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 Claims
Claims 1-6, and 9-13 are under examination. Claims 7-8 are cancelled.
WITHDRAWN REJECTION
Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (WO2010065239A1; Published Jun 10, 2010; hereinafter "Zhang"); in view of Hong (Stem Cells Dev. 2011 May; hereinafter "Hong"); Pricola (J Cell Biochem. 2009 Oct 15; hereinafter "Pricola") and Lee et al (DNA Cell Biol. 2016 Sep; hereinafter "Lee") and further in view of Manaph et al (Stem Cell Res Ther. 2018 Aug 22; hereinafter "Manaph").
The rejection is withdrawn in view of amendments. New rejections are set forth below.
MAINTAINED REJECTIONS
Claim Interpretation
The claim amendments to claim 1 encompasses leaving urine at pH7 at a temperature form 20-30ºC for no time (0-96 hours). As such, the claim encompasses urine collection has a pH of 7-8 after 0 hours and urine being left at 20-30ºC for 0 hours.
Claim Rejections - 35 USC § 112
Claim 1 is directed to a method of “massively” proliferating urine-derived multipotent cells. (See claim 1(b)). It is not clear from the wording of the claim as to what the comparator is for the relative term “massively” is used in this application. The term “massively” in claim 1 is a relative term which renders the claim indefinite. The term “massively” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 2-6, and 9-13 are rejected for their dependence on the rejected claim.
Claim Rejections - 35 USC § 103
Claims 1-6 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (WO2010065239A1; Published Jun 10, 2010; hereinafter "Zhang;" see IDS filed 12-5-2022); in view of Hong (Stem Cells Dev. 2011 May; hereinafter "Hong;" See PTO-892 previously provided); Pricola (J Cell Biochem. 2009 Oct 15; hereinafter "Pricola;" See PTO-892 previously provided) and Lee et al (DNA Cell Biol. 2016 Sep; hereinafter "Lee;" See PTO-892 previously provided) and further in view of Manaph et al (Stem Cell Res Ther. 2018 Aug 22; hereinafter "Manaph;" See PTO-892 previously provided).
Regarding claims 1, 3-6 and 10: Zhang is directed to methods for producing a culture of stem cells from urine. Zhang taught centrifugation of urine and plating in a stem cell medium comprising FBS (Fetal bovine serum), hydrocortisone, insulin, transferrin, EGF and penicillin-streptomycin, after washing in sterile PBS. (See Zhang; p. 8, lines 15-25). FBS reads on serum, EGF reads on growth factor, penicillin-streptomycin reads on antibiotic, hydrocortisone reads on corticosteroid, and transferrin reads on a plasma derived content. Zhang taught subculture of the single cells after growth to 50% confluency. This reads on claim 10. Zhang did not teach taking the urine in a tube containing a precipitate solution, before centrifugation as required by claim 1. (See Zhang; p. 7, lines 10-20). However, it is understood by a person of ordinary skill in the art that the invention seeks to replace PBS with the culture medium taught by Zhang to discard unwanted materials. Further, it is considered well within the purview of a person of ordinary skill in the art, absent unexpected results, to dilute the urine solution in a culture medium to maintain the pH and stability of the cells during the centrifugation process. Additionally, it would have been obvious to one having ordinary skill in the art at the time of filing the invention to substitute culture medium for the disclosed PBS since Zhang has shown both reagents are known for using as cell diluents/washing reagents in cell culture methods. (See Zhang p. 15, lines 12-18) Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of cell diluent/washing reagent for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
Zhang did not teach use of estrogen steroid hormone, cytokine or use of ECM (Extracellular matrix protein) in the culture medium. However, Hong taught that “[s]upplements of 17-b estradiol (E2) significantly increase the proliferation of human MSCs in vitro.” (See Hong Abstract). Hong also indicated that “estrogen might have the potential to inhibit the senescence of MSCs” (See Hong p. 925, col. 2, last para). Further Pricola taught that IL6 (an interleukin, cytokine) regulates both MSC proliferation and inhibits differentiation. (See Pricola Abstract; FIG. 2A). Furthermore, Lee taught hat ECM proteins such as gelatin induced significant increases in MSC proliferation during primary culture, and the proportion of MSCs was maintained at more than 99% throughout the subculture. (See Lee Abstract, FIG. 3). As such one of ordinary skill in the art would have been motivated to use cytokines such as IL6, ECM protein such as gelatin coated plates and 17bEstradiol for enhancing proliferation of the multipotent cells derived from urine. The person would also have a reasonable expectation of success due to the teachings of Manaph, that “isolated urine cells behave like mesenchymal cells and MSC” (See Manaph, p. 7, col. 1, para 2) Manaph also indicated that the due to the “high expression of MSC markers, research suggests that urine stem cells are mesenchymal cells derived from urine” (See Manaph, p. 8, col. 2, para 1). The person will also have a reasonable expectation of success due to the teachings of Hong Pricola and Lee that the claimed these factors increase the proliferation of MSC. The person would be motivated to combine Zhang, Hong, Lee and Pricola, due the teachings of Manaph, that claimed cells are all MSCs and have the properties of MSC.
Regarding claim 2: Zhang taught that the stem cell medium comprises DMEM. (See Zhang; p. 8, lines 15-25)
Regarding claim 11: Manaph taught that the Urine stem cells have properties of MSC. (See Manaph, p. 8, col. 2, para 1).
