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 .
1. Claims 1 – 4, 6 – 10, 20, and 23 – 32 are pending.
Election/Restrictions
2. Applicant's election with traverse of Group I (claims 1 – 10 and 20) and the MAPK inhibitor is a chemical inhibitor and the TGF pathway inhibitor is a chemical inhibitor and the BMP inhibitor is a chemical inhibitor in the reply filed on 10/08/2025 is acknowledged.
3. New claims 24, 25, 27, 28, 30, and 31 are withdrawn from consideration as they do not recite the elected species of “chemical inhibitor”. Only the elected species of “chemical inhibitor” is examined in claims 23, 26, and 29.
4. Claims 1 – 4, 6 – 10, 20, 23, 26, 29, and 32 are under consideration.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 04/08/2026 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Specification Objection
6. The objection to the specification is withdrawn in view of Applicant’s amendment to delete the embedded hyperlink.
Withdrawn Claim Objections
7. The objection to claim 1 is withdrawn in view of Applicant’s amendment to the claim.
8. The objection to claim 5 is rendered moot in view of Applicant’s cancellation of the claim.
9. The objection to claim 20 is withdrawn in view of Applicant’s amendment to the claim.
Withdrawn Improper Markush Grouping Rejection
10. The rejection of claims 7 – 9 on the basis that it contains an improper Markush grouping of alternatives is withdrawn in view of Applicant’s amendment to the claims.
Withdrawn Claim Rejections
11. The rejection of claim 5 under 35 U.S.C. 102(a)(1) is rendered moot in view of Applicant’s cancellation of the claim.
Claim Interpretation
12. For the purpose of applying prior art, “amniotic-like epithelial cells” of claim 1 is interpreted as cells having one or more of the following characteristics: the cells are flat squamous epithelial cells; the cells from a continuous layer of cells (an epithelium); and/or the cells express one or more marker associated with amniotic epithelial cells such as CDH1, CDX2, HAND1, TFAP2C, TFAP2A, GATA2, GATA3 as disclosed in Applicant’s specification at page 10, lines 27 – 32.
13. For the purpose of applying prior art, “naïve pluripotent stem cells” of claim 4 is interpreted a pluripotent stem cell that can undergo differentiation into any of the three germ layers and “primed pluripotent stem cells” of claim 4 is interpreted as a capacitated naïve pluripotent stem cell by treatment with an inhibitor of Wnt signaling as disclosed in Applicant’s specification at page 13, lines 4 - 25.
Maintained Claim Rejections and New Claims 23, 26, and 32 Rejection - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
14. Claim(s) 1, 4, 7, 8, and 20 remain rejected and new claims 23, 26, and 32 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wei (Wei, Yanxing, et al. Placenta 51 (2017): 28-37; previously cited), hereinafter Wei. Although maintained, the rejection is revised in view of Applicant’s amendment to claim 1, cancellation of claim 5, and new claims 23, 26, and 32.
Claim 1 is drawn to a method for differentiating pluripotent stem cell into amniotic-like epithelial cells, said method comprising: culturing the pluripotent stem cells with an inhibitor of the MAPK pathway and an inhibitor of the TGF pathway to produce the amniotic-like epithelial cells,
wherein the pluripotent stem cells are not primed pluripotent stem cells.
Regarding claims 1, 7, and 8, Wei teaches a method of culturing induced pluripotent stem cells (iPSCs; “pluripotent stem cells” of claim 1) with PD173074 (“an inhibitor of the MAPK pathway” of claim 1 and “receptor tyrosine kinases” of claim 7 and “chemical inhibitor” of claim 23 and “the inhibitor of the MAPK pathway is a chemical inhibitor” of claim 32) and A83-01 (“an inhibitor of the TGF pathway” of claim 1 and “TGF beta type I receptor” of claim 8 and “chemical inhibitor” of claim 26 and “the inhibitor of the TGF pathway is a chemical inhibitor” of claim 32) and the resulting cells expressed CDX2 and had epithelial morphology (page 29, right col. para. 1; page 33, right col. last para.; page 34, left col. para. 1; Figure 3A – C; page 34, right col. para. 4 – 5). Wei teaches the iPSCs generated teratomas containing three germ layers when injected into mice (“pluripotent stem cells in a naïve state” of claim 4 and “not a primed pluripotent stem cell” of claim 1) (page 33, left col. para. 4; Figure 2E).
