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 .
Status of the Claims
Claims 53, 55, 57-59, 61, 63-67, and 69-77 are pending.
Claims 54, 62, and 68 are newly cancelled.
Claims 53, 55, 64-65, 67 are newly amended.
Claims 75-77 are newly added.
Claims 67 and 69-72 are withdrawn pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made as being treated without traverse in the reply filed on 08/16/2022.
Claims 53, 55, 57-59, 61, 63-66, and 73-77 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The prior rejection of claims 53, 55, 57-58, 61-63, 65-66, and 73-74 under 35 U.S.C. 103 as being unpatentable over Hu et al. Cell Stem Cell, 2015, including supplement, on IDS 04/23/2020, previously cited) in view of Efe et al. (WO2011159726A2, 2011, 09/22/2023, previously cited) is withdrawn due to amendment of the claims and in order to incorporate Boucherie et al. (Stem Cells, 2013, previously cited) as discussed below.
The prior rejection of claim 54 under 35 U.S.C. 103 as being unpatentable over Hu et al. Cell Stem Cell, 2015, including supplement, on IDS 04/23/2020, previously cited) in view of Efe et al. (WO2011159726A2, 2011, previously cited), as applied to claims 53, 55-58, 60-63, and 65-66 above, and further in view of Boucherie et al. (Stem Cells, 2013, previously cited) is withdrawn due to cancellation of the claim as discussed below.
The prior rejection of claim 59 under 35 U.S.C. 103 as being unpatentable over Hu et al. Cell Stem Cell, 2015, including supplement, on IDS 04/23/2020, previously cited) in view of Efe et al. (WO2011159726A2, 2011, previously cited), as applied to claims 53, 55-58, 60-63, and 65-66 above, and further in view of Bao et al. (PLOS ONE, 2012, previously cited) and Parvini et al. (In Vitro Cell. Dev. Biol - Animal, 2015, previously cited) is withdrawn due to amendment of the claims and in order to incorporate Boucherie et al. (Stem Cells, 2013, previously cited) as discussed below.
The prior rejection of claim 64 under 35 U.S.C. 103 as being unpatentable over Hu et al. Cell Stem Cell, 2015, including supplement, on IDS 04/23/2020, previously cited) in view of Efe et al. (WO2011159726A2, 2011, previously cited), as applied to claims 53, 55-58, 60-63, and 65-66 above, and further in view of Bakondi (Expert Review of Ophthalmology, 2016, previously cited) is withdrawn due to amendment of the claims and in order to incorporate Boucherie et al. (Stem Cells, 2013, previously cited) as discussed below.
Res Judicata
Claims 53-55, 57-59, 61, and 63 are precluded from patentability under the doctrine of res judicata.
According to MPEP 2190(II), a patent owner or applicant may be precluded from seeking a claim that is not patentably distinct from a claim that was finally refused or canceled during an administrative trial or federal court proceeding under the doctrine of res judicata.
A patent owner or applicant may be precluded from seeking a claim that is not patentably distinct from a claim that was previously rejected if the rejection was affirmed on appeal and the decision on appeal became final. A res judicata rejection should be applied only when the earlier decision was a decision of the Patent Trial and Appeal Board (or its predecessor Board) or any one of the reviewing courts and when there is no opportunity for further court review of the earlier decision. See In re Hitchings, 342 F.2d 80, 85, 144 USPQ 637, 641 (CCPA 1965) (holding that unappealed rejections from examiners cannot have a preclusive effect).
In the following cases, a rejection of a claim based on the ground of res judicata was sustained where it was based on a prior adjudication, against the inventor, on the same claim, a patentably nondistinct claim, or a claim involving the same issue. Edgerton v. Kingsland, 168 F. 2d 121, 75 USPQ 307 (D.C. Cir. 1947). In re Katz, 467 F.2d 939, 167 USPQ 487 (CCPA 1970) (prior decision by a district court).
In the instant case, the claims as amended are not patentably distinct from the previously rejected claims and the Patent Trial and Appeal Board (PTAB) affirmed the final rejection of the previous claims 53-66. No Notice of Appeal to the Federal Circuit was filed.
