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 .
This Action is in response to the papers filed August 27, 2025. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 27, 2025 has been entered.
Claims 37-39, 41, 45-46, 48-49 and 52 are pending in the application in accordance with the claim set filed January 10, 2025. No claims are newly added. Claim 40 is canceled. Claims 37, 39, 41, 45-46, 48-49 and 52 are amended. Claims 37 and 52 are independent claims.
Claims 45-46, 48 and 49 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 with traverse in the reply filed on 08/24/2021.
Thus, claims 37-39, 41 and 52 are examined on the merits.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).
A certified copy of the foreign patent application CL20172357 (Filing date: 09/16/2017) as well as PCT/CL2018/050087 (WO2019/051623; filing date: 09/16/2018) have been provided with the instant application.
Additionally, a certified English translation of said foreign patent application has been provided in the papers filed 01/10/2025.
Thus, the earliest possible priority for the instant application is September 16, 2017.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112 (a) Enablement
The rejection of claim 52 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement has been withdrawn.
Applicant’s arguments and amendments filed 08/27/2025 have been considered and are persuasive.
In particular, Applicant’s amendments reciting specific media and passaging time in order to arrive at the claimed invention.
Claim Rejections - 35 USC § 112 (b)
The rejection of claim 52 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn.
Applicant’s arguments and amendments filed 08/27/2025 have been considered and are persuasive.
In particular, Applicant’s amendments reciting specific media and passaging time in order to arrive at the claimed invention.
Claim Rejections - 35 USC § 103
The rejection of claims 37 and 39 and independent claim 52 under 35 U.S.C. 103 as being unpatentable over Gatta (BMC Genomics 2013, 14:635) in view of Lee (Molecular Therapy vol. 20 no. 1, 155–167; 2012; IDS Reference filed 08/03/2020), Ikeyama (WO2017188403; effectively filed 04-27-2017), and Bocelli-Tyndall (Annals of the Rheumatic Diseases 2015;74:260-266; IDS Reference filed 08/03/2020) is withdrawn.
Applicant’s arguments and amendments filed 08/27/2025 have been considered and are persuasive.
In particular, Applicant’s amendments reciting specific media, passaging time, and TGF-β3 expression in order to arrive at the claimed invention and arguments pertaining to the lack of rationale and disclosure in the previously set forth rejection’s references to address the newly recited limitations.
However, in light of the amendments made, a new ground of rejection is set forth below with additional references.
The rejection of claim 38 under 35 U.S.C. 103 as being unpatentable over Gatta (supra) in view of Lee (supra), Ikeyama (supra) and Bocelli-Tyndall (supra) as applied to Claim 37 above, and in further view of Fong et al. (Journal of Cellular Biochemistry 113:658–668 (2012); previously presented) is withdrawn.
Applicant’s arguments and amendments filed 08/27/2025 have been considered and are persuasive.
In particular, Applicant’s amendments reciting specific media, passaging time, and TGF-β3 expression in order to arrive at the claimed invention and arguments pertaining to the lack of rationale and disclosure in the previously set forth rejection’s references to address the newly recited limitations.
However, in light of the amendments made, a new ground of rejection is set forth below with additional references.
In view of Applicants’ cancelation of claim 40 and amendment of the claims, the rejection of claims 40 and 41 under 35 U.S.C. 103 as being unpatentable over Gatta (supra) in view of Lee (supra), Ikeyama (supra), and Bocelli-Tyndall (supra) as applied to claim 37 above, and in further view of Sharaf-Eldin (Published online Dec 2015. Stem Cells International, vol. 2016, Article ID 1908365, 13 pages) is withdrawn.
Applicant’s arguments and amendments filed 08/27/2025 have been considered and are persuasive.
In particular, Applicant’s amendments reciting specific media, passaging time, and TGF-β3 expression in order to arrive at the claimed invention and arguments pertaining to the lack of rationale and disclosure in the previously set forth rejection’s references to address the newly recited limitations. Additionally, Examiner agrees with Applicant’s argument that Sharaf-Eldin only discloses TGF-β1.
