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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05-11-2026 has been entered.
Applicant's amendments to the claims and arguments filed on 05-11-2026 have been received and entered. Claims 1 and 10 have been amended. Claims 2 has been canceled. Claims 1, 3-18 are pending.
Election/Restrictions
Applicant’s election of Group I (Claims 1-9 and 16), species FOXG1 as the retinal cell marker species, and species a) the second cells form at least one lens, at least one cornea, or combinations thereof (from claim 5) in the reply filed on 18-12-2023 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 6-8, 10-15, 17-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 18-12-2023.
Claims 1, 3, 4 (species FOXG1 as the retinal cell marker species), 5 (species: the second cells form at least one lens, at least one cornea, or combinations thereof), 9 and 16 are under consideration.
Priority
It is noted that there is no claim in this application for priority either from foreign application or US provisional application. Thus, the effective filing date for this application is the filing date on 01/06/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05-11-2026 are in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Withdrawn - Claim Rejections - 35 USC § 102 - necessitated by amendments
Claims 1, 3-5, 9 and 16 were rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Lako et al (Pub. No.: US 2017/0218335 A1, Pub. Date: Aug. 3, 2017) as evidenced by Valiente-Soriano et al(Scientific Reports | (2020) 10:7273 | doi: 10.1038/s41598-020-64131-z). In view of Applicants' amendment of base claim 1, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over the prior art of record, as set forth below.
Claim Objections
Claim 4 is objected to because of the following informalities:
Regarding to claim 4(a), the claim recite “a retinal cell marker selected from the group consisting of……..Distal-Less Homeobox 2 (OLX2), Syntaxin 1A (STX1A);”. It appears claim 4(a) lacks an “and” between the penultimate and final members of the Markush group of retinal cell markers.
Regarding to claim 4(b), the claim recites “Retinoid lsomerohydrolase (RPE65), cellular retinaldehyde binding protein (CRALBP), ADP Ribosylation Factor Like GTPase 13B (Arl13B), Actin, Bestrophin 1 (BEST1). It appears claim 4(b) lacks a conjunction (e.g., ‘and’ or ‘or’) between the penultimate and final members of the Markush group of markers. The claim as currently written is unclear if this alternative requires expression of all of the markers or only one from the Markush group.
Regarding to claim 4(c), the claim recites “Synapsin 1 (SYN1), Myelin binding protein (MBP), class Ill beta tubulin (TUJ1), Purkinje Cell Protein 4 (PCP4); ” It appears claim 4(c) lacks a conjunction (e.g., ‘and’ or ‘or’) between the penultimate and final members of the Markush group of markers. The claim as currently written is unclear if this alternative requires expression of all of the markers or only one from the Markush group.
Appropriate correction is required.
New - Claim Rejections - 35 USC § 103 - necessitated by amendments
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.
Claims 1, 3-5, 9 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Lako et al (Pub. No.: US 2017/0218335 A1, Pub. Date: Aug. 3, 2017) in view of Knoblich et al (Pub. No.: US 2015/0330970 A1, Pub. Date: Nov. 19, 2015) as evidenced by Valiente-Soriano et al (Scientific Reports | (2020) 10:7273 | doi: 10.1038/s41598-020-64131-z).
Claim interpretation:
The specification of the claimed invention teaches that the first cells may comprise a structure that represents an optic vesicle. The first cells may comprise retinal pigment epithelium (RPE) cells, photoreceptor cells, amacrine cells, bipolar cells, horizontal cells, ganglion cells, Muller cells or combinations thereof ([00177], page 42). Thus, the above cells are interpreted as the first cells.
The specification of the claimed invention teaches that the second cells may form at least one lens, at least one cornea, or combinations thereof ([00179], page 43). Thus, lens and corneal cells are interpreted as second cells.
Regarding to claim 1, Lako et al provides a method of producing a synthetic retina, comprising: i) providing a three-dimensional stem cell culture throughout the differentiation time course, ii) differentiating the three-dimensional stem cell culture for a first time period in a first neural cell culture medium (Abstract). Lako et al teach 3D differentiation culture and development of the optic cup with hESC/hiPSC: polarized neuroepithelium occurred bilaterally, reminiscent of the early optic vesicles (FIG. 8E), or akin to the optic diverticula of the ventral forebrain prior to the closure of the neural tube (FIG. 8F) ([0156], page 11, right column). Lako et al teach “The inventors have now surprisingly identified that the addition of a single factor, insulin-like growth factor 1 (IGF-1), to hESC/hiPSC cultures for the entire period of differentiation can orchestrate the generation of ocular-like structures containing various elements of the developing eye including retinal pigmented epithelium (RPE), neural retina, primitive lens and cornea. Furthermore, the retinal tissue observed is advantageously organized with a laminar pattern reminiscent of the developing human retina. The hESC/hiPSC-derived retinal tissue comprises multiple phenotypes, including photoreceptors, bipolar, amacrine and ganglion cells, which form synaptic connections and allow the formation of a visible plexiform layer……” ([0086], page 6). (Note: As mentioned above in the claim interpretation, cells such as photoreceptor cells are interpreted as the first cells (neuronal) and lens and corneal cells are interpreted as second cells (non-neuronal)).