Specifically, the PTAB affirmed the rejection of the previous (now cancelled and incorporated into claim 54), of a step of culturing the somatic cell in the presence of a second reprogramming composition comprising enhancing agents sonic hedgehog (S), taurine (T) and/or retinoic acid (R) (see Final Rejection on 04/09/2024, p8; see PTAB decision on 09/22/2025, Decision Summary, p18)
Furthermore, the PTAB affirmed not only the rejection of claim 62, which identified photoreceptors as being a species of retinal cell (see Final Rejection on 04/09/2024, p5; see PTAB decision on 09/22/2025, Decision Summary, p18), but also, as above, the step of a second reprogramming composition comprising enhancing agents sonic hedgehog (S), taurine (T) and/or retinoic acid (R), which promote the maturation of photoreceptors (see Final Rejection on 04/09/2024, p5 and 8; see PTAB decision on 09/22/2025, Decision Summary, p18)
Therefore, it is determined that Applicant is precluded from the instant claims 53, 55, 57-59, 61, and 63.
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 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.
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 53, 55, 57-58, 61, 63, 65-66, and 73-77 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et al. Cell Stem Cell, 2015, including supplement, on IDS 04/23/2020, previously cited) in view of Efe et al. (WO2011159726A2, 2011, 09/22/2023, previously cited) and Boucherie et al. (Stem Cells, 2013, previously cited).
In regards to claims 53 and 61, Hu teaches a method for the direct conversion (thus, without passing through) of a fibroblast (a non-stem somatic cell) to neuronal cell (thus, not producing a stem cell) (Title, summary, p204; Graphical Abstract, cover page). Hu teaches that this method comprises contacting cells with a chemical cocktail comprising a chemical cocktail (Summary, p204) comprising VPA (valproic acid), CHIR99021, Repsox, and forskolin (Figure 1, p205).
Hu does not explicitly teach that the cocktail comprises IWR-1 or XAV939.
However, Efe teaches methods for reprogramming/transdifferenting non-pluripotent cells to other non-pluripotent cells (Abstract). Efe teaches that the starting cells can be fibroblasts (paragraph [0008]). Efe also teaches that the cells be transdifferentiated broadly to cells of an ectodermal fate (Abstract), but more particularly neurons (paragraph [0027]) or retinal pigmented epithelium cells (paragraph [0026]).
In particular, Efe teaches that this method may include contacting cells with Wnt inhibitors such as IWR-1 which increases Axin2 protein levels and promotes β-catenin phosphorylation by stabilizing Axin-scaffold destruction complexes (paragraph [0152]).
Therefore, a person of ordinary skill in the arts would have been motivated to include IWR-1, because as taught by Efe is would increase Axin2 levels and promote β-catenin phosphorylation. Furthermore, because Efe teaches that IWR-1 can be used for the direct reprogramming of non-pluripotent cells, that the starting cells may be fibroblasts, and that cells could be transdifferentiated into neurons or retinal pigment epithelial cell, it could have been done with predictable results and a reasonable expectation of success.
In regards to a step of culturing in the presence of a second reprogramming composition, while neither Hu nor Efe explicitly teaches a second reprogramming composition comprising sonic hedgehog, taurine, or retinoic acid, a person of ordinary skill in the arts would have been motivated to include sonic hedgehog, taurine, or retinoic acid in a second reprogramming composition because Boucherie teaches that retinoic acid and taurine promote maturation of rhodopsin+ and opsin+ photoreceptors, and that combinations of sonic hedgehog, taurine, and retinoic acid show increased efficiency of expression of cone opsin (60%) and rhodopsin (10%) (Introduction, p408). Furthermore, because Boucherie teaches culturing conditions for contacting cells with sonic hedgehog, taurine, and retinoic acid show (Retinal induction, p409), it could have been done with predictable results and a reasonable expectation of success.
Applicant should note that in regards to whether the method converts somatic cells to a retinal photoreceptor cell or does not produce a stem cell, that these are inherent property of the method as in claim 53 and does not recite additional method steps clarifying these limitations.
Providing guidance on instances when the method steps of the prior art and the instant claims are the same, Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) states “that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims.”
