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
Claims 1-3, 5-6, 8, 11-13, 17, 19-21, 25-27, 29-31 are pending.
Applicant's election with traverse of Group I, claims 1-3, 5-6, 8, 11-13, and 17, and the species of CD40-ligand and healthy patients in the reply filed on 12/22/2025 is acknowledged. The traversal is on the ground(s) that Group III (claims 20-21 and 25) has been amended to require the same inventive feature of Group I (Remarks, p5).
In regards to Applicant’s traversal of Group III (claims 20-21 and 25), Applicant’s arguments have been considered and persuasive. Therefore, the restriction requirement in regards to claims 20-21 and 25 has been withdrawn.
In regards to the species elections, in view of the amendment of the claims, upon further consideration, the species election requirements have been withdrawn.
In regards to claims 19, 26-27, and 29-31 since Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the requirement is still deemed proper and is therefore made FINAL.
Claims 19, 26-27, and 29-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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, and 25 have been examined on their merits.
Drawings
The drawings are objected to because: Fig. 6A is cutoff, while Fig. 6B is illegible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 3 is objected to for the following informalities: claim 3 recites the abbreviated term “RE:MC” which is abbreviation for the term “renal growth medium: Mesenchymal Cell” (see paragraph [0201]). Abbreviated terms should be spelled out in the first instance.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 25 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), 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 or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 25 describes a nephrospheroid wherein the nephrospheroid is “CD13+/EMA+/EpCAM+/Ace2+ and the protein level and CD13+/EMA+/EpCAM+/Ace2- at the RNA level.”
The plain language of the claim suggests that the nephrospheroid expresses Ace2+ protein, but not Ace2 RNA.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. “Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement.” Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
Actual Reduction to Practice, State of the Art, and Quantity of Experimentation
Claim 25 claims a nephrospheroid that is “CD13+/EMA+/EpCAM+/Ace2+ and the protein level and CD13+/EMA+/EpCAM+/Ace2- at the RNA level.”
In regards to CD13, EMA, and EpCAM, both these proteins and RNAs are expressed in the nephrospheroids. As discussed in the specification, CD13 is a kidney proximal tubular epithelial cell marker, EMA (also known as MUC1 or CD227) is a kidney distal tubular epithelial cell marker, while EpCAM is expressed in both proximal and distal tubular epithelial cells (paragraph [0075, 0132]).
It is noted that this confirms what is known in the art in regards to the markers profiles of proximal and distal tubular cells in regards to CD13, EMA, and EpCAM.
Thus, the nephrospheroids appear to comprise both proximal and distal tubular epithelial cells. Indeed, the specification explicitly states “Accordingly, characterization via flow cytometry, for example, demonstrates that the vast majority of cells within UD-nSPH, express the epithelial marker EpCAM, and that both proximal tubular CD13+ and, to a lesser extent, distal tubular EMA+ cells are present within the nSPH” (paragraph [0132]).
In regards to Ace2, as discussed in the specification, it is known in the art that Ace2 is expressed in proximal tubular cells (paragraph [0014]).
As evidenced by Menon et al. (Kidney International, 2020), kidney proximal tubule epithelial cells express Ace2 transcripts, but that distal proximal tubule epithelial cells are negative for Ace2 transcripts (Fig. 3, p1507). Thus, Ace2 is a marker for proximal but not distal tubule epithelial cells.
Indeed, the specification explicitly states and demonstrates that Ace2 transcript (RNA) is expressed at low levels (paragraph [0229]; Fig. 9A) in kidney epithelial cells (the cells of the nephrospheroid). Low level expression of RNA is still positive expression of that RNA.
While this suggests that distal tubular cells in a nephrosperoid could be negative for Ace2 RNA, while the proximal tubular cells in the nephrospheroid could be positive for Ace2 protein, as discussed above, the plain language of the claim requires that the nephrospheroid expresses Ace2+ protein, but not Ace2 RNA. Thus, the nephrospheroid as a whole – not individual subpopulations within the spheroids – is required to be Ace2+ at the protein level and Ace2- at the RNA level.
In other words, the claim is not a nephrospheroid comprising kidney epithelial cells that are Ace2+ at the protein level and Ace2- at the RNA level, but rather a nephrospheroid that is Ace2+ at the protein level and Ace2- at the RNA level
Since the nephrospheroid appears to comprise proximal tubule epithelial cells which express Ace2 RNA and protein, even if the neurospheroid also comprises distal tubule epithelial cells, the nephrospheroid would still express Ace2 RNA.
Furthermore, as a basic science matter, a person of ordinary skill in the art would have recognized that positive expression of a transmembrane receptor protein such as Ace2 would have required translation of mRNA in order to make that protein.
Therefore, because expression of a protein requires RNA, because as demonstrated in the art Ace2 protein-expressing cells also express Ace2 RNA, and because the specification indicates that cells that make up the nephrospheroid in fact express Ace2 RNA, the Examiner concludes that there is insufficient written description of the instantly claimed nephrospheroid that is “Ace2+ at the protein level and . . . Ace2- at the RNA level”.
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, and 17 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. Dewitte teaches that these cells proliferated (Fig. 3, p7).
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 ne “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.
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.
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 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).
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]).
Therefore, the combined teachings of Dewitte, Ajzenberg, Weiler, and Dekel render the invention unpatentable as claimed.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631