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 .
Applicant's request for reconsideration of the finality of the rejection of the last Office action is persuasive and, therefore, the finality of that action is withdrawn.
Applicant’s amendment and response filed on 5/26/2026 has been received and entered into the case.
Claims 2 and 18 have been canceled, and claims 1, 3-17 and 19-22 have been considered on the merits. All arguments have been considered.
The claim rejection under 35 USC 103 presented in the previous OA has been withdrawn as the applicant’s argument was persuasive and replaced with the following claim rejection.
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.
Claim(s) 1, 3, 5-7, 9-17 and 19-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (2020, Stem Cell Research & Therapy; IDS ref.) in view of Ta et al. (WO2012/131618; of record), and Balasubramanian et al. (2012, Cytotherapy) in further view of Deskin et al. (2013, Stem Cells Translational Medicine), Gao et al. (2016, Cell Death and Disease; of record), Solomon et al. (2018, Biol. Blood Marrow Transplant; IDS ref.) and Ardanaz et al. (2016, BMC Veterinary Research; of record)
Zhang et al. teach a method of treating patients with COVID-19 pneumonia by administering human umbilical cord Wharton’s jelly-derived mesenchymal stem cells (hWJCs)(see entire document). Zhang et al. teach that the hWJCs have shown very significant immunomodulation and tissue repair effects with low immunogenicity, which makes them a very ideal candidate for allogeneic adoptive transfer therapy, and may have beneficial effects on preventing or attenuating the cytokine storm (p.2, 1st col., 1st para.). According to the hWJC preparation taught by Zhang et al. (p.2), it is considered that the hWJCs of Zhang et al. are isolated allogeneic MSCs.
Zhang et al. do not teach the isolated allogeneic MSCs utilized by the method of Zhang et al. are pooled MSC population.
Ta et al. teach a method of isolating, culturing and pooled allogeneic Wharton’s jelly-derived mesenchymal cell population from multiple donors (Abstract). Ta et al. teach that Wharton’s jelly derived MSCs (WJ-MSCs) from each individual are cultured and passaged and Master Cell Bank (MCB) of each individual umbilical cord is established, and pooling is from plurality of established MCB to establish a Working Cell Bank (WCB), and both MCB and WCB are cryopreserved in cryopreservation composition for further use or used directly (p.8, lines 16-31; p.15, lines 6-12).
Regarding the MSCs having at most been subject to ten passages, Ta et al. teach that MCB is established at P1 (p.19, lines 21-23). Furthermore, Ta et al. teach WJ-MSCs at passage 2 (P2/P3) can be used for as therapeutic composition (p.20, lines 8-10), and this teaching would meet the limitation.
It would have been obvious to a person skilled in the art to use isolated allogeneic pooled hWJCs taught by Ta et al. in the method of Zhang et al. with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because the use of pooled MSCs is known in the art as taught by Ta et al., and the use of pooled MSCs is beneficial because they are more constant or consistent characteristics as compared to the individual cells, and the pooled MSCs have equal if not more efficient effect in suppressing T cell proliferation (p.12, lines 20-22; p.24, lines 2-11). Furthermore, Balasubramanian et al. teach that pooling the MSCs would minimize the donor to donor variability while assuring consistent availability of MSC for both experimental and therapeutic use according to (p.31, 1st col. Discussion).
Regarding the step of assaying each individual donor derived MSC population using at least 3 assays to obtain at least 3 assay results for each individual donor derived MSC population, allocating individual ranking score value to individual donor derived MSC population, allocating a total score value based on the at least 3 assay results, and selecting a subset with desirable population properties based on the total score values for pooling (claim 1), Zhang et al. in view of Ta et al. and Balasubramanian et al. do not teach the limitation.
Deskins et al. teach that to maximize efficacy of MSCs, prediction of their therapeutic abilities must be made so that only the best cells will be used, and such prediction of MSC potency can be made by feasible and reproducible in vitro assays (Abstract). Deskins et al. teach the use of scoring system for the MSC properties from the assay analyzing various different donors/cell lines for engraftment in a mouse wound model, and MSCs with higher scores for in vitro tests show higher engraftment and vascularity (see Fig. 5).