Regarding claim 20, Wei teaches the iPSCs were derived from villous and amniotic cells taken from pregnant women (page 29, left col. para. 2 – 3).
Therefore, Wei anticipates claims 1, 4, 7, 8, 20, 23, 26 and 32.
Maintained Claim Rejections and New Claim 29 Rejection - 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.
15. Claim(s) 1 – 4, 7, 8, and 20 remain rejected and new claims 23, 26, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Wei (Wei, Yanxing, et al. Placenta 51 (2017): 28-37; previously cited), hereinafter Wei in view of Ezashi (Ezashi, Toshihiko, et al. Biology of reproduction 85.4 (2011): 779-787; previously cited), hereinafter Ezashi. Although maintained, the rejection is revised in view of Applicant’s cancellation claim 5 and new claims 23, 26, and 32.
Wei anticipates claims 1, 4, 7, 8, 10, 20, 23, 26, and 32 as set forth above. Wei does not anticipate the amniotic-like epithelial cells from a continuous layer of claim 2 that forms a membrane or 3D structure of claim 3 or culturing pluripotent stem cells in suspension of claim 10. However, Wei teaches culturing iPSCs under 20% oxygen conditions for 9 days in medium containing A8301 and PD173074 prior to subculturing in medium without A8301 and PD173074 (Figure 5A; page 29, right col. para. 1; page 33, right col. last para.; page 34, left col. para. 4). Wei teaches iPSC differentiation most likely occurred through a trophoblastic stem cell stage (page 34, right col. last para.). Wei teaches the method provides a model of early trophoblast development from individual-specific amnion via the bridge of iPS technology and differentiating strategy (page 36, left col. last para.). Wei teaches despite the high incidence of trophoblast-related diseases, the molecular mechanism of inadequate early trophoblast development is still unclear due to the lack of an appropriate cellular model in vitro (Abstract). Wei teaches any defect in early trophoblast development may result in inadequate placentation and subsequent adverse pregnancy outcomes (page 28, left col.). Wei teaches understanding the inadequate placentation is essential to identify therapeutic intervention for such pregnancy disorders (page 28, right col.).
Regarding claims 2 and 3, Ezashi teaches culturing during reprogramming of porcine mesenchymal stem cells to iPSCs, patches of cells (“continuous layer of cells” of claim 2) with an epithelial phenotype (termed iTR cells where TR stands for trophoblast) formed raised domes (“3D structure” of claim 3) under 20% oxygen after the second passage with upregulated expression of genes associated with trophoblast lineage including CDX2, HAND1, and GATA2 (Abstract; page 781; Figure 2C and E; page 782, left col. and right col. para. 1; page 783, left col. para. 1 and 3).
Regarding claim 10, Ezashi teaches culturing iTR cells in dishes with a nonadherent surface as used with pluripotent cells to test their ability to form embryoid bodies (page 784, left col. para. 2; Figure 5). Ezashi teaches the iTR cells formed floating spheres that were quite unlike embryoid bodies in appearance and size and also in the fact that they consisted of a single layer of cells with an epithelioid appearance (page 784, left col. para. 2).
