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 .
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 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.
DETAILED ACTION
Notice of Change of Examiner
The examiner assigned to the application has changed from Maytee Contes De Jesus to Emily Cordas.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 Oct. 20, 2025 has been entered. All arguments and the IDS submitted on Oct. 20, 2025 and the affidavit/Declaration under 37 CFR §1.132 have been fully considered.
Status of the Claims
Claims 1, 5-32 and 34 are currently pending.
Claim 1 is amended.
Claims 6-28 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 2-4 and 33 are cancelled.
New claims 34 has been added.
Claims 1, 5, 29-32 and 34 have been considered on the merits.
Claim Rejections - 35 USC § 112
New claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ) have been added upon further consideration.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 32 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In claim 32, lines 1-3, the phrase “wherein the RPE cells are obtained at early stages of differentiation or at more advanced stages of differentiation”, renders the claim and its dependents indefinite, since it is unclear whether this limitation is referring to a product-by-process limitation or whether the limitation is no longer relevant for claim 1 from which it depends from. Claim 1 requires functionally mature retinal pigment epithelial (RPE) cells whereas claim 32 is describing the cells as not fully differentiation and immature. For the purposes of compact prosecution, the claims will be interpreted to mean that the RPE cells are obtained once the cells are functionally mature to be in line with claim 1.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5, 29-32 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Chiou et al. (US 2016/0331867 A1) (ref. of record) in view of Nasonkin et al. (US 2021/0155895 A1, priority to Oct. 5, 2017).
With respect to claim 1, Chiou teaches a three-dimensional (3D) tissue product derived from human induced pluripotent stem cells (hiPSCs) (abstract, 0002, 0006-0007, 0062, Fig. 5A and 5F). Chiou teaches that the 3D tissue product is responsive to light after transplantation (0021, 0068, and 0071). Chiou teaches the 3D tissue product containing functionally mature retinal pigment epithelial (RPE) cells, photoreceptor cells (a portion of 3D neural retina), and a laminin modified substrate that is a biocompatible polymer (a biocompatible scaffold) (0006-0008, 0024-0025, 0060, Fig. 5A and 5F). Chiou teaches that the photoreceptors and RPE cells are physically and functionally integrated to form a complex containing a layer of photoreceptor cells (neural retina) and an underlying layer of RPE cells (0065 and 0072). Chiou teaches the 3D tissue product where the RPE cells are grown on top of the biocompatible scaffold prior to integration with 3DNR and where the 3DNR is positioned on top of the RPE cells (0064-0065 and Fig. 5A).
Chiou does not teach that the RPE cells and the 3DNR cells are both obtained from human retinal organoids derived from hiPSCs as recited in claim 1. Although, Chiou does not teach the method by which RPE cells and the 3DNR are obtained (from human retinal organoids) as in claim 1, this limitation is interpreted as a product by process type limitation. It is noted that the patentability of a product does not depend on its method of production. If the claimed product is the same or obvious from a product in the prior art (i.e. the product disclosed in the cited reference), the claim is unpatentable even though the reference product was made by a different process. When the prior art discloses a product which reasonably appears to be identical with or slightly different than the claimed product-by-process, rejections under 35 U.S.C 102 and/or 35 U.S.C 103 are proper. (MPEP 2113). In this case, there appears to be no difference in the RPE cells and the 3DNR cells derived from hiPSCs of Chiou with RPE cells and the 3DNR cells derived or obtained from human retinal organoids derived from hiPSCs.
Chiou does not teach the 3D tissue product containing an additional biocompatible component containing a hydrogel which is physically and functionally integrated with the 3DNR and RPE layers as recited in claim 1.