In the instant case, claim 53 indicates that culturing non-stem somatic cells in the presence of the chemical cocktail as in claim 53 is sufficient to produce a retinal photoreceptor cell and not produce stem cells. Therefore, since the method of Hu, as modified by Efe and Boucherie carries out these steps, the reference method would inherently produce a retinal photoreceptor cell and not produce stem cells either.
Additionally, as discussed above, as taught by Boucherie teaches that retinoic acid and taurine promote maturation of rhodopsin+ and opsin+ photoreceptors, and that combinations of sonic hedgehog, taurine, and retinoic acid show increased efficiency of expression of cone opsin (60%) and rhodopsin (10%) (Introduction, p408), therefore, a retinal photoreceptor cell would be the expected result.
In regards to claim 55, Hu teaches that the cells can be collected and assessed for expression profiles (p208, Figure 3). Since the combined method of Hu, Efe, and Boucherie produces a retinal photoreceptor, this cell would be collected and assessed for expression as taught by Hu.
In regards to claim 57 and 58, Hu teaches that the cells could be cultured with the reprogramming agents (maturation medium) for 8 days (p203, Figure 1), which is close to a range 6 or 7 days or less.
In regards to amount that are close, MPEP 2144.05(I) states, “[A] a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
Furthermore, a person of ordinary skill in the arts could have arrived at timing ranges of 6 or 7 days or less by routine optimization, and the disclosure does not point to a criticality in these timings (see MPEP2144.04(II) for guidance on routine optimization). Hu teaches that cocktails were tested over a range of 0 to 21 days (Fig. S1C, second page of supplement; Fig. S1C legend, sixth page of supplement) while, Efe teaches that cell can be reprogrammed in as few as 7 days (paragraph [0013]). Therefore, a person of ordinary skill in the arts could have arrived at ranges of 6 or 7 days or less by routine optimization with predictable results and a reasonable expectation of success.
In regards to claim 63, as above, Hu teaches that fibroblasts were derived from human foreskin (p204-205, Results, Induction of neuronal cells from adult fibroblasts by small molecules), which reads on being harvested from a patient. Additionally, as above, Hu teaches that teaches that these cells can be reprogrammed to neural cells. A person of ordinary skill in the arts would have found it prima facie obvious to reprogram fibroblasts to retinal cells over Hu as modified by Efe as discussed above. Furthermore, Hu teaches that in another study that utilized fibroblasts from skin, their results indicate that the chemical induction protocol might be a feasible way to generate patient-specific neuronal cells that might be useful for neurological disease modeling, related mechanical studying, and drug screening (p209, Generation of hciNs from FAD patient fibroblasts) which reads on treating the cells with a potential therapeutic agent to determine the effectiveness of the agent to improve cell health or reduce cell death in a subject.
In regards to claim 65-66, Hu teaches that the method is useful for regenerative medicine (Abstract, p205), but does not explicitly teach the step of delivering a target cell to subject in need thereof.
However, Efe teaches that retinal pigmented epithelium cells can be used to treat individuals in need suffering from age-related macular degeneration or photoreceptor dystrophy (paragraph [0288]), and a person of ordinary skill in the arts would have been motivated to treat these patients as to alleviate their suffering. Furthermore, because both Hu and Efe teach that the cells can be sued for treating pathological conditions, and Efe teaches specific retinal conditions that overlap with the group as in claim 686, it could have been done with predictable results and a reasonable expectation of success.
In regards claim 73, in regards to culturing the somatic cell in the presence of a combination of (i) valproic acid, (ii) CHIR99021, (iii) Repsox, and (iv) forskolin, prior to the culturing in the presence of (v) IWR-1 or XAV939, according to MPEP 3144.04(IV)(A), changes in the sequence of adding ingredients is prima facie obvious absent unexpected results.
Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) (Prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps.). See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946) (selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results); In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930) (Selection of any order of mixing ingredients is prima facie obvious).
In regards to claim 74, in regards to whether converting the somatic cell into the retinal cell comprises directly converting the somatic cell into the retinal cell without an intermediate progenitor stage, as discussed above, Hu teaches that fibroblasts (somatic cells) are “directly” converted to neuronal cells bypassing a neural progenitor stage (Title, summary, p204; Graphical Abstract, cover page), and therefore, would not have passed through an “intermediate progenitor stage.”
