium comprises a B-RAF inhibitor, a person of ordinary skill in the art would have been motivated to add a B-RAF inhibitor (such as SB590885) because Lee teaches that it supports maintenance of a naïve pluripotent state, and therefore, allows for obtaining a global gene expression profile that most closely resembles the cells of human preimplantation embryos (Kinase inhibitors and the Naïve Primed Pluripotent State Transition, p4; Fig. 2, p5). Furthermore, because Lee teaches that a B-RAF inhibitor (such as SB590885) can be added to chemical cocktails for reprogramming somatic cells comprising MAPK inhibitor PD0325901 and CHIR99021 (the second dual inhibitor molecule as taught by Deng) (Kinase inhibitors and the Naïve Primed Pluripotent State Transition, p4; Fig. 2, p5), it could have been done with predictable results and a reasonable expectation of success.
Additionally, as taught by Deng, these cocktails promote for expression of Oct4, SOX2, and Nanog (paragraphs [0013, 0025, 0152-0159]) and therefore, appear to have the same property of establishment of a fully established pluripotency network as measured by Oct4, SOX2, and Nanog co-expression. It is noted that this clause has been interpreted as a property of cells if Oct4, SOX2, and Nanog were measured, not a specific step of measure these markers.
In regards to claim 2, Deng teaches that media can be supplemented with a Dot1L inhibitor such as EPZ004777 to induce pluripotency (paragraph 0056], claim 9). Thus, a person of ordinary skill in the art would have been motivated to include a Dot1L inhibitor in the Stage 1 condition in order to induce pluripotency. Furthermore, because Zhao demonstrates that EPZ004777 can be added to a first condition medium to boost reprogramming to intermediates (Graphical Abstract, first page; p1681), it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 3-6, in regards to the timings of the stages, Deng teaches that cells may initially be reprogrammed “VC6TF” medium for about 16-20 days (claim 24, Fig. 4C). As discussed above, this medium can refer to both stage I and stage 2 media (see paragraph [0127], media is changed every 4 days). Together this overlaps with a timing of 4-12 days in stage I conditions and 8-20 days in stage II conditions.
In regards to stage III conditions, Deng teaches that cells can be cultured in “VC6TFZ” (i.e., stage III) for the remaining time (claim 24, Fig. 4C), but that the medium should be switched to “2i-medium” (i.e., stage IV) between day 28 and day 48 (paragraph [0072; Fig. 4C). Therefore, taken together, the stage III of Deng may be performed for at least 8 days which overlaps with the claimed range.
In regards to stage IV conditions, Deng teaches that cells may be cultured in “2i-medium” (i.e., stage IV) from 4-20 days (paragraph [0011]) which overlaps with the claimed range.
In regards to claims 17-18, Deng teaches that the somatic cells can be skin fibroblasts (paragraph [0062]).
In regards to claim 7, a person of ordinary skill in the art would have been motivated to reprogram cells under 5% hypoxic conditions because Matthieu teaches that 5% O2 enhances iPSCs generation (Introduction, p592-593; Fig. 2, p596).