However, Nasonkin teaches a similar 3D retinal organoid composition derived from human induced pluripotent stem cells (abstract, 0003, 0010,0037 and 0118 and Fig. 10). Nasonkin teaches the 3D tissue product containing RPE cells and a layer of retinal ganglion cells (RGCs), a layer of second-order retinal neurons (INL), and a layer of photoreceptor (PR) cells which correspond to a portion of the neural retina or 3DNR (0011 and 0121). Nasonkin teaches the cells are grown on a substrate that is biocompatible (0143). In addition, Nasonkin teaches the 3D retinal organoid containing a hydrogel where the hydrogel is mixed with the organoid prior to administration or as a component of a hydrogel (0147, 0177 and Fig. 16). Nasonkin teaches the graft with two layers of hydrogel (Fig. 16). Nasonkin teaches the hydrogel can be embedded with one or more trophic factors, mitogens, morphogens and/or small molecules (0040) and be used as a delivery system for the 3D retinal tissue (0067).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to include a hydrogel in the 3D tissue product of Chiou for the benefits of including factors beneficial for tissue growth and for using the 3D tissue construct to repair tissue as taught by Nasonkin. It would have been obvious to one of ordinary skill in the art to modify the 3D tissue product of Chiou to include a hydrogel that is functionally integrated with the RPE and 3DNR cells, since similar tissue constructs were known to include hydrogels for beneficial features as taught by Nasonkin. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to Chiou, since Nasonkin teaches a similar 3D tissue construct with RPE and 3DNR cells derived from hiPSCs grown on a substrate.
Chiou does not teach the 3DNR comprising i) undifferentiated pseudostratified neural retinal epithelium; ii) laminated neural retina tissue including all retinal layers and their corresponding retinal precursor cell types; or iii) advanced differentiated retinal tissue including an outer nuclear layer (ONL) and a bipolar cell layer (BCL), wherein the ONL could be rod-enriched, cone- enriched, or any combination thereof as recited in claim 1.
However, Nasonkin teaches a similar 3D retinal organoid composition derived from human induced pluripotent stem cells (abstract, 0003, 0010,0037 and 0118 and Fig. 10). Nasonkin teaches the 3D tissue product containing RPE cells and a layer of retinal ganglion cells (RGCs), a layer of second-order retinal neurons (INL), and a layer of photoreceptor (PR) cells which correspond to a portion of the neural retina or 3DNR (0011 and 0121). The second-order retinal neurons are bipolar cells. Nasonkin teaches the cells are grown on a substrate that is biocompatible (0143). Nasonkin further teaches that the tissue product is suitable for transplantation in cell-based therapies for retinal degeneration and as a tissue model for discovery-based screening since it preserves the complexity of the RPE-PR-2nd order neuron niche (0010).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to additional retinal layers and a 3DNR containing advanced differentiated retinal tissue including an ONL and a bipolar cell layer wherein the ONL in the 3D tissue product of Chiou for the benefits of recapitulating the native retina for more suitable transplant products and tissue models as taught by Nasonkin. It would have been obvious to one of ordinary skill in the art to modify the 3D tissue product of Chiou to include additional retinal layers in the 3DNR, since similar tissue constructs were known to include the claimed layers in the 3DNR for similar uses as taught by Nasonkin. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to Chiou, since Nasonkin teaches a similar 3D tissue construct with RPE and 3DNR cells derived from hiPSCs grown on a substrate and teaches the benefits of including multiple layer of the retina such as bipolar cells.
With respect to claim 5, Chiou teaches the biocompatible polymer (a biocompatible scaffold) is polydimethylsiloxane (PDMS), poly(methyl methacrylate) (PMMA), Glycidoxypropyltrimethoxysilane (GPTES), aminopropyltriethoxysilane (APTES), Xylene or acetone which are synthetic scaffolds (0025). With respect to claim 29, Chiou teaches the use of the 3D tissue product for treating a retinal defect or disorder by administering a retinal cell implant (retinal tissue graft) (0002 and 0005). With respect to claim 30, Chiou teaches the use of the 3D tissue product for age-related macular degeneration (0005). With respect to claim 31, Chiou teaches the RPE cells are obtained from an initial plating (0062). With respect to claim 32, Chiou teaches the RPE cells are mature (0060 and 0062).