Furthermore, Hu also teaches that fibroblasts treated with media comprising VPA, CHIR99021, Repsox, and forskolin quickly exit the cell cycle, suggesting that that the chemical induction of neuronal cells from human fibroblasts might bypass a proliferative intermediate (p210, left column), and therefore, the method of Hu also reprograms fibroblasts without a proliferative intermediate (whether as a progenitor or not) either.
In regards to claims 75-77, Hu teaches that converted cells can be matured to neuronal cells after about 8 days and for at least another 20 ( Graphical Abstract, cover page; Fig. 1205), which overlaps with a timing of 3 days or more after initially contacting the somatic cells with reprogramming agents. A person of ordinary skill in the art would have been motivated to contact the somatic cells with the second reprogramming composition during this timeframe because Hu teaches that this is a suitable timing for neural maturation of these cells (as above, as taught by Boucherie, the second reprogramming composition promotes maturation to photoreceptors). Moreover, because Hu indicates that this is a sufficient amount of time to allow for reprogramming of somatic cells and subsequent neural maturation, it could have been done with predictable results and a reasonable expectation of success.
Furthermore, a person of ordinary skill in the art could have arrived at a timing of 3 days or more after initially contacting the somatic cells with reprogramming agents by routine optimization, and the disclosure does not point to a criticality in this timing (see MPEP 2144.05(II)(A), 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)).
In the instant case because Hu teaches that converted somatic cells can neuronally matured for a broad range of 8 to 28 days (Graphical Abstract, cover page; Fig. 1, p205), which overlaps with the timing of 3 days or more after initially contacting the somatic cells with reprogramming agents, a person of ordinary skill in the art could have arrived at this timing by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hu, Efe, and Boucherie renders the invention unpatentable as claimed.
Claim 59 is rejected under 35 U.S.C. 103 as being unpatentable over Hu et al. Cell Stem Cell, 2015, including supplement, on IDS 04/23/2020, previously cited) in view of Efe et al. (WO2011159726A2, 2011, previously cited) and Boucherie et al. (Stem Cells, 2013, previously cited), as applied to claims 53, 55-58, 60-63, and 65-66 above, and further in view of Bao et al. (PLOS ONE, 2012, previously cited) and Parvini et al. (In Vitro Cell. Dev. Biol – Animal, 2015, previously cited).
In regards to claim 59, the combined teachings of Hu, Efe, and Boucherie includes a Wnt inhibitor as discussed above. While Efe lists other Wnt inhibitors other than IWR-1 (such as IWP-2, DKK1, etc.), and states that the list is not limiting (paragraph [0152]), Efe is silent as to XAV939 specifically.
However, as taught by Bao, both IRW-1 and XAV939 are known in the art to induce Axin stabilization and attenuate Wnt signaling (Introduction, p1, column 2, last paragraph). Furthermore, the Specification acknowledges that other WNT inhibitors other inhibitors such as IWP-2 (Specification, paragraph [0075]). Therefore, both IWR-1 and XAV939 are art recognized equivalents known for the same purpose (see MPEP 2144.06).
Additionally, a person of ordinary skill in the arts would have been motivated to use XAV939 specifically because Parvini teaches XAV939, specifically, is effective for driving differentiation to eye field cell (such as retinal cells) (p311, Differentiation of hESCs). Furthermore, since Parvini teaches methods for specifically using XAV939 (p311, Differentiation of hESCs), Efe teaches that their list is not limiting, and Bao teaches that IWR-1 and XAV939 are art recognized equivalents known for the same purpose, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hu, Efe, Boucherie, Bao, and Parvini renders the invention unpatentable as claimed.
Claim 64 is rejected under 35 U.S.C. 103 as being unpatentable over Hu et al. Cell Stem Cell, 2015, including supplement, on IDS 04/23/2020, previously cited) in view of Efe et al. (WO2011159726A2, 2011, previously cited) and Boucherie et al. (Stem Cells, 2013, previously cited), as applied to claims 53, 55-58, 60-63, and 65-66 above, and further in view of Bakondi (Expert Review of Ophthalmology, 2016, previously cited).
In regards to claim 64, none of Hu, Efe, or Boucherie explicitly teach that a somatic cell or target cell can be manipulated through gene editing to silence or repair a defective gene.