PNG
media_image1.png
689
1154
media_image1.png
Greyscale
Also, Lako et al teach murine ESC derived optic cups undergo differentiation to give rise to a fully laminated neural retina containing all the main retinal cell types including the light sensitive photoreceptors, following the normal sequence of retinal development (FIG. 10) ([0005], page 1).
Regarding to claim 1, the claimed: “An artificial three-dimensional (3D) brain organoid comprising a cortical region, cortical neurons in the cortical region”: Although Lako et al teach producing a synthetic retina with a three-dimensional stem cell culture throughout the differentiation time course (abstract) and “…Inner retinal neurons were identified .” ([0160], page 12), Lako et al do not expressly identify a cortical region containing cortical neurons. Knoblich et al cure the deficiency.
Knoblich et al teach:
Knoblich et al teach three-dimensional cerebral organoids: “The present invention relates to an artificial three-dimensional neuronal tissue culture comprising a heterogenous population of cells of at least two different progenitor and neuronal differentiation layers, wherein at least one progenitor layer comprises outer radial glia cells. The new neuronal tissue is also referred to as "organoid" or "cerebral organoids" herein. The cerebral organoids display heterogeneous regionalization of various brain regions as well as development of complex, well-organized cerebral cortex. Furthermore, these tissues display several characteristics specific to humans, namely the presence of a substantial outer radial glial population and the organization of extra cortical subventricular zone layers not present in mouse.” ([0015], page 1).
Knoblich et al teach various discrete, interdependent, brain regions including cortical region containing cortical neurons: “…The resulting cerebral organoids develop a variety of regional identities organized as discrete domains capable of influencing one another, much like the brain as a whole. Furthermore, cerebral cortical regions display an organization similar to the developing human brain as well as the presence of a considerable oRG population. Moreover, cerebral cortical neurons mature to form various pyramidal identities and even organize in an inside-out manner reminiscent of cortical layers in vivo. The organoid can be used to model neurological diseases, e.g. MCPH…” ([0018], page 2).
Knoblich et al also teach different brain region identities can coexist in a single 3D cerebral organoid, including cortical tissue and immature retinal tissue: Knoblich et al teach Fig. 1c and d: “…. c. Sectioning and immunohistochemistry revealed that advanced tissues displayed complex morphology with heterogeneous regions of neural tissues containing neural progenitors (Sox2, red) and neurons (Tuj 1, green) (arrow). d. Low magnification bright field imaging further revealed large fluid-filled cavities reminiscent of ventricles (white arrow) as well as a variety of developing neural tissues including retina, as indicated by the presence of a retinal pigmented epithelium (black arrow). ….” ([0070], page 6), and “FIG. 10. Human cerebral organoids recapitulate various brain region identities …. d. Hematoxylin-eosin staining of retinal tissue exhibiting stereotypical layering: retinal pigment epithelium (RPE)….” ([0079], page 7), and “Furthermore, staining for other cerebral cortical regions, namely the ventral cortex (FIG. 2e) and hippocampus (FIG. 21), ……. Finally, other brain structures separate from these cerebral cortical identities could be observed, namely choroid plexus (FIG. 2g) and even immature retina (FIG. 10d) ……These results suggest that cerebral organoids developed a variety of brain region identities organized into discrete, though interdependent, domains.” ([0122]- [0123], page 12).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior arts to modify the method and 3D hiPSC-brain organoids of Lako et al by using the method and 3D hiPSC-brain organoids of Knoblich et al to reproduce multiple neural/retinal developmental structure in vitro, as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to apply the multi-regional 3D organoid approach comprising cerebral cortical region and cortical neuronal population as taught by Knoblich et al to the 3D iPSC derived optic vesicle system of Lako et al because Knoblich et al stated that:
“….The cerebral organoids display heterogeneous regionalization of various brain regions as well as development of complex, well-organized cerebral cortex. Furthermore, these tissues display several characteristics specific to humans, namely the presence of a substantial outer radial glial population and the organization of extra cortical subventricular zone layers not present in mouse. The presence of outer radial glia cells appears to be one of the most distinguishing features, but of course others exist as well….” ([0015], page 1).
