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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 26, 2025 has been entered.
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
3. Applicant’s amendment filed June 26, 2025 is acknowledged. Claims 3-4, 8, 17-18 and 21 are cancelled. Claims 1-2 and 6-7 are amended. Claims 23-25 are newly added. Claims 1-2, 5-7, 9-16, 19-20, 22 and new claims 23-25 are pending in this Application. Claims 5, 9-16 and 19-20 are withdrawn with traverse (filed 8/23/22) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on August 23, 2022.
4. Claims 1-2, 6-7, and 22-25 are under examination in this office action.
5. Applicant’s arguments filed on June 26, 2025 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
6. The rejection of claims 1-2, 4, 6-7, 18 and 22 under 35 U.S.C. 103 as being unpatentable over Kuwahara et al. (US2017/0313976) in view of Mikhailova et al. (US2016/0060595) and Ilmarinen et al. (US2019/0264171) is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 4 and 18.
The rejection of claims 1-2, 4, 6-7, 18 and 22 under 35 U.S.C. 103 as being unpatentable over Kuwahara et al. (US2017/0313976) in view of Mikhailova et al. (US2016/0060595) and Ilmarinen et al. (US2019/0264717) as applied to claims 1-2, 4, 6-7,18 and 22 above, and further in view of Kern et al. (US10457915) is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 4 and 18.
The rejection of claims 1-2, 4, 6-7, 18 and 22 on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of US11371016 in view of Mikhailova et al. (US2016/0060595), Ilmarinen et al. (US2019/0264717) and Kern et al. (US10457915) is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 4 and 18.
The provisional rejection of claims 1-2, 4, 6-7, 18 and 22 on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 17-19, 21-26, 28-45 of copending Application No. 16/766529 or claims 1-21 of copending Application No. 17/870569 in view of Mikhailova et al. (US2016/0060595), Ilmarinen et al. (US2019/0264717) and Kern et al. (US10457915) is withdrawn in response to Applicant’s amendment to the claims and cancelation of claims 4 and 18.
New Grounds of Rejection Necessitated by the Amendment
The following rejections are new grounds of rejections necessitated by the amendment filed on June 26, 2025.
Claim Rejections - 35 USC § 112
7. 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 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], 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.
Claim 23 is 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 23 recites “all of the culturing steps are performed by suspension culturing” and also depends from claim 1 that recites “(1) suspension-culturing pluripotent stem cells…….(2) suspension-culturing the cell aggregate formed in (1)….”, which are suspension culturing. Thus, claim 23 does not further limit the subject matter of the claim upon which it depends. 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.
Claim Rejections - 35 USC § 103
8. 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-2 and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Kuwahara et al. (US11214771, as in IDS; also published as US2017/0313976, cited previously) in view of Sasai et al. (US11274277, issued, priority Aug 6, 2013; also published as US2016/0186136).
Claims 1 and 22-25 as amended are drawn to a method for producing a cell mass comprising i) neural cell or neural tissue and ii) nonneural epithelial tissue, the method comprising
(1) suspension-culturing pluripotent stem cells (PSCs) to form a cell aggregate
in the presence of 1) a Wnt-inhibitor and 2) a TGFb-inhibitor and
in the absence of a FGF activator; and
(2) suspension-culturing the cell aggregate formed in step (1)
in the presence of 1) a BMP-activator, 2) a Wnt-inhibitor and 3) a TGFb-inhibitor and
in the absence of an FGF-activator to obtain the cell mass comprising 1) neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue,
wherein the BMP activator in (2) is added on from day 1 to day 2 from the start of the suspension culturing PSCs in (1),
wherein the neural cells are retina cells or precursor cells thereof, the neural tissue is retina or precursor tissue thereof and the nonneural epithelial tissue is cornea or a precursor tissue thereof.
Claim 2 as amended is drawn to a method for producing a cell mass as in claim 1, the method comprising:
a) maintenance-culturing PSCs in the absence of feeder cells and in a medium comprising (1) a TGF inhibitor and/or a SHH activator, and (2) a factor for maintaining an undifferentiated state under adhesion culturing, wherein the factor is selected from bFGF, FGF4 or EGF; and the same steps (1)-(2) recited in the method of claim 1.