However, Bakondi teaches that a variety of methods that employ CRISPR/Cas-9 mediated repair of cells that could potentially be used to treat retinal dystrophy are known in the art (p389, Ex vivo repaired cells for autologous transplants). Bakondi also teaches that these techniques could be used to treat retinal diseases (p389, Ex vivo repaired cells for autologous transplants). Additionally, Bakondi teaches that the ability to modify the genome at specific sites has generated much hope because it would be possible to cure monogenetic diseases by eliminating the mutations that cause them (p399, Future outlook).
Therefore, a person of ordinary skill in the arts would be motivated to modify the method of Hu, as suggested by Efe, and manipulate cells gene editing to silence or repair a defective gene because Bakondi teaches that it could eliminate genetic mutations that cause disease. Furthermore, because Bakondi teaches that methods for using gene editing to silence or repair genes, and specifically in to context of retinal disease, Hu teaches that their methods are applicable to regenerative medicine, (Abstract, p205), and Efe teaches that the cells can be used to treat patients with retinopathies (paragraph [0188]), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Hu, Efe, Boucherie and Bakondi renders the invention unpatentable as claimed.
Response to Arguments
Applicant argues that the res judicata rejection does not apply because claim 53 as amended contains two further limitations that were not present in the claims before the PTAB, specifically: (1) that the retinal cell is a photoreceptor cell, and (2) that the method requires culturing the somatic cells in the presence of a second reprogramming composition comprising enhancing agents sonic hedgehog (S), taurine (T), and/or (S), retinoic acid (R) (Remarks, p6).
Applicant’s arguments filed 03/02/2026 have been fully considered but are not found persuasive.
As discussed above, in the instant case, the claims as amended are not patentably distinct from the previously rejected claims and the Patent Trial and Appeal Board (PTAB) affirmed the final rejection of the previous claims 53-66. No Notice of Appeal to the Federal Circuit was filed.
Specifically, the PTAB affirmed the rejection of the previous (now cancelled and incorporated into claim 54), of a step of culturing the somatic cell in the presence of a second reprogramming composition comprising enhancing agents sonic hedgehog (S), taurine (T) and/or retinoic acid (R) (see Final Rejection on 04/09/2024, p8; see PTAB decision on 09/22/2025, Decision Summary, p18).
Furthermore, the PTAB affirmed not only the rejection of claim 62, which identified photoreceptors as being a species of retinal cell (see Final Rejection on 04/09/2024, p5; see PTAB decision on 09/22/2025, Decision Summary, p18), but also, as above, the step of a second reprogramming composition comprising enhancing agents sonic hedgehog (S), taurine (T) and/or retinoic acid (R), which promotes the maturation of photoreceptors (see Final Rejection on 04/09/2024, p5 and 8; see PTAB decision on 09/22/2025, Decision Summary, p18).
Therefore, it is determined that Applicant is precluded from the instant claims 53, 55, 57-59, 61, and 63.
Applicant argues that the claims as amended demonstrate unexpected results (Remarks, p6-7). Specifically, Applicant argus that results are unexpected because the prior art does not teach the direct conversion of fibroblasts into retinal photoreceptors as claimed (Remarks, p7). Applicant also argues that specific experimental data including fluorescence microscopy, flow cytometry, RT-PCR, qPCR, ERG analysis, pupillometry, and patch-clamp electrophysiology, and therefore, represents results that are both unexpected and of practical significance (Remarks, p7-8).
Applicant’s arguments filed 03/02/2026 have been fully considered but are not found persuasive.
Neither the specification not the Declaration filed 12/14/2022 demonstrate results that are unexpected that are commensurate in scope with the claims, and do not demonstrate that differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength “are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration.”).
Indeed, the results do not compare the prior art, and not demonstrate differences of statistical and practical significance, bur rather assert that the presence of photoreceptors is itself per se unexpected.
However, as taught by Boucherie, as discussed above, it was known in the prior art before the effective filing date that maturation with sonic hedgehog, taurine, and retinoic acid leads to differentiation of photoreceptors. Therefore, the presence of a photoreceptor is not itself unexpected, and would have been the expected result.
