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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found
in a prior Office action.
This application is in response to the papers filed on July 29, 2026. Pursuant to the amendment filed on July 29, 2026, claims 1-20 are currently pending. Claims 1, 3-6, 8, 11-16, 18, and 19 have been amended in Applicant’s amendment filed on May 15, 2024. No claims have been cancelled, and no claims have been newly added.
Therefore, claims 1-20 are currently under examination to which the following grounds of rejection are applicable.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/US22/40853 filed on August 19, 2022. Applicant’s claim for the benefit of a prior-filed parent provisional application 63/235,380 filed on August 20, 2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Thus, the earliest possible priority for the instant application is August 20, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on September 24, 2026 was filed. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections/Rejections:
Claim Objections
The objection to claim 18 has been withdrawn in view of the amendment to the claims dated July 29, 2026.
Claim Rejections - 35 USC § 112(b)
The rejections to claims 3-9, 11-16, and 18 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inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, have been withdrawn in view of the amendment to the claims dated July 29, 2026.
Claim Rejections - 35 USC § 102
The rejections to claims 1-3 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brainard et al. (Annual review of vision science 1 (2015): 519-546) have been withdraw in view of the amendment to the claims dated July 29, 2026. The rejections are withdrawn because Brainard does not teach the limitation of “produced in vitro from pluripotent stem cells into retinal tissue.”
Claim Rejections - 35 USC § 103
The rejections to claims 1 and 6 rejected under 35 U.S.C. 103 as being unpatentable over Brainard et al. (Annual review of vision science 1 (2015): 519-546), as applied to claim 1 above, and further in view of Wells-Gray et al. (Eye (Lond). 2016 May 27;30(8):1135–1143) have been withdraw in view of the amendment to the claims dated July 29, 2026.
The rejections to claims 1, 6, 8, 10, 11, and 17 rejected under 35 U.S.C. 103 as being unpatentable over Brainard et al. (Annual review of vision science 1 (2015): 519-546) in view of Wells-Gray et al. (Eye (Lond). 2016 May 27;30(8):1135–1143) as applied to claim 6 above, and further in view of Eldred et al. (Science, 362(6411), 18 pages (2018); of record IDS filed 11/22/2024) have been withdraw in view of the amendment to the claims dated July 29, 2026.
Applicants’ arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
Maintained Objections/Rejections in response to Applicants’ arguments or amendments:
Claim Rejections - 35 USC § 112(a)
Claims 19-20 remain rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a modified rejection necessitated by the amendment to the claims filed on July 29, 2026.
Applicants are claiming a method of treating age-related macular degeneration (AMD) or retinal degeneration (RD) comprising engraftment into the macula of a patient in need thereof of a cellular composition comprising a population of L cones and M cones, wherein the ratio of L cones to M cones (L:M) falls within a predetermined range, wherein the predetermined L:M range is from about 1.3:1 to about 2.8:1 [composition recited in claim 1]. Furthermore, the retinal degeneration is due to age-related macular degeneration, Stargardt disease, cone dystrophy, achromatopsia, Best disease, mitochondrial macular degeneration, pattern dystrophy, or RDS-associated macular degeneration.
The Specification describes particular cellular compositions that fall within the scope of composition recited in the claims that are to be engrafted into the macula of a patient in need thereof. However, there is no support throughout the Specification of any procedures or specific methods wherein this process has occurred, and therefore no indication that the claimed composition has shown success in treatments of AMD and/or RD. The Specification provides Examples 1-3 starting on page 24, all of which describe progress in the preparation of organoids via differentiation into select cone types. However, there is no support for the cellular compositions described therein for the methods of treatment as the only examples presented are merely prophetic.
Section 5.4 of the instant Specification, paragraphs 0062-0079, titled “Methods of Treatment Using Macular Repair Cell Compositions” described the conditions the claimed composition can be employed, and further lists particular embodiments of the claimed composition for use as seen in describing specific eccentricities, rod and/or cone percentages, and ratios thereof. The section further describes delivery devices for the claimed composition by citing WO 2020/028892, and then describes how this device operates by delivery to the subretinal space. However, it remains unclear how this particular device will operate with the claimed composition for delivery to effectively treat for AMD or RD by delivery to the macula. The device appears to be designed for delivery to sub-retinal space, so it is unclear how delivery would reach the macula, an anatomical structure in the center of the retina, for effective treatment.