Kuwahara (US11214771) teaches a method for producing a cell aggregate (cell mass) comprising neural cell or a neural tissue and epithelial-like cells, the method comprising:
Step (1) maintenance-culturing PSCs in the absence of feeder cells and in a medium comprising 1) a TGF inhibitor and/or a SHH activator, and 2) a factor for maintaining an undifferentiated state under adhesion culturing (see col.2, lines 32-55; col. 4, lines 14-17; col. 17, lines 11-19; col. 17, line 33-col.22, line 61; col. 25, lines 23-col. 26, line 23; col. 30, lines 10-63; col. 38, line 9-col. 46, line 28),
Step (2) suspension-culturing the PSCs from step (1) to form a cell aggregate in the presence of 1) a Wnt-inhibitor and 2) a TGF-inhibitor and in the absence of a FGF activator; (see col. 53, lines 7-59; col.2, lines 56-67; col. 17, lines 21-22; col. 26, lines 24-26; col. 27, line 64-col.28, line 10; col. 38, line 9-col. 46, line 28);
Step (3) suspension-culturing the cell aggregate from step (2) in the presence of a differentiation-inducing factor to obtain an aggregate containing neural cells or a neural tissue that is a retina or precursor thereof and epithelial-like cells, wherein the differentiation-inducing factor is a BMP activator, a TGF-b inhibitor and a Wnt inhibitor (see col. 35, lines 14-19; col.2; lines 58-67; col. 3, lines 23-35; col.3, lines 66-col. 4, line3; col. 17, lines 23-26; col. 32, line 46-col.33, line 21; col. 35, lines 4-col. 36, line 30; col. 38, line 9-col. 46, line 28; col. 53, lines 7-59;col. 61-98, Examples 1-30);
wherein the TGF- inhibitor includes SB431542, A-83-01, Lefty, or LDN193189 (col.3, lines 10-19; col. 4, lines 4-6; col. 20, lines 8-col.22, line 39);
wherein the SHH activator includes Shh, SAG, Purmophamine (see col.3, lines20-22);
wherein the factor for maintaining an undifferentiated state includes bFGF, FGF4, FGF8, EGF (see col.3, lines 1-2);
wherein the BMP activator includes BMP4, BMP2, BMP7 and GD7 (see col.3, lines 23-32; col. 33, lines 12-); and
wherein Wnt inhibitor includes IWP-2 (see col.4, lnes7-9; col. 53, lines 9-53); and
wherein the neural cell or a neural tissue includes a retinal tissue, retinal progenitor cell, neural retinal progenitor cell, photoreceptor precursor cell, photoreceptor cell, rod photoreceptor cell, cone photoreceptor cell, horizontal cell, amacrine cell, interneuron, ganglion cell, retinal pigment epithelial cell, and ciliary marginal zone cell, which is retina or retina precursor thereof (see col.3, lines 30-43; col. 15, lines 26-col. 16, line 32; col. 38, lines 9).
Kuwahara teaches that the BMP activator and differentiation-inducing factor including a Wnt inhibitor and a TGFb inhibitor are added to the medium from day 1-day 9 or simultaneously with or within about 24hrs or on day 0-18, day 1-9 from the start of the second step (col. 35, lines 4-19; col. 35, lines 46-col.36, line 30; col. 53, lines 7-59;), which meets the limitation “wherein the BMP…is added on from day 1 to day 2 from the start of the suspension-culturing in (1) recited in claims 1-2. Kuwahara teaches that the period for culturing in the first step is 0.5-144hrs, not less than 1hr, 2hr,6hr, 12hr, 18hr, 24hr, within 96hr or 72hr, 2-96hr, 6-48hr, 12-48hr, 18-28hr (col. 4, lines 14-17; col. 24, lines 20-27) and under adhesion culturing method as in claim 2 (see col. 4, lines 14-17; col. 24, lines 49-66). Kuwahara teaches that the period for suspension-culturing in the second step is 12hr-6days or 12hr-48hr, which meets the limitation recited in claim 22(see col. 29, lines 4-7). The steps 2-3 disclosed by Kuwahara are perform by suspension culturing as in claim 23. Kuwahara teaches that the duration of the suspension in the presence of TGF-b inhibitor in steps of forming cell aggregates and differentiation of retinal neural tissue or precursor thereof and nonneural epithelial tissue or precursor thereof is 1-100 days, 7-200 days, 20-70 days or 30-60 days, which meets the limitation “at least 21 days” or “21-28 days” recited in claims 24-25 (see col. 35, lines 8-13; 35-40;; col. 45, lines 1-2; col. 49, lines11-12).