It would have been obvious to a person skilled in the art to carry out quality analyses on MSCs from multiple donors in order to obtain MSCs with highest quality measured by assays for immunomodulatory properties in the method of Zhang et al. in view of Ta et al. and Balasubramanian et al. This is because Deskins et al. teach that the prediction of their therapeutic abilities of MSCs by in vitro assay to determine their properties would allow the best cells used in clinical applications in order to maximize efficacy of MSCs. Deskins et al. particularly disclose that their assays do not assess immunomodulatory properties of MSCs, however, different potency assays may be necessary for different clinical applications (p.157, 2nd col., 1st full para.), suggesting that immunomodulatory properties of MSCs would be assayed for obtaining the best cells for the intended purpose of the MSCs.
Regarding the immunomodulatory/immunosuppressive properties of MSCs being assayed including IDO activity, PGE2 secretion and proliferation of PBMCs (claims 1 and 9-11), Zhang et al. in view of Ta et al. and Balasubramanian et al. in further view of Deskins et al. do not particularly teach the claimed assays.
However, these are well known parameters to determine the immunosuppressive or immunomodulatory properties of MSCs according to Gao et al.
Gao et al. teach that immunomodulation of MSCs is mediated by soluble factors including TGF-b, PGE2, HGF, IDO, NO and IL-10, and MSCs secrete various enzymes and soluble factors such as COX-2, PGE2 and IDO that mediate immunosuppressive activity (p.2, 2nd col.). Gao et al. teach that PGE2 is dramatically upregulated after co-culture of MSCs with peripheral blood mononuclear cells (PBMCs) and to inhibit T-cell proliferation (p.2, 2nd col.).
It would have been obvious to a person skilled in the art to assay using at least 3 assays for the ability of the MSCs from each donor for the method of Zhang et al. in view of Ta et al. and Balasubramanian et al. in further view of Deskin et al. in order to obtain the MSCs having the best immunomodulatory properties by measuring the IDO activity/secretion on inhibiting allogeneic T-cell responses (i.e. 1st of the at least 3 assays), PGE2 secretion by MSCs which is shown to inhibit T-cell proliferation (2nd of the at least 3 assays), and at the same time the use of MSCs co-culturing with PBMCs to inhibit their proliferation (i.e. 3rd of the at least 3 assays) as taught by Gao et al. with a reasonable expectation of success.
Regarding the ranking score value from each individual assay on the donor MSCs, and the total score value based on the at least 3 individual ranking score value from the at least 3 assays (claim 1), while the cited references do not particularly teach to obtain the scores and the sum of the scores (i.e. total score value) to determine what to include or exclude in the pooling of MSCs, it would have been obvious to a person skilled in the art to use the scoring system to identify and select the best candidate for the pooled MSCs utilized in the method of Zhang et al. in view of Ta et al., Balasubramanian et al. in further view of Deskins et al. and Gao et al. as such system is extremely well known in the art. A scoring system is known in the art being utilized for donor selection for a cell therapy (e.g. transplantation) according to Solomon et al. Solomon et al. teach the use of a donor selection scoring system based on the various donor characteristics, variables on a certain outcome (p.792, 2nd col., last para.; Table 4). According to Table 4, each donor is given with a score for each variable, and the best donor to optimize survival or relapse reduction is chosen with highest score from the added up points (i.e. total score). Thus, one skilled in the art would have considered to generate a donor selection scoring system similar to that of Solomon et al. for selecting the best donor MSCs using the assays for immunosuppressive properties of MSCs of each donor with a reasonable expectation of success.
Thus, it would have been obvious to a person skilled in the art to utilize a scoring system as exemplified by Solomon et al. for selecting the MSCs having highest quality based on the assay and the scoring system known in the art.
Regarding the wherein clause directed to the number of MSCs derived from any one donor does not exceed 50% of the total cell number (claim 1), the wherein clause is a product-by-process limitation limiting the pooled MSCs. The product-by-process limitation does not require the process steps as active steps required by the claimed method of treating. Rather the product-by-process limitation would provide a structure limitation to the pooled MSCs but does not require the process steps per se. See MPEP2113. Therefore, at most, the product produced by the steps of the wherein clauses is isolated pooled allogeneic MSC population comprises the number of cells from any one donor without exceeding 50% of the total cell number, and they are from at least 3 individual donors. As Ta et al. teach that the pooling is in equal number of MSCs from each cord (p.20, lines 1-2) and Ta et al. exemplified 5 individual samples (Fig. 1), the combined teachings of Zhang et al. in view of Ta et al., Balasubramanian et al. in further view of Deskins et al., Gao et al. and Solomon et al. would meet the limitation.
