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 .
DETAILED ACTION
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-11, drawn to a method for differentiating a spherical neural mass into retinal outer layer cells, in the reply filed on 01/20/2026 is acknowledged.
Claim 12 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Status
Claims 1-12 are pending.
Claim 12 is withdrawn.
Claims 1-11 are considered on the merits.
Priority
This application is a 371 of PCT/KR2022/001533 (filed on 01/27/2022), which claims benefit from foreign application KR10-2021-0015038 (filed on 02/02/2021). The priority claim of the instant application has been granted and the earliest benefit date is 02/02/2021 from the application KR10-2021-0015038.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/01/2023, 08/29/2024 and 01/03/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
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 1-11 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 1 recites “the spherical neural mass” in the last line. There is insufficient antecedent basis for this limitation in the claim because claim 1 recites two structures of a spherical neural mass prior to this limitation: (1) spherical neural mass single cells and (2) a cystic structure of spherical neural mass. Thus, it is not clear which structure this limitation is referring to. It is examined as (1) spherical neural mass single cells. Claims 2-11 are rejected as being dependent from claim 1 but not resolving the ambiguity.
Claim Rejections - 35 USC § 103
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 1-3 and 5-11 are rejected under 35 U.S.C. 103 as being unpatentable over Amirpour et al., (Int J Prev Med. 2013;4:1243‑1250, cited in IDS 08/29/2024) in view of Yun et al., (Tissue Eng Regen Med. 2017;14(1):39-47, cited in IDS 08/29/2024), Cho et al., (Stem Cell Res. 2012;9(2):101-109, cited in IDS 08/29/2024) and Jeil Pharmaceutical (“Jeil”, US 2019/0330590, published 2019 Oct).
With respect to claim 1, directed to a method comprising co-culturing retinal cells to produce retinal outer layer cells, Amirpour teaches methods of indirect and direct co-culturing retinal progenitor cells (RPCs) with retinal pigment epithelial cells (RPE cells) to improve the differentiation of the RPCs into photoreceptor cells (i.e., retinal outer layer cells, see e.g., abstract), thus teaches a method comprising culturing RPCs and RPE cells together in a single medium and differentiating the RPCs into retinal outer layer cells.
However, Amirpour teaches the RPCs are differentiated from hESC and the RPE cell sheet is isolated from rabbit eyes (e.g., abstract), but is silent on the RPCs being derived from spherical neural mass (SNM) or the RPE cells being derived from a cystic structure of SNM.
In regard to RPCs derived from SNM, Yun teaches a method of generating retinal progenitor cells (RPCs) from human iPSC-derived spherical neural mass (SNMs) (e.g., title and abstract). Yun teaches SNMs have advantages of long-term passaging capability with high yield, easy storage, and thawing (e.g., abstract).
In regard to RPE cells derived from a cystic structure of SNM, Cho teaches a method of generating retinal pigment epithelial (RPE) cells from human ESC (or hiPSC)-derived spherical neural masses (SNMs) (e.g., title and abstract). Cho teaches approximately 5% of SNMs form the cystic portions which show typical RPE morphologies (see e.g., p. 104, left col, last para). These cystic portions are cultured in a monolayer and are characterized to confirm RPE differentiation (see e.g., p. 104, right col, section “Characterization of RPE cells derived from cystic vesicles”).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for differentiating RPCs into retinal outer layer cells by co-culturing RPCs and RPE cells disclosed by Amirpour, by substituting the RPCs with RPCs derived from hiPSC-derived SNMs as suggested by Yun and by substituting the RPE cells from rabbit eyes with RPE cells derived from a cystic structure of hiPSC-derived SNMs as suggested by Cho with a reasonable expectation of success. Since Amirpour aims to improve the generation of neural photoreceptors by co-culturing hESC-derived RPCs with RPE cells isolated from rabbit eyes, for the treatment of retinal diseases (e.g., p. 1249, right col.), and since Yun teaches hiPSC-derived SNMs have advantages of long-term passaging capability with high yield, easy storage, and thawing and reduces to practice a method of differentiating SNMs into RPCs (e.g., abstract), and since Cho reduces to practice a method of differentiating the cystic structure of SNMs into RPE cells (e.g., abstract), one of ordinary skill in the art would have had a reason to substitute the RPCs and RPEs of Amirpour with the SNMs and a cystic structure of SNMs as suggested by Yun and Cho in order to take advantages of the hiPSC-derived SNMs such as long-term passaging capability with high yield, easy storage, and thawing, and to use a human iPSC as the source for RPE cells to obtain a xeno-free condition for clinical therapy. Furthermore, since all cited art teach the same culture medium (i.e., an N2B27 medium, see Amirpour, p. 1245, left col, “Tissue culture” - right col, para 1; Yun, p. 40, left col, last para; and Cho, p. 108, left col, para 2), one of ordinary skill in the art would have had a reasonable expectation of success in co-culturing SNMs and a cystic structure of SNMs to differentiate the SNMs into retinal outer layer cells.
