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 .
Withdrawn Rejections/Objections
The rejection of claims 5-17 and 32-37, under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement, is withdrawn. The amendments cancel these claims, rendering their rejection moot.
The objection to claims 26-30 is withdrawn as per applicant’s arguments.
The rejection of claims 12, 15-17, and 32-33, 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn. The amendments cancel these claims, rendering their rejection moot.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 3-4, and 26-30, as amended or previously presented, is/are rejected under 35 U.S.C. 103 as being unpatentable over Srivastava (Srivastava et al. Journal of Immunological Methods 389:61-68, 2013) in further view of Choudhary (US 2015/0159134 pub date:6/11/2015; effectively filed: 12/11/2013).
Regarding claim 1, Srivastava teaches the development of a method of determining purity of a primary human RPE culture for planning future therapeutic strategies (p. 62, col 1). Srivastava teaches method of subjecting primary cultured human RPE cells to flow cytometry measuring RPE specific markers on the presence of the RPE cells and determining the purity and the cell viability of the RPE population (p. 62-63, section 2.4). FC can be used for quick, sensitive, robust, reliable, reproducible, and thus, routine detection of RPE cell purity in primary hRPE cell cultures and to test the cell viability and cycle and the presence of contaminating fibroblasts or other cell types in a series of RPE primary cell cultures. Thus, implementation of FC in the regular evaluation of the stability of hRPE primary cell cultures is advantageous over fluorescence microscopy methods (p. 67, section 5). Thus Srivastava teaches a method of assessing purity of a cultured human RPE cells for intended experimental and therapeutic use comprising providing a human RPE population measure RPE specific markers on the RPE cell population to determine purity, viability, and contamination. Srivastava does not teach that the RPE specific markers used for flow cytometry are PMEL17 and CRALBP or alternatively that these are measured using immunostaining. Srivastava does not teach that the PEDF:VEGF vectoral section ratio is determined and that the RPE cells are on the basis of 95% of the population has polarize secretion of PEDF:VEGF and coexpression of PMEL17 and CRALBP.
However, Chouhary teaches the production of RPE cells and methods of verifying that the produced cells are RPE cells. Chouhary teaches RPE cells have a cobblestone morphology, are pigmented and express at least one of the following RPE markers: MITF, PMEL17, CRALBP, MERTK, BEST1 and ZO-1. In some embodiments, the produced RPE cells secrete VEGF and PEDF ([0085]). In some embodiments, the RPE cell secretes VEGF. In some embodiments, the RPE cell secretes PEDF. In some embodiments, the RPE cell secretes PEDF and VEGF. In some embodiments, VEGF and/or PEDF secretion by RPE cells is measured by a quantitative immunoassay. In some embodiments, VEGF and/or PEDF secretion by RPE cells is measured as disclosed in the examples ([0182]). RPE cells expressed RPE markers such as PMEL17, ZO-1, CRALBP, Bestrophin and MERTK as observed by immunostaining ([0360]). Cells were seeded onto Transwells.RTM. at a density of 116000 cells/Transwell.RTM. and cultured for a period of 10 weeks. The two chambers of the Transwell.RTM. were maintained as separate and media were not allowed to mix. Media were collected from the bottom and top chamber and analysed for secretion of VEGF and PEDF. As shown in FIG. 10A, the ratio of [VEGF]:[PEDF] is higher in the media collected from the bottom chamber and lower in the media from the top chamber indicating higher basolateral secretion of VEGF and higher apical secretion of PEDF. This indicates that the RPE obtained by directed differentiation method disclosed herein are polarized and functional ([0370]).
Thus Choudary teaches that (i) determining the percentage of a population that are RPE cells or RPE purity of an established RPE culture by measuring co-expression of a RPE markers, PMEL17 and CRALBP by immunostaining, was well established and being conventionally used in the prior art; and (ii) measuring and determining the ratio of basolateral section of VEGF to apical secretion of PEDF was a well-established method of measuring polarity, function and maturation of RPE cells in culture. Further, both method are taught by Choudary to be quantitative methods of measuring properties of RPE cells.
Thus it would have been obvious to one of ordinary skill in the prior art before the time of effectively filing to further apply the method of establishing the percentage of RPE cells in a population co-expressing PMEL17 and CRALBP by flow cytometry or immunostaining and PEGF to VEGF vector secretion ratios taught by Choudary to the provided population of cultured RPE cell population and purity methods of Srivastava to predictably arrive at the method steps of claim 1 with a reasonable expectation of successfully determining the purity, functionality, and maturing of the human RPE population. Srivastava and Choudary does not expressly teach to select 95% of the cells co-expressing PMEL17 and CRALBP. However, Srivastava and Choudary express a need for a highly purified population of RPE cells with little contamination. As such an artisan of ordinary skill reasonably should 95% purity from a finite number of desired high purity/low contamination percentages for therapeutic application. As such, Srivastava in view of Choudary render claim 1 obvious.