“The resulting cerebral organoids develop a variety of regional identities organized as discrete domains capable of influencing one another, much like the brain as a whole. Furthermore, cerebral cortical regions display an organization similar to the developing human brain as well as the presence of a considerable oRG population. Moreover, cerebral cortical neurons mature to form various pyramidal identities and even organize in an inside-out manner reminiscent of cortical layers in vivo. The organoid can be used to model neurological diseases, e.g. MCPH.” ([0018], page 2), and “…. Such cells isolated from the inventive culture or tissue have the benefit of representing similar morphological properties as cells isolated from cerebral tissue of a nonhuman animal, as mentioned above, or a human” ([0057], page 5)
“….cerebral organoids could be reproducibly generated with similar overall morphology and complexity from both human ES cells and induced pluripotent stem cells (iPSCs) (FIG. 7a, b), suggesting this approach could be applied to a variety of human pluripotent stem cells.” ([0117], page 11).
“We have established a novel approach to studying human neurodevelopmental processes through in vitro culture of cerebral organoids from human pluripotent stem cells. This method recapitulates not only these basic mechanisms of neurodevelopment shared with mice and rats, but also displays many characteristics of human brain development……. We have modeled at least some aspects of the human neurodevelopmental disorder microcephaly in these cerebral organoids…… Overall, our findings suggest we can utilize this in vitro culture system to model aspects of human neurodevelopment and neurological disease and hopefully provide novel insight into the root causes of these disorders.” ([0158]-[0160], page 15).
One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Knoblich et al were successful in developing a human pluripotent stem cell-derived three-dimensional organoid culture system to generate cerebral organoids that develop various discrete, interdependent, brain regions.
Regarding to claim 1, the claimed: “wherein the 3D brain organoid is devoid of vasculature” Lako et al are silent about any step of generating vasculature or description of any vasculature. Furthermore, Lako et al teach 3D differentiation culture (In-vitro differentiation culture) and development of the optic cup with hESC/hiPSC: polarized neuroepithelium occurred bilaterally, reminiscent of the early optic vesicles (FIG. 8E) ([0156], page 11, right column, also see Figure 8). Given that there’s no apparent evidence that Lako et al performed the step to generate vasculature (via in-vitro differentiation of hiPSC) that is precluded by the language of claim 1, it is reasonable conclude that Lako et al anticipates the claimed: “wherein the 3D brain organoid is devoid of vasculature”.
Regarding to claim 1, the claimed: “the first cells comprise a layer of retinal pigment epithelium (RPE) cells having a honeycomb shape” Lako et al teach the generation of ocular-like structures containing various elements of the developing eye including retinal pigmented epithelium (RPE), neural retina, primitive lens and cornea ([0086], page 6). Thus, Lako et al teach generation of retinal pigmented epithelium (RPE) cells which inherently have a honeycomb shape as evidenced by Valiente-Soriano et al who teach the classical honeycomb pattern of hexagonal RPE cells densely packed along the entire retina (Page 14, 6th para.). Furthermore, Lako et al teach the generation of RPE cells from induced pluripotent stem cell to form a synthetic retina which is identical to the claimed invention. Thus, it is expected that the RPE cells of Lako et al are morphologically identical to the claimed invention.
Regarding to claim 3, Lako et al teach the retinal tissue comprises one or more, preferably at least two, of the following cell types: bipolar cells, amacrine cells, ganglion cells and retinal pigmented epithelium (RPE) cells ([0023], page 2).
Regarding to claim 4, Lako et al teach that emergence of the early synthetic retina is characterized by phase bright neuroepithelium (expressing RaX/Pax6), and the outer wall of the cup gives rise to retinal pigmented epithelium, characterized by its dark pigmentation and expression of RPE65 ([0126], page 8). Also, examples of retinal cells arising from hiPSC cultures on day 60 of differentiation which were expressing the photoreceptor marker Crx ([0075], page 5, right column, and also see Fig. 8 (G-L)).
Regarding to claim 5, Lako et al report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of ocular-like structures containing retinal pigmented epithelium, neural retina, primitive lens and cornea from hESC/hiPSC in vitro ([0153], page 10).
Regarding to claim 9, Lako et al teach FIG. 7 shows IGF-1 treatment facilitates the emergence of ocular accessory structures alongside retinal tissues with markers stained for lens (CRYAA, CRYAB, Y-crystallin, AQPO, BFSP1) ([0074], page 5).
Regarding to claim 16, Lako et al provided the aforementioned synthetic retina or pharmaceutical composition for use in the treatment of retinal disease or ocular injury ([0051], Page 3).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHOA NHAT TRAN whose telephone number is (571)270-0201. 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 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.
/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
Prosecution Insights