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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/3/2026 has been entered.
Claim Status
As of the Final Office Action mailed 6/2/2026, claims 1-10, 12, and 14-20 were pending.
In Applicant's Response filed on 8/3/2026, claim 1 was amended and claim 19 was canceled.
As such, claims 1-10, 12, 14-18, and 20 are pending and have been examined herein.
Withdrawn Objections/Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of record of claims 1-4, 8-10, and 14-20 under 35 USC § 103 as being unpatentable over Reichman et al (Stem Cells. 20 Feb 2017; 35(5):1176-1188; of record) in view of Sowden et al (WO2018154295A1, 2/21/2018; Published 8/30/2018; of record) have been withdrawn in view of Applicant’s amendments to claim 1. Applicant’s arguments with respect to claim(s) 1-4, 8-10, and 14-20 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 rejection of record of claims 5-7 under 35 USC § 103 as being unpatentable over Reichman et al (Stem Cells. 20 Feb 2017; 35(5):1176-1188; of record) in view of Sowden et al (WO2018154295A1, 2/21/2018; Published 8/30/2018; of record) as applied to claims 1-4, 8-10, and 14-20 and further in view of Cowan et al (Cell. 2020 Sep 17;182(6):1623-1640.e34; of record)have been withdrawn in view of Applicant’s amendments to claim 1.
Claim Interpretation
Claim 10 recites, inter alia, “wherein the retinal cell population comprises at least 70% single cells”. The examiner is interpreting that a single-cell suspension of retinal organoid comprising a mixed population of retinal cells (as described below) is sufficient to meet this limitation absent evidence to the contrary.
Claim Rejections - 35 USC § 102/103
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
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.
Claim(s) 1-4, 8-10, and 14-20 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Kim et al (PNAS, 9 May 2019; 116(22): 10824-10833).
Regarding claim 1, Kim teaches generation, transcriptome profiling, and functional validation of cone-rich human retinal organoid.
Regarding claim 1, 3-4, and 20, Kim teaches that hESCs were used to produces retinal cells (Materials and methods).
Kim continues to teach that the to gain insight into cell composition and single-cell transcriptomes of retinal organoids, we performed scRNA-seq of 8-mo retinal organoids (45). Transcriptome profiles were generated from a total of 1,130 individual cells from 10 retinal organoids. Four major groups, C0 to C3, were identified, with each accounting for 34%, 25%, 25%, and 15% of the total cells, respectively (Fig. 5A).
8-mo retinal organoids were mostly composed of photoreceptor cells, with cone and rod photoreceptors accounting for about 60% of all cells (“Single-Cell RNA-seq of 8-mo Organoids” para 1).
Kim is silent to the presence of CD15, CD133, A2B5, CD38 expression in the photoreceptor cell populations. As such, absent evidence to the contrary, the cells of Kim do not express these markers.
Regarding claim 2, Kim teaches that at day 105, retinal organoids expressed VSX2, PAX6, OTX2, and photoreceptor marker RCVRN in a laminar manner (Fig. 1 I and J; n = 3/4 retinal organoids), indicating that retinal differentiation in retinal organoids mimicked embryonic retinogenesis. At the stages from 6.5 mo to 11 mo, retinal organoids highly expressed cone photoreceptor marker OPN1MW/LW and rod photoreceptor marker RHO in protruding hair-like structures (Fig. 1 K–N; Movie S1; n = 6/6 retinal organoids), indicating differentiating inner/outer segments of cone and rod photoreceptors. A large set of transcription factors, including OTX2, THRB, CRX, NRL, and NR2E3, play critical roles in photoreceptor development and maturation (“Temporal expression of cell differentiation markers” para 1). Up-regulation of these genes was initially observed at 3 mo and further increased at 6.5 and 9 mo, consistent with their critical roles in photoreceptor differentiation (same para).
Regarding claim 8-10, Kim teaches that to prepare single-cell suspensions of retinal organoids (i.e., 100% of the population are single-cell; see claim interpretation above), ten retinal organoids on day 248 were dissociated using papain-based enzymatic digestion as described previously with slight modifications (SI Appendix, Table S1). Briefly, 45 U of activated papain solution (LS003126; Worthington) with 1.2 mg l-cysteine (Sigma) and 1,200 U of DNase I (Affymetrix) in 5 mL of HBSS buffer was added to the organoids and incubated at 37 °C for 40 min to release live cells. Post incubation, the single-cell solution was centrifuged at 200 × g and the papain was deactivated with ovomucoid solution [15 mg ovomucoid (Worthington Biochemical) and 15 mg BSA (Thermo Fisher Scientific) in 10 mL of MEM (Thermo Fisher Scientific)] (“Preparation of Single-Cell Suspensions” para 1).
