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 1-3, 5-6, 8, 11-13, 17, 19-21, 25-27, 29-31, and 39 are pending.
Claims 1, 3, and 25 are newly amended.
Claim 39 is newly added.
Claims 19, 26-27, and 29-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/22/2025.
Claims 1-3, 5-6, 8, 11-13, 17, 20-21, 25, and 39 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Withdrawn Objections & Rejections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 Any objections or rejections not specifically reiterated are hereby withdrawn.
The previous rejection of claim 25 under 35 USC 112(a) as failing to comply with the written description requirement is withdrawn due to amendment of the claim.
The previous rejection of claims 1-2, 11-13, 17, and 39 under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001) as evidenced by Menon et al. (Kidney International, 2020) and Steinle et al. (Molecular Therapy Nucleic Acids, 2019) is withdrawn in order to address the claims as amended.
The previous rejection of claim 3 under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001), as applied to claim 1 above, and further in view of Steinle et al. (Molecular Therapy: Nucleic Acids, 2019) is withdrawn in order to address the claims as amended.
The previous rejection of claim 5 under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001), as applied to claim 1 above, and further in view of Liu et al. (Am J Respir Cell Mol Biol, 2002) and Staruschenko et al. (Am J Physiol Renal Physiol, 2013) is withdrawn in order to address the claims as amended.
The previous rejection of claim 6 under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024), Weiler et al. (J Am Soc Nephrol, 2001), Liu et al. (Am J Respir Cell Mol Biol, 2002), and Staruschenko et al. (Am J Physiol Renal Physiol, 2013), as applied to claims 1 and 5 above, and further in view of Kim et al. (Nature Scientific Reports, 2018) is withdrawn in order to address the claims as amended.
The previous rejection of claim 8 under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001), as applied to claim 1 above, and further in view of Innoprot (0.2% Gelation Solution (GSN), 2018) is withdrawn in order to address the claims as amended.
The previous rejection of claims 20-21 under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001), as applied to claim 1 above, and further in view of Dekel (US20130059325A1, 2013) is withdrawn in order to address the claims as amended.
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.
Claims 1-2, 11-13, 17, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001) as evidenced by Menon et al. (Kidney International, 2020) and Steinle et al. (Molecular Therapy Nucleic Acids, 2019).
In regards to claim 1, Dewitte teaches methods of contacting kidney epithelial cells with CD154 (which is the same as CD40L) (Title, Abstract, p1). Dewitte teaches that the kidney epithelial cells were grown in plates (Materials and Methods, p2), which a person of ordinary skill in the art would have recognized suggests adherent culture.
While the kidney epithelial cells as taught by Dewitte are a cell line (Materials and Methods, p2), a person of ordinary skill in the art would have been motivated to use kidney epithelial cells obtained from urine (which would thus be “urine-derived epithelial cells (UD-EPCs)” because Ajzenberg teaches that kidney epithelial cells may be found in urine and that collecting these cells from urine provides a non-invasive way of collecting cells for personalized medicine (Abstract, p1). Furthermore, because Ajzenberg teaches methods for obtaining primary kidney epithelial cells from urine (Urine-derived epithelial cells, p4), it could have been done with predictable results and a reasonable expectation of success.
In regards to effective amounts of CD40 ligand and whether this was enough to promote proliferation of the cells, it is noted that the claim does not require any specific level of proliferation or in comparison to any other condition, but only requires that it occurs.
Turning to the art, while Dewitte teaches that “rsCD154 did not stimulate HK-2 proliferation in normal growth condition or hypoxic condition” (Resistance of HK-2 Cells to Hypoxic Conditions and Association to Stress Responses, p4), at the same time, as demonstrated in Fig. 3 (p7), cells treated with CD154 still demonstrate proliferation (Figure 3, p7; specifically, at least, in normoxic conditions, cells with initial cell densities of about 25 and 50 have cell densities of about 55 and 75 respectively, after 48 hours (Figure 3, p7).