The method of Kuwahara i) culturing pluripotent stem cells (PSCs) in the absence of feeder cells and in a medium containing a TGF- inhibitor (SB431542, A-83-01, Lefty, or LDN193189) and/or a SHH activator including Shh, SAG, Purmophamine, and a factor for maintaining undifferentiated state including a bFGF under adhesion culturing (as in step (a) of instant claim 2); ii) suspension-culturing the PSCs that were maintained in (a) to form a cell aggregate in the presence of a Wnt inhibitor (IWP-2) and a TGF- inhibitor (SB431542, A-83-01, Lefty, or LDN193189) (as in step (1) of instant claims 1-2); iii) suspension-culturing the cell aggregate in the presence a differentiation-inducing factor including a BMP activator (BMP4, BMP2, BMP7 and GD7), a Wnt inhibitor (IWP-2) and a TGF- inhibitor (SB431542, A-83-01, Lefty, or LDN193189) to obtain an aggregate containing neural cells or a neural tissue that is a retina or precursor thereof and epithelial-like cells (as in step (2) of instant claims 1-2).
But Kuwahara does not explicitly teach that the cell aggregate/cell mass comprising neural tissue in the inside and the nonneural epithelial tissue on the outside and a space formed between the neural tissue in the inside and the nonneural epithelial tissue.
Sasai et al. (US11274277) teach that “when a pluripotent stem cell aggregate is cultured in suspension in a medium containing a bone morphogenic factor signal transduction pathway activating substance (BMP4 etc.), a neural retinal tissue is induced in the inside of the aggregate” and “When the aggregate containing a neural retinal tissue in the inside…. is continuously cultured in suspension in a medium containing a bone morphogenic factor signal transduction pathway activating substance (BMP4 etc.), an ectodermal epithelial cell layer is formed on the outside of the neural retinal tissue, and the neural retinal tissue induces differentiation of the ectodermal epithelial cell layer into a corneal epithelial precursor tissue and/or a lens placode to form a corneal epithelial precursor tissue and/or a lens placode in the surface layer of the cell aggregate. In the aggregate, the corneal epithelial precursor tissue and/or the lens placode constitute(s) the surface layer of the cell aggregate, the neural retinal tissue is contained in the inside of the cell aggregate, and the corneal epithelial precursor tissue and/or the lens placode are(is) adjacent to the neural retinal tissue” (col. 15, line 64-col.16, line 30; col. 16, line 64-col.17, line 44).
Sasai teaches a method of producing a cell aggregate comprising an anterior eye segment tissue or a partial structure thereof or a precursor tissue thereof,
(a) culturing pluripotent stem cells (PSCs) in suspension in a serum free medium to form an aggregate (col. 9-11),
(b) culturing the cell aggregate from step (a) in suspension in the absence of a substance that activates the BMP4 signaling pathway (a BMP4 activator) (col.12-13);
(c-1) culturing the cell aggregate from step (b) in suspension in a medium in the presence of a BMP4 activator to form (i) an Rx+ Chx10+ neuroepithelial-like structure in the inside of the aggregate and (ii) an Rx- ectodermal epithelial cell layer on the surface of the aggregate (col. 15-16), and
(c-2) culturing the cell aggregate from step (c-1) in suspension in a medium in the presence of a BMP4 activator in a concentration reduced to half or less than step (c-1) to form (iii) a corneal epithelial precursor tissue that is pan-cytokeratin positive, (iv) a lens placode that is L-Maf positive or (v) both a corneal epithelial precursor tissue that is pan-cytokeratin positive and a lens placode that is L-Maf positive on the surface of the aggregate (col. 16, lines 63-col.17, line 44);
(d) culturing the cell aggregate from step (c-2) in suspension in a medium in the presence of a BMP4 activator in a concentration reduced to half or less than that in step (c-1) to induce a corneal epithelium from the corneal epithelial precursor tissue, thereby obtaining a cell aggregate comprising a corneal epithelial constituting the surface layer of the cell aggregate, and a neural retinal tissue in the inside of the cell aggregate (col. 17, line 45-col. 18, line 12);