Regarding claim 12, Kim teaches cone photoreceptor markers (ARR3, GUCA1C, PDE6C, and PDE6H) were up-regulated starting at 3 mo and remained highly expressed through 9 mo (“Temporal expression of cell differentiation markers” para 1).
Regarding claim 14-16, Fig. 3b of Kim shows that the rod cells have increased normalized expression of NR2E3 and RHO. 15% of the total cells where a mixed population of bipolar cells, RGCs, and amacrine cells (“Single-Cell RNA-seq of 8-mo Organoids” para 1).
Regarding claim 17, Kim teaches the decline in expression of RGC markers at 6.5 and 9 mo confirmed the gradual death of RGCs in retinal organoids due to limitations of the culture system (7). A similar expression pattern was observed for horizontal cell markers FOXN4, PTF1A, NTRK1, and ONECUT2 (“Temporal expression of cell differentiation markers” para 1).
Regarding claim 18, Kim teaches RGC markers POU4F2 and POU4F1 were not found in RNA-seq samples at day15 (Fig. 3B).
Kim teaches that the ratio of cones to rods was in the range of 1:1 to 2.8:1 based on immunostaining, but based on cell clusters, the ratio of cones to rods was 1.4:1 (Discussion, para 1). Kim teaches that the cone cells made up approx.. 34% of the total cells (overlaps with 15% to 45% cone receptor cells as claimed) and rod cells made up 25% (“Single cell RNA-Seq of 8-mo Organoids” para 1). Thus, Kim does not teach that the organoid is rod-rich. However, Kim also teaches that the long-term culture medium utilized in the current study did not contain any exogenous retinoic acid, which promotes rod development, likely contributing to a permissive condition for cone differentiation (Discussion para 2). The reference notes that other researchers who supplemented retinoic acid in their culture medium and generated retinal organoids that had “rod-dominant ONL” and confirmed that their retinal organoids were rod-dominant (same para). This shows that modifying the method of generating the organoids via supplementation of the culture medium with retinoic acid can produce rod-dominant organoids.
Accordingly, the claimed invention was anticipated by, or in the alternative, rendered prima facie obvious by the teachings of Kim. It would have been obvious prior to the effective filing date of the instantly claimed invention to quantify photoreceptor cells in a retinal organoid as taught by Kim, where the organoid is rod-rich as taught by Kim, to arrive at the instantly claimed invention. Kim shows that retinal organoids can be generated from hESCs and dissociated to quantify photoreceptor cell quantity. One of ordinary skill would have been motivated to modify the method of Kim to include retinoic acid in the culture medium as taught by Kim with a reasonable expectation of advantageously producing rod-dominant organoids as taught by the prior art. It would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to modify the culture medium producing the retinal organoid to include retinoic acid to make the organoid rod-dominant as taught by Kim with a reasonable expectation of success.
Claim(s) 5-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kim et al as applied to claims 1-4, 8-10, and 14-20 above, and further in view of Cowan et al (Cell. 2020 Sep 17;182(6):1623-1640.e34; of record).
The teachings of Kim were recited in the above 35 U.S.C. 102/103 rejection as applied to claim 1 and 3 of which claim 5-7 depend. The teachings will not be repeated here.
Kim does not teach:
the retinal cells are contacted with a composition to ensure that the cells remain in a dissociated cell suspension, wherein
the composition is an enzyme, and
the enzyme is DNAse (related to claim 7).
Regarding i)-iii), Cowan et al teaches cell types of the human retina and its organoids at single-cell resolution (title).
Cowan continues to teach the dissociation of organoids and human retina into single cells. The single-cell dissociation protocol was adapted from an existing protocol (“Single-cel RNA sequencing of retinal organoids” para 1). The retinal piece (derived from human retina or retinal organoid) was washed 2 × at 37°C with 1 mL ‘ringer solution’ without calcium. Activated papain solution was prepared by mixing 8 U of papain with 48 μl of ‘activator’ containing H2O with 1.1 μM EDTA, 5.5 mM L-cysteine and 0.07 mM 2-mercaptoethanol and incubating for 30 minutes at 37°C before diluting with 950 μl of 37°C ringer solution (same para). Tissue pieces were incubated at 37°C in activated papain solution: 300 μl per organoid for 35 minutes; 500 μl per human retinal piece for 30 minutes.
