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
Amendments
In the reply filed on 07/27/2026, Applicant has amended claims 1-2, 6 and 8, and has canceled claims 4-5, 9-10 and 12.
Claim Status
Claims 1-3, 6-8 and 11 are pending and are considered on the merits.
Withdrawn Claim Rejections - 35 USC § 112
The prior rejection of claims 1-3, 6-8 and 11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for insufficient antecedent basis is withdrawn in light of Applicant’s amendment to claim 1.
New Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6-7 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 recites the SNM is differentiated from stem cells, claim 7 recites the stem cells are selected from the group including adult stem cells and stem cells generated by direct reprogramming. However, amended base claim 1 recites the SNM is made from pluripotent stem cells. Since the stem cells, such as adult stem cells and stem cells generated by direct reprogramming recited in claims 6 and 7 encompass a broader or distinct scope than pluripotent stem cells recited in base claim 1, claims 6-7 fail to further limit the subject matter, or fail to include all the limitations of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 1-3 and 5-11 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) is withdrawn in light of Applicant’s cancellation of claims 5 and 9-10 and amendment to claim 1 to recite new limitations of differentiating the SNM single cells and the cystic structure of SNM into photoreceptor cells and retinal pigment epithelial cells.
The prior rejection of claim 4 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), and further in view of Cho et al., (“Cho 2008”, Nat Protoc. 2008;3(12):1888-1894) is withdrawn in light of Applicant’s cancellation of claim 4.
New 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, 6-8 and 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., (“Cho 2008”, Nat Protoc. 2008;3(12):1888-1894. Prior art of record), Jeil Pharmaceutical (“Jeil”, US 2019/0330590, published 2019 Oct. Prior art of record) and Cho et al., (Stem Cell Res. 2012;9(2):101-109, cited in IDS 08/29/2024).
With respect to claim 1, Amirpour teaches a method of indirect co-culturing dissociated neural tube-like structures with retinal pigment epithelial cell (RPE) sheet to improve the differentiation of photoreceptor cells (see e.g., abstract), thus teaches a method comprising culturing dissociated NTs and RPE sheet together in a single medium to obtain retinal outer layer cells, e.g., photoreceptor cells.
Amirpour teaches the indirect co-culturing method comprises culturing the isolated RPE sheet on a filter insert and the dissociated NTs in a six well plate (p. 1245, right col, para 1), thus teaches in the culturing, the dissociated NTs and the RPE sheet are separated by a porous structure (i.e., a filter insert).
However, regarding the cell types used in the co-culture, Amirpour teaches co-culturing dissociated NTs (“the neural tube (NT)-like structures”, see p. 1245, para 1) differentiated from hESC with isolated RPE sheet (see e.g., 1245, left col, last para “In vitro explant co‑culture experiments” – right col, para 1), but is silent on co-culturing spherical neural mass (SNM) single cells and a cystic structure of SNM, nor teach the SNM single cells are derived from a non-cystic structure of the SNM.
In regard to a non-cyctic structure of SNM, Yun teaches spherical neural mass (SNM) is a mass of neural precursors and teaches human pluripotent stem cells (iPSCs) are differentiated in a neural medium and “To form SNMs, neural rosettes and neural tube-like structures that were observed during neural expansion culture were mechanically isolated and cultured onto a Petri dish containing neural expansion medium” (p. 40, left col, last para “2.1 Differentiation of human iPSCs into retinal progenitor cells”), thus teaches the SNM is a spherical form of an aggregate of neural progenitor cells made from pluripotent stem cells, and the SNMs are formed from neural tube-like structures differentiated from human pluripotent stem cells and can differentiate into RPCs. Accordingly, one of ordinary skill in the art would have expected that Yun’s SNMs, that are formed from “neural tube-like structures” differentiated from human pluripotent stem cells and can differentiate into RPCs, are functionally equivalent to Amirpour’s NTs (“the neural tube (NT)-like structures”) differentiated from hESC that can differentiate into RPCs and further into photoreceptor cells. Furthermore, Cho 2008, being the reference of Yun cited in the above para 2.1, teaches the cystic structures of the SNMs usually form epithelia-like cells at the later stage (p. 1891, 1st Critical Step, also see Cho below) and in most cases, cystic structures are mostly removed after four times of purification processes (p. 1891, 2nd Critical Step). Thus, Cho 2008 teaches the pure SNMs of Yun are derived from a non-cystic structure of the SNM.
Regarding the SNM single cells, as stated supra, Amirpour teaches co-culturing dissociated NTs (see e.g., 1245, left col, last para “In vitro explant co‑culture experiments”, thus teaches culturing single cells, i.e., dissociated NTs. Furthermore, Jeil teaches a method for producing a spherical neural mass (SNM) having improved purity 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]).