Additionally, the use of experimental data including fluorescence microscopy, flow cytometry, RT-PCR, qPCR, ERG analysis, pupillometry, and patch-clamp electrophysiology, may weight in favor of enablement of the method, but without a demonstration of differences in results as required by MPEP 716.02, are insufficient to demonstrate that the results are in fact unexpected and unobvious and of both statistical and practical significance.
Applicant argues that the references fail to teach or suggest a method of converting a fibroblast to a retinal photoreceptor cell (Remarks, p8).
Specifically, Applicant argues that Hu only reprograms fibroblasts into general neurons with no specialized retinal properties, does not IWR-1 or XAV939, and does not teach sonic hedgehog, taurine, or retinoic acid (Remarks, p8).
Applicant argues that Efe does not cure the deficiencies of Hu (Remarks, p8). Specifically, Applicant argues that Efe describes a multi-step protocol in which fibroblasts are first converted to neural progenitor cells, and then to retinal pigmented epithelium, or other cells, none of which are photoreceptors (Remarks, p8). Applicant argues that Efe does not teach sonic hedgehog, taurine, or retinoic acid (Remarks, p8).
Applicant argues that Boucherie does cure these deficiencies (Remarks, p8-9). Specifically, Applicant argues that while Boucherie teaches that sonic hedgehog, taurine, or retinoic acid promote the maturation of photoreceptors, this in the context of differentiating stem cell-derived retinal progenitor cells, not in the context of directly reprogramming fibroblasts (Remarks, p9). Thus, Applicant concludes that a person of ordinary skill in the art would not have had a reasonable expectation of success in applying Boucherie’s maturation factors to a direct reprogramming protocol starting with fibroblasts (Remarks, p9).
Applicant’s arguments filed 03/02/2026 have been fully considered but are not found persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Specifically, as discussed above, Hu teaches a method for the direct conversion (thus, without passing through) of a fibroblast (a non-stem somatic cell) to neuronal cell (thus, not producing a stem cell) (Title, summary, p204; Graphical Abstract, cover page). Hu teaches that this method comprises contacting cells with a chemical cocktail comprising a chemical cocktail (Summary, p204) comprising VPA (valproic acid), CHIR99021, Repsox, and forskolin (Figure 1, p205).
Hu does not explicitly teach that the cocktail comprises IWR-1 or XAV939.
However, Efe teaches methods for reprogramming/transdifferenting non-pluripotent cells to other non-pluripotent cells (Abstract). Efe teaches that the starting cells can be fibroblasts (paragraph [0008]). Efe also teaches that the cells be transdifferentiated broadly to cells of an ectodermal fate (Abstract), but more particularly neurons (paragraph [0027]) or retinal pigmented epithelium cells (paragraph [0026]).
In particular, Efe teaches that this method may include contacting cells with Wnt inhibitors such as IWR-1 which increases Axin2 protein levels and promotes β-catenin phosphorylation by stabilizing Axin-scaffold destruction complexes (paragraph [0152]).
Therefore, a person of ordinary skill in the arts would have been motivated to include IWR-1, because as taught by Efe is would increase Axin2 levels and promote β-catenin phosphorylation. Furthermore, because Efe teaches that IWR-1 can be used for the direct reprogramming of non-pluripotent cells, that the starting cells may be fibroblasts, and that cells could be transdifferentiated into neurons or retinal pigment epithelial cell, it could have been done with predictable results and a reasonable expectation of success.
In regards to a step of culturing in the presence of a second reprogramming composition, while neither Hu nor Efe explicitly teaches a second reprogramming composition comprising sonic hedgehog, taurine, or retinoic acid, a person of ordinary skill in the arts would have been motivated to include sonic hedgehog, taurine, or retinoic acid in a second reprogramming composition because Boucherie teaches that retinoic acid and taurine promote maturation of rhodopsin+ and opsin+ photoreceptors, and that combinations of sonic hedgehog, taurine, and retinoic acid show increased efficiency of expression of cone opsin (60%) and rhodopsin (10%) (Introduction, p408). Furthermore, because Boucherie teaches culturing conditions for contacting cells with sonic hedgehog, taurine, and retinoic acid show (Retinal induction, p409), it could have been done with predictable results and a reasonable expectation of success.
