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 .
Applicant's claims filed on 08-11-2025 have been received and entered. Claims 1-14 are pending in the instant application.
Election/Restrictions
Applicant’s election of Group I (claims 1-7) in the reply filed on 08-11-2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 8-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08-11-2025.
Claims 1-7 are under consideration.
Priority
This application is a 371 of PCT/JP2021/007320 filed on 02/26/2021 which claims priority from foreign applications JAPAN 2020-033848 filed on 02/28/2020.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 11-29-2022 and 04-25-2024 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Objections
Claim 1, 3-4 are objected to because of the following informalities:
Claim 1 employs the acronyms for LIN28 and L-MYC
Claim 3 employs the acronyms for RPE.
Claim 4 employs the acronyms for bFGF and 2-ME
These terms should be identified by its full name followed by acronyms at its recitation in the text of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 2, 3-6 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 2 is vague and indefinite in that there is no clear antecedent basis for the phrase “the exogenous factor” as recited in the claim. For example, claim 2 depends from claim 1, which already recites the administration of four “exogenous factors” into a mammalian somatic cell that are different from the CRX gene or expression product thereof recited in claim 2. Thus, it is not clear from the plain language of the claim how the CRX factor can be “the” single exogenous factor introduced into the mammalian somatic cell. It appears from a review of the disclosure that Applicant may have intended the claim to read “....... further comprising a step of introducing CRX (cone-rod homeobox) gene or expression product thereof as an additional exogenous factor”.
Claim 3 recites the phrase “comprising 3 stages of a period of overexpressing the introduced exogeneous factors in the somatic cell to yield genomic plasticity (phase 1)”. It is unclear if there are 3 stages within phase 1 as recited in claim 1 or if the term “stage” is intended to be equivalent to the term “phase”. For example, the plain language of the claim appears to indicate that there are three different stages within phase I of the method as recited. On the other hand, the instant disclosure appears to indicate that the terms “stage” and “phase” can be synonymous with one another, at least some of the time. For example, at page 2, lines 22-25, the specification states: “…(3) The method of the above-mentioned (1) or (2), comprising 3 stages (phases) of a period of overexpressing the introduced exogenous factors in the somatic cell to yield genomic plasticity (phase1), a period of converting the somatic cell identity to an RPE cell (phase 2), and a period of maturing the converted RPE cell (phase 3).”. The parenthetical recitation of “phases” after the recitation of “stages” implies that the two terms are synonymous at least some of the time. Thus, it is not clear whether the terms “stage” and “phase” are intended to be synonymous with one another, overlap in scope or to refer to different things, particularly when they are recited together in the manner they are in the method of instant claim 3.”
Claims 4-6 are included in the rejection because they directly or indirectly depend from the rejected base claim. 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.
Claims 1-4, 7 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Protein Cell 2014, 5(1):48–58, DOI 10.1007/s13238-013-0011-2) in view of Bharti et al (Pub .No.: US 2019 /0169569 A1, Pub. Date : Jun. 6, 2019).
Regarding to claim 1, 2, 7 Zhang et al teach direct conversion of human fibroblasts into retinal pigment epithelium-like cells by defined factors (Title). By monitoring a human RPE specific Best1::GFP reporter, Zhang et al reported the conversion of human fibroblasts into RPE lineage using defined sets of transcription factors (Abstract). Human foreskin fibroblasts (HFF-1, HFF-693) were plated on Matrigel-coated six-well plates at 75,000 cells per well. The next day, cells were infected with an equal ratio of a combination of eight retroviruses encoding PAX6, RAX, CRX, MITF-A, OTX2, NRL, KLF4 and c-MYC (8F) as well as pGZ-BEST1-GFP lentivirus (Page 56, right column, 1st para.). Zhang et al concluded that “These data indicated that cMyc, Mitf, Otx2, Rax, and Crx are crucial for reprogramming of human fibroblasts into Best1::GFP+ cells” (Page 51, left column, 1st para).
Zhang et al do not specifically teach LIN28 and L-MYC. Bharti et al cure the deficiency.
Bharti et al teach method for reproducible differentiation of clinical -grade retinal pigment epithelium cells (Title). Bharti et al teach L -myc or a nucleic acid that encodes L-myc, and Lin28 or Lin28b or a nucleic acid that encodes Lin28 or Lin28b , can be utilized as nuclear reprogramming substances for a somatic cell ([0078], page 7).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Zhang et al by expressing L-myc, and Lin28 in a somatic cells to generate retinal pigment epithelium cells as taught by Bharti et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Bharti et al teach that “Factors like Nanog, Lin28 , Klf4, or c-Myc can increase reprogramming efficiency and can be expressed from several different expression vectors” ([0078], page 7, right column). Generally, it is advantageous to transfect cells with the construct. Suitable vectors for stable transfection include, but are not limited to retroviral vectors , lentiviral vectors and Sendai virus ([0082], page 8, left column). Bharti et al stated that “the present method of RPE differentiation has a distinct advantage over any methods that produce RPE cells from embryoid bodies as it provides more consistent and reproducible results across donor genotypes and when performed by different operators” ([0200], page 20, bridging left to right column). Bharti et al teach Medium that may improve both purity of the RPE population (meaning a decrease in contaminating cells ) as well as maturity of the resulting RPE population ([0195], page 19). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Bharti et al were successful in generating clinical -grade retinal pigment epithelium cells with working examples and data.