The prior art shows that this field is relatively new. A review published by Klymenko et al. in 2024 describes that clinical trials are still underway for AMD treatments (p 333, par 1). Organoids are discussed as being developed, wherein they may serve as a source of photoreceptors, i.e. cones, for transplantation. There have been work in photoreceptor transplantation using human embryonic stem cell (ESC)- and iPSC-derived retinal sheets and suspensions and have demonstrated some recovery of light sensitivity. Furthermore, photoreceptor transplants have been shown to establish meaningful non-synaptic connections with host photoreceptors to promote host photoreceptor survival in pre-clinical models (p 333, col 2). Altogether, despite the outcomes described in the review, it can be seen that the field of cell therapies involving photoreceptors for the treatment of AMD or RD are still young, and this can be further seen in Klymenko Table 2 that lists studies of retinal transplantation wherein results are still largely unknown.
In conclusion, the Specification does not provide an adequate written description on the methods of treatment for AMD and/or RD with the claimed composition.
Response to Applicants’ Arguments as they apply to rejection of claims 19-20 under 35 USC § 112(a)
Starting on page 7 of the remarks filed on July 29, 2026, Applicants essentially argue the following:
The Written Description Requirement Does Not Mandate Proof of Efficacy or Working Examples
The Specification Adequately Conveys Possession of the Claimed Methods
The Examiner's Reliance on the State of the Art is Misplaced
In response to these arguments, they have been fully considered but are not persuasive due to the following reasons:
Regarding the first presented argument, the Applicant states the Written Description (WD) requirement does do not demand that an applicant demonstrate that the invention actually works or provide working examples of every claimed embodiment in view of Ariad, 598 F.3d at 1352. However, in the instant case a single example of treatments with the claimed invention is necessary in view of the lack of information disclosed pertaining to the particular steps of treatment for MD or RD by delivery to the macula for a patient in need thereof; and secondly, in view of the large uncertainty in the art regarding treating these diseases with cell therapy as described above. The Applicant states it is not necessary to show the invention actually works for the WD requirement, which may be true for certain functional language of a composition claim when there is sufficient support in the disclosure, yet the instant claims are directed to a method of treatment, and therefore treatment outcomes are considered relevant being they would support or not support the claimed method for treating. Lastly, the Applicant arguments that not providing relevant examples or showing the invention functions as having no impact on the WD are not convincing. It is well understood that these are not requirements across all patent examination for patentability, but in the instant case these are seen as necessary based on the total lack of support in the Specification for these claimed methods.
Regarding the second presented argument, the Applicant states there is adequate support for possession of the claimed methods of treatment, yet this is not true in view of the modified rejection set forth above. The Specification provides zero examples of clinical nor prophetic examples of treatment with the claimed composition. Secondly, the vast majority of the section for methods of treatments only describes different embodiments of the claimed composition rather than particular steps for treatment. Lastly, the Specification cites a reference for a delivery device of cell to the retina, yet it is unclear how this device would function with the instant composition for successful delivery, and subsequently effective treatments. It appears this device only delivers to the sub-retinal space which is in contrast with the claimed method that is restricted to the macula. Moreover, the claimed composition appears to be based on particular ratios of cones to rods at select eccentricities, and it is unclear how these characteristics can be attained with such delivery device and in the absence of detailed treatment steps.
Regarding the third presented argument, the Applicant states the state of ongoing clinical trials does not bear on whether the inventor possessed the claimed invention at the time of filing. This argument is not convincing because the written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention, and therefore it is essential to determine what is known in the art in view of the claimed invention and disclosure. Therefore, in view of there being no examples provided for methods of treatment, the prior art should be examined to determine what is known. With that said, clinical outcomes are of concern to determine if the inventors were in full possession of the claimed inventions, which encompasses methods of treating for RD or MD.
Claim Rejections - 35 USC § 101
Claims 1-17 remain rejected under 35 U.S.C. 101 because the claimed invention is directed to product of nature without significantly more. This is a modified rejection necessitated by the amendment to the claims dated July 29, 2026. This is a modified rejection necessitated by the amendment to the claims filed on July 29, 2026.