Therefore, even if Dewite does not identify CD40L as a causative agent of proliferation, the cells are still proliferating. Therefore, taken collectively, the method of Dewitte of culturing kidney epithelial cells under adherent conditions in the presence of CD40L still promotes proliferation of these cells as claimed.
While Dewitte is silent on whether the cells are specifically passaged, a person of ordinary skill in the art would have been motivated to passage cells in order to provide them fresh nutrients, remove wastes, and provide more space for cells to grow. Furthermore, because passaging cells is a typical lab practice, and because Weiler teaches that kidney epithelial cells can be passaged (Cell Cultures, p81), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 2, Dewitte teaches that cells were cultured in the presence of serum (Materials and Methods, p2).
In regards to claim 11, in regards to whether passaging is performed “to enrich UD-EPC and deplete epithelial cells of vagina and/or bladder origin”, Applicant should note that this is an intended use of the claim, describes a property of the cells as a result of passaging, and does not recite additional active method steps.
In the instance case, because it would have been prima facie obvious to passage the cells of Dewitte as describe above, the method of Dewitte would also naturally enrich UD-EpCs and deplete epithelial cells of vagina and/or bladder origin absent evidence to the contrary.
In regards to claim 12, Ajzenberg teaches that urine can be collected from adults (Title, Abstract, p1). A person of ordinary skill in the art would have been motivated to collect urine from adults in order to provide personalized medicine for these patients. Furthermore, because Ajzenberg teaches that cells can be isolated from the urine of these patients, it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 13, Ajzenberg teaches that the cells obtained in urine were collected from patients with the AGORA study (Urine-derived epithelial cells, p3), which is well-known to contain patients suffering from kidney diseases. A person of ordinary skill in the art would have been motivated to obtain cells from these patients in order to provide them with personalized medicine. Furthermore, because Ajzenberg teaches that cells can be obtained from the urine of these patients and teaches that they are useful for testing for ciliopathies (kidney disease) (Discussion, p5), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 17, while Ajzenberg is silent on whether kidney epithelial cells express Ace2, as evidence by Menon, ACE2 is expressed in kidney proximal epithelial cells (Abstract, 1502; Fig. 3, p1507), and as evidenced by Steinle, urine-derived epithelial cells comprise proximal tubule epithelial cells (Introduction, column 2, p907). Therefore, the kidney epithelial cells are considered to express Ace2 absent evidence to the contrary.
In regards to claim 39, Dewitte teaches that cells can be contacted with a wide range of concentrations of CD40L, including 1, 12.5, 25, 50, 100, and 200 ng/mL (Figure 5, p9).
A concentration of 1 and 12.5 ng/mL is close to the claimed range of 2-10 ng/mL (see MPRP2144.06(I), 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 art could have arrived at a concentration range of 2-10 ng/mL and the disclosure does not point to a criticality in this rage (see MPEP 2144.06(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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.")
In the instant case, because Dewitte teaches a broad range of concentrations that is greater than and less than the claimed ranges, a person of ordinary skill in the art could have arrived at a concentration range of 2-10 ng/mL by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Dewitte, Ajzenberg, and Weiler render the invention unpatentable as claimed.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001), as applied to claim 1 above, and further in view of Steinle et al. (Molecular Therapy: Nucleic Acids, 2019).
In regards to claim 3, in regards to a “RE:MC”, a renal epithelial and mesenchymal growth medium, a person of ordinary skill in the art would have been motivated to culture cells in a medium comprising REGM Bullet Kit Supplement and Mesenchymal stem cell proliferation medium because Steinle teaches a medium with this composition is suitable for culturing renal epithelial cells derived from urine (Isolation and Cultivation of RECs from Urine, p917). Furthermore, because Steinle demonstrates that renal epithelial cells can be cultured in a medium comprising 1:1 REGM Bullet Kit Supplement and Mesenchymal stem cell proliferation medium, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Dewitte, Ajzenberg, Weiler, and Steinle render the invention unpatentable as claimed.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001), as applied to claim 1 above, and further in view of Liu et al. (Am J Respir Cell Mol Biol, 2002) and Staruschenko et al. (Am J Physiol Renal Physiol, 2013).