However, Amirpour, Yun and Cho are silent on the SNMs in the co-culture being SNM single cells.
Jeil teaches a method for producing a spherical neural mass (SNM) having improved purity of the neuronal progenitor cells, suppressed teratoma formation, and increased viability (e.g., abstract). Jeil teaches the method includes performing single - cellularization of SNMs (e.g., [0010], [0025], [0035], see Example 3 in page 5 and claims 1 and 10), and teaches performing fragmentation and single-cellularization of the SNMs into a single cell, significantly increased the viability and recovery percentage of the cells (see FIG. 4) ([0039], [0047]).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for differentiating SNMs into retinal outer layer cells by co-culturing SNMs and a cystic structure of SNMs suggested by Amirpour, Yun and Cho, by substituting the SNMs with SNM single cells as suggested by Jeil with a reasonable expectation of success. Since Jeil teaches the single-cellularization of the SNMs into a single cell significantly increases the viability and recovery percentage of the cells with improved purity of neuronal progenitor cells and suppressed teratoma formation (see above), one of ordinary skill in the art would have had a reason to substitute with SNM single cells in order to take advantages of the increased viability and improved purity of neuronal progenitor cells as suggested by Jeil.
With respect to claim 2 and claim 3, Amirpour exemplifies an indirect co-culturing method comprising culturing the isolated RPE sheet (equivalent to the cystic structure of SNM as discussed above) on filter insert (i.e., in the upper portion above a porous structure, and the filter insert is equivalent to a porous mesh in claim 3), and culturing the dissociated neural tube-like structures (equivalent to the SNM single cells as discussed above) in the six well plates (i.e., in the lower portion below the porous structure). Amirpour teaches RPE cells secret a variety of factors such as pigment epithelium‑derived factor and vascular endothelial growth factor that are important for survival of photoreceptors (p. 1244, left col.) and upon co‑culture of RPCs with RPE sheet using insert for 2 weeks, these cells differentiated to neural retina and expressed photoreceptor‑specific markers (e.g., abstract). Furthermore, Cho teaches the RPE cells derived from the cystic structure of SNMs secret pigment epithelium-derived factor and vascular endothelial growth factor (p. 106, section “secretion of PEDF and VEGF” and see Fig 5).
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen co-culturing the SNM single cells and the cystic structure of SNM using an insert as suggested by Amirpour with a reasonable expectation of success. Since Amirpour teaches upon co‑culture using insert for 2 weeks, the RPC cells differentiated to neural retina and expressed photoreceptor‑specific markers (e.g., abstract), one of ordinary skill in the art would have had a reason to choose co-culturing the two types of cells using an insert to facilitate differentiation and separation of retinal photoreceptor cells.
Furthermore, since both Amirpour and Cho teach the RPE cells secret PEDF and VEGF that are important for survival of photoreceptors (see above), one of ordinary skill in the art would have chosen to dispose the SNM single cells in the upper portion above the porous structure and to dispose the cystic structure of SNM in the lower portion below the porous structure with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so since this arrangement is a simple reversal of parts compared to the arrangement exemplified by Amirpour, and it has been held that mere reversal of parts is an obvious modification. See MPEP 2144.04 (VI) (A).
With respect to claim 5 directed to the cystic structure of SNM being isolated from a SNM-derived transparent cyst, Cho teaches the cystic vesicles of SNM are SNM-derived cysts (see e.g., p. 104, left col, last para) and the cyst is transparent (see Fig 4E and 4F).
