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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 46-48, 50-55, 57 and 64-72) in the reply filed on Jan. 13, 2026 is acknowledged.
Claims 73 and 74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on Jan. 13, 2026.
Claims 46-48, 50-55, 57, and 64-72 examined on their merits below.
Priority
The application is a CON of application 16/557,897, which claims priority to provisional applications 62/728646, filed Sept. 7, 2018; as such the earliest possible priority date is Sept. 7, 2018.
Information Disclosure Statement
The information disclosure statements filed Oct. 10, 2023, Jan. 17, 2024, April 22, 2025, and Oct. 30, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
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 (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.
Claim(s) 46-48, 52-55, 57 and 64-72 are rejected under 35 U.S.C. 103 as being unpatentable over Kolomeyer et al. (Investigative Opthamology, 2011) in view of Lu et al. (Biomed Microdevices, 2012).
The claims are directed to methods of forming a therapeutic composition through seeding a permeable substrate with cells, where the permeable substrate is configured to generate a monolayer from the cells and induce polarity of the cells to allow for secretion of apical, basal, and non-polar specific secretions; collecting the secretions; and purifying the cell secretions by selection specific ones for a therapeutic composition.
With respect to independent claim 53, Kolomeyer et al. teach that cultured retinal pigment epithelial (RPE) cells secrete trophic factors and these trophic factors aid in in vivo retinal survival. (Abstract). More specifically, Kolomeyer et al. teach that RPE cells (both fetal and adult) were isolated and cultured in a monolayer on uncoated and extracellular matrix coated cell culture plates, and conditioned medium was collected from each of the cell types and substrate conditions, at day 7 and day 30. (pg. 5974, “Conditioned Medium Collection”). Kolomeyer et al. teach that trophic secretions are produced, collected and purified; and that these trophic factors act as a therapeutic composition. (pg. 5974-5975, “Trophic Factor Quantification”, Table 1; pg. 5980-5981, “Discussion”).
Kolomeyer et al. is silent on the induced polarity of the cells, but teaches that the cells secrete many of the apical, basal and non-polar secretions (such as BDNF, HB-EGF, PEDF, and VEGF) that the claim identify. (pg. 5974, Table 1). Kolomeyer et al. does not teach seeding the cells on a permeable substrate that is configured to induce polarity of the cells.
Lu et al. teach culturing RPE cells on mesh-supported submicron parylene-C membrane, as this functions as an artificial Bruch’s membrane, enabling the cells to adopt in vivo-like morphology and function, including polarity. (Abstract, pg. 660, 1st col., 1st full para.). More specifically, Lu et al. teach that submicron parylene-C (6 µm thick) was deposited on hexamethyldisilazane (HMDS) treated silicon (to provide the necessary mechanical strength) to create a permeable substrate that supports and nourishes the cells, induces polarity and results in an in vivo-like RPE layer. (whole doc., specifically, pg. 660, “2.1 Design and fabrication”; pg. 663, Fig. 6; pg. Fig. 9).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the method of making a therapeutic composition from a conditioned media of RPE cells taught by Kolomeyer et al. to incorporate culturing the RPE cells on a mesh-supported submicron parylene-C membrane (as taught by Lu et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating this modification would have led to predictable results with a reasonable expectation of success because both references are directed to the therapeutic potential of cultured RPE cells; Lu et al. explicitly teaches that culturing RPE cells on a mesh-supported submicron parylene-C membrane mimics Bruch’s membrane, resulting in a cultured cell product that has in vivo-like morphology and function, including polarity; and Kolomeyer et al. explicitly teach that “[v]arious underlying substrates have been shown to affect RPE cell secretions”. (pg. 5980, “Discussion”). As such, modifying the process taught by Kolomeyer et al. to include a RPE cell culture substrate model that produces an in vivo-like RPE layer would be expected to result in conditioned medium with a trophic factors with a high therapeutic value.
With respect to claims 46-48, Kolomeyer et al. teach that the cells secrete (and thus the product is or could be isolated from the conditioned medium) PEDF (claim 46); VEGF (claim 47); and BDNF, HB-EGF and LIF (claim 48).
With respect to claims 54, 55, 64 and 70, Kolomeyer et al. teach the presence of different trophic factors and the molecular weight of these (see Table 1 & Table 8); as such, a person of ordinary skill in the art could have employed routine and conventional lab techniques to concentrate the desired compound using a molecular weight cut-off and used size-exclusion techniques (fractionation, chromatography) to isolate the desired components in the conditioned medium. Specifically with respect to claim 64, Kolomeyer et al. teach that RPE cells secrete other constituents that regulate the microenvironment, and they “may not have identified all the factors (not necessarily proteins) that RPE cells provide to the retina that help maintain proper structure and function”. (pg. 5984, 1st col., 2nd para.).
With respect to claim 57, Kolomeyer et al. teach the therapeutic composition would not contain cells. (as conditioned medium is centrifuged and cellular debris is removed, pg. 5974, “Conditioned Media Collection”).
With respect to claim 65, Kolomeyer et al. teach RPE cells. (Abstract)
With respect to claims 66 and 68, Lu et al. teach the RPE cells exhibit mature characteristics and the permeable substrate include parylene. (whole doc., especially Fig. 9).
With respect to claims 52, 67, and 69-72, Kolomeyer et al. teach the presence of at least the enumerated therapeutic compositions in the conditions medium and potentially more; as such, further routine optimization of the those compositions and preparation of them as suitable for therapeutic administration would have been routine for one of ordinary skill in the art.
Claim(s) 50 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Kolomeyer et al. (Investigative Opthamology, 2011) and Lu et al. (Biomed Microdevices, 2012) as applied to claims 46-48, 52-55, 57 and 64-72 above, and further in view of Zhu et al. (U.S. Patent 10,470,457, cited in IDS filed on Oct. 10, 2023).
Kolomeyer et al. does not teach a culture medium that is controlled growth of non-mature RPE cells, or that the culture medium is for controlled maturation of non-mature RPE cells to mature RPE cells.
Zhu et al. teach human embryonic stem cells (hESCs) are seeded, cultured and cryopreserved on polymeric, implantable substrates, such as parylene. (col. 3, II. 22-39), which would inherently result in a timepoint when a substrate is provided having a monolayer of immature RPE cells, as Zhu et al. teach the hESCs are cultured to fully differentiated RPE. (col. 10, II. 55-64). Zhu et al. teach that the cells are cultured until confluent or until they reach a desired degree of confluence (col. 11, II. 9-12). Zhu et al. teach that a wide variety of cell types can be seeded onto the substrates, including stem cells and/or their partially or fully differentiated cellular derivatives, as is most suited to the application for which the substrate is being used. (col. 8, I. 41 - col. 9, I. 10).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the method of making a therapeutic composition from a conditioned media of RPE cells taught by Kolomeyer et al. to incorporate culturing non-mature RPE cells in a culture medium that is for controlled maturation of non-mature RPE cells to mature RPE cells (as taught by Zhu et al.) because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating this modification would have led to predictable results with a reasonable expectation of success because both references are directed to the therapeutic potential of cultured RPE cells. As such, modifying the process taught by Kolomeyer et al. to include medium for immature RPEs would be expected to result in conditioned medium with a trophic factors with a different high therapeutic value.
Conclusion
No claims are allowed.
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/TERESA E KNIGHT/ Primary Examiner, Art Unit 1634
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