Furthermore, because Matthieu teaches that cells can be effectively reprogrammed to iPSCs in 5% O2 (Cell Culture and Reprogramming, p602), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 11, a person of ordinary skill in the art would have been motivated to use a ROCK inhibitor (such as Y27632) because Ihry teaches that ROCK inhibitors (including Y27632) can be useful for preventing disassociation-induced death in iPSCs cultures and is beneficial for maintaining their viability (claims 1 and 17-18; paragraphs [0002, 0174, 0277]). Furthermore, because Ihry teaches that ROCK inhibitors including Y27632 can be added to cell media for preventing stem cell death (claims 1 and 17-18; paragraph [0002, 0174, 0277]), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 12, a person of ordinary skill in the art would have been motivated to add an RTK inhibitor, because Ichida teaches that RTK inhibitors such as tyrphostin-derived inhibitors (of which AG1296, is a type) or PTK787 (Vatalanib) can be added to reprogramming methods in order to replace exogenous SOX or KLF4 (by inhibiting EGF signaling) requirements (paragraphs [0126, 1105, and 1188-1198]). Furthermore, because Ichida teaches that RTK inhibitors can be used for the reprogramming of cells and teaches examples of tyrphostin-derived inhibitors (of which AG1296 is a type) and PTK787 (Vatalanib), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 27, a person of ordinary skill in the art would have been motivated to include a WNT inhibitor, such as IWR-1 because Wang teaches that inhibiting WNT (with IWR-1) enhances a substantial increase in more mature, homogeneous TRA-1-60+ colony formation at the middle to late reprogramming stage (Abstract; p1; Fig. 7, p9) and because the addition of IWR1 produced flat-shaped iPSC colonies that more morphologically resemble human ESCs than the other conditions (p5, left column)/ Furthermore, because Wang demonstrates that cells can be reprogrammed with WNT inhibitor IWR-1 (Human somatic cell reprogramming, p9-10), a person of ordinary skill in the art could have incorporated a WNT inhibitor, such as IWR1 into Step IV with predicable results and a reasonable expectation of success.
Claims 1-6, 8-10, 13-19, and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 20-25 of co-pending application No. 19/174, 084 in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), and Fang et al. (Cell Stem Cell, 2014).
Claim 7 is rejected is on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 20-25 of co-pending application No. 19/174, 084 in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), and Fang et al. (Cell Stem Cell, 2014) as applied to claim 1 above, and further in view of Matthieu et al. (Cell Stem Cell, 2014).
Claim 12 is rejected is on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 and 20-25 of co-pending application No. 19/174, 084in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), and Fang et al. (Cell Stem Cell, 2014) as applied to claim 1 above, and further in view of Ichida et al. (US20120021519A1).
Claim 27 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 9,982,237B2 in view of Deng et al. (US20160145581A1, on IDS 04/10/2025), Zhao et al. (Cell, 2015, on IDS 10/03/2023), Moon et al. (Cell Research, 2011), Fang et al. (Cell Stem Cell, 2014), and Lee et al. (Stem Cells International, 2019) as applied to claims 1 and 2 above and further in view of Wang et al. (Biology Open, 2019).
While the instant claims and the claims of the patent are not identical, they are not patentable distinct because they are both drawn to methods for chemically reprogramming somatic cells, which can be skin fibroblasts to induced pluripotent stem cells with chemical cocktails, including GSK inhibitors, TGFβ receptor inhibitors, SAH inhibitors, HDAC inhibitors, ROCK inhibitors etc. over multiple stages.
In regards to the specifics of the stages, these are all embodiments as taught by Deng. As discussed above, Deng teaches methods for reprogramming human somatic cells to into human chemically induced pluripotent cells (hCiPSCs, or hereafter “PSCs” for simplicity) (Title, Abstract; paragraphs [0002-0005, 0062]; claims 1 and 13; Fig. 4C).
Deng teaches that this is a multi-stage method that uses differing chemical cocktails (Fig. 4C).
In regards to step (a) stage 1, Deng teaches that the somatic cells are cultured in a medium supplemented with the small molecules CHIR99021 (a glycogen kinase inhibitor) and 616452 (a TGFβ inhibitor) (Fig. 4C, claims 1-2, 26; referred to as “VC6TF”).
Deng also teaches that RAR agonists (including AM580) can be added in the media compositions to induced pluripotency (paragraph [0056]). A person of ordinary skill in the art would have been motivated to include a RAR agonist in the medium of step (a) stage 1 because Deng teaches that it improves pluripotency. They would be further motivated to add a RAR agonist such as AM580 because Zhao teaches that this improves formation of intermediates (p1681).
Furthermore, because Deng broadly teaches that compositions can be supplemented with a RAR agonist (such as AM580), because Zhao teaches that a RAR agonist can be added to the first stage of a multistage method for chemically reprogramming somatic cells to iPSCs (which also uses the same chemical cocktails as taught by Deng, see Graphical Abstract, first page), and because Deng and Zhao are the same research group, it could have been done with predictable results and a reasonable expectation of success.