The USPTO's current eligibility guidance is found in Section 2103 through 2106.07 of the Manual of Patent Examining Procedure (MPEP).
Claim 1 recites a cellular composition produced in vitro from pluripotent stem cells into retinal tissue comprising a population of L cones and M cones, wherein the ratio of L cones to M cones (L:M) falls within a predetermined range, wherein the predetermined L:M range is from about 1.3: 1 to about 2.8: 1 wherein the cellular composition is configured to mimic the cone subtype distribution of a selected retinal eccentricity in a normal trichromatic subject.
Step 1: Regarding claim 1, the claim is directed to a composition comprising a population of L cones and M cones derived from pluripotent stem cells at a select ratio. The claim is directed to the statutory category of a composition of matter, and therefore, the requirements of Step 1 are met.
Step 2A, Prong One: Regarding Step 2A Prong One, claim 1 is directed to a natural phenomenon (product of nature) based on the lack of elements that would differentiate the claimed composition comprising cone cells from a non-natural product, e.g. human retina. The claim
The composition is not markedly different from the product’s naturally occurring counterpart in its natural state in view of the L:M ratio, in view of the recitation of the process of derivation, and the limitation of “wherein the cellular composition is configured to mimic the cone subtype distribution of a selected retinal eccentricity in a normal trichromatic subject”.
Hagen et al. (Vision Res. 2019 Jul 11;162:20–28; of record) describes the L:M ratio varies between individuals, and the mean ratio differs between ethnic groups. A L:M cone ratio of 2.7:1 has been reported in colour normal American Caucasian males. Additionally, in Asians the mean L:M cone ratio in colour normal males has been reported to be considerably lower than in Caucasians (p 2, par 2).
Neitz et al. (US-10,487,361-B2; of record) states “Among humans with normal color vision there is tremendous variation in the amino acid sequences of the L and M opsins that has arisen via unequal homologous recombination… For example, in the control sample described above, there were 34 different L opsin sequences in 320 subjects, and 17 different M opsin sequences in 261 subjects. The ratio of L to M cones also varies widely among humans. For example, among Caucasian males with normal color vision, the ratio of L:M cones ranges hum 1.1:1 to 19:1, with an average of 2.7:1” (col 13, ln 50-67). Figure 2 depicts differences in this ratio across ethnic groups, wherein a higher L:M ratio was observed in Caucasian males and the lowest ration in Asian (Japanese) males. Furthermore, Neitz describes the L:M cone ratio bias was strongly negatively associated with axial length, and thus with susceptibility to myopia, an eye-length related disorder (col 14, ln 25-28).
McMahon et al. (Journal of Vision 2008;8(2):5; of record) in describing the L:M ratio states “The ratios for the males of African descent ranged from 42% to 85% L cones, with an average of 65% L cones and a standard deviation of 10.7%. Males of Caucasian descent ranged from 37% to 95% L cones, with an average of 73% L cones and a standard deviation of 11.1%. Thus, the degree of variance for these two groups was similar; however, the mean ratio for the Africans was significantly lower as compared with the Caucasians (p = .0015 Student's t test, and p = .0013 Mann–Whitney nonparametric test).” (Results, par 1).
Patterson et al. (Invest Ophthalmol Vis Sci. 2016 Jul 22;57(8):3853–3863; of record) describes large individual differences being demonstrated in L:M cone ratios in normal subjects, ranging from 28% to 93% L-cones, corresponding to more than a 30-fold range in L:M ratio. Paterson further states L and M opsin genes are often associated with X-linked cone dysfunction, e.g. Bornholm Eye Disease (BED), and that the L:M ratio can be further shifted in individuals with such condition (p 3859, col 2; abstract).
Therefore, it can be understood that the composition claimed is naturally occurring because the ratio claimed is encompassed across human populations, wherein the prior art describes there is L:M cone variation across populations based on variables such as ethnicity and health.
