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 .
Election/Restriction
Claims 1-25 are pending.
Claims 1 and 24 are newly amended.
Applicant's election with traverse of Group I, claims 1-19 drawn to the method claims in the reply filed on 04/24/2026 is acknowledged. The traversal is on the ground(s) that claim 24 is now amended to require the method of claim 1 , that the prior art does not teach the combination of small molecules in stages I-IV as claimed, and therefore, the feature is a special technical features, and as a result, the claims do not lack unity of invention under PCT Rule 13.1 (Remarks, p9-10).
This is not found persuasive because the combination of small molecules in stages I-IV is prima facie obvious 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) as discussed in depth below.
Therefore, the technical feature is not a specifical technical features, and the requirement is still deemed proper and is therefore made FINAL.
Claims 20-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 have been examined on their merits.
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 8 is objected to for the following informalities: claim 8 redundantly recites “CHIR99021” and “CHIR 99021”. Removing one of the instances of this chemical would be ameliorative.
Claim 12 is objected to for the following informalities: claim 12 recites “Valatanib” which is a misspelling of “Vatalanib.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 11-12 and 17-19 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.
Claim 11, recites, “The method of claim 1, wherein the inhibitor of [ROCK].” There is insufficient antecedent basis for this limitation in the claim, as claim 1 does not require a ROCK inhibitor. For compact prosecution, claim 11 has been interpreted as an additional component that may be added to any of the stages in claim 1.
Claim 12, recites, “The method of claim 1, wherein the receptor tyrosine kinase inhibitor.” There is insufficient antecedent basis for this limitation in the claim, as claim 1 does not require a receptor tyrosine kinase inhibitor. For compact prosecution, claim 12 has been interpreted as an additional component that may be added to any of the stages in claim 1.
Claim 17 recites, “(for example, hepatocytes)”, which is exemplary and renders the claim indefinite because it is unclear whether the limitation is part of the claimed invention. See MPEP § 2173.05(d). For compact prosecution, hepatocytes have been interpreted as optional.
Claim 18 recites, “(for example, adipocytes)”, which is exemplary and renders the claim indefinite because it is unclear whether the limitation is part of the claimed invention. See MPEP § 2173.05(d). For compact prosecution, adipocytes have been interpreted as optional.
Claim 19, recites, “The method of claim 1, wherein, when present . . . the Wnt inhibitor.” There is insufficient antecedent basis for this limitation in the claim, as claim 1 does not require or provide the option for a receptor Wnt. For compact prosecution, since the claim states “when present”, the Wnt inhibitor has been interpreted as an additional optional component that may be added to any of the stages in claim 1.
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, and 13-19 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]).
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.
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).
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, 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.
Claims 1-6, 8-10, and 13-19 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).
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, 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 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.
Conclusion
No claims are allowed.
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