Chiou does not teach the method of preparing the RPE cells recited in claim 34. Although, Chiou does not teach the method by which RPE cells prepared (by culturing human retinal organoids) as in claim 34, this limitation is interpreted as a product by process type limitation. It is noted that the patentability of a product does not depend on its method of production. If the claimed product is the same or obvious from a product in the prior art (i.e. the product disclosed in the cited reference), the claim is unpatentable even though the reference product was made by a different process. When the prior art discloses a product which reasonably appears to be identical with or slightly different than the claimed product-by-process, rejections under 35 U.S.C 102 and/or 35 U.S.C 103 are proper. (MPEP 2113). In this case, there appears to be no difference in the RPE cells derived from hiPSCs of Chiou with RPE cells obtained from cultured human retinal organoids derived from hiPSCs.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Oct. 20, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that Zhu, Zhong and Hunt do not teach the claimed three-dimensional tissue that is responsive to light after transplantation into a subject and only relate to studies done in tissue culture (Remarks pg. 11 para. 3 to pg. 12 para. 1). Specifically, Applicant argues that there is no teaching in either Zhong or Zhu that suggests that light responsiveness could be achieved and maintained after transplantation into a subject (Remarks pg. 12 para. 2). Applicant argues that the light responsiveness observed in Zhong was limited to a few cells and with only light response occurring once in the few cells that responded which would not have led a person of ordinary skill in the art to expect that the cells could durably provide light responsiveness once transplanted into a subject (Remarks pg. 12-13 bridging para.). Applicant argues that the claimed invention unexpectedly responded to light after implantation into an animal eye model of retinal degeneration and that the claimed tissue product is durable and healthy enough to withstand the transplantation process and survive for extended periods of time. Applicant argues that this is further supported by additional data presented in the 132 Declaration showing that the light response is sustained over repetitive measurements for at least 12 weeks post-transplantation (Remarks pg. 13 para. 2). Additionally, Applicant argues that Hunt fails to remedy the deficiencies of Zhu and Zhong (Remarks pg. 13 para. 2). The Applicant’s amendments limiting the claims to include the limitation of the tissue product being responsive to light after transplantation necessitated the withdrawal of the previous rejections. Applicant’s arguments are drawn to Zhu, Zhong and Hunt failing to teach this new limitation. However, this new limitation is addressed in the new rejection.
Applicant argues that a person of ordinary skill would not have had a reasonable expectation of success in using the hydrogel of Hunt in a three dimensional tissue product (Remarks pg. 13 point 2). Specifically, Applicant argues that the Office mischaracterized the teachings of Hunt and Hunt only teaches the hydrogel for human embryonic stem cells (EBs) and immature stem cells prior to differentiation to mature retina or RPE cells whereas the claimed invention requires the hydrogel to be functionally integrated with mature RPE cells and 3DNR (Remarks pg. 14 para. 2). Applicant further argues that there is nothing in Hunt that points to or teaches the functional integration of RPE and 3DNR into a hydrogel to create a three-dimensional tissue product that is capable of responding to light after transplantation (Remarks pg. 14-15 bridging para.). Applicant argues that the purpose of the hydrogel in Hunt is to support the differentiation of EBs derived from hESCs and hiPSCs and this is different from the claimed invention’s purpose of providing an appropriate biomechanical environment for cell survival and function and allows for manipulation of the 3D tissue product containing mature cells (Remarks pg. 15 para. 2). Applicant further argues that the EBs are just encapsulated in the hydrogel and are not in any particular configuration or arrangement and Hunt does not teach the hydrogel can be used to support functional physical and integration of a 3D tissues product with RPE cells grown on top of the scaffold and a 3DNR positioned on top of the RPE cells (Remarks pg. 15 para. 3). Applicant argues that the hydrogel of Hunt would not support the functional integration of the neural retina and RPE cells, since it has an elastic modulus of 2 kPa which is analogous to the retinal inner surface, whereas the it is the photoreceptor inner/outer segment area of the retina that is relevant to the claimed tissue product and it has a Young’s modulus of 25.9 ± 7.36 kPa as evidenced by Qu (Remarks pg. 15-16 bridging para.). Applicant argues that Hunt does not teach that the hydrogel can be directly used in transplantation and only uses the hydrogels to prepare the cells that may then be used for transplantation (Remarks pg. 16 para. 2). Applicant argues that one would have not have been motivated to combine Hunt’s hydrogel with the neural retinal and RPE cells in view of the known properties and compatibility of the hydrogel taught by Hunt and have a reasonable expectation that the properties would support the functional integration of the neural retina and RPE cells, since the EB cells taught by Hunt are biological distinct from the claimed RPE and 3DNR cells and would require different conditions for growth/survival (Remarks pg. 16-17 bridging para.).