wherein the medium in steps (c-1),(c-2) and (d) is free of an SHH signal promoter (SHH activator), and wherein the suspension culture in steps (a), (b), (c-1), (c-2) and (d) is performed in the absence of a feeder cell (see abstract; col.2, line 65-col.3, line 48;; col.9-18; col.22-26 Examples 1-5; col. 26-27, claims 1-17); and wherein a medium to be used for aggregate formation may be the medium used for induction of differentiation of pluripotent stem cells into an anterior eye segment tissue or a partial structure thereof, or a precursor tissue thereof (see col. 9, lines 55-59). Sasai teaches that FGF may be used for further suspension culture for a cell aggregate containing stratified corneal epithelium, a mesenchymal tissue (corneal stroma or a precursor tissue thereof, and corneal endothelium or a precursor tissue thereof), and a neural retinal tissue but not required (see col.18, lines 23-26). Sasai teaches that the duration of suspension culturing to form cell aggregates and differentiation of neural retinal tissue inside of the cell aggregates is in 8, 9, 10…or 15 days, and for corneal epithelial precursor tissue formed outside of the cell aggregates is 10,…28 days and for long term culture of cell aggregates, a corneal epithelium is formed on the surface of the cell aggregates in 20, 25,…70 days from the start of the floating culture (col.16, lines 10-12; col.16, lines 41-45; col. 17, lines 24-26).
The teaching of Sasai teaches that suspension-culturing PSC-cell aggregates in a medium comprising BMP4 can result in induction and self-organization of neural retinal tissue in the inside of the cell aggregates and nonneural epithelial on the outside of the cell aggregates and a space formed between the neural retinal tissue in the inside and nonneural epithelial on the outside.
A person of ordinary skill in the art would have recognized that selecting and applying the known feature of induction and self-organization of retinal neural in the inside of the cell aggregates and nonneural epithelial tissue including corneal epithelial cells or corneal epithelial precursor tissue on the outside and a space formed between the neural tissue in the inside and the nonneural epithelial tissue outside of the cell aggregates from PSC-cell aggregates cultured in suspension in a medium containing a BMP activator including BMP4 and the known technique disclosed by Sasai to the Kuwahara’s method would have yielded the predictable result of obtaining a cell mass comprising (1) neural retinal tissue including retina or a precursor thereof in the inside and (2) nonneural epithelial tissue including cornea or precursor thereof on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue, and resulted in an improved method.
Using and including suspension-culturing a PSC cell aggregate in a medium containing a BMP activator including BMP4 in the Kuwahara’s method would result in induction and self-organization of neural retinal tissue including retina or a precursor thereof in the inside of the PSC-derived cell aggregate and a nonneural epithelial cell layer/ corneal epithelial precursor tissue formed on the outside of the PSC-derived cell aggregate and a space formed between the neural tissue in the inside and the nonneural epithelial tissue, and expand application of the Kuwahara’s method in producing cell mass comprising , and would increase the production of cell mass containing an anterior eye segment tissue or partial structure thereof and its use for pharmaceutical or therapeutic purposes or increase patient’s satisfaction with treatment of corneal and retinal disorders using cell therapy because the PSC-derived cell aggregates cultured in suspension in a medium comprising a BMP activator or BMP4 result in induction and self-organization of neural retinal tissue including retina or a precursor thereof in the inside of the PSC-derived cell aggregate and a nonneural epithelial cell layer/corneal epithelial precursor tissue formed on the outside of the PSC-derived cell aggregate and a space formed between the neural tissue in the inside and the nonneural epithelial tissue to form an anterior eye segment tissue or a partial structure thereof.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known feature of induction and self-organization of retinal neural in the inside of the cell aggregates and nonneural epithelial tissue including corneal epithelial cells or corneal epithelial precursor tissue on the outside and a space formed between the neural tissue in the inside and the nonneural epithelial tissue outside of the cell aggregates from PSC-cell aggregates cultured in suspension in a medium containing a BMP activator including BMP4 and the known technique disclosed by Sasai to the Kuwahara’s method, and yield the predictable result of producing a cell mass comprising (1) neural retinal tissue including retina or a precursor thereof in the inside and (2) nonneural epithelial tissue including cornea or precursor thereof on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue.
