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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/12/2025 has been entered.
Claim 10 has been amended. Claim 14 has been newly canceled and no claims have been newly added.
Claims 1-8 and 10-13 are currently pending.
Claims 1-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 10/29/2024.
Claims 10-13 have been examined on their merits.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Interpretation
Claim 10 is drawn to a method for treating kidney injury comprising transplanting the urine-derived kidney stem cells prepared by a specific culturing method into the kidney injury. The limitation “the urine-derived kidney stem cells prepared by a method” is 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, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)
The use of 35 U.S.C. §§ 102 and 103 rejections for product-by-process claims has been approved by the courts. “[T]he lack of physical description in a product-by-process claim makes determination of the patentability of the claim more difficult, since in spite of the fact that the claim may recite only process limitations, it is the patentability of the product claimed and not of the recited process steps which must be established. We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable. As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Regarding the new limitation wherein the feeder cells are mouse embryonic fibroblasts 3T3-J2, this is part of the process of preparing the cell product for transplantation and is only given patentable weight in so far as it affects the structure of the cell product and the effect that this cell product has on the transplantation method.
Regarding the new limitations wherein the urine-derived kidney stem cells express kidney stem cell markers SOX9 and PAX2, these are broadly recited in the claims and not limited to any specific amount or concentration. Therefore, as long as the prior art contains, or is motivated to include, urine-derived kidney stem cells with even the smallest amount of kidney stem cells expressing these markers, then the claim limitations are deemed to be met.
Regarding the limitation “at 14 days post-transplantation of human urine-derived kidney stem cells, human urine-derived kidney stem cells have successfully integrated into the damaged kidneys” is interpreted as requiring that at least one human urine-derived kidney stem cell is found within the damaged kidney. The phrase “successfully integrated” is not limited to any specific degree of success, property or number of cells within the damaged kidney.
Therefore, baring evidence to the contrary, any urine-derived kidney stem cells that contains, or is motivated to contain, at least some cells expressing SOX9 and PAX2 and can be found in the damaged kidney that are disclosed or rendered obvious in the prior art are deemed to read on these claim limitations.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10-13 are 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.
Claim 10 recites the limitation "of human urine-derived kidney stem cells" in line 15 of the claim. There is insufficient antecedent basis for this limitation in the claim as there is no prior recitation of human urine-derived kidney stem cells, only generic “urine-derived kidney stem cells”.
Appropriate correction is required.
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) 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Tian et al (Molecular Medicine Reports, 2017) in view of Zhang et al (Chinese Doctoral Dissertations Medical and Health Sciences 2015, from IDS filed 03/16/2022), Puri et al (The American Journal of Pathology, published January 2018-newly cited), O’Shea et al (US 2018/0221423-newly cited) and Gao et al (Current Stem Cell Research & Therapy, 2016-newly cited).
Regarding claim 10, Tian teach a method of treating acute kidney injury (AKI) by transplanting urine-derived kidney stem cells into the kidney injury (abstract, page 5542, column 2). The urine derived kidney stem cells are cultured in a culture medium that contains many of the same ingredients as claimed by applicant (DMEM, FBS, L-glutamine, insulin, epidermal growth factor) (page 5542, column 1).
Tian teach wherein treatment with the urine-derived stem cells improves kidney function (page 5544) and the administered cells were labeled and detected in the treated kidney (pages 5545-5546) and thus deemed to be successfully integrated at least to some extent into the damaged kidney.
Tian do not disclose using a feeder cell layer to culture their urine-derived stem cells.
Zhang disclose urine-derived kidney stem cells that are obtained by a method that is similar to that claimed in that the culture medium contains the same claimed ingredients and there is a teaching to provide motivation to use a fibroblasts as trophoblasts for a feeder layer in stem cell culture as well (page 5 of 88). Mouse embryonic fibroblasts 3T3-J2 are a very well-known feeder layer used in the art of cell culture and thus an obvious choice. Zhang teach a method for treating kidney injury (kidney disease) by transplanting urine-derived kidney stem cells into the kidney injury (page 13 of 88 of translation, first paragraph, Results part 3). The cell culture medium used to culture the urine-derived stem cells contains the same ingredients as claimed by Applicant (DMEM, F12, FBS (fetal bovine serum), L-glutamine, epidermal growth factor, hydrocortisone, insulin and adenine) (page 2 of 88).
One of ordinary skill in the art would have been motivated to include a mouse feeder layer, such as the well-known 3T3-J2, in the method of Tian because Zhang teach and suggest that this is a suitable and beneficial addition to a method of making urine-derived stem cells. One of ordinary skill in the art would have had a reasonable expectation of success because Tian and Zhang were both directed to the culture and therapeutic use of urine derived stem cells for the repaired of damaged kidneys.
Neither Zhang nor Tian specifically teach wherein the urine-derived kidney stem cells express SOX9 and PAX2.
Puri disclose that Pax2 and Sox9 are expressed in nephron progenitors (kidney progenitor cell) and/or immature derivatives (page 91 column 2) and are crucial during kidney development (page 92 column 1).
O’Shea disclose that Pax2 and Sox9 are known for promoting tissue regeneration or healing of damaged kidney tissue and can be encoded into a synthetic adenovirus for administration in a pharmaceutical composition (page 10 para 127 and 136).
Gao disclose methods of making and using urine derived stem cells for tissue engineering (Title and abstract). Urine-derived progenitor cells (UPCs) were first isolated from human urine and then eventually accepted as urine-derived stem cells as people began to pay more attention to the field (page 547, column1). Gao also disclose that urine derived stem cells express pax2 (page 549, column1).
