DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-9 were previously pending in the instant Application.
Applicant’s election of the invention of group I drawn to a trophoblast stem cell-like cell (claims 1-5) in the reply filed on 05 December, 2025 was previously acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election was treated as an election without traverse (MPEP § 818.01(a)).
Receipt is acknowledged of Applicant’s claim amendments submitted on 15 April, 2026. Claims 1, 4, and 6-8 are amended. Claims 3, 5, and 9 are cancelled.
Claims 6-8 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 1-2, 4, and 6-8 are pending with claims 1-2, and 4 being the subject of the present Official Action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/JP2020/027766, filed 17 July, 2020.
The earliest possible priority for the instant application is 17 July, 2020.
Claim Objections
The objection to claims 1-5 because abbreviations/acronyms need to be spelled out upon their first encounter in the claims (for example: SALL4, MYC) is withdrawn in view of Applicant’s amendments to the claims. Applicant has spelled out the abbreviations/acronyms.
Claim Interpretation
"[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). The second clause of claim 1, “which is induced from a trophoblast cell isolated from a placenta of or after the second trimester of pregnancy”, is product-by-process language. There is no indication in the claims or the instant specification of what structures distinguish a trophoblast cell derived from a first trimester placenta from an identically-named cell derived from a second or third trimester cell. Thus, for the purpose of applying prior art, a trophoblast cell from a placenta of the first trimester is interpreted as being identical to a trophoblast cell from a placenta of the second or third trimester.
Withdrawn Rejections in view of Applicant’s amendments to the claims
Claim Rejections - 35 USC § 112
The rejection of claims 1-5 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 is withdrawn in view of Applicant’s amendments to the claims. Applicant has corrected previously raised issues of indefiniteness or else has cancelled previously rejected claims.
Claim Rejections - 35 USC § 103
The rejection of claims 3-5 under 35 U.S.C. 103 as being unpatentable over Okae, Hiroaki, et al., Cell stem cell 22.1 (2018): 50-63, hereinafter “Okae”, Of Record on the IDS submitted 13 January, 2023, Zhang et al., Nature cell biology 8.10 (2006): 1114-1123, hereinafter “Zhang”, Of Record, Miller, et al., Development 143.17 (2016): 3074-3084, hereinafter “Miller”, and US20140342369 (hereinafter “Elling”) as applied to claims 1-2 above, and further in view of US2019/0112575, published 18 April, 2019 (hereinafter “Takahashi”) is withdrawn in view of Applicant’s amendments to the claims. Applicant has subsumed the p53 limitations into claim 1 necessitated withdrawal of this rejection in favor of combining it with the other previously-presented 103 rejection (See below).
Maintained Rejections in view of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 103
Claims 1-2, and 4 remain rejected under 35 U.S.C. 103 as being unpatentable over Okae, Hiroaki, et al., Cell stem cell 22.1 (2018): 50-63, hereinafter “Okae”, Of Record on the IDS submitted 13 January, 2023 in view of US2019/0112575, published 18 April, 2019 (hereinafter “Takahashi”), Zhang et al., Nature cell biology 8.10 (2006): 1114-1123, hereinafter “Zhang”, Of Record, Miller, et al., Development 143.17 (2016): 3074-3084, hereinafter “Miller”, and US20140342369 (hereinafter “Elling”). This rejection has been modified as necessitated by Applicant’s amendments to the claims.
Applicant has amended claim 1 to require an exogenous p53 dominant negative gene functionally linked to a second exogenous inducible promoter. This limitation was previously found in claim 4 which was rejected separately with reliance on Takahashi. Thus, the previous two obviousness rejections have been combined below as necessitated by Applicant’s amendments to the claims.
Regarding claim 1, Okae teaches the differentiation of cytotrophoblast cells into trophoblast stem cells (Okae, page 50, fourth paragraph). Okae teaches that the human placenta is comprised of cytotrophoblast cells, extravillous cytotrophoblast cells, and syncytiotrophoblast cells (Okae, page 50, first paragraph). Okae also teaches the differentiation of the trophoblast stem cells into syncytiotrophoblast cells and extravillous trophoblast cells (Okae, Figure 2). Thus, Okae teaches trophoblast stem cells having potential to differentiate into a placenta-constituting cell. Regarding the product-by-process language in claim 1, Okae teaches first trimester trophoblast cells as the starting cells (Okae, page e3, “Isolation of trophoblast and stromal cells”). Trophoblast stem cells induced from a trophoblast cell derived from a placenta of or after the second trimester of pregnancy are interpreted as being substantially identical to the trophoblast stem cells derived from a trophoblast cell of a first trimester placenta as in Okae (See claim interpretation above).
Okae does not teach a trophoblast stem cell comprising a SALL4 gene functionally linked to a first exogenous inducible promoter or an exogenous p53 dominant negative gene functionally linked to a second exogenous inducible promoter.
Miller teaches embryonic stem cells comprising a SALL4 gene functionally linked to an inducible promoter (Miller, Figure 2). Miller also teaches that the dosage of SALL4 within cells is very important because too little might inappropriately activate genes while too much could interfere with expression of lineage-specific genes (Miller, page 17, first partial paragraph).
Zhang teaches that reducing SALL4 activates transcription of Pou5f1 which encodes Oct4 and is important for early cell fate decisions (Zhang, Abstract). Zhang also teaches that reduction in SALL4 leads to specification of embryonic stem cells into trophoblast cells (Zhang, page 1, third paragraph). Zhang also teaches that SALL4 is required to appropriately regulate Oct4 levels to maintain pluripotent cells (Zhang, page 8, fourth paragraph).