Applicant’s arguments with respect to Hunt have been considered but are moot because the arguments do not apply to any of the references being used in the current rejection.
Response to Evidentiary Declaration under 37 CFR §1.132
The declaration of Valeria Canto-Soler, Ph.D., filed on Oct. 20, 2025 under 37 CFR §1.132 has been considered but is ineffective to overcome the present rejections of the claims under 35 U.S.C. §103.
In the Declaration, Dr. Canto-Soler states that they have provided data demonstrating the physical and functional integration of the RPE and the 3DNR into a complex in the Response filed on Oct. 10, 2024 (Declaration para. 6). Dr. Canto-Soler explains that tissue product was implanted into an animal eye model of retinal degeneration, a mini pig eye, and the mini pig eye exhibited increased light responses in areas of the implant compared to adjacent non-transplanted areas two weeks after implantation as shown in Fig. 8 (Declaration para. 7-8). Dr. Canto-Soler explains that a longitudinal mfERG analysis for 12 weeks post-implantation showed a sustained significant increase in light response the transplanted area of the retina compared to before transplantation and to adjacent non-transplanted areas As shown in Fig. A of the Declaration (Declaration para. 9-10). As stated above in the response to the arguments, the new amendments limiting the claims to include the limitation of the tissue product being responsive to light after transplantation necessitated the withdrawal of the previous rejections. As explained in the new rejections, three dimensional retinal tissue products that respond to light after transplantation into a subject were known in the art as taught by Chiou.
Dr. Canto-Soler states that the use of the hydrogel in Hunt is drastically different from the claimed use in the claimed 3D tissue product and that Hunt uses the hydrogel to support the differentiation of embryoid bodies whereas the hydrogel in the claimed invention is being used to provide and appropriate biomechanical environment for cell survival and function, allow for the manipulation of the 3D tissue containing mature cells, and to function integrate with the mature RPE and 3DNR (Declaration para. 11). Dr. Canto-Soler states that the claimed use of the hydrogel improves the product so that the there is a distinct protein profile produced by the RPE cells and human retinal organoids which also changes over time as shown in Oct. 24 Response in Fig. 5 and 6, and it is attributed to the physical and functional integration of the RPE cells, 3DNR and hydrogel within the claimed tissue product. Dr. Canto-Soler states that there is no teaching in Hunt that suggests these improved functional capabilities of the claimed tissue product (Declaration para. 12).
Dr. Canto-Soler states that Franz teaches the elastic modulus of the retinal inner surface is in the range of 940-1800 Pa. Dr. Canto-Soler states Franz further teaches that the retinal inner surface includes the ganglion cell layer, nerve fibers, inner limiting membrane and Muller cell end feet which is a different layer from the claimed invention which includes the RPE and 3D neural retina (Declaration para. 13-17). Dr. Canto-Soler states that different regions of the retina have different elastic modulus as taught by Qu. Qu reports the Young’s modulus for the retinal inner surface is 1.33± 0.37 kPa and the photoreceptor inner/outer segment area, which corresponds to the claimed structure, is 25.9±7.36 kPa which is significantly different from the RGD alginate modulus of Hunt (Declaration para. 18-19).
Dr. Canto-Soler statements with respect to Hunt have been considered but are moot because the arguments do not apply to any of the references being used in the current rejection.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632