Additionally, the resultant cells, appear to be monolayers of epithelial-like cells (Fig. 4C).
In regards to step (b) stage 2, as above, Deng teaches a medium comprising a chemical cocktail supplemented with CHIR99021 (a glycogen kinase inhibitor) and 616452 (RepSox, a TGFβ inhibitor) (Fig. 4C, claims 1-2, 26). As above, it would have been predictably obvious to supplement this chemical cocktail with a RAR agonist (such as AM580; see also stage 2 of Zhao, Graphical Abstract, first page).
Deng does not explicitly teach that the media was supplemented with a SMO agonist (which is well known in the art to activate Shh signaling). However, a person of ordinary skill in the art would have been motivated to add a SMO agonist (such as purmorphamine) because Moon teaches that activation of Shh by purmorphamine promotes reprogramming efficiency of fibroblasts (somatic cells) to iPSCs, and results in an intermediate cell type that expresses Sox2, Klf4, and N-Myc (Abstract, p1305; Fig. 5, p1313; which are noted are pluripotency related transcription factors). Furthermore, because Moon demonstrates that SHH (SMO) agonist purmorphamine, enhance reprogramming of fibroblasts with Oct4 (it is noted that the chemical cocktails of Deng or Zhao results in expression of Oct4 in intermediates (see Highlights, first page; Fig. 1, p1679), a person of ordinary skill in the art could have added a SMO/SHH agonist with predictable results and a reasonable expectation of success.
Deng also does not explicitly teach that the media was supplemented with a c-Jun inhibitor. However, a person of ordinary skill in the art would have been motivated to supplement the media with a c-Jun inhibitor (a JNK inhibitor such as SP600125) in order to promote a naïve pluripotency during reprogramming of cells as taught by Fang (Conversion Condition Optimization for Rhesus Monkey Naive iPSCs, p490; Fig. 1, p489). Furthermore, because Fang teaches that a JNK inhibitor such as SP600125 can be supplemented in media to promote naïve pluripotency during reprogramming, and since Deng and Fang are the same research group, it could have been done with predictable results and a reasonable expectation of success.
In regards to the difference between a Stage I and Stage II, Deng teaches that the media can be changed every 4 days (paragraphs [0127]). Therefore, the VC6TF media as taught by Deng, can refer to both Stage I and Stage II conditions.
In regards to step (c) stage III, Deng teaches a step comprising reprogramming cells with another medium comprising an HDAC inhibitor, a TGFβ inhibitor, and a SAH inhibitor (DZNep) (claim 21; paragraphs [0006-0007]; Fig. 4C; referred to as “VC6TFZ”).
In another step, Deng teaches that cells are reprogrammed with MAPK inhibitor PD0325901 (paragraph [0073]; Fig. 4C; as part of a “dual inhibitor” medium and referred to as “2i-medium”).
However, Applicant should note that according to MPEP § 2144.04, In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); in re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any mixing ingredients is prima facie obvious).
Indeed, since the claims and the method of Deng produce identical cells, the ordering does not appear critical.
It would have been predicably obvious to add a MAPK inhibitor because Deng teaches that this is suitable for maturation to chemically induced pluripotent stem cells (paragraph [0073]; Fig. 4C).
Additionally, as taught by Deng, these cocktails promote for expression of Oct4 (paragraphs [0152-0159]) and therefore, appear to have the same property of establishment of an initial pluripotency network as measured by Oct4 expression. It is noted that this clause has been interpreted as a property of cells if Oct4 is measured, not a specific step of measuring Oct4 expression.
In regards to (d) stage IV, as above, Deng teaches a final maturation step comprising reprogramming with MAPK inhibitor PD0325901 (paragraph [0073]; Fig. 4C; as part of a “dual inhibitor” medium).