However, in light of the amendments made, a new ground of rejection is set forth below with additional references.
New grounds of objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
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 37, 39, 41 and independent claim 52 are rejected under 35 U.S.C. 103 as being unpatentable over Gatta (BMC Genomics 2013, 14:635; of record) in view of Nekanti (Stem Cells Dev. 2010 Jan; 19(1):117-30), Lee (Molecular Therapy vol. 20 no. 1, 155–167; 2012; IDS Reference), Ikeyama (WO2017188403; effectively filed 04-27-2017; of record), Bocelli-Tyndall (Annals of the Rheumatic Diseases 2015;74:260-266; IDS Reference), and Wang (MOLECULAR MEDICINE REPORTS 14: 5514-5520, 2016)
The broadest reasonable interpretation Claim 37 is:
A method for selecting a composition that contains a specific population of umbilical cord MSCs wherein the claimed passaging time and DMEM, MEM or supplemented glucose media yields a heterogenous population of any amount of cells which would express all of the recited markers.
Based on the Figures of 15-19 as well as Table 7, at most the yield of the claimed method of selecting cells, which express all markers of CD44, CD56, CD105, RANKL, and N-cadherin as claimed in the heterogenous populations is 10% for Lot CU-745-3 (limited by the expression of RANKL), 32% in Lot CU-108-6 (limited by the expression of CD56), and 23% in Lot CU-668K (limited by the expression of RANKL). Therefore, there is not a step of selection to isolate the cells to have a population of cells which would all have expression of all markers recited in a homogenous population.
PNG
media_image1.png
243
425
media_image1.png
Greyscale
Claim 52 recites specific % of cells which supports this interpretation of a heterogenous and non-isolated population.
Regarding claim 37, Gatta teaches culturing and expanding umbilical cord derived MSCs from Wharton’s Jelly (WJ-MSC) which are passaged for 4 passages and then 12 passages (which reads on 3-6 passages) over 6 experiments (Abstract).
In claim 37, the term “select” in step b. is broadly interpreted by choosing to detect specific markers and thereby the antibody selects a marker within the population. As the composition contains a specific population of umbilical cord mesenchymal stem cells, the population need not be isolated to read on the claims. Gatta teaches utilizing anti-CD73, anti-CD13, anti-CD90, anti-CD117, antiCD14, anti-CD34, anti-CD105 and anti-CD45, anti-CD29, anti-CD44 and anti-CD166 antibodies in flow cytometry (p. 2, Immunophenotype). Therefore, markers such as CD44 and CD105 are selected in the umbilical cord mesenchymal cells. Gatta found that the populations of WJ-MSCs are CD44 positive and CD105 positive (Table 1).
However, Gatta does not teach that the cells are cultivated and expanded in the presence of a culture medium such as Dulbecco's Modified Eagle Medium (DMEM)-F12, DMEM with or without high glucose concentration, or Alpha-Minimum Essential Medium (MEM) with or without high glucose concentration. Gatta does not teach the markers N-cadherin, CD56 and RANKL.
Nekanti teaches that utilizing DMEM F12 media in the cultivation and expansion of MSCs isolated from Wharton’s Jelly (WJ-MSC) is superior in vitro than other types of media (Abstract). Greater growth potential based on the number of population doublings pointed towards the benefit of utilizing DMEM F12 (p. 120, 2nd column). The cells were cultured in both early passages (P3-P5) and late passages (P15-P20) with the consistent presence of CD44 and CD105 (Table 1; p. 121, 1st column)
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to expand and cultivate the WJ-MSCs in DMEM F12 as taught by Nekanti instead of the culture media of Gatta with a reasonable expectation of success. An artisan would have been motivated to utilize DMEM F12 as Nekanti teaches DMEM F12 media in the cultivation and expansion of MSCs isolated from Wharton’s Jelly (WJ-MSC) is superior in vitro than other types of media (Abstract).