Elling teaches that trophoblast stem cells can be converted into ES-like pluripotent stem cells when overexpressing Oct4 (Elling, [0055]).
Thus, a person having ordinary skill in the art would have known from the teachings of Elling, Zhang, and Miller that (1) trophoblast stem cells and ES cells are related stem cells which are connected through Oct4 activity, (2) SALL4 is required to appropriately regulate Oct4 levels to maintain pluripotency, and (3) SALL4 can be functionally linked to an inducible promoter to control the dosage of SALL4 within cells which is very important because too little might inappropriately activate genes while too much could interfere with expression of lineage-specific genes.
Takahashi teaches an assortment of reprogramming factors that have been used in the art to induce somatic cells into pluripotent stem cells (Takahashi, [0033]). Takahashi specifically teaches SALL4, dominant-negative form p53, and Myc as several reprogramming factors that have been used in the art to induce somatic cells into pluripotent stem cells (Takahashi, [0033]). Takahashi teaches the production of induced pluripotent cells by introducing MYC and a dominant-negative form of p53 (Takahashi, [0149]). Takahashi teaches that dominant-negative form p53 is an inhibitor of p53 (Takahashi, [0034]). Thus, Takahashi suggests to a person having ordinary skill in the art to express dominant-negative form p53 and/or MYC alongside SALL4 to induce a somatic cell into a pluripotent cell. With regard to the second exogenous inducible promoter, it would have been well within the level of ordinary skill in the art to have used different inducible promoters in front of each exogenous gene to add a further layer of tunability and control to the system as Miller teaches the desirability of such tunable control.
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have used an inducible promoter to express SALL4 as taught by Miller in the trophoblast stem cells of Okae and to have expressed p53 alongside SALL4 in the trophoblast stem cells of Okae, Miller, Elling, and Zhang and to have arrived at the invention in claim 1 with a reasonable expectation of success because they would have been motivated to do so to control the dosage of SALL4 in order to appropriately regulate Oct4 levels in the cells to maintain pluripotency as taught by Zhang and Elling and because Takahashi suggests such a combination and such reprogramming factors would be reasonably expected to induce pluripotency. There would have been a reasonable expectation of success in doing so insofar as a person having ordinary skill in the art would have reasonably expected an inducible SALL4 gene to allow for the regulation of Oct4 in trophoblast stem cells just as it does in ES cells because Elling teaches that trophoblast stem cells are related to ES cells through Oct4 activity.
Regarding claim 2, the SALL4 of Zhang is an exogenous SALL4 (Zhang, page 8, “Plasmid construction”).
Regarding claim 4, Takahashi suggests to a person having ordinary skill in the art to express dominant-negative form p53 and/or MYC alongside SALL4 to induce a somatic cell into a pluripotent cell.
Response to Arguments
Applicant argues against the obviousness of the instant claims by arguing (1) the prior art of record do not teach or suggest the amended claims (Remarks, pages 6-7), (2) A person having ordinary skill in the art would not be motivated to use any of the factors of Takahashi in the method of Okae because pluripotent cells can differentiate into any type of cell while TS-like-cells can only differentiate into placenta-constituting cells (Remakrs, page 7), and (3) the protocol used to produce the cells claimed successfully led to establishment of TS-like cells without inducer when SALL4 was combined with p53DN which is an unexpected effect that could not have been predicted (Remarks, page 8). These arguments have been fully considered but have not been found persuasive for the following reasons.
(1) In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant lists which teachings of each reference individually are lacking without addressing the combination of the references as applied in the instant rejection. This is unpersuasive because the rejection is based upon a combination of the references and not any one of the references in isolation.
(2) Applicant argues that a person having ordinary skill in the art would not be motivated to use any of the factors of Takahashi in the method of Okae because pluripotent cells can differentiate into any type of cell while TS-like-cells can only differentiate into placenta-constituting cells (Remakrs, page 7). This argument seizes upon a singular distinction between pluripotent stem cells and TS-like cells without addressing their similarities. As discussed in the instant rejection, trophoblast stem cells and ES cells are related stem cells which are at least connected through Oct4 activity. Both cells have differentiation capacity and both require the expression of genes to prevent a terminal cell fate (e.g. pluripotency genes). It is these similarities which a person having ordinary skill in the art would have understood from the teachings of the prior art which would have led them to considering other genes involved in the maintenance of pluripotency which Takahashi provides. Accordingly, this argument has been fully considered but has not been found persuasive.
(3) Applicant also argues that the protocol used to produce the cells claimed successfully led to establishment of TS-like cells without inducer when SALL4 was combined with p53DN which is an unexpected effect that could not have been predicted (Remarks, page 8). It is noted that the claims are directed to the cells themselves not to their method of making. Consequently, a person having ordinary skill in the art need not be able to predict whether the presence or absence of inducer beginning at the 21st day of culture has any effect at all on the cells. They only need to reasonably expect to successfully possess a trophoblast stem cell-like cell which itself comprises the combination of SALL4 and p53DN for a prima facie case of obviousness to exist here. Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Here, a person having ordinary skill in the art would have reasonably expected the trophoblast stem cell-like cells of Okae expressing SALL4 and p53DN to have similar properties to the tunable cell state taught in the other prior art references owing to the observed similarities between TS-like cells and other pluripotent cell types and the suggestion of various factors for maintaining pluripotency in cells regardless of the method of manufacture of those cells. Accordingly, this argument has been fully considered but has not been found persuasive.
Conclusion
No claim is 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 BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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, MARIA G LEAVITT can be reached at 571-272-1085. 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.
/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
Prosecution Insights