While Deng does not explicitly teach that the medium comprises a B-RAF inhibitor, a person of ordinary skill in the art would have been motivated to add a B-RAF inhibitor (such as SB590885) because Lee teaches that it supports maintenance of a naïve pluripotent state, and therefore, allows for obtaining a global gene expression profile that most closely resembles the cells of human preimplantation embryos (Kinase inhibitors and the Naïve Primed Pluripotent State Transition, p4; Fig. 2, p5). Furthermore, because Lee teaches that a B-RAF inhibitor (such as SB590885) can be added to chemical cocktails for reprogramming somatic cells comprising MAPK inhibitor PD0325901 and CHIR99021 (the second dual inhibitor molecule as taught by Deng) (Kinase inhibitors and the Naïve Primed Pluripotent State Transition, p4; Fig. 2, p5), it could have been done with predictable results and a reasonable expectation of success.
Additionally, as taught by Deng, these cocktails promote for expression of Oct4, SOX2, and Nanog (paragraphs [0013, 0025, 0152-0159]) and therefore, appear to have the same property of establishment of a fully established pluripotency network as measured by Oct4, SOX2, and Nanog co-expression. It is noted that this clause has been interpreted as a property of cells if Oct4, SOX2, and Nanog were measured, not a specific step of measure these markers.
In regards to claim 2, Deng teaches that media can be supplemented with a Dot1L inhibitor such as EPZ004777 to induce pluripotency (paragraph 0056], claim 9). Thus, a person of ordinary skill in the art would have been motivated to include a Dot1L inhibitor in the Stage 1 condition in order to induce pluripotency. Furthermore, because Zhao demonstrates that EPZ004777 can be added to a first condition medium to boost reprogramming to intermediates (Graphical Abstract, first page; p1681), it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 3-6, in regards to the timings of the stages, Deng teaches that cells may initially be reprogrammed “VC6TF” medium for about 16-20 days (claim 24, Fig. 4C). As discussed above, this medium can refer to both stage I and stage 2 media (see paragraph [0127], media is changed every 4 days). Together this overlaps with a timing of 4-12 days in stage I conditions and 8-20 days in stage II conditions.
In regards to stage III conditions, Deng teaches that cells can be cultured in “VC6TFZ” (i.e., stage III) for the remaining time (claim 24, Fig. 4C), but that the medium should be switched to “2i-medium” (i.e., stage IV) between day 28 and day 48 (paragraph [0072; Fig. 4C). Therefore, taken together, the stage III of Deng may be performed for at least 8 days which overlaps with the claimed range.
In regards to stage IV conditions, Deng teaches that cells may be cultured in “2i-medium” (i.e., stage IV) from 4-20 days (paragraph [0011]) which overlaps with the claimed range.
In regards to claims 17-18 and 26, Deng teaches that the somatic cells can be skin fibroblasts (paragraph [0062]) or adipose-derived mesenchymal stromal cells (paragraph [0010]).
In regards to claim 7, a person of ordinary skill in the art would have been motivated to reprogram cells under 5% hypoxic conditions because Matthieu teaches that 5% O2 enhances iPSCs generation (Introduction, p592-593; Fig. 2, p596).
Furthermore, because Matthieu teaches that cells can be effectively reprogrammed to iPSCs in 5% O2 (Cell Culture and Reprogramming, p602), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 12, a person of ordinary skill in the art would have been motivated to add an RTK inhibitor, because Ichida teaches that RTK inhibitors such as tyrphostin-derived inhibitors (of which AG1296, is a type) or PTK787 (Vatalanib) can be added to reprogramming methods in order to replace exogenous SOX or KLF4 (by inhibiting EGF signaling) requirements (paragraphs [0126, 1105, and 1188-1198]). Furthermore, because Ichida teaches that RTK inhibitors can be used for the reprogramming of cells and teaches examples of tyrphostin-derived inhibitors (of which AG1296 is a type) and PTK787 (Vatalanib), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 27, it is noted that a Wnt inhibitor is optional in Stage IV in claim 2. Since claim 27 identifies that the Wnt inhibitor is selected from the group consisting of IWP-2, IWR-1 etc. and then optionally identifies other possible reagents, it is considered requires in claim 27.
Deng does not explicitly teach a Wnt inhibitor in Step IV.