However, Gatta and Nekanti do not teach that the WJ-MSCs are selected for N-cadherin.
Lee teaches through umbilical cord blood mesenchymal stem cell expression of N-cadherin, that cells with high expression of N-cadherin may be more suitable for transplantation into a damaged heart and could more effectively contribute to interactions with host cardiomyocytes (p. 164, 1st column). Lee further teaches that umbilical cord blood mesenchymal stem cells additionally express CD44 and CD105 (p. 156, 1st column).
It would have been obvious to one of ordinary skill in the art to select N-cadherin, a marker inherent to UC-MSCs as taught by Lee via the method of flow cytometry as taught by Gatta with a reasonable expectation of success. An artisan would be motivated to further select by N-cadherin as they are suggested to be more suitable for transplantation into damaged hearts (Lee, p.164, 1st column). Therefore, an artisan would be motivated to utilize flow cytometry to select these markers as it would further select the population of MSCs and would be combining the selections of known markers for the same population of umbilical cord MSCs thus improving accuracy and purity of the selection method.
However, Gatta, Nekanti and Lee do not teach that the cells are CD56 positive.
Ikeyama teaches sorting and selecting WJ-MSCs which are CD56 positive via FACs (p. 7, Preparation of MSC expressing specific markers; Fig 1). The WJ-MSCs obtained which express CD56 have properties of superior actions to inhibit production of inflammatory cytokines such as IL-6 and to enhance barrier function (p. 9, pharmaceutical composition). Ikeyama provide evidence that a ucMSC cell population comprising 99.7% ucMSCs (Figure 2) naturally comprises at least 70% CD56+ ucMSCs (Figure 1, p. 3, (7); p. 7, Preparation of MSC expressing specific markers).
It would have been obvious to further select the cells of Gatta and Lee which express CD44, CD105, and N-cadherin by CD56 as taught by Ikeyama with a reasonable expectation of success. An artisan would be motivated to select the WJ-MSCs by CD56 as Ikeyama teaches MSCs obtained which express CD56 have properties of superior actions to inhibit production of inflammatory cytokines such as IL-6 and to enhance barrier function (p. 9, pharmaceutical composition).
However, Gatta, Nekanti, Lee and Ikeyama do not teach further selecting the cells by their expression of RANKL.
Bocelli-Tyndall teaches that the expression of RANKL on MSCs and stromal progenitor cells with this phenotype could have an osteoimmunological role during bone regeneration (Abstract). RANKL is essential in bone remodeling via immune response (p. 260).
It would have been obvious to additionally select based on RANKL expression in the WJ MSCs of Gatta with a reasonable expectation of success. An artisan would be motivated to selected based on RANKL expression as Bocelli Tyndall teaches that expression of RANKL could have an osteoimmunological role during bone regeneration (Abstract).
Additionally, as each and every method step before the selection of these markers is taught by Gatta, the population of cells of Gatta would inherently have such markers present for selection within the population taught even though there is no specific disclosure of all of them.
Regarding step c of claim 37, Gatta does not teach that after step b)’s marker selection, an additional a selection is made by TGF-β3 expression, wherein the selection made by TGF-β3 expression is of cultures that express the highest levels of relative expression of TGF-β3 among samples evaluated.
Wang teaches that MSCs which have been modified to have TGF-β3 overexpressed (Abstract). Wang further teaches that TGF-β3 in previous studies provided results which show that it may serve as a promoter to accelerate and induce bone formation (p. 5518, 2nd column). Moreover, the addition of TGF-β3 increased the osteogenic effect exerted by BMP-2 in vitro (p. 5519, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to select WJ-MSCs from the population made obvious by Gatta, Nekanti, Lee, Ikeyama, and Bocelli-Tyndall by an increased expression level of TGF-β3 with a reasonable expectation of success. An artisan would be motivated to select based on TGF-β3 upregulation as Wang further teaches that TGF-β3 in previous studies provided results which show that it may serve as a promoter to accelerate and induce bone formation (p. 5518, 2nd column). Moreover, the addition of TGF-β3 increases the osteogenic effect exerted by BMP-2 in vitro (p. 5519, 1st column).