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (WO2010065239A1; Published Jun 10, 2010; hereinafter "Zhang"; see IDS filed 12-5-2022); in view of Hong (Stem Cells Dev. 2011 May; hereinafter "Hong;" See PTO-892); Pricola (J Cell Biochem. 2009 Oct 15; hereinafter "Pricola;" See PTO-892 previously provided) and Lee et al (DNA Cell Biol. 2016 Sep; hereinafter "Lee;" See PTO-892 previously provided) and Manaph et al (Stem Cell Res Ther. 2018 Aug 22; hereinafter "Manaph;" See PTO-892 previously provided) and further in view of Lang et al (PLoS One. 2013; hereinafter "Lang;" See PTO-892 previously provided).
Regarding claim 9: Lang indicated that they stored urine in a preservation medium at 10% (v/v) concentration. “e.g. 25 ml solution in 225 ml voided urine.” (See Lang p. 2, col. 1, para 2). This translates to 25:225 or 1:9 ratio of precipitate solution to urine. It is noted that optimization of dosages/concentrations would have been prima facie obvious to one of ordinary skill in the art at the time of filing. “[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 reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
NEW GROUNDS OF REJECTION NECISDSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 112
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.
Claims 1-6, and 9-11 are 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 1 requires isolating multipotent cells in urine, isolating and proliferating multipotent cells by adding specific ingredients, wherein the multipotent cells in urine are isolated from the urine after being left for 0 to 96 hours at a temperature from 20 to 30C in the tube containing the precipitate solution for urine collection.
The claim requires that the multipotent cells in urine are isolated from the urine after being left for 0 to 96 hours at a temperature from 20 to 30ºC in the tube containing the precipitate solution for urine collection.
Example 1 of the specification demonstrated stability of urine with a sedimentation solution where, 150 ml of urine collected in the tube was separated and left at room temperature for 72 hours. Room temperature is not numerically described in the specification. However, room temperature is generally defined as 20-25 ºC (See Butler p. 1389, col. 2, 4th para, PTO-892). As such it is submitted that the specification supports preservation of proliferating stem cells in urine when left at room temperature for 72 hours. However, no working data support conditions beyond 25ºC and above 72 hours. For example, there is no disclosure or experimental support for storage at 30ºC for 96 hours, which is encompassed by the claim.
As such it is submitted that the specification does not reasonably convey to those skilled in the art that the inventor was in possession of a method effective for all storage times from 0-96 hours and all temperatures from 20-30ºC.
Thus, Applicants were not in possession of the full scope of the claimed invention at the time of filing of the instant invention.
Claim 2-6, 9-11 are rejected for their dependency on the rejected for their dependency.
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 1-6, and 9-11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 1 recites “urine collection has a pH of 7 to 8 after 0 to 96 hours” and “urine after being left for 0 to 96 hours at a temperature from 20 to 30ºC”. The claim requires a pH of 7-8 after 0 hours or storing urine at 20-30ºC for 0 hours. As such it is not clear how long the urine is stored at the claimed temperature. It is noted that storing an entity for 0 hours requires no storage at all.
Claims 2-6 and 9-11 are rejected for their dependency on the rejected claim.
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 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (WO2010065239A1; Published Jun 10, 2010; hereinafter "Zhang"); in view of Hong (Stem Cells Dev. 2011 May; hereinafter "Hong"); Pricola (J Cell Biochem. 2009 Oct 15; hereinafter "Pricola"); Le Pape et al (Artif Organs. 2017 Apr; hereinafter "Le Pape"; See PTO-892) and Lee et al (DNA Cell Biol. 2016 Sep; hereinafter "Lee") and further in view of Manaph et al (Stem Cell Res Ther. 2018 Aug 22; hereinafter "Manaph").
Regarding claim 12-13: As indicated in the office action of 07/11/2025, Zhang taught a stem cell medium comprising FBS (Fetal bovine serum), hydrocortisone, insulin, transferrin, EGF and penicillin-streptomycin. Zhang taught that the described culture medium can be used for culture of urine-derived MSC. (See Zhang; p. 8, lines 15-25). However, Zhang did not teach use of estrogen steroid hormone, cytokine or hemoglobin. As indicated in the office action of 07/11/2025, Hong taught the use of 17b-estradiol and Pricola taught the use of cytokines such as IL6 for proliferation of MSC. Further, Le Pape taught the use of hemoglobin as an additive in cell culture medium for mesenchymal stem cells. Le Pepe taught that “one of the main challenges is to improve oxygen supply to hypoxic areas to reduce oxygen gradient formation while preserving MSC differentiation potential and viability. For this purpose, a marine hemoglobin, HEMOXCell, was evaluated as an oxygen carrier for culturing human bone marrow MSCs in vitro for future three-dimensional culture applications. “ (See Le Pepe Abstract). As such one of ordinary skill in the art would have been motivated to combine cytokines such as IL6, and 17b Estradiol in the stem cell medium taught by Zhang for enhancing proliferation of the multipotent cells derived from urine. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re. Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). The person would also have a reasonable expectation of success in combining the teachings of the cited prior art due to the teachings of Manaph, that “isolated urine cells behave like mesenchymal cells and MSC” (See Manaph, p. 7, col. 1, para 2) Manaph also indicated that the due to the “high expression of MSC markers, research suggests that urine stem cells are mesenchymal cells derived from urine” (See Manaph, p. 8, col. 2, para 1). The person will also have a reasonable expectation of success due to the teachings of Hong, Le Pepe and Pricola that the claimed these factors increase the proliferation of MSC.
Conclusion
No claim is free of art.
No claim is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633