However, a person of ordinary skill in the art would have been motivated to include a WNT inhibitor, such as IWR-1 because Wang teaches that inhibiting WNT (with IWR-1) enhances a substantial increase in more mature, homogeneous TRA-1-60+ colony formation at the middle to late reprogramming stage (Abstract; p1; Fig. 7, p9) and because the addition of IWR1 produced flat-shaped iPSC colonies that more morphologically resemble human ESCs than the other conditions (p5, left column)/ Furthermore, because Wang demonstrates that cells can be reprogrammed with WNT inhibitor IWR-1 (Human somatic cell reprogramming, p9-10), a person of ordinary skill in the art could have incorporated a WNT inhibitor, such as IWR1 into Step IV with predicable results and a reasonable expectation of success.
Response to Arguments
Applicant argues that the prior art is directed to non-human cells while the instant invention is drawn to human cells (Remarks, p11). Specifically, Applicant argues the prior induction protocols are based on mouse somatic cells, but that mouse and human cells are fundamentally different in their epigenic stability and resistance to external stimuli (Remarks, p11-12; citing paragraph [0048] of the instant specification “because of their committed cell identities and stable epigenomes, human somatic cells resist external perturbations to modulate their plasticity to unrestricted potency . . .” and paragraph [0175], “To induce human fibroblasts into pluripotent stem cells by small molecules, a previously disclosed chemical cocktail which successfully induced the mouse pluripotency (7-10) was first tested on human embryonic fibroblasts (HEFs). However, those HEFs proliferated poorly and showed apoptotic phenotypes after the treatment . . . human cells, compared to mouse cells, were more refractory to exogenous signals”).
Applicant argues that Deng does not reduce to practice human cells (Remarks, p14).
Regarding the art specifically (Lee), Applicant argues that Lee acknowledges that “The chemical compounds VC6T can generate iPSCs from mouse and human somatic cells only with exogenous Oct4 factor” and “Untol now, CiPSCs can be generated from mouse cells such as adult neonatal fibroblasts, and adipose-derived stem cells, but not from human somatic cells.” Thus, as argued by Applicant, Lee expressly teaches away from the success of chemical reprogramming in human somatic cells without exogenous transcription factor (Remarks, p12).
Applicant argues that Zhao and Moon are directed to mouse not human cells (Remarks, p14-15).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive.
As discussed above, Deng explicitly teaches that the cells can be human cells (paragraph [0062], “The induced pluripotent stem cells are obtained by inducing partially or completely differentiated cells obtained from . . . preferably a human”).
Regarding Applicant’s arguments concerning human and mouse cells, these amount to assertions without evidence and the claims do not identify any different characteristics between human and mouse cells beyond being limited to human cells. Additionally, as above, Deng preferably uses human cells.
Regarding arguments regarding embodiments of Deng, see MPEP 2123, “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) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
Additionally, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component).
Again, as above, a human cells is a preferred embodiment as taught by Deng.
Regarding the secondary references, in response to applicant's argument that mouse cells are used, 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).
Again, as above, Deng preferably uses human cells, and as above, Applicant’s arguments regarding differences between human and mouse cells are assertions without evidence.
Applicant argues unexpected results (Remarks, p12-13; citing Tables 4 and 8; Figs. 6 and 7).
Applicant argues the combination of molecules in stage I demonstrate synergistic effects (Remarks, p15, citing paragraph [0185]; “The studies showed in stage I, removing CHIR99021, 6161452 or TTNPB severely reduced LIN28A activation and inhibited the downregulation of the somatic program (FIG. 4A and FIG. 15A-C) . . . (Fig. 4I)”).
Applicant argues that in stage II, the five compounds produces a synergistic effect (Remarks, p16; citing paragraph [0185], “In stage II, JNKIN8 is required for the activation of SALL4 (FIG. 4C and FIG. 16A-C) . . . (Fig. 4B and D)”).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive.
In regards to Applicant’s allegations of unexpected results, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (see MPEP 716.02(d)).
In the instant case, the claims do not require any specific result.
Regarding stage I, Applicant argues that Deng does not teach the three molecule combination, but only teaches two stages with optional “boosters” for improving efficiency, not as core components (Remarks, p13).