Regarding claim 39, Gatta teaches obtaining Wharton’s Jelly MSCs (Abstract).
Regarding claim 41, Gatta teaches that the WJ-MSCs express CD73, CD105, CD90, and HLA-ABC and do not express CD45, CD34, CD14 and HLA-DR (Table 1). As shown through the MFI ratios, the more than 98% and less than 2% values are achieved.
Regarding independent claim 52, Gatta does not teach selecting the umbilical cord mesenchymal cells by the presence of N-cadherin in at least 10% of the cells, CD 105 in at least 90% of the cells, CD44 in at least 10% of the cells, RANKL in at least 10% of the cells, and CD56 in at least 15% of the cells.
Based on the rationale and the method of above in the rejection of independent claim 52, the cells selected by the presence of N-cadherin, CD105, CD44, RANKL, and CD56, cultured in DMEM F12 and express TGF-β3 would be in the percentages claimed with a reasonable expectation of success as each and every step (i.e. cultivating, expanding, selecting) is taught by the combination of references above. Additionally, as the motivation for the selection of these markers is taught, it is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are close enough that one skilled in the art would have expected them to have the same properties. See M.P.E.P. §2144.05(I).
Therefore, the invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 38 are rejected under 35 U.S.C. 103 as being unpatentable over Gatta (supra) in view of Nekanti (supra), Lee (supra), Ikeyama (supra), Bocelli-Tyndall (supra) and Wang (supra) as applied to Claim 37 above, and in further view of Fong et al. (Journal of Cellular Biochemistry 113:658–668 (2012); previously cited).
As discussed in the above 103 rejection, Gatta, Nekanti, Lee, Ikeyama, Bocelli-Tyndall, and Wang render obvious a method of selecting Wharton’s Jelly umbilical cord MSCs which have been cultured, expanded and selected for the markers for N-cadherin, RANKL, CD44, CD105 and CD56 in DMEM F12 media and then selected again for TGF-β3 expression.
Regarding claim 38, these references do not teach that the cell selection is based upon the production of the cells wherein 1000 pg/mL of HGF is produced in culture media.
Fong teaches in conditioned media from Wharton’s jelly MSCs, MSCs secrete over 2000 pg/mL HGF as compared to the control (Fig 5). Therefore, the selected cells of Gatta would secrete over 2000 pg/mL HGF as a natural function. Fong teaches that based on this data HGF secretion by these WJ-MSCs are potentially important players in bringing about ex vivo expansion of HSCs as HGF is shown to be effective in hematopoietic progenitor cell maintenance (p. 666, 1st column).
Based on such teachings, it would have been obvious to one of ordinary skill in the art to further select the N-cadherin, RANKL, CD44, CD105 and CD56 of the references above for their secretion of HGF as taught by Fong with a reasonable expectation of success. An artisan would be motived to so so as HGF secretion by these WJ-MSCs are potentially important players in bringing about ex vivo expansion of HSCs as HGF is shown to be effective in hematopoietic progenitor cell maintenance (p. 666, 1st column).
Therefore, the invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
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 37-39, 41 and 52 are newly 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 applicant regards as the invention.
Claims 37 and 52 have been amended to recite “that express the highest levels of relative expression of TGF-63 among samples evaluated.”. However, the claim does not define which are the samples evaluated and in relation to which markers or passages. As such the metes and bounds of the claims are indefinite.
Claims 38, 39, 41 are indefinite insofar as they depend from claim 37.
Claim objection
Claims 37 and 52 are objected to because of the following informalities. Step “a.” of both claims recites “in a culture medium selected from “. However, a Markush group should be in the form “a culture medium selected from the group consisting of A, B, and C”.
Appropriate correction is requested,
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA CONNORS whose telephone number is (571)272-7010. The examiner can normally be reached Monday - Friday (9AM-5PM).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MARIA LEAVITT can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634