In regard to a cystic structure of SNM, Cho teaches early SNMs consist of neural tube-like structures (see Fig 1C, consistent with Yun’s teaching) and these opened neural tube-like structures can be purified and expanded to form cystic vesicles (see Fig 1D and E), and 3D cultured cystic vesicles have RPE cells and pigmentation in their surface (see Fig 1F and Fig 3A&B, also see p. 104, left col, last para, “Membranous cells of the cystic vesicles showed typical RPE morphologies, such as a polygonal-shaped epithelial monolayer, and pigmentation began to form”), thus teaches the cystic structure of SNM is a blister-like transparent cyst present in the SNM (see Fig 1D and 1F). Accordingly, one of ordinary skill in the art would have expected that Cho’s cystic structure of SNM, that have RPE cells and pigmentation in their surface, are functionally equivalent to Amirpour’s isolated RPE sheet that has RPE cells and pigmentation in their surface.
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 obtaining retinal outer layer cells by co-culturing dissociated neural tube (NT)-like structures and isolated RPE sheet disclosed by Amirpour, by substituting the dissociated neural tube (NT)-like structures with SNM single cells derived from a non-cystic structure of SNM consisting of neural tube-like structures as suggested by Yun, Cho 2008 and Jeil, and by substituting the isolated RPE sheet with a cystic structure of SNM as suggested by Cho with a reasonable expectation of success. Since Amirpour aims to improve the generation of neural photoreceptors for the treatment of human retinal diseases (e.g., p. 1249, right col.), since Yun’s non-cystic structure of SNMs, that is formed from neural tube-like structures differentiated from human pluripotent stem cells and can differentiate into RPCs, is functionally equivalent to Amirpour’s neural tube (NT)-like structure used in the co-culture (see above) and Yun teaches hiPSC-derived SNMs have advantages of long-term passaging capability with high yield, easy storage, and thawing (abstract), since Jeil teaches single - cellularization of SNMs significantly increases the viability and recovery percentage of the cells (see FIG. 4 and [0039], [0047]), and Cho teaches the cystic structure of SNM has RPE cells and pigmentation in the surface and thus is functionally equivalent to Amirpour’s isolated RPE sheet (see above), one of ordinary skill in the art would have had a reason to substitute the dissociated NTs and isolated RPE sheet of Amirpour with the SNM single cells (derived from a non-cystic structure of SNM) and a cystic structure of SNMs as suggested by Yun, Cho 2008, Jeil 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 human pluripotent stem cells as the source for RPE cells to obtain a xeno-free condition for facilitating clinical therapy. Furthermore, since all cited art use similar culture media (i.e., an N2B27 medium supplemented with noggin, Dkk-1, IGF-1 and bFGF in Amirpour, p. 1245, left col, “Tissue culture” - right col, para 1 and Yun, p. 40, left col, last para; and bFGF in N2B27 in 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 SNM single cells and a cystic structure of SNMs to differentiate the SNM single cells into photoreceptor cells (see Amirpour, Fig 6 and Yun, Fig 4) and to differentiate the cystic structure of SNM into retinal pigment epithelial cells (see Cho, Fig 3A&B).
Furthermore, since Yun’s non-cystic structure of SNM is functionally equivalent to Amirpour’s neural tube (NT)-like structure used in the co-culture and since Cho’s cystic structure of SNM is functionally equivalent to Amirpour’s isolated RPE sheet (see above), these corresponding structures are thus art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted Yun’s non-cystic structure of SNM for Amirpour’s neural tube (NT)-like structure and have substituted Cho’s cystic structure of SNM for Amirpour’s isolated RPE sheet. See MPEP 2144.06.
With respect to claim 2 and claim 3, as stated supra, Amirpour teaches an indirect co-culturing method comprising culturing the isolated RPE sheet (equivalent to the cystic structure of SNM as discussed above) on a filter insert (i.e., in the upper portion above the 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 (PEDF) and vascular endothelial growth factor (VEGF) that are important for survival of photoreceptors (p. 1244, left col.) and upon co‑culture of dissociated NTs 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 in 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).
However, Amirpour is silent on the dissociated neural tube-like structures (equivalent to the SNM single cells) being disposed in the upper portion and the RPE sheet (equivalent to the cystic structure of SNM being disposed in the lower portion.
Accordingly, one of ordinary skill in the art would have substituted with disposing the SNM single cells in the upper portion above the porous structure and disposing the cystic structure of SNM in the lower portion below the porous structure with a reasonable expectation of success. Since both Amirpour and Cho teach the RPE cells secret PEDF and VEGF into the medium that are important for survival of photoreceptors (see above), 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 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 pluripotent stem cells through the steps of forming embryoid bodies from the pluripotent stem cells, 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 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 (e.g., 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.