Ezashi teaches the iTR cells produce estradiol and expressed pregnancy-associated proteins similar to elongating pig conceptuses during the period when placentation has been initiated and TR has begun to assume a transport function and is actively signaling to the mother (Abstract; page 783, right col. para. 1; Figure 3B; page 785, left col. para. 2). Ezashi teaches dome and vesicle formation from TR outgrowths of pig conceptuses and production of estrogen are well-described phenomena associated with porcine TR (page 785, left col. last para. and right col. para. 1). Ezashi teaches the iTR cells did not form structures containing cells representative of the three germ lines and thus lack full pluripotent potential (page 786, left col. para. 3 – 4). Ezashi teaches well-established human embryonic stem cells tend to default to TR spontaneously under standard culture conditions, particularly if the culture is prolonged and carried out under a gas environment that features 20% oxygen (page 785, right col.). Ezashi teaches iTR colonies contained a mixture of cells in the early passages and as the iTR passage number increased the flattened epithelial cells began to predominate suggesting that the phenotype was not stable and that the more differentiated cells gradually outcompeted the smaller cells (page 785, right col. page 786, left col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Wei regarding a method of culturing iPSCs with an inhibitor of the MAPK pathway and an inhibitor of the TGF pathway under 20% oxygen to produce CDX2-expressing cells with the teachings of Ezashi regarding culturing passage 2 iTR cells to form a continuous layer of cells with domes and culturing iTR cells on a nonadherent surface to form spheres to arrive at the claimed method where said amniotic-like epithelial cells form a continuous layer of cells and the pluripotent stem cells are cultured in suspension. One would have been motivated to combine the teachings of Wei and Ezashi in a method for differentiating pluripotent stem cells into amniotic-like epithelial cells for studying placentation disorders as Wei teaches understanding the inadequate placentation is essential to identify therapeutic intervention for such pregnancy disorders. One would have a reasonable expectation of success in combining the teachings as Ezashi teaches the iTR cells produce estradiol and expressed pregnancy-associated proteins similar to elongating pig conceptuses during the period when placentation has been initiated and Ezashi teaches dome and vesicle formation from TR outgrowths of pig conceptuses and production of estrogen are well-described phenomena associated with porcine TR and Ezashi teaches well-established human embryonic stem cells tend to default to TR spontaneously under standard culture conditions, particularly if the culture is prolonged and carried out under a gas environment that features 20% oxygen.
16. Claim(s) 1, 4, 6 – 10, and 20 remain rejected and new claims 23, 26, 29, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Wei (Wei, Yanxing, et al. Placenta 51 (2017): 28-37; previously cited), hereinafter Wei in view of Graham (Graham, Sarah JL, et al. Nature communications 5.1 (2014): 5667; previously cited), hereinafter Graham in view of Ghimere (Ghimire, Sabitri, et al. Stem Cells and Development 24.4 (2015): 497-506; previously cited), hereinafter Ghimere. Although maintained, the rejection is revised in view of Applicant’s cancellation claim 5 and new claim 29.
Wei anticipates claims 1, 4, 7, 8, 10, 20, 23, 26, and 32 as set forth above. Wei teaches culturing with BMP4 and does not anticipate the culturing with a BMP inhibitor of claim 6 that targets “BMP type I receptor” and “Smad1” of claim 9 that is a chemical inhibitor of claim 29. However, Wei teaches culturing iPSCs under 20% oxygen conditions for 9 days in medium containing A8301 and PD173074 (Figure 5A; page 29, right col. para. 1; page 33, right col. last para.; page 34, left col. para. 4). Wei teaches the method provides a model of early trophoblast development from individual-specific amnion via the bridge of iPS technology and differentiating strategy (page 36, left col. last para.). Wei teaches despite the high incidence of trophoblast-related diseases, the molecular mechanism of inadequate early trophoblast development is still unclear due to the lack of an appropriate cellular model in vitro (Abstract). Wei teaches any defect in early trophoblast development may result in inadequate placentation and subsequent adverse pregnancy outcomes (page 28, left col.). Wei teaches understanding the inadequate placentation is essential to identify therapeutic intervention for such pregnancy disorders (page 28, right col.).
Regarding claims 6, 9, and 29, Graham teaches culturing embryos with dorsomorphin an inhibitor of Bmpr1 that leads to inhibition of Smad1 phosphorylation (“BMP inhibitor” of claim 6 and “chemical inhibitor” of claim 29 and “BMP type I receptors” and “Smad1” of claim 9) (page 3, right col. para. 2; page 10, left col. para. 2). Graham teaches preimplantation development results in the formation of a blastocyst comprising trophectoderm (TE), primitive ectoderm (PE) and epiblast (EPI) (page 2, left col.). Graham teaches dorsomorphin reduced the TE lineage but did not affect the EPI lineage (page 4, left col. para. 1 – 2; Figure 3d – f; Figure 7). Graham teaches isolating ICM and outside cells from 16-cell stage embryos and Cdx2 and Gata3 were enriched in outside cells (page 3, left col. para. 1; Figure 1). Graham teaches inside cells express Bmp4 and the receptor that binds Bmp 4 is expressed in both inside and outside cells at similar levels but that the receptor necessary for signal transduction is expressed exclusively in outside cells, suggesting that outside cells are the predominant recipients of the signal (page 3, left col. para. 2; page 8, right col.). Graham teaches BMP signals produced by the pluripotent inside cells are critical for regulating the development of TE and PE (page 9, right col. para. 2). Graham teaches the transcriptional identities of the first progenitors of TE (outside cells) and the ICM (inside cells; pluripotent EPI) currently remain unknown (page 2, left col.). Graham teaches mice lacking core BMP signaling pathway components do not arrest embryogenesis until after implantation suggesting that BMP signaling might by dispensable for pre-implantation development (page 2, right col. para. 1).