In relation to the recitation, “cellular composition produced in vitro from pluripotent stem cells into retinal tissue”, the process of derivation of the claimed cell types is considered a product-by-process limitation. M.P.E.P. § 2113 reads, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.” “Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 111 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted). Therefore, unless the process of derivation imparts structural differences than what occurs in the natural product, such limitation is not sufficient to differentiate the claimed composition from the natural product.
Eldred et al. (Science, 362(6411), 18 pages (2018); of record IDS filed 11/22/2024) describes human retinal organoids, that are derived from pluripotent stem cells, as being similar to human retinas, stating “Organoids and retinas have similar distributions, expression profiles, and morphologies of cone subtypes.” (abstract; p 4, col 1) of which is cited within the instant Specification, paragraph 0082. In summary, the recitation of a process of derivation is not sufficient to differentiate the claimed composition that a naturally occurring product, e.g. human retina.
In summary, the claimed composition is found naturally, and is considered a natural product.
Step 2A, Prong Two: The judicial exception is not integrated into a practical application based on the claims not reciting additional elements of the composition that would integrate the composition into a practical application as the structural limitations currently recited are not different than naturally occurring compositions, and secondly, the claims for usage are set forth in claims 19-20 (both of which not rejected under 35 USC 101). Furthermore, if an intended usage was recited in the currently rejected claims, limitations that amount to merely indicating a field of use or technological environment in which to apply a judicial exception do not amount to significantly more than the exception itself, and cannot integrate a judicial exception into a practical application. See MPEP 2106.05(h).
Step 2B: The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception as the only elements are cones that are naturally found. The examiner is recommending including elements in the composition wherein the combination of elements are not naturally occurring, and moreover wherein the additional elements integrate the judicial exception, i.e. product of nature, into a practical application.
In conclusion, based on the Subject Matter Eligibility Test recited in MPEP 2106, claims 1-17 remain rejected under 35 U.S.C. 101.
Response to Applicants’ Arguments as they apply to rejection of claims 1-17 under 35 USC § 101
Starting on page 9 of the remarks filed on July 29, 2026, Applicants essentially argue the following:
The Amended Claims Are Not Directed to a Product of Nature
The Claimed Compositions Possess Markedly Different Characteristics
Step 2A, Prong 2: The Claims Are Integrated Into a Practical Application
The Claims Recite Significantly More Than Any Alleged Natural Phenomenon
In response to these arguments, they have been fully considered but are not persuasive due to the following reasons:
Regarding the first presented argument, the Applicant states, “The claimed "cellular composition" is an in vitro manufactured product-a population of photoreceptor cells produced via directed differentiation of stem cells to retinal tissue. See Specification ,-i,i [0049]-[0059]; Table 1. This is a fundamentally different context from cone cells residing in their natural environment within a living human retina.”. The argument is not convincing based on claim 1 not reciting any structural differences than is found in a naturally occurring retina that comprises both cones and rods, specifically L cones and M cones at the claimed ratio. The claims have been amended to recite the process of derivation of the cells types, yet it appears that the cells derived from pluripotent stem cells are identical to the natural counterpart as stated in the Specification paragraph 0082 when describing a reference that used such process of derivation, “Thus, Eldred et al. noted that cone subtypes in human retinal organoids displayed distributions, gene expression patterns, and morphologies similar to those of cones of the human retina.”.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the composition not comprising a complex, multi-layered retinal tissue architecture, integrated with retinal pigment epithelium, ganglion cells, bipolar cells, Muller glia, and an intricate neural network) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In particular, the claimed composition does not recite an isolated population of L cones and M cones.
Regarding the second presented argument, the Applicant describes the following:
(1) Structural Differences: The specification discloses that pluripotent stem cell-derived cone photoreceptors have shorter outer segments than adult retinal cones, consistent with their in vitro origin and developmental state as described in Specification par 0082, further stating “This is a structural difference resulting from the manufacturing process.” As described above, the argument is not convincing based on this citation being taken out of context. The section states the organoids and human retinas as being similar, wherein the cone subtypes in human retinal organoids displayed distributions, gene expression patterns, and morphologies similar to those of cones of the human retina. The citation described in the Remarks is a comparison between organoids and adult retinas, wherein the outer segments were shorter in the organoids which is expected since adults retinas are matured versions of the retina. This is the reason the section states this as being consistent with postnatal maturation. The structure remains to be understood as being similar between the claimed composition and the human retina.