In regards to claim 5, Dewitte does not explicitly teach a step of culturing cells in the presence of neuregulin-1 (NGR1). However, a person of ordinary skill in the art would have been motivated to culture cell in the presence of NGR1 because Liu teaches that NGR-1 is structurally similar to epidermal growth factor (EGF), that NRGs act as mitogens, that NRG-induced receptor activation results in multiple biological activities in epithelial cells, and stimulates proliferation of epithelial cell types through binding with HER2/HER3 (ErbB2/ErbB3) (Title, Abstract, p306; Introduction, p306). Furthermore, because Liu teaches that NGR1 induces proliferation of epithelial cell-types (Cell Proliferation Assay, p307; AG490 Inhibits NRG-1177–244–Induced Proliferation, p310; Fig. 9, p312; Table 1, p312), and because as taught by Staruschenko it is known in the art that ErbB2/ErbB3 are found in renal epithelial tissues and dimerize (ErbB Receptors, pF12; Fig. 1, pF13; Fig. 2, pF14), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Dewitte, Ajzenberg, Weiler, Liu, and Staruschenko render the invention unpatentable as claimed.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024), Weiler et al. (J Am Soc Nephrol, 2001), Liu et al. (Am J Respir Cell Mol Biol, 2002), and Staruschenko et al. (Am J Physiol Renal Physiol, 2013), as applied to claims 1 and 5 above, and further in view of Kim et al. (Nature Scientific Reports, 2018).
In regards to claim 6, Dewitte does not explicitly teach a step of culturing cells in the presence of isolated mitochondria.
However, a person of ordinary skill in the art would have been motivated to culturing the cells in the presence of isolated mitochondria because Kim teaches that direct mitochondrial transfer of isolated can restore cellular functions of cells with inherited or acquired and normalizes ATP production, mitochondrial membrane potential, mitochondrial ROS levels, and oxygen consumption in target cells (Abstract, p1). Furthermore, because teaches that mitochondrial isolation and transfer is simple and easy and can be applied to any cell type (Abstract, p1) it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Dewitte, Ajzenberg, Weiler, Liu, Staruschenko, and Kim render the invention unpatentable as claimed.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001), as applied to claim 1 above, and further in view of Innoprot (0.2% Gelation Solution (GSN), 2018).
In regards to claim 8, Dewitte does not explicitly teach that the adherent conditions comprise gelatin coating.
However, a person of ordinary skill in the art would have been motived to coat dishes with gelatin because Innoprot teaches that coating plates with gelatin promotes cell attachment (Product Description, p1). Furthermore, because Innoprot teaches method for coating dishes with gelatin (Procedure, p1), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Dewitte, Ajzenberg, Weiler, and Innoprot render the invention unpatentable as claimed.
Claims 20-21 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Dewitte et al. (Mediators of Inflammation, 2020) in view of Ajzenberg et al. (Cilia, 2015, on IDS 03/25/2024) and Weiler et al. (J Am Soc Nephrol, 2001), as applied to claim 1 above, and further in view of Dekel (US20130059325A1, 2013) as evidenced by Menon et al. (Kidney International, 2020), Steinle et al. (Molecular Therapy Nucleic Acids, 2019), and Harari-Steinberg et al. (Cell Reports, 2020).
In regards to claim 20, Dewitte as modified by Ajzenberg and Weiler teache a step of expanding kidney epithelial cells from urine to obtain UD-EpCs according to claim 1 as discussed above.
Dewitte does not explicitly teach a step of culturing these cells under non-adherent conditions, thereby generating nephrospheroids.
However, Dekel teaches that nephrospheroids can be used to renal damage in patients (paragraph [0021]). Furthermore, Dekel teaches that these cells can be obtained by culturing kidney cells under non-adherent conditions (Claim 1). Therefore, a person of ordinary skill in the art would have been motivated to culture the cells under non-adherent conditions because Dekel indicates that this will result in nephrospheroids which are useful for treating renal damage in patients. Furthermore, because Dekel teaches methods for culturing kidney cells under non-adherent conditions in order to obtain spheroids (claims 1-8), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 21, Dekel teaches that the nephrospheroids are capable of forming proximal distal tubules (paragraph [0109]).