Ghimere teaches culturing mouse embryos with PD032591 (MAPK pathway inhibitor) and SB431542 (TGF pathway inhibitor) increases epiblast proliferation (page 503, left col. para. 2; Figure 6; page 505, left col. para. 4; Abstract). Ghimere teaches the number of epiblast cells (Nanog positive) decrease in the presence of BMP4 (page 504, left col. para. 3; Abstract).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Wei regarding a method of culturing iPSCs with an inhibitor of the MAPK pathway and an inhibitor of the TGF pathway to produce CDX2-expressing cells with the teachings of Graham regarding dorsomorphin increases epiblast cells with the teachings of Ghimere regarding culturing embryos with a MAPK pathway inhibitor and a TGF pathway inhibitor increases epiblast proliferation to arrive at the claimed method comprising culturing the pluripotent stem cells with a BMP inhibitor that is a chemical inhibitor. One would have been motivated to combine the teachings of Wei, Graham, and Ghimere in a method for differentiating pluripotent stem cells into amniotic-like epithelial cells for studying placentation disorders as Wei teaches understanding the inadequate placentation is essential to identify therapeutic intervention for such pregnancy disorders. One would have a reasonable expectation of success in combining the teachings as Graham teaches dorsomorphin increases epiblast cells, the epiblast cells express BMP4 and outside cells including TE are the predominant recipients of the signal, BMP signals produced by the pluripotent inside cells are critical for regulating the development of TE, and Ghimere teaches culturing embryos with a MAPK inhibitor and TGF inhibitor without BMP4 increases epiblast proliferation.
Rejections Necessitated By Amendment
Improper Markush Grouping Rejection
17. Claims 23, 26, and 29 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
18. The Markush grouping of MAPK pathway inhibitor (claim 23) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives are not all members of the same art-recognized class because they do not share a common structure (e.g., a polypeptide is a polymer of amino acids while polynucleotide is a polymer of nucleic acids where both differ structurally from a chemical inhibitor).
19. The Markush grouping of TGF pathway inhibitor (claim 26) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives are not all members of the same art-recognized class because they do not share a common structure ((e.g., a polypeptide is a polymer of amino acids while polynucleotide is a polymer of nucleic acids where both differ structurally from a chemical inhibitor).
20. The Markush grouping of BMP inhibitor (claim 29) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives are not all members of the same art-recognized class because they do not share a common structure (e.g., a polypeptide is a polymer of amino acids while polynucleotide is a polymer of nucleic acids where both differ structurally from a chemical inhibitor).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Applicant’s Arguments/Response to Arguments
21. Applicant Argues: Applicant asserts Wei does not disclose producing amniotic-like epithelial cells or using pluripotent stem cells that are not in a primed state to produce amniotic-like epithelial cells and Wei relates to the generation of trophoblast-like cells. Applicant asserts that a person of ordinary skill in the art would have understood the expression of CDX2 and epithelial morphology to be consistent with trophoblast cells, not amnion cells. Applicant asserts that Ezashi, Graham, and Ghimire do not disclose or suggest differentiating pluripotent stem cells into amniotic-like epithelial cells or using pluripotent stem cells that are not in a primed state.
Response to Argument: This is not found persuasive because Wei anticipates the method of claim 1 based on the definitions of “pluripotent stem cells are not primed pluripotent stem cells” (page 12, lines 4 – 5) and “amniotic-like epithelial cells” (page 10, lines 27 – 36) in Applicant’s specification that state that amniotic-like epithelial cells are epithelial cells that express CDX2.
Conclusion
No claims 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.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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