Regarding to claim 3, Zhang et al teach cells were infected with an equal ratio of a combination of eight retroviruses encoding PAX6, RAX, CRX, MITF-A, OTX2, NRL, KLF4 and c-MYC (8F) as well as pGZ-BEST1-GFP lentivirus (equivalent to Phase 1 of claimed invention). ….. 24 h later, the medium was switched to CDF12 medium with medium changes every day. Cells were covered with 2% ESC qualified-Matrigel diluted in N2B27 medium at day 7. After overnight incubation, fresh RPE medium without Matrigel was added and changed every other day. At day 21, Best1::GFP+ colonies were picked and cultured in Matrigel coated 12 well plates (equivalent to Phase 2 of claimed invention), followed by 10 days treatment with 100 ng/mL Activin A or 500 nmol/L RA plus 25 ng/mL SHH in base RPE medium (equivalent to Phase 3 of claimed invention ) (Page 56, right column, 1st para.).
Regarding to claim 4, Zhang et al teach “CDF12 medium: DMEM/F12 (Invitrogen) supplemented with ……. 55 μmol/L β-mercaptoethanol (Invitrogen) and 10 ng/mL bFGF” (Page 56, left column, 1st para.), and transfected Human foreskin fibroblasts were cultured with CDF12 medium Page 56, right column, 1st para.).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Protein Cell 2014, 5(1):48–58, DOI 10.1007/s13238-013-0011-2) in view of Bharti et al (Pub .No.: US 2019 /0169569 A1, Pub. Date : Jun. 6, 2019) as applied to claims 1-4, 7 above, and further in view of Maruotti et al (WO 2015/175504 A1, International Publication Date: 19 November 2015).
The teachings of Zhang et al and Bharti et al above are incorporated herein in their entirety. Zhang et al and Bharti et al do not teach combination of Chetomin and Nicotinamide. Maruotti et al cure the deficiency.
Regarding to claim 5, Maruotti et al teach that “ …. A molecule, chetomin (CTM, a disruptor of the CHI domain ofp300) was identified that consistently increases the yield of RPE cells by 30-40% after one month of differentiation. Indicating the power of broad-based screening, CTM has never been described in the context of pluripotent stem cell differentiation. By combining CTM with nicotinamide (NIC), a small molecule previously reported to modestly increase RPE differentiation, up to 60% of differentiating hPSCs were converted into RPE. This efficiency is similar to the best growth factor-based differentiation protocols reported to date ….” (Page 32, lines 7-14).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Zhang et al and Bharti et al by using Chetomin and Nicotinamide to increase the yield of RPE cells as taught by Maruotti et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Maruotti et al teach that combining Chetomin with nicotinamide increase RPE differentiation and this efficiency is similar to the best growth factor-based differentiation protocols. (Page 32, lines 7-14). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Maruotti et al were successful in generating RPE cells with detailed instructions and data.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (Protein Cell 2014, 5(1):48–58, DOI 10.1007/s13238-013-0011-2) in view of Bharti et al (Pub .No.: US 2019 /0169569 A1, Pub. Date : Jun. 6, 2019) as applied to claims 1-4, 7 above, and further in view of Takahashi et al (Pub. No.: US 2013/0224156A1, Pub. Date: Aug. 29, 2013) (Applicant own work).
The teachings of Zhang et al and Bharti et al above are incorporated herein in their entirety. Zhang et al and Bharti et al do not teach combination of SB431542 and bFGF. Takahashi et al cure the deficiency.
Regarding to claim 5, Takahashi et al teach method of producing human retinal pigment epithelial cells (Title). Takahashi et al teach the use of RPE culture medium as RPE maintenance
medium with 10 ng/ml bFGF, 0.5uM SB431542 ([0088], page 7).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Zhang et al and Bharti et al by using RPE maintenance medium with 10 ng/ml bFGF, 0.5uM SB431542 as taught by Takahashi et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Takahashi et al stated that “the method is superior in safety, can simplify the working process, and shows less variation of differentiation induction efficiency between cells. Furthermore, since differentiation is induced by adhesion culture, the period for producing RPE cells can be drastically shortened, and the production cost can be suppressed. Furthermore, since unnecessary cells can be easily removed by the use of a specific culture vessel, work efficiency can be improved and a highly pure RPE cell population can be conveniently produced” ([0063], page 6). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Takahashi et al were successful in generation of retinal pigment epithelial cell with working examples and data.
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632