Claim Rejections - 35 USC § 103
9. Claims 1-2 and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Kuwahara et al. (US11214771) in view of Sasai et al. (US11274277) as applied to claims 1-2 and 22-25 above, and further in view of Kern et al. (US10457915, cited previously).
Kuwahara and Sasai are set forth above but fail to teach different Wnt inhibitors, different TGF- inhibitors recited in independent claims.
Kern et al. (US10457915) teaches TGF- inhibitors including A83-01, D4476, GW788388, ITD1, LY2109761, Galunisertib (LY2157299), LY364947, 8268712, RepSox, SB431542, SB505124, SB525334, SD-208 or SIS3 and Wnt inhibitors including Cardionogen 1, Calphostin C, CCT031374 hydrobromide, FH535, ICG-001, iCRT14, IWP-2, IWP-4, IWP-12, IWP-L6, IWR-1, JW55, JW67, KY02111, LGK-974, MN64, PNU74654, QS11, TAK715, TC-E5001, WAY316606 hydrochloride, WIKI4, WNT-059 or XAV-939 for generating retinal epithelial cells and retinal pigmented epithelial cells from hPSCs (see col.2, lines 4-32; col. 8, lines 12-20;38-43)
A person of ordinary skill in the art would have recognized that selecting and applying the known TGF- inhibitors, the known Wnt inhibitors and the known technique disclosed by Kern to the method of Kuwahara and Sasai would have yielded the predictable result of producing a cell mass comprising 1) neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue and wherein the neural tissue is retina or a precursor thereof, and the nonneural epithelial tissue is cornea or a precursor thereof, and resulted in an improved method.
Using different known TGF- inhibitors and different known Wnt inhibitors in the method of Kuwahara and Sasai would expand application of the method of Kuwahara and Sasai, and would increase patient’s satisfaction with treatment of corneal and retinal disorders using cell therapy because these different Wnt inhibitors, different TGF- inhibitors recited in independent claims have been used to successfully generate retinal epithelial cells and retinal pigmented epithelial cells from hPSCs.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known TGF- inhibitors, the known Wnt inhibitors and the known technique disclosed by Kern to the method of Kuwahara and Sasai, and yield the predictable result of producing a cell mass comprising 1) neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue and wherein the neural tissue is retina or a precursor thereof, and the nonneural epithelial tissue is cornea or a precursor thereof.
Claim Rejections - 35 USC § 103
10. Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Kuwahara et al. (US11214771) in view of Sasai et al. (US11274277) and Kern et al. (US10457915) as applied to claims 1-2 and 22-25 above, and further in view of Mikhailova et al. (US2016/0060595, cited previously).
Kuwahara and Sasai are set forth above and teach the steps (1)-(2) of claim 6 and steps (a) and (1)-(2) of claim 7. Sasai also teaches that corneal tissue, corneal epithelial cells or precursor tissue thereof can be separated from the cell aggreges containing the corneal tissue, corneal epithelial cells or precursor tissue thereof and a neural retinal tissue using FACS, and the purified corneal tissue, corneal epithelial cells or precursor tissue thereof can be cultured to in the form of a sheet for transplantation (see col.21, lines 36-col.22, line 42).
But Kuwahara, Sasai and Kern do not explicitly teach the steps of collecting and dispersing nonneural epithelial tissue from the cell mass and culturing the nonneural epithelial cell on a flat plane to produce nonneural epithelial tissue sheet recited in claims 6-7.
Mikhailova et al. (US2016/0060595) teach a method of producing corneal epithelial precursor cells, corneal epithelial cells or stratified corneal epithelium or producing early pigmented RPE precursor cells, comprising culturing PSCs including ESCs or iPSCs in a culture medium comprising a TGF- inhibitor including SB-505124, a Wnt inhibitor including IWP-2 and a FGF including bFGF or FGF-2 to form three dimensional cell clusters, which are cell masses comprising nonneural epithelial tissue that is a corneal precursor (see paragraphs [0041]-[0071]; [0073]; [0091]-[0095]; [0101]-[0110]). Mikhailova also teaches methods for producing a corneal epithelial tissue sheet comprising the steps of collecting and culturing the corneal epithelial precursor cells from the cell mass obtained above; and dispersing the corneal epithelial precursor cells and culturing the cells on a flat plane culture plate to obtain a corneal epithelial tissue sheet (see [0062]-[0071]; [0073]; [0094]-[0095]).