Regarding the administering step of the isolated, pooled allogeneic MSC population without further culturing after the pooling step and before the administering step (claim 1), Zhang et al. in view of Ta et al., Balasubramanian et al., in further view of Deskins et al., Gao et al. and Solomon et al. do not teach the limitation.
Ardanaz et al. teach that pooled allogeneic MSCs from 5 donors are administered to a horse to treat musculoskeletal injuries (Abstract; Method at p.6, 2nd col. “Study design”).
It would have been obvious to a person skilled in the art to use the pooled MSCs populations from multiple donors without further culturing prior to the administration. A person of ordinary skilled in the art would have been motivated to do so because one skilled in the art would recognize that there are two options that the pooled cells can be used directly without further culturing after pooling or the pooled cells can be further cultured. As it is known in the art that pooled cells can be administered without further culturing the pooled cells according to Ardanaz et al., using the pooled MSCs directly without further culturing would be one obvious option, particularly in the absence of any evidence supporting unexpected results.
Regarding claims 3 and 16 directed to an additional step of exposing the isolated pooled allogeneic MSC population to proinflammatory factors before administration, Gao et al. teach that the immunomodulation by MSCs is enhanced when the MSCs are pretreated/preconditioned with IFN-g (p.6, 2nd col.; p.8, 1st col., Modification of MSCs).
It would have been obvious to a person skilled in the art to precondition the isolated pooled allogeneic MSCs taught by Zhang et al. in view of Ta et al., Balasubramanian et al. in further view of Deskin et al., Gao et al., Solomon et al. and Ardanaz et al. with IFN-g to enhance their immunomodulatory effect taught by Gao et al. for the method of treating COVID-19 with a reasonable expectation of success.
Regarding claim 5 directed to the MSCs being derived from a native MSC source, the hWJCs of Zhang et al. are considered as native MSCs, and one skilled in the art would utilize pooled hWJCs in the method of Zhang et al. based on the teaching of the teaching by Ta et al. Thus, the combined teachings of Zhang et al. in view of Ta et al., Balasubramanian et al. and Ardanaz et al. would meet the limitation.
Regarding claim 8 directed to the MSC population is derived from at least four individual donors, Ta et al. as well as Ardanaz et al. teach multiple individual donors, and one skilled in the art would recognize that at least 4 individual donors as claimed is within the scope of the “multiple” donors for the pooling of MSCs taught by Ta et al. and Ardanaz et al. Thus, it would have been obvious to a person skilled in the art to use at least 4 individual donors to pool the MSCs from individual donors.
Regarding claims 9, 12-15 and 22, the wherein clause of the claim is directed to the results, and they do not require any active steps to be carried out for the claimed method. Thus, these limitations do not provide any patentable weight in determining patentability of the claimed method. Furthermore, as the combined teachings of Zhang et al. in view of Ta et al., Balasubramanian et al. and Ardanaz et al. meet the claimed steps, the same results as claimed are expected from the method taught by the cited references.
Regarding claim 17, Zhang et al. teach the administration of MSCs is intravenously (Abstract).
Regarding claim 20, as discussed above, Ta et al. teach that pooling MSCs from 5 individual donors (Fig. 1). Thus, it would have been obvious to a person skilled in the art to pool 5 individual donors for the pooled allogeneic MSCs for the method of treating COVID-19.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. in view of Ta et al., Balasubramanian et al. in further view of Deskin et al., Gao et al., Solomon et al. and Ardanaz et al. as applied to claims 1 and 3 above, and further in view of Wang et al. (2016, Human Vaccines & Immunotherapeutics; of record).
Regarding claim 4 directed to an additional step of exposing the isolated pooled allogeneic MSC population to proinflammatory factors for a period of about 1-24 hours before administration, while Gao et al. teach the preconditioning, however, they do not teach the limitation directed to the duration, i.e. about 1-24 hours.
However, Wang et al. teach that the priming or pretreatment of Wharton’s jelly derived human MSCs with IFN-g for 24 hours (Abstract; p.93, 2nd col., 1st full para.).