One of ordinary skill in the art would have been motivated to use urine-derived stem cells that express SOX9 and PAX2 in the method of Tian because Gao disclose that urine-derived stem cells express pax2 and because Puri disclose that Pax2 and Sox9 are expressed in nephron progenitors (kidney progenitor cell) and/or immature derivatives (page 91 column 2) and are crucial during kidney development (page 92 column 1). Additional motivation to select for urine derived stem cells that express SOX9 and PAX 2 is provided by O’Shea which disclose that Pax2 and Sox9 are known for promoting tissue regeneration or healing of damaged kidney tissue (page 10 para 127 and 136). If cells expressing these markers are not found in the Tian culture method then the incorporation of PAX2 and SOX9 into the urine-derived stem cells using a synthetic adenovirus for administration in a pharmaceutical composition is also a possibility as taught and suggested by O’Shea (page 10 para 127 and 136). Arriving at urine-derived stem cells that express PAX2 and SOX9 by including additional steps is not excluded by the claimed invention.
The use of human derived stem cells would have been motivated by the teaching and suggestion of Gao as they disclose that they were first isolated from human urine and then eventually accepted as urine-derived stem cells as people began to pay more attention to the field (page 547, column1). One of ordinary skill in the art would have had a reasonable expectation of success because Tian, Zhang, Gao, and Puri are all drawn to methods of treating damaged kidneys with urine-derived stem cells.
Regarding claim 11, Tian disclose a cell density of 1x105 USCs (urine-derived kidney stem cells) suspended in a total of 200 µl solution (sucrose/hydrogel/PBS) (page 5542, column 2).
With regard to the concentrations of the urine-derived kidney stem cells in the injected suspension, generally, 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) (MPEP 2144.05).
The selection of specific concentrations clearly would have been a routine matter of optimization and experimentation on the part of the artisan of ordinary skill, said artisan recognizing that the therapeutic effect and repair of the damaged kidney would have been affected by these concentrations. One of ordinary skill in the art would have had a reasonable expectation of success because Tian provide a starting point for the optimization of the cell density of the injected suspension and found motivation to increase the density in order to increase the effect of the cells on the damaged tissue.
Regarding claim 12, Tian teach labeling the urine-derived kidney stem cells with green fluorescent protein (GFP) prior to transplanting (abstract, page 5542, column 1, last paragraph).
Regarding claim 13, Tian teach wherein the GFP labeled staining was present in tubular epithelial cells in the kidney specimens after administration of the urine derived stem cells which indicates that the GFP labeled cells were kidney epithelial stem cells (pages 5545-5546).
Therefore, the combined teachings of Tian et al, Zhang et al, Puri et al, O’Shea et al and Gao et al render obvious Applicant’s invention as claimed.
Response to Arguments
Applicant's arguments filed 08/12/2025 have been fully considered but they are not persuasive. Applicant’s arguments have been addressed in so far as they relate to the new rejections recited above.
Applicant argues that the amended claim 10 differs from the Zhang 2015 reference (D1) and thus cannot be anticipated by the Zhang 2015 reference. Applicant asserts that the composition and content of the culture medium in the present application are different from those in the Zhang 2015 reference. Applicant asserts that the different culture medium results in different types of kidney stem cells obtained and different differentiation abilities of the kidney stem cells.
This is found partly persuasive and the anticipation rejection has been withdrawn. However, it has been replaced with a new obviousness rejection described above.
Applicant has provided experiments using the methods disclosed in their Specification, specifically Example 1, and including a long list of main experimental materials many of which are not required by the claims. Example 1 in Applicant’s specification includes steps for passaging the cells and selection steps for isolating their urine-derived kidney stem cells based on the kidney stem cell markers SOX9 and PAX2 as well as other steps and elements that would have affected the final cell product produced and are thus not commensurate in scope with the claimed cells.
In addition, Applicant asserts that in the results of their experiments that Zhang’s method only produced 5.04% of cells that express SOX9 in contrast to their method that showed SOX9 expression in 96.9% of their cells.
However, this is not relevant to the claimed invention as the claims do not include a selection step for isolating urine-derived kidney stem cells that express SOX9 or PAX2 and also do not recite a requirement that the administered cell population had a specific level of expression of these markers. Thus Applicant’s evidence is not commensurate ins cope with the claimed invention.
In addition, Applicant points to the expression of CD73 as evidence for the novelty of their claimed cells. The results are shown in grey scale images but reference the colors of blue and red with regard to the peaks that demonstrate cell marker expression.
This is not found persuasive because the claims do not recite the expression of cell markers CD73 and thus this evidence is not commensurate in scope with the claims. Also, the reliance on color renders the grey scale peaks impossible to decipher.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kumar et al., “Sox9 Activation Highlights a Cellular Pathway of Renal Repair in the Acutely Injured Mammalian Kidney”, Cell reports, 2015, Vol. 12, pp. 1325-1338.
Kang et al., “Sox9 positive progenitor cells play a key role in renal tubule epithelial regeneration in mice”, Cell Reports, 2016, 14(4), pp. 1-25.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA J SCHUBERG whose telephone number is (571)272-3347. The examiner can normally be reached 8:30-5:00 EST.
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LAURA J. SCHUBERG
Primary Examiner
Art Unit 1631
/LAURA SCHUBERG/ Primary Examiner, Art Unit 1631