A person of ordinary skill in the art would have recognized that applying the known method of producing a sheet of nonneural epithelial tissue that is cornea or a precursor tissue thereof disclosed by Mikhailova to the method of Kuwahara, Sasai and Kern would have yielded the predictable result of producing a nonneural epithelial tissue sheet from the cell mass, wherein the cell mass comprises 1) neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue and wherein the neural tissue is retina or a precursor thereof, and the nonneural epithelial tissue is cornea or a precursor thereof, and resulted in an improved method.
Nonneural epithelial tissue sheet or corneal epithelial tissue sheet can be produced by collecting nonneural epithelial tissue that is cornea or a precursor thereof generated from the cell mass produced and differentiated from PSCs in the medium comprising a BMP activator/BMP4, a TGF- inhibitor and a Wnt inhibitor, and dispersing and culturing the nonneural epithelial tissue that is cornea or a precursor thereof from the cell mass on a flat plane to obtain a nonneural epithelial tissue sheet as taught by Sasai and Mikhailova.
Including the steps of collecting and dispersing nonneural epithelial tissue from the cell mass and culturing the nonneural epithelial tissue on a flat plane to produce a nonneural epithelial tissue sheet in the method of Kuwahara, Sasai and Kern would produce a nonneural epithelial tissue sheet or a corneal epithelial tissue sheet, and would expand application of the method of Kuwahara, Sasai and Kern in therapeutic purposes and would increase patient’s satisfaction with treatment of corneal and retinal disorders using cell therapy.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply known method of producing a sheet of nonneural epithelial tissue that is cornea or a precursor tissue thereof disclosed by Mikhailova to the method of Kuwahara, Sasai and Kern, and yield the predictable result of producing a nonneural epithelial tissue sheet from the cell mass by collecting the nonneural epithelial tissue including cornea, corneal epithelial tissue or a precursor thereof, and dispersing and culturing the nonneural epithelial tissue on a flat plane to obtain a nonneural epithelial tissue sheet, wherein the cell mass comprises 1) neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue and wherein the neural tissue is retina or a precursor thereof, and the nonneural epithelial tissue is cornea or a precursor thereof.
Double Patenting
11. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-2, 6-7, and 22-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of US11371016 or claims 1-21 of US12378520 of in view of Sasai et al. (US11274277), Kern et al. (US10457915) and Mikhailova et al. (US2016/0060595).
Claims 1-22 of US11371016 (the ‘016 patent) recite the same method steps and using the same materials as in instant claims and appear to be directed to achieving the same goal of producing a cell mass comprising retinal progenitor cells, photoreceptor cells, rod photoreceptor cells, cone photoreceptor cells, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells and retinal pigment epithelial cells, which are retinal cells or precursors thereof and nonneural epithelial cells and also obtaining retinal pigment epithelial cells.
Claims 1-21 of US12378520 (the ‘520) recite the same method steps and using the same materials as in instant claims and appear to be directed to achieving the same goal of producing a cell mass comprising retinal tissue or retinal progenitor cells and nonneural epithelial tissue or precursor thereof.
While the claims of the ‘016 patent or the ‘520 patent do not explicitly recite that the BMP is added at the time that is exactly identical to the claimed time of day 1 to day 2 from the start of suspension-culturing PSCs in (1), the time recited in the claims of the ‘016 patent or the ‘520 patent for adding BMP activator in the medium is day 1 (24hr) or later from the start of the second step (i.e. suspension culturing PSCs in the presence of Wnt inhibitor to form a cell aggregate), which is within or overlapping with the claimed range of day 1 to day 2.
While the claims of the ‘016 patent or the ‘520 patent do not explicitly recite nonneural epithelial tissue or cornea or a precursor thereof and is encompassed in the cell mass comprising a neural retinal tissue or a precursor thereof and nonneural epithelial tissue or cornea or a precursor thereof; or producing a nonneural epithelial tissue sheet from the cell mass, Sasai and Mikhailova teach these limitations for the reasons set forth above under 103 rejections. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known nonneural epithelial tissue that is cornea or a precursor tissue thereof produced by PSC cell aggregates cultured in a medium containing a BMP activator/BMP4, a TGF- inhibitor and a Wnt inhibitor, and the known technique of producing a nonneural epithelial tissue sheet that is cornea or a precursor tissue thereof disclosed by Sasai and Mikhailova to the method of the ‘016 patent or the ‘520 patent, and yield the predictable result of producing a cell mass or producing a nonneural epithelial tissue sheet from the cell mass, wherein the cell mass comprises neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue and wherein the neural tissue is retina or a precursor thereof, and the nonneural epithelial tissue is cornea or a precursor thereof.