It would have been obvious to a person skilled in the art to pretreat the pooled hWJCs of Zhang et al. in view of Ta et al. with IFN-g prior to administration because such pretreatment/preconditioning/priming would enhance immunomodulation effect of MSCs in the therapeutic application as taught by Gao et al. as well as Wang et al., and the duration of such pretreatment would be 24 hours as taught by Wang et al. with a reasonable expectation of success.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. in view of Ta et al., Balasubramanian et al. in further view of Deskin et al., Gao et al., Solomon et al. and Ardanaz et al. as applied to claim 1 above, and further in view of Liu et al. (2019, Brain Research; of record)
Regarding claim 8 directed to measuring the effect of the MSCs on microglia including measuring the shift from the M1 to M2 microglia phenotype, Zhang et al. in view of Ta et al., Balasubramanian et al. in further view of Deskin et al., Gao et al., Solomon et al. and Ardanaz et al. do not teach the limitation.
Liu et al. teach that MSCs enhance microglia M2 polarization (see entire document). According to Liu et al., MSCs can attenuate neuroinflammation by promoting polarization of M2 microglia (Abstract).
It would have been obvious to a person skilled in the art to assay the MSCs to select the MSCs having higher effect on M2 microglia polarization as an indicative of producing higher anti-inflammatory effects, and thus, one skilled in the art would utilize M2 microglia polarization as an assay to identify MSCs with higher anti-inflammatory effects which are considered to be beneficial for the method of Zhang et al. in view of Ta et al., Balasubramanian et al. in further view of Deskin et al., Gao et al., Solomon et al. and Ardanaz et al.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1, 3-17 and 19-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-7, 14-20 and 23 of copending Application No. 17/634,436 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘436 application disclose a method of obtaining an isolated, pooled allogeneic MSC population using at least 3 assays, any one donor not exceeding 50% of the total cell number, and the 3 assays include measuring IDO activity, PGE2 secretion, and measuring proliferation of PBMC, and at least one of the at least 3 assays being MSCs effect on T cells to suppress an immune response, or assay on monocytes or microglia cell, and the selection is based on the scoring system allocated to the results of each assay and the total score value being used for the selection. These are the same method steps disclosed in the claims of the instant application. The type of MSCs of the ‘436 application includes WJ-MSCs as the instant application.
Regarding the step of administering the isolated, pooled allogeneic MSC population to treat COVID-19 infection of the instant application (claim 1), claims 17-19 of the ‘436 application teach the limitation.
Regarding the administering step without further culturing the pooled allogeneic MSC after pooling, the claims of the ‘436 discloses the limitation (claim 1).
Regarding claims 3-4 and 16, claim 20 of the ‘436 application teach an additional step of exposing the isolated pooled allogeneic MSC population to proinflammatory factors for a period of up to about 1 hour or about 1-24 hours before administration.
Thus, the claims of the ‘436 application render the claims of the instant application obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 3-17 and 19-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-11, 19, 21, 24-26 of copending Application No. 19/003,915 (reference application) in view of Zhang et al. (supra), Wang et al. (supra) and Rogulska et al. (2019, Stem Cells International; of record). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘915 application, while they are directed to the method of using, disclose substantially similar subject matter as the claims of the instant application. The claims of the ‘915 application teach that isolated pooled allogeneic MSC population comprising MSCs derived from at least 3 individual donors, and the step of culturing and assaying using at least 3 assays, and the at least 3 assays comprising IDO activity, PGE2 and proliferation of PBMC, microglial proliferation, marker expression in microglia, etc. The claims of the ‘507 application teach the type of MSCs being WJ-MSCs or UC-MSCs. As indicated above, the wherein clause of claim 1 of the instant application directed to the method steps for obtaining the pooled MSCs does not require any particular active steps to be carried out, rather they are considered to provide structure to the pooled MSCs as an isolated pooled allogeneic MSC population comprises the number of cells from any one donor without exceeding 50% of the total cell number, and they are from at least 3 individual donors. The claims of the ‘915 application disclose the pooled MSCs having the identical structure as the instant application.
Regarding the method of treating COVID-19 infection, the claims of the ‘915 application do not particularly disclose the limitation. However, as the ‘915 application is intended to treat inflammatory disease (claim 11), and it is known in the art that COVID-19 infection which is associated with inflammation can be treated by administering Wharton’s jelly derived MSCs according to Zhang et al. Thus, it would have been obvious to a person skilled in the art to treat COVID-19 infection using the method of the ‘915 application.