Specifically, Applicant argues Deng does not teach combining a GSK inhibitor, TGFbeta inhibitor, and a RAR agonist as essential first step components (Remarks. P13).
Applicant argues that Deng’s essential components are different (a GSK inhibitor, TGFbeta inhibitor, and a cAMP agonist), and therefore, a POSITA would have no motivation to replace cAMP with a RAR agonist or add a RAR agonist (Remarks, p14). Applicant argues that the Office’s assertion that a POSITA would simply add a RAR agonist ignores Deng’s clear teaching that forskolin is essential (Remarks, p14).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive.
Regarding the three small molecules of step I, as discussed above, Deng teaches that the somatic cells are cultured in a medium supplemented with the small molecules CHIR99021 (a glycogen kinase inhibitor) and 616452 (a TGFβ inhibitor) (Fig. 4C, claims 1-2, 26; referred to as “VC6TF”).
Deng also teaches that RAR agonists (including AM580) can be added in the media compositions to induced pluripotency (paragraph [0056]). A person of ordinary skill in the art would have been motivated to include a RAR agonist in the medium of step (a) stage 1 because Deng teaches that it improves pluripotency. They would be further motivated to add a RAR agonist such as AM580 because Zhao teaches that this improves formation of intermediates (p1681).
Furthermore, because Deng broadly teaches that compositions can be supplemented with a RAR agonist (such as AM580), because Zhao teaches that a RAR agonist can be added to the first stage of a multistage method for chemically reprogramming somatic cells to iPSCs (which also uses the same chemical cocktails as taught by Deng, see Graphical Abstract, first page), and because Deng and Zhao are the same research group, it could have been done with predictable results and a reasonable expectation of success.
Additionally, regarding Applicant’s argument that forskolin is essential to the method of Deng, the claims are open-ended, do not disallow forskolin, and therefore, whether the method of Deng uses forskolin is not germane to the claims as limited.
Regarding stage I, regarding Zhao specifically, Applicant argues that the fact that Deng and Zhao are part of the same research group does not provide a motivation to combine (Remarks, p14).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive.
The fact that Deng and Zhao are the same research group is not relied upon to provide a motivation to combine, but rather to demonstrate predictability.
As discussed above, Deng also teaches that RAR agonists (including AM580) can be added in the media compositions to induced pluripotency (paragraph [0056]). A person of ordinary skill in the art would have been motivated to include a RAR agonist in the medium of step (a) stage 1 because Deng teaches that it improves pluripotency. They would be further motivated to add a RAR agonist such as AM580 because Zhao teaches that this improves formation of intermediates (p1681).
Furthermore, because Deng broadly teaches that compositions can be supplemented with a RAR agonist (such as AM580), because Zhao teaches that a RAR agonist can be added to the first stage of a multistage method for chemically reprogramming somatic cells to iPSCs (which also uses the same chemical cocktails as taught by Deng, see Graphical Abstract, first page), and because Deng and Zhao are the same research group, it could have been done with predictable results and a reasonable expectation of success.
Regarding stage II, regarding Moon, Applicant argues that Moon is directed to a fundamentally different reprogramming pathway (specifically Bmi1-mediated transdifferentiaiton; Remarks, p16). Specifically, Applicant argues that Moon’s mechanism relies on the expression of Oct4 whereas SHH activation (by purmorphamine) is used for transdifferentiating mouse fibroblasts into NSC-like cells, but does not teach adding a SHH activator to a chemical reprogramming medium (Remarks, p15).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive.
As discussed above, a person of ordinary skill in the art would have been motivated to add a SMO agonist (such as purmorphamine) because Moon teaches that activation of Shh by purmorphamine promotes reprogramming efficiency of fibroblasts (somatic cells) to iPSCs, and results in an intermediate cell type that expresses Sox2, Klf4, and N-Myc (Abstract, p1305; Fig. 5, p1313; which are noted are pluripotency related transcription factors). Furthermore, because Moon demonstrates that SHH (SMO) agonist purmorphamine, enhance reprogramming of fibroblasts with Oct4 (it is noted that the chemical cocktails of Deng or Zhao results in expression of Oct4 in intermediates (see Highlights, first page; Fig. 1, p1679), a person of ordinary skill in the art could have added a SMO/SHH agonist with predictable results and a reasonable expectation of success.
