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 .
Claim Status
As of the Non-Final Office Action mailed 8/26/2025, claims 1-21 were pending.
In Applicant's Response filed on 1/23/2026, claim 1 was amended and claims 16-21 were canceled.
As such, claims 1-15 are pending and have been examined herein.
Withdrawn Objections/Rejections
Objections and rejections of record (112b, 101, 102, and 103) posited in the Non-Final Office actions mailed 8/26/2025 of claims 16-21 are moot in view of their cancelation.
The rejection of record of claims 1-13 and 15-19 under 35 USC § 103 as being unpatentable over McCabe in view of Shimmura et al (US20140315305A1) have been withdrawn in view of Applicant’s amendments to claim 1. The rejection of claims 16-19 are moot in view of their cancelation.
The rejection of record of claim 14 under 35 USC § 103 as being unpatentable over McCabe in view of Shimmura et al (US20140315305A1) and further in view of Okumura (Invest Ophthalmol Vis Sci 2015 May; 56(5):2933-42) have been withdrawn in view of Applicant’s amendments to claim 1
New Grounds of Rejections Necessitated by Amendments
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.
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.
Claim(s) 1-4, 6-13, and 15 is/are rejected under 35 U.S.C. 103 as obvious over Zhao et al (WO2017190136A1, 5/1/2017; Published 11/2/2017).
Zhao teaches methods for producing major ocular cell types, including retinal ganglion cells, photoreceptors, retinal pigmented epithelium and corneal endothelial cells, from human pluripotent stem cells under defined culture conditions (abstract). Pluripotent stem cells can originate from a variety of animal sources including, for example, humans. Suitable pluripotent stem cells for use in accordance with this disclosure include, for example, induced pluripotent cell (para 61) (“wherein the pluripotent stem cells are selected from the group consisting of induced pluripotent stem cells” as in instant claim 12). The reference teaches providing a culture of ocular neural crest stem cells (NCSCs), and suppressing TGF and ROCK signaling in the culture, thereby culturing CECs (see claim 1 of Zhao), wherein the small molecule differentiator is selected from a ROCK inhibitor, a TGF inhibitor, or both (see claim 3 of Zhao). The TGF inhibitor is SB431542 (see claim 4 of Zhao) (“wherein the TGF-beta inhibitor is selected from the group consisting of SB431542” as in instant claim 2). The method further comprises the earlier step of providing a culture of eye field stem cells (EFSCs) and promoting WNT signaling in the EFSCs to produce the culture of NCSCs (see claim 6 of Zhao) and further comprising the earlier step of providing a culture of pluripotent stem cells (PSCs) and inducing differentiation to become EFSCs (see claim 9 of Zhao). The cells are cultured in a medium containing retinoic acid (para 56). Exemplary small molecules suitable for use in the present disclosure can include, for example, GSK-3 signaling inhibitors (e.g. CHIR99021) (para 55) (“wherein the Wnt activator is selected from the group consisting of GSK3 inhibitors” as in instant claim 3; “wherein the GSK3 inhibitor is CHIR99021” as in instant claim 4). CEC-like cells became visible after a week in culture (para 7) (“wherein the duration of step a) is from 3 to 10 days” as in instant claim 6). CECs are maintained in culture for about 1 day to about 2 months (para 67) (“wherein the duration of step b) is from 1 to 20 days” as in instant claim 7). The TGF-beta inhibitor is present in an amount of 1 uM (“wherein the concentration of SB431542 is from about 1 uM” as in instant claim 8). Neural crest stem cells are cultured in a cell differentiation environment that induces NCSCs to differentiate into corneal endothelial cells (CECs). In some embodiments, NCSCs are cultured in the presence and/ or absence of one or more differentiation regulator agents to induce or guide NCSCs to differentiate into CECs (para 61). The majority of CECs express markers ZO-1, N- cadherin and Na+/K+-ATPase (see claim 16 of Zhao) (“wherein the CEC-like cells express one or more markers selected from the group consisting of ZO-1, ATPase Na+/K+” as in instant claim 15). The concentration of CHIR99021 can be 3 uM (para 86) (“wherein the concentration of CHIR99021 is from about 1 uM to about 15 uM” as in instant claim 9; In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (see MPEP 2144.05)). While the Zhao reference does not state that the concentration of the retinoic acid in step a) is about 10 uM, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05)). The cells may or may not tightly adhere to the solid surface or to the substrate. The substrate for the adherent culture may further comprise, for example, any one or combination of polyornithine, laminin, poly-lysine, purified collagen, gelatin, extracellular matrix, fibronectin, tenacin, vitronectin, poly glycolytic acid (PGA), poly lactic acid (PLA), poly lactic-glycolic acid (PLGA), Matrigel, and feeder cell layers (para 27) (“wherein the cells are cultured on a cell culture substrate coated with one or more ECM proteins selected from the group consisting of laminins, collagens, vitronectin, fibronectin” as in instant claim 13).