Regarding claims 3-4, Srivastava in view of Choudary teach immunostaining and flow cytometry as discussed above.
Regarding claims 26-30, these claims further specify the ratio as greater than 1 and 1.5. It would be obvious to the ordinary artisan to choose from greater than 1 and 1.5 from a definite number of known ratios that demonstrate polarity, optimal function, and maturity as taught by Choudary to predictably arrive at the limitations of claims 26-30 with a reasonable expectation of success.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationales A, E and G are applicable. The claimed method was known in the art at the time of filing as indicated by Srivastava in view of Choudary. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Response to Arguments
Applicant's arguments filed 3/3/2026 have been fully considered but they are not persuasive.
Applicant submits that the combined cited prior art does not teach or suggestion a method for therapeutic selection. Srivastava focuses on assessing purity and contamination of primary hRPE cultures for experimental use, focuses on RPE65 a marker, detecting fibroblast contamination and culture stability. Srivastava does not measure PMEL17 and CRALBP parameters as a selection criterion for selecting a population for pharmaceutical use. Thus Srivastava does not teach criteria for a clinically suitable RPE therapy. Applicant submits Choudary also does not teach criteria to use when selecting a RPE cell population for pharmaceutical use.
In response, Applicant is not giving the claims their broadest reasonable interpretation. The claims are to a screening method that has the end-result of “providing a retinal pigment epithelial (RPE) cell population” as recited in the preamble. The preamble also recites that the cell population end-product is “suitable for treating an eye condition”. The method is not a treatment or therapeutic method. The method also does not provide any steps or limitations in the body of the claims that indicate a descriptive distinction of a therapeutic population. The steps subject the cell population comprising RPE to well-establish cell sorting or immunostaining step as well as measure prior art accepted markers of RPE markers, as taught by both Srivastava and Choudary. The steps also polarized secretion parameters of PEDF and VEGF taught by Choudary to be an functional measure of RPE cells. As such the cells provided by the combined teachings would predictably be expected to result in the same structural/functional RPE cell population end product. Further, the claims do not require any specific therapeutic function by the end-product cells and only need to be “suitable” or have the capacity to treat. Thus, the only requirement for an RPE population “suitable for treating an eye condition” is to have the capacity to be delivered to the eye. One of ordinary skill would have a reasonable expectation of success in administering the RPE cell population provided by the combined teachings of the cited prior art, thus treating an eye condition as claimed.
A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In this instant, “suitability for treatment of an eye condition” as recited in the claims is an intended use for the screening method rather a structural limitation to the claimed method as one therapeutic steps or limitations are required. As such, the prior art cited would have a reasonable expectation successfully arriving at the same method.
Applicant further submits that Examiner’s rationale for obviousness relies upon impermissible hindsight. The combined teaches provide no guidance that the claimed combination of parameters should be used for selecting a RPE cell for pharmaceutical use nor indicate which markers should be used for this purpose.
Again, as discussed above. Applicant is suggesting impermissible hindsight on an intended use for the claimed method rather than a structural/functional distinction to the method. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant submits that claimed methods demonstrate benefits that could not have been predicted from the cited documents. Applicant submits that the selected cells have superior barrier function and polarized secretion. The selected RPE cells demonstrate therapeutic efficacy in a retinal degeneration model following subretinal transplantation with significant increase in ONL thickness, cone preservation, survival in vivo, rescue of visual acuity and physiological function including rhodopsin ingestion as opposed to rats that did not receive the cell transplantation.
In response, none of these examples of benefits are recited by the claims. As such, they are not required by the claims. RPE cell transplantation was known in the prior art and also known to improvement in visual parameters. For example, the prior art of Zarbin et al. (Stem Cell Translation Medicine 2019:466-477) reports “The first clinical trials of retinal pigment epithelium (RPE) transplantation for vision-threatening complications of age-related macular degeneration (AMD) have begun with some preliminary signs of success (e.g., improvement in vision in some patients, anatomic evidence of transplant-host integration with some evidence of host photoreceptor recovery…” see abstract and conclusion. As such, the implications by Applicant that these RPE produced have a benefit or superior function able those produced by prior art methods, such as the combined teaching of the prior art, is not convincing. Further it is notes that the rescue therapy relied upon in applicant’s remarks compares to control wherein the cells were not administered. This would not be considered a demonstration of benefit or improvement over prior art method of provided RPE cells for transplantation and visual function rescue that it does not use a prior method of obtained cells as controls. As such, Applicant has not provided adequate showing of a unexpected or unpredictable benefit over that found in the prior art.
In conclusion, the obviousness rejection of record is maintained because the limitations of the amended claims are taught by the cited combined prior art and Applicant arguments are not persuasive because Applicant is not giving the claims their broadest reasonable interpretation and reading limitations into the claims that are not required.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
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MARCIA S. NOBLE
Primary Examiner
Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
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