Regarding Applicant’s arguments that the Moon activates SHH with purmorphamine for different purposes, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding stage II, regarding Fang, Applicant argues that Fang teaches using a JNK inhibitor in a medium of already established iPSC lines, with its role to prime iPSCs into naïve iPSCs, but does not teach using a c-Jun kinase inhibitor in the initial reprogramming of somatic cells (Remarks, p16).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive.
As discussed above, a person of ordinary skill in the art would have been motivated to supplement the media with a c-Jun inhibitor (a JNK inhibitor such as SP600125) in order to promote a naïve pluripotency during reprogramming of cells as taught by Fang (Conversion Condition Optimization for Rhesus Monkey Naive iPSCs, p490; Fig. 1, p489). Furthermore, because Fang teaches that a JNK inhibitor such as SP600125 can be supplemented in media to promote naïve pluripotency during reprogramming, and since Deng and Fang are the same research group, it could have been done with predictable results and a reasonable expectation of success.
Regarding Applicant’s arguments that Fang teaches using a JNK inhibitor in a medium of already established iPSC lines, again, In response to applicant's argument that, 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).
As above, it would have been prima facie obvious to incorporate a JNK inhibitor such as SP600125 in order to promote naïve pluripotency during reprogramming.
Regarding Stage III, Applicant argues that Deng does not teach the claimed five-molecule combination and Deng’s VC6TFZ does not contain a MAPK inhibitor (Remarks, p17). Specifically, Applicant argues the MAPK inhibitor used by Deng (PS0325901) is used only in the 2i medium after reprogramming is complete, and therefore, the MAPK inhibitor is used for maturation and maintenance (Remarks, p17).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive.
As above, in regards to step (c) stage III, Deng teaches a step comprising reprogramming cells with another medium comprising an HDAC inhibitor, a TGFβ inhibitor, and a SAH inhibitor (DZNep) (claim 21; paragraphs [0006-0007]; Fig. 4C; referred to as “VC6TFZ”).
In another step, Deng teaches that cells are reprogrammed with MAPK inhibitor PD0325901 (paragraph [0073]; Fig. 4C; as part of a “dual inhibitor” medium and referred to as “2i-medium”).
However, Applicant should note that according to MPEP § 2144.04, In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); in re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any mixing ingredients is prima facie obvious).
Indeed, since the claims and the method of Deng produce identical cells, the ordering does not appear critical.
It would have been predicably obvious to add a MAPK inhibitor because Deng teaches that this is suitable for maturation to chemically induced pluripotent stem cells (paragraph [0073]; Fig. 4C).
Additionally, as taught by Deng, these cocktails promote for expression of Oct4 (paragraphs [0152-0159]) and therefore, appear to have the same property of establishment of an initial pluripotency network as measured by Oct4 expression. It is noted that this clause has been interpreted as a property of cells if Oct4 is measured, not a specific step of measuring Oct4 expression.
Applicant argues that the references documents are directed to different stages, that there is no motivation to combine them, and therefore, could only have been pieces together with hindsight reasoning (Remarks, p17).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive.
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 argues that the rejections of claims 7 and 11-12 under 35 USC 103 should be withdraw (Remarks, p18-19).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive because the teachings of Deng et al., are not deficient for the reasons discussed above.
Applicant argues that the double-patenting rejections should be withdrawn (Remarks, p19).
Applicant’s arguments filed 09/11/2026 have been fully considered but are not found persuasive because the teachings of Deng et al., are not deficient for the reasons discussed above, and therefore, the double-patenting rejections have been maintained as discussed above.
Conclusion
No claims are 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 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 JOSEPH (PAUL) MIANO whose telephone number is (571)272-0341. The examiner can normally be reached Mon-Fri from 8:30am to 5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