With respect to claim 6 directed to the SNM being differentiated from stem cells, and claim 7 directed to the stem cells being ESCs or iPSCs, Yun teaches human iPSC-derived SNMs (e.g., abstract). Cho teaches human ESC or human iPSC-derived SNMs (e.g., abstract and p. 104, right col, para 1).
With respect to claim 8, both Yun and Cho teach the SNM is differentiated from stem cells through the steps of forming embryoid bodies, forming neural rosettes and neural tube-like structures from EBs and forming SNMs from the neural rosettes and the neural tube-like structures (see e.g., Yun, p. 40, left col, para 2.1, and Cho, p. 108, left col, para 2).
With respect to claim 9 and claim 10, Amirpour teaches the RPCs differentiate into photoreceptor cells expressing photoreceptor‑specific markers such as rhodopsin (see e.g., Figs 5-6). Accordingly, one of ordinary skill in the art would have immediately expected that the retinal outer layer cells (i.e., photoreceptor cells that are neurons) would have had increased expression of βIII-tubulin (that is a marker for neurons) as well as rhodopsin.
With respect to claim 11 directed to the retinal outer layer cells alleviate or prevent blindness, since the base claim 1 is silent on a method of alleviating or preventing blindness, the limitation in claim 11 is examined as the retinal outer layer cells are capable of alleviating or preventing blindness. As stated supra, Amirpour aims to generate neural photoreceptors for use in the treatment of some retinal disease such as macular degeneration and retinitis pigmentosa through cell replacement (e.g., p. 1247, right col, para 2 and p. 1249, right col.). Accordingly, one of ordinary skill in the art would have immediately expected that the retinal outer layer cells (i.e., the photoreceptor cells) would be capable of alleviating or preventing blindness.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Amirpour et al., (Int J Prev Med. 2013;4:1243‑1250, cited in IDS 08/29/2024) in view of Yun et al., (Tissue Eng Regen Med. 2017;14(1):39-47, cited in IDS 08/29/2024), Cho et al., (Stem Cell Res. 2012;9(2):101-109, cited in IDS 08/29/2024) and Jeil Pharmaceutical (“Jeil”, US 2019/0330590, published 2019 Oct), as applied to claim 1 above, and further in view of Cho et al., (“Cho 2008”, Nat Protoc. 2008;3(12):1888-1894).
Claim 4 is directed to the SNM single cells being isolated from a SNM-derived noncystic structure.
As stated supra, Yun teaches a method of generating RPCs from human iPSC-derived SNMs (e.g., abstract). Yun teaches “Differentiation of human iPSCs to SNMs followed Cho et al. with minor modifications [15]” and “Pure SNMs were used for differentiation into retinal progenitor cells.” (p. 40, left col, para 2.1). Jeil suggests to obtain single cells from SNMs (see above).
However, Amirpour, Yun, Cho and Jeil are silent on the SNM single cells being isolated from a SNM-derived noncystic structure.
Cho 2008, being the reference [15] of Yun cited above, teaches a highly efficient method to differentiate hESCs into neurons including a unique step of the formation of spherical neural masses (SNMs) (abstract). Cho 2008 teaches non-neural (cystic- or spot-forming) structures are frequently observed at the initial stage of sphere formation and also during the purification processes (Fig 4 legend), and these cystic parts are removed from the SNM bodies (see e.g., p. 1890, step 9 and p. 1891. Para 1, also see p. 1889, Fig 1, Stage 1 last row). Cho 2008 teaches the cystic structures of the SNMs usually form epithelia-like cells at the later stage (p. 1891, 1st Critical Step) and in most cases, cystic structures are mostly removed after these four times of purification processes (p. 1891, 2nd Critical Step). Thus, Cho 2008 teaches the pure SNMs of Yun do not have cystic structures and thus are isolated from a SNM-derived noncystic structure.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen a SNM-derived noncystic structure to isolate SNM single cells as suggested by Cho 2008 with a reasonable expectation of success. Since Cho 2008 teaches the cystic structures of the SNMs usually form epithelia-like cells and are mostly removed after four times of purification processes (p. 1891, 1st and 2nd Critical Step), one of ordinary skill in the art would have had a reason to choose noncystic structure of SNMs to isolate SNM single cells in order to obtain purified SNMs for highly efficient differentiation into photoreceptor neurons (e.g., Cho 2008, abstract).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
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/JIANJIAN ZHU/Examiner, Art Unit 1631
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