In regards to claim 25, expression of CD13, EMA, EpCam, and Ace2 is a natural property of forming spheroids according to the method of clam 20. According to claim 20, culturing the kidney epithelial cells in non-adherent conditions is sufficient nephrospheroids. Therefore, since Dewitte as modified by Dekel carries out the same method steps the nephrospheroids would express the same markers, absent evidence to the contrary. Additionally, as taught by Dekel, nephrospheroids express at least EpCAM (Fig. 9A). Additionally, as evidenced by Menon above, ACE2 is expressed in kidney proximal epithelial cells (Abstract, 1502; Fig. 3, p1507), and as evidenced by Steinle, urine-derived epithelial cells comprise proximal tubule epithelial cells (Introduction, column 2, p907). Furthermore, as evidenced by Hariri-Steinberg, neohrospheroids derived from kidney epithelial cells express EpCam, CD13, and EMA which are known markers for these cells (p856, left column, Fig. 2, p855).
Therefore, the combined teachings of Dewitte, Ajzenberg, Weiler, and Dekel render the invention unpatentable as claimed.
Response to Arguments
Applicant argues that the amendment of claim 25 renders the rejection under 35 USC 112(a) moot (Remarks, p7).
Applicant’s arguments filed 05/26/2026 is found persuasive and therefore, the rejection under 35 USC 112(a) as failing to comply with the written description requirement is withdrawn. However, the claim is still prima facie as discussed above.
Applicant argues that nowhere in Dewitte is the addition of rsCD154 contributed to cell proliferation under any concentration analyzed at hypoxic or normoxic conditions (Remarks, p8).
Continuing, Applicant argues that Dewitte explicitly shows in Figure 3C that rsCD154 does not affect the proliferation of kidney derived epithelial cells and teaches specifically that “rsCD154 did not stimulate HK-2 proliferation in normal growth condition or hypoxic condition” (Remarks, p8-9).
Applicant’s arguments filed 05/26/2026 have been fully considered but are not found persuasive.
As discussed above, in regards to effective amounts of CD40 ligand and whether this was enough to promote proliferation of the cells, it is noted that the claim does not require any specific level of proliferation or in comparison to any other condition, but only requires that it occurs.
Turning to the art, while Dewitte teaches that “rsCD154 did not stimulate HK-2 proliferation in normal growth condition or hypoxic condition” (Resistance of HK-2 Cells to Hypoxic Conditions and Association to Stress Responses, p4), at the same time, as demonstrated in Fig. 3 (p7), cells treated with CD154 still demonstrate proliferation (Figure 3, p7; specifically, at least, in normoxic conditions, cells with initial cell densities of about 25 and 50 have cell densities of about 55 and 75 respectively, after 48 hours
PNG
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307
348
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(Figure 3, p7, see Figure adjacent, as modified).
Therefore, even if Dewite does not identify CD40L as a causative agent of proliferation, the cells are still proliferating. Therefore, taken collectively, the method of Dewitte of culturing kidney epithelial cells under adherent conditions in the presence of CD40L still promotes proliferation of these cells as claimed.
Applicant argues that Dewitte uses soluble recombinant (sr)CD154 which is similar to CD40L (Remarks, p8).
Applicant’s augments filed 05/26/2026 have been fully considered but are not found persuasive. Neither the specification nor the claims identify or define the specific type of CD40L. As evidenced by BioLegend, CD154 and CD40L are synonyms for the same protein (first page). Therefore, a recombinant variant (such as srCD154) reads on the claim and is the same.
Applicant argues that none of Ajzenberg, Steinle, Weiler, Staruschenko, Kim, Innoprot, or Dekel overcomes the deficiencies of Dewitte (Remarks, p9).
Applicant’s arguments filed 05/26/2025 have been fully considered but are not found persuasive because Dewitte is not deficient as discussed above.
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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