Applicant should note that in regards to whether the method converts somatic cells to a retinal photoreceptor cell or does not produce a stem cell, that these are inherent property of the method as in claim 53 and does not recite additional method steps clarifying these limitations.
Providing guidance on instances when the method steps of the prior art and the instant claims are the same, Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) states “that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims.”
In the instant case, claim 53 indicates that culturing non-stem somatic cells in the presence of the chemical cocktail as in claim 53 is sufficient to produce a retinal photoreceptor cell and not produce stem cells. Therefore, since the method of Hu, as modified by Efe and Boucherie carries out these steps, the reference method would inherently produce a retinal photoreceptor cell and not produce stem cells either.
Additionally, as discussed above, as taught by Boucherie teaches that retinoic acid and taurine promote maturation of rhodopsin+ and opsin+ photoreceptors, and that combinations of sonic hedgehog, taurine, and retinoic acid show increased efficiency of expression of cone opsin (60%) and rhodopsin (10%) (Introduction, p408), therefore, a retinal photoreceptor cell would be the expected result.
Furthermore, critically, this conclusion was affirmed by the PTAB as discussed above.
Specifically, the PTAB affirmed the rejection of the previous (now cancelled and incorporated into claim 54), of a step of culturing the somatic cell in the presence of a second reprogramming composition comprising enhancing agents sonic hedgehog (S), taurine (T) and/or retinoic acid (R) (see Final Rejection on 04/09/2024, p8; see PTAB decision on 09/22/2025, Decision Summary, p18).
Furthermore, the PTAB affirmed not only the rejection of claim 62, which identified photoreceptors as being a species of retinal cell (see Final Rejection on 04/09/2024, p5; see PTAB decision on 09/22/2025, Decision Summary, p18), but also, as above, the step of a second reprogramming composition comprising enhancing agents sonic hedgehog (S), taurine (T) and/or retinoic acid (R), which promote the maturation of photoreceptors (see Final Rejection on 04/09/2024, p5 and 8; see PTAB decision on 09/22/2025, Decision Summary, p18).
Applicant argues that Parvini is directed to differentiating human embryonic stem cells, Bao is silent reprograming or differentiation, and that Bakondi does not cell reprogramming (Remarks, p9).
Applicant’s arguments filed 03/02/2026 have been fully considered but are not found persuasive. None of Parvini, Bao, or Bakondi is relied upon to directed reprogramming.
Moreover, the PTAB affirmed the rejection of claims (59 and 64) in view of Parvini, Bao, or Bakondi (see PTAB decision on 09/22/2025, Decision Summary, p18).
Applicant argues that new claims 75 and 77 require that the second reprogramming composition is applied 3 or more days after initial contacting, and that this temporal relationship is not taught by the prior art (Remarks, p9).
Applicant’s arguments filed 03/02/2026 have been fully considered but are not found persuasive.
As discussed above, Hu teaches that converted cells can be matured to neuronal cells after about 8 days and for at least another 20 ( Graphical Abstract, cover page; Fig. 1205), which overlaps with a timing of 3 days or more after initially contacting the somatic cells with reprogramming agents. A person of ordinary skill in the art would have been motivated to contact the somatic cells with the second reprogramming composition during this timeframe because Hu teaches that this is a suitable timing for neural maturation of these cells (as above, as taught by Boucherie, the second reprogramming composition promotes maturation to photoreceptors). Moreover, because Hu indicates that this is a sufficient amount of time to allow for reprogramming of somatic cells and subsequent neural maturation, it could have been done with predictable results and a reasonable expectation of success.
Furthermore, a person of ordinary skill in the art could have arrived at a timing of 3 days or more after initially contacting the somatic cells with reprogramming agents by routine optimization, and the disclosure does not point to a criticality in this timing (see MPEP 2144.05(II)(A), 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)).
In the instant case because Hu teaches that converted somatic cells can neuronally matured for a broad range of 8 to 28 days (Graphical Abstract, cover page; Fig. 1, p205), which overlaps with the timing of 3 days or more after initially contacting the somatic cells with reprogramming agents, a person of ordinary skill in the art could have arrived at this timing by routine optimization with predictable results and a reasonable expectation of success.
Conclusion
No claims are 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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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