(2) Compositional Control: The Remarks describe the claimed ratios as being predetermined and as occurring only from human engineering, not a product of nature. The argument is not convincing based on the ratio that is claimed, L:M range is from about 1.3: 1 to about 2.8: 1, being found naturally as described above in the 101 rejections across various prior art references. In relation to the limitation of “predetermined”, this limitation does not amount to a particular structural difference because the ratio is found naturally, regardless of if it was “predetermined.”
(3) Depletion of non-neuroretinal cells: The Remarks describes that MARC compositions are depleted of forebrain-like cells, forebrain progenitor cells, and retinal pigment epithelial cells, however the claimed composition does not recite these elements as not being included. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In particular, the MARC composition being described in the Remarks is not reflected or rather recited to the same extent in the claims.
(4) Multi-region compositions: The Remarks describes that claim 17 recites the composition as comprising two regions of different M:L ratios, yet this limitation does not differentiate itself from the natural product as seen by Wells-Gray et al. (Eye (Lond). 2016 May 27;30(8):1135–1143; of record) which describes the ratio of cones to rods as shifting based on increasing eccentricity within in the human eye (Fig. 3). Therefore, the natural product, e.g. the human retina, has this claimed structural composition of regions with different cone ratios.
(5) The Examiner Improperly Focuses on a Single Claimed Limitation in Isolation: The arguments are not convincing as they are in relation to limitations not recited in the claims, i.e. “manufactured composition-an isolated, ex vivo population of defined photoreceptor cells”. The claims as currently, recited do not reflect such cells, but rather recites “A cellular composition produced in vitro from pluripotent stem cells into retinal tissue comprising a population of L cones and M cones”, which are different for the reasons described above.
Regarding the third presented argument, the Applicant describes that “the amended claims integrate any such exception into a practical application. The claimed compositions are specifically designed as cell-based therapeutics for retinal and macular repair. The specification makes clear that MARC compositions are designed to be engrafted into the macula to regenerate cone photoreceptor cells and thereby treat degenerative macular diseases. See Specification ,-i,i [0022]-[0024], [0062]-[0074]. While claims 1-17 are composition claims rather than method claims, the compositions are not merely isolated natural products described in a vacuum- they are precision-engineered therapeutic constructs designed for a specific medical application.” The modified 101 rejection above describes how the amended claims do not integrate any such exception into a practical application. The amended claims recite no additional elements that clearly would be necessary for the composition to be integrated into practical application.
Regarding the fourth presented argument, the Applicant describes that the claims recite significantly more than the natural phenomenon as seen in the amendment to the claims, yet these amendments do not overcome the 101 rejections as described above because they amount to no structural differences from the natural composition. In particular, the pluripotent stem cell derivation does not impart a structural difference due to the composition being identical to human retina as described in the instant Specification par 0082. Additionally, the limitation that the composition is configured to mimic a cone subtype distribution at a selected retinal eccentricity does impart a structural difference that what is naturally occurring.
For these reasons, claims 1-17 remain rejected under 35 USC 101.
New Grounds of Objection:
Claim Objections
Claims 3, 8, 11 are objected to because of the following informalities: In view of the Amendments to the claims dated July 29, 2026, claims 3, 8, 11 are objected to for not separating the optional method claims appropriately. In reference to claim 3, the claim recites options a) and b); however, the claims should recite options a) - d) based on the amendment to the claim removing the conjunction “and” replaced with “or”.
In reference to claim 8, the claim recites options a) and b); however, the claims should recite options a) - c) based on the amendment to the claim removing the conjunction “and” replaced with “or”.
In reference to claim 11, the claim recites options a) - e); however, the claims should recite options a) – j) based on the amendment to the claim removing the conjunction “and” replaced with “or”.
Appropriate corrections are required.
Allowable Subject Matter
Claims 18 is allowed.
Conclusion
Claims 1-17, 19-20 are rejected. Claims 18 is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL A RIGA whose telephone number is (571)270-0984. The examiner can normally be reached Monday-Friday (8AM-6PM).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G Leavitt can be reached at (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/TERESA E KNIGHT/Primary Examiner, Art Unit 1634
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