Response to Traversal:
Applicant’s arguments filed on 07/27/2026 are acknowledged.
Applicant firstly argues that (A) there is no motivation to combine the cited references because Amirpour begins with already-generated RPCs and RPE cells. The cited references describe separate technologies directed to different goals: Amirpour studies RPC/RPE co-culture, Yun generates RPCs from SNMs, Cho generates RPE cells from cystic SNM structures, and Jeil improves purity and reduces teratoma formation through SNM dissociation and re-aggregation. Therefore, the Office's rationale relies on selecting isolated features from multiple references directed to different objectives and reconstructing the co-culture system of amended claim 1 using the present Specification as a roadmap. Absent impermissible hindsight, there is no teaching or suggestion in the cited references that would have led a PHOSITA to combine the cited references in the suggested manner. (Remarks, p. 5-6).
Applicant’s argument has been fully considered but it is not persuasive.
As a first matter, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, as stated supra, the cited references describe technologies in the exact same field (i.e., in vitro culturing human pluripotent stem cells into neural tube-like structures and further differentiating into retinal progenitor cells and retinal outer layer cells). One of ordinary skill in the art would have expected that Yun’s SNMs, that are formed from neural tube-like structures differentiated from human pluripotent stem cells and can differentiate into RPCs, are functionally equivalent to Amirpour’s neural tube-like structures differentiated from hESC that can differentiate into RPCs and further into photoreceptor cells, and have expected that Cho’s cystic structure of SNM, that have RPE cells and pigmentation in their surface, are functionally equivalent to Amirpour’s isolated RPE sheet that has RPE cells and pigmentation in their surface. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted Yun’s non-cystic structure of SNM for Amirpour’s neural tube-like structure and have substituted Cho’s cystic structure of SNM for Amirpour’s isolated RPE sheet. See MPEP 2144.06.
Furthermore, regarding Amirpour begins with already-generated RPCs and RPE cells, as stated supra, Amirpour actually teaches co-culturing dissociated NTs (“the neural tube (NT)-like structures”, see p. 1245, para 1) differentiated from hESC with isolated RPE sheet (see e.g., 1245, left col, last para “In vitro explant co‑culture experiments” – right col, para 1). As stated supra, one of ordinary skill in the art would have expected that Yun’s SNMs, that are formed from neural tube-like structures differentiated from human pluripotent stem cells and can differentiate into RPCs, are functionally equivalent to Amirpour’s neural tube-like structures differentiated from hESC that can differentiate into RPCs, and have expected that Cho’s cystic structure of SNM, that have RPE cells and pigmentation in their surface, are functionally equivalent to Amirpour’s isolated RPE sheet that has RPE cells and pigmentation in their surface. Therefore, one of ordinary skill in the art would have had motivation to combine the cited references in order to take advantages of the hiPSC-derived SNMs such as long-term passaging capability with high yield, easy storage, and thawing taught by Yun, and to use human pluripotent stem cells as the source for RPE cells as taught by Cho to obtain a xeno-free condition for facilitating clinical therapy. See also MPEP 2144.06.
Applicant further argues that (B) there is no reasonable expectation of success because none of the cited references teaches or suggests that these particular SNM-derived populations should be maintained together in such a co-culture system, or that doing so would result in the recited differentiation outcomes (Remarks, p. 7).
Applicant’s argument has been fully considered but it is not persuasive.
As stated supra, one of ordinary skill in the art would have expected that the particular SNM-derived populations (SNM single cells derived from a non-cystic structure, and SNM-derived cystic structures) are equivalent to the cell types (dissociated neural tube-like structures and RPE sheet) used in co-culture taught by Amirpour. Furthermore, since all cited art use similar culture media (i.e., an N2B27 medium supplemented with noggin, Dkk-1, IGF-1 and bFGF in Amirpour, p. 1245, left col, “Tissue culture” - right col, para 1 and Yun, p. 40, left col, last para; and bFGF in N2B27 in 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 SNM single cells and a cystic structure of SNMs to differentiate the SNM single cells into photoreceptor cells (see Amirpour, Fig 6 and Yun, Fig 4) and to differentiate the cystic structure of SNM into retinal pigment epithelial cells (see Cho, Fig 3A&B).
Furthermore, Applicant is reminded that the instant method claims do not require any specific compositions of the culture medium or culture duration, thus one of ordinary skill in the art would have had a reasonable expectation of success in co-culturing SNM single cells and a cystic structure of SNMs derived from pluripotent stem cells to differentiate them into photoreceptor cells and retinal pigment epithelial cells according to the claimed genus of methods.
Conclusion
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 extension fee 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 date of this final action.
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