While the claims of the ‘016 patent or the ‘520 patent do not explicitly recite using different TGF- inhibitors, different Wnt inhibitors, different SHH activators and different BMP activators recited in independent claims, Mikhailova and Kern teach these limitations for the reasons set forth above. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known different TGF- inhibitors, different Wnt inhibitors, different SHH activators and different BMP activators recited in independent claims and the known technique disclosed by Mikhailova and Kern to the method of the ‘016 patent or the ‘520 patent, and yield the predictable result of producing a cell mass or producing a nonneural epithelial tissue sheet from the cell mass, wherein the cell mass comprises neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue and wherein the neural tissue is retina or a precursor thereof, and the nonneural epithelial tissue is cornea or a precursor thereof.
Double Patenting
12. Claims 1-2, 6-7, and 22-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of copending Application No. 19/284393 in view of Sasai et al. (US11274277), Kern et al. (US10457915) and Mikhailova et al. (US2016/0060595).
Claims 1-11 of the Application Nos. 19/284393 (the ‘393 Application) recite the same method steps and using the same materials as in instant claims and appear to be directed to achieving the same goal of producing a cell mass comprising neural cells that are retinal cells or precursor thereof/retinal progenitor cells or retina tissue or precursor thereof and (ii) nonneural epithelial tissue that is cornea or precursor and also obtaining retinal pigment epithelial cells.
While the claims of the ‘393 Application do not explicitly recite that the BMP is added at the time that is exactly identical to the claimed time of day 1 to day 2 from the start of suspension-culturing PSCs in (1), the time recited in the claims of the ‘393 Application for adding BMP activator in the medium is day 1-day 15 from the start of the second step (i.e. suspension culturing PSCs in the presence of Wnt inhibitor to form a cell aggregate; see claim 11), which is within or overlapping with the claimed range of day 1 to day 2.
While the claims of the ‘393 Application do not explicitly recite nonneural epithelial tissue or cornea or a precursor thereof and is encompassed in the cell mass comprising a neural retinal tissue or a precursor thereof and nonneural epithelial tissue or cornea or a precursor thereof; or producing a nonneural epithelial tissue sheet from the cell mass, Sasai and Mikhailova teach these limitations for the reasons set forth above under 103 rejections. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known nonneural epithelial tissue that is cornea or a precursor tissue thereof produced by PSC cell aggregates cultured in a medium containing a BMP activator/BMP4, a TGF- inhibitor and a Wnt inhibitor, and the known technique of producing a nonneural epithelial tissue sheet that is cornea or a precursor tissue thereof disclosed by Sasai and Mikhailova to the method of the ‘393 Application and yield the predictable result of producing a cell mass or producing a nonneural epithelial tissue sheet from the cell mass, wherein the cell mass comprises neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue and wherein the neural tissue is retina or a precursor thereof, and the nonneural epithelial tissue is cornea or a precursor thereof.
While the claims of the ‘393 Application do not explicitly recite using different TGF- inhibitors, different Wnt inhibitors, different SHH activators and different BMP activators recited in independent claims, Mikhailova and Kern teach these limitations for the reasons set forth above. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known different TGF- inhibitors, different Wnt inhibitors, different SHH activators and different BMP activators recited in independent claims and the known technique disclosed by Mikhailova and Kern to the method of the ‘393 Application, and yield the predictable result of producing a cell mass or producing a nonneural epithelial tissue sheet from the cell mass, wherein the cell mass comprises neural tissue in the inside and 2) nonneural epithelial tissue on the outside, and a space formed between the neural tissue in the inside and the nonneural epithelial tissue and wherein the neural tissue is retina or a precursor thereof, and the nonneural epithelial tissue is cornea or a precursor thereof.
Conclusion
13. NO CLAIM IS ALLOWED.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
June 25, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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