Regarding claim 5-7, Cowan teaches that the papain digestion reaction was stopped by placing the tubes on ice and adding equal volumes of ‘stop solution’ containing Neurobasal A medium, 2 mM GlutaMAX, 10% FBS and 20 U / ml DNase (same para). Samples were centrifuged at 200 g and 4°C for 30 s and washed using Neurobasal A supplemented with 2 mM GlutaMAX and 10% FBS: 1 mL per organoid; 1.5 mL per retinal piece (same para). A single cell suspension was generated by gently triturating 20 × with a 1,000-μl pipette tip in ice cold Neurobasal A, 2 mM GlutaMAX, 2% B27 supplement without vitamin A, and 20 U / ml DNase until no large clumps were visible: 300 μl per organoid; 500 μl per human retinal piece (Same para). Finally, the reference teaches that cell viability post-suspension creation was typically above 80% (same para). This shows that papain can be combined with DNAse to successfully digest retinal organoids to form single cell suspensions.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a population of retinal cells from retinal organoid as taught by Kim, where DNase is used to create single cell suspension as taught by Cowan, to arrive at the instantly claimed invention. As Cowan shows using papain and DNase to digest retinal organoids, one of ordinary skill would have been motivated to combine papain with DNase according to known methods to yield the predictable result of advantageously obtaining a single cell suspension of retinal cells with viability above 80% as taught by the prior art.
Double Patenting
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8-10, and 14-20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 and 8-17 of copending Application No. 18936315 in view of Kim et al.
Claim 1 of ‘315 recites “An in vitro method to produce sorted population of retinal cells, comprising: a) generating a three-dimensional retinal organoid; b) dissociating the three-dimensional retinal organoid; and c) positively sorting retinal cells based on one or more marker of photoreceptor cell identity and/or negatively sorting retinal cells based on one or more marker of non-photoreceptor cell identity to produce the sorted population of retinal cells”.
Claim 8 of ‘315 recites “wherein the three-dimensional retinal organoid is enzymatically dissociated”.
Claim 9 of ‘315 recites “wherein the enzyme is papain and/or trypsin”.
Claim 10 of ‘315 recites “herein the retinal cells are contacted with a composition to ensure that the cells remain in a dissociated cell suspension”.
Claim 11 of ‘315 recites “wherein the composition comprises an enzyme”.
Claim 12 of ‘315 recites “wherein the three-dimensional retinal organoid reaches between about DD 45 and DD 300 prior to being dissociated”.
Claim 13 of ‘315 recites “wherein the three-dimensional retinal organoid reaches about DD 90 to about DD 140 prior to being dissociated”.
Claim 14 of ‘315 recites “wherein the retinal cell population consists of at least about 70% single cells”.
Claim 15 of ‘315 recites “wherein the retinal cell population comprises about 55% to about 85% rod photoreceptor cells”. Please note that 55 to 85% rod photoreceptor cells would mean 15 to 45% cone photoreceptor cells are present in the population.
Claim 16 of ‘315 recites “wherein the stem cells are selected from pluripotent or multipotent stem cells; human, nonhuman primate or rodent nonembryonic stem cells; human, nonhuman primate or rodent embryonic stem cells; human, nonhuman primate or rodent induced pluripotent stem cells; and human, nonhuman primate or rodent recombinant pluripotent cells”.
Claim 17 of ‘315 recites “A sorted population of in vitro differentiated retinal cells, wherein said in vitro differentiated retinal cells are obtained by a method comprising: a) generating a three-dimensional retinal organoid; b) dissociating the three-dimensional retinal organoid; and c) positively sorting retinal cells based on one or more marker of photoreceptor cell identity and/or negatively sorting retinal cells based on one or more marker of non-photoreceptor cell identity to produce the sorted population of retinal cells”.
‘315 does not teach that the retinal cell population contains no more than one cell expressing CD15 or CD133 and less than 30% of cells expressing A2B5 and CD38.
However, Kim teaches generation, transcriptome profiling, and functional validation of cone-rich human retinal organoid. Kim teaches that hESCs were used to produces retinal cells (Materials and methods). Kim continues to teach that the 8-mo retinal organoids were mostly composed of photoreceptor cells, with cone and rod photoreceptors accounting for about 60% of all cells (“Single-Cell RNA-seq of 8-mo Organoids” para 1). Kim is silent to the presence of CD15, CD133, A2B5, CD38 expression in the photoreceptor cell populations. As such, absent evidence to the contrary, the cells of Kim do not express these markers.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s arguments have been fully considered but are not persuasive.
On p. 12 of Remarks, Applicant argues that claim 15 of ‘315 recites “about 55% to about 85% rod photoreceptor cells” but does not anticipate amended claim 1 because the lack of CD15/CD133 and A2B5/CD38 expression as recited in previous claim 19 (currently in amended claim 1) is not recited in said co-pending application.
While the argument has been considered it is not persuasive. Newly cited Kim shows that a retinal organoid can have its photoreceptor population quantified, with cone cells being at 35%. It also teaches that the culture method can be optimized by the inclusion or exclusion of retinoic acid to drive the organoid to be either cone-dominant or rod-dominant. Thus, applicant’s argument is not persuasive.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 9-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras Jr can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/G.R./Examiner, Art Unit 1632
/DAVID A MONTANARI/Examiner, Art Unit 1632
Prosecution Insights