While Zhao does not explicitly state that the retinoic acid is decreased or absent in subsequent culture, based on the teachings of Zhao, it would have been a matter of routine optimization using standard laboratory techniques available at the time of filing to determine the appropriate time to remove or reduce the amount of differentiation regulators, such as retinoic acid. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). Thus, absent evidence to the contrary, Zhao reads on “method of producing corneal endothelial cell-like cells from pluripotent stem cells, comprising a) culturing the pluripotent stem cells in the presence of at least one TGF-beta inhibitor, at least one Wnt activator, and retinoic acid, but in the absence of insulin, Noggin, platelet-derived growth factor, DKK-2, and ROCK inhibitors, and b) culturing cells from step a) in the presence of at least one TGF-beta inhibitor and at least one Wnt activator, but in the absence of or gradually decreasing concentration of retinoic acid, and in the absence of insulin, Noggin, PDGF, DKK-2, and ROCK inhibitors, thereby producing CEC-like cells” as in instant claim 1 and “wherein the concentration of retinoic acid is gradually decreased to the concentration of 0 in step b” as in instant claim 11.
The reference is silent on the presence of insulin, DKK2, PDGF, and Noggin in the medium. While Zhao discusses preferred embodiments including ROCK inhibitors, the claims do not require the use of ROCK inhibitors (see claim 3 of Zhao). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004) (see MPEP 2123(II).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create CEC cells from induced pluripotent stem cells by culturing in TGF-beta inhibitor, Wnt activator, and retinoic acid as taught by Zhao to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill to use the method of Zhao to arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill would have been motivated to use the method of Zhao with the reasonable expectation of advantageously having cells that have the capacity to integrate into recipient retinas after transplantation as taught by the prior art.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al as applied to claims 1-4, 6-13, and 15 above, and further in view of Chen et al (Exp Ther Med. 2015 Feb;9(2):351-360. Epub 2014 Dec 3.).
The difference between the Zhao reference and the instant invention is that it does not teach that the retinoic acid is all-trans retinoic acid.
Chen teaches treatment with retinoic acid and lens epithelial cell-conditioned medium in vitro directed the differentiation of pluripotent stem cells towards corneal endothelial cell-like cells (title). The reference teaches induced pluripotent stem cells (iPSCs) have extensive self-renewal capacity and the potential to differentiate into all tissue-specific cell lineages, including corneal endothelial cells (CECs) (abstract). Mouse ESCs and iPSCs were induced to differentiate into CECs using CEC embryonic development events as a guide (Materials and Methods). All-trans retinoic acid (RA) treatment during the embryoid body (EB) differentiation step was used to promote neural crest (NC) cell differentiation as first step and was followed by a second induction in CEC- or lens epithelial cell (LEC)-conditioned medium (CM) to ultimately generate CEC-like cells. The data indicated that 4 days of treatment with 1 μM RA starting on day 4 of EB formation favored NC cell differentiation and that plating on gelatin-coated plates led to cell migration out of the EBs (abstract). The CECs had positive immunostaining of ZO-1, AQP1, Na+-K+-ATPase, VE-cadherin, N-cadherin and vimentin, which have been used as general markers for CECs, was used to identify the cultured cells as CECs (Fig. 1B–G).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create corneal endothelial cells from pluripotent stem cells as taught by Zhao, where the retinoic acid is all-trans retinoic acid as taught by Chen, to arrive at the instantly claimed invention. As Chen shows that all-trans retinoic acid can be successfully used to create corneal endothelial cells, one of ordinary skill would have been motivated to simply substitute one known element (retinoic acid of Zhao) for another (all-trans retinoic acid of Chen) to obtain the predictable result of advantageously producing Zo-1, AQP1, Na+/K+-ATPase, N-cadherin positive corneal endothelial cells as taught by the prior art.
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al as applied to claims 1-4, 6-13, and 15 above, and further in view of Okumura et al (Invest Ophthalmol Vis Sci. 2015 May; 56(5):2933-42; previously cited).
The difference between the Zhao reference and the instant invention is that it does not teach that the ECM protein is laminin-521.
Okumura teaches the usefulness of laminin isoforms as substrates for culturing human corneal endothelial cells (abstract). Specific laminin isoforms expressed in Descemet's membrane may transduce biological signals to CECs, and that these signals may trigger the in vitro expansion of CECs for clinical use (Introduction, para 4). Primary HCECs seeded on laminin-511 and -521 formed a monolayer of cells with a hexagonal phenotype after 48 hours of culture (“Effect of Laminin-511 and -521” para 1) (“wherein the ECM protein is laminin-521” as in instant claim 14). In contrast, control HCECs seeded on laminin-211 coated or uncoated culture plates formed patchy colonies rather than a confluent monolayer (same para; Fig. 2A). The reference concludes that laminin-511 and -521 were the laminin isoforms present in the Descemet's membrane, and that these laminins modulate the adhesion and proliferation of CECs (Discussion, last para).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to produce CEC-like cells from pluripotent cells by culturing on ECM substrate as taught by Zhao, where the ECM is laminin-521 as taught by Okumura, to arrive at the instantly claimed invention. As Okumura shows that CECs can be cultured on laminin-521, one of ordinary skill would have been motivated to simply substitute one known element [laminin substrate of Zhao] for another [laminin-521 as taught by Okumura] to advantageously obtain the predictable result of having a substrate that modulates the adhesion and proliferation of the CEC-like cells and have the cells obtain their hexagonal phenotype during culture as taught by the prior art.
Response to Arguments
Applicant’s arguments with respect to the McCabe and Shimmura references have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. The response to arguments does not contain any arguments directed to the teachings of Okumura.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632