Regarding the administering step for treating COVID-19 infection without further culturing the cells after pooling step, while the claims of ‘915 application disclose that the isolated, pooled allogeneic MSC population is not further cultured after the pooling step, however, they do not teach the administering step without further culturing the pooled MSCs for treating COVID-19. However, it would have been obvious to a person skilled in the art that the cryopreserved pooled allogeneic MSC population of the ‘915 application can be thawed and administered without any further manipulation including culturing. Rogulska et al. teach that the cryopreserved MSCs can be used in clinical applications without further manipulation, i.e. direct administration (see Abstract; p.2, 1st col.). Thus, it would have been obvious to a person skilled in the art that the cryopreserved pooled MSCs of the ‘915 application can be directly administered without further culturing after thawing taught by Rogulska et al. with a reasonable expectation of success.
Regarding claim 3 directed to the pretreatment with a proinflammatory factors prior to the administration, the claims of the ‘915 application do not particularly disclose the limitation. However, it is known in the art that preconditioning or pretreatment of MSCs with proinflammatory factors such as IFN-g would enhance the immunomodulatory effect of MSCs including those from Wharton’s jelly according to Wang et al. Thus, it would have been obvious to a person skilled in the art to pretreat the isolated pooled allogeneic MSCs of the ‘915 application with a proinflammatory factor such as IFN-g to enhance the effect of their use in treating inflammation diseases including COVID-19 according to Zhang et al.
Regarding claim 4 directed to the duration of the pretreatment/exposure to the proinflammatory factors being about 1-24 hours, Wang et al. teach the pretreatment of MSCs with IFN-g for 24 hours and thus, it would have been obvious to a person skilled in the art to treat the MSCs of the ‘915 application with IFN-g for 24 hours.
Thus, the claims of the ‘915 application render the claims of the instant application obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments with regard to the “product-by-process” analysis or inherency argument are moot as the previous claim rejection has been withdrawn as indicated above. The new claim rejection presented above has addressed the steps related to assaying and selecting donors for pooling MSCs from the multiple donors.
Regarding the applicant’s argument that Ardanaz teaches away, as discussed previously, Ardanaz et al.'s method is for treating different condition, and the teaching of Ardanaz et al. that the claim rejection is relying on is the pooled MSCs are injected without culturing. In other words, one skilled in the art would recognize that for a therapeutic purpose, the MSCs can be pooled from multiple donors. Based on the teaching of Ta et al., the pooled MSCs can be cultured before and after pooling. However, one skilled in the art would also recognize that the pooled MSCs without further culturing can be directly used in a therapeutic application according to Ardanaz et al. Therefore, it would have been obvious to a person skilled in the art to use the pooled MSCs of Ta et al. in the method of treating COVID-19 taught by Zhang et al. As Ardanaz et al.'s method of using the pooled MSCs is directed to the different condition than COVID-19, the effect of Ardanaz et al.'s method does not necessarily teach away from the use of pooled MSCs in treating COVID-19.
Applicant asserted that the claim rejection has incorrectly interpreted the teaching of Ardanaz et al. as they teach culturing prior to the injection. The Examiner disagrees with this assertion. Ardanaz et al. teach (at p.6, 2nd col):
“One of the joints was injected with 3 mL of LRS (control)
and the contralateral was inoculated with a pool of
25x106 allogeneic BM-MSCs (5x106 BM-MSCs from
each donor) diluted in 3 mL of LRS.”
This teaching of Ardanaz et al. cannot be achieved if the pooled BM-MSCs are cultured after pooling.
The paragraph cited by applicant should be construed as the procedure for isolating each individual MSCs from different donors prior to the pooling. The paragraph states that “… for three days to re-adjust the culture conditions prior to being characterized…” This sentence should be understood that the MSCs isolated from the each individual donor would be characterized for determining the phenotype of the BM-MSCs prior to the use of BM-MSCs from each individual donors for pooling.
Applicant’s argument that Ardanaz is inapplicable due to its categorical differences. The Examiner respectfully disagrees with this argument. The difference between BM-MSCs and WJ-MSCs does not prevent a person skilled in the art to combine these teachings to address the claimed limitations, particularly the claims do not limit the type of MSCs. Applicant is reminded that the claimed rejection is not about the method taught by Ardanaz using intra-articular injection for treating musculoskeletal injuries. As stated, as Ardanaz teaches the pooled MSCs without further culturing, and Ta et al. teach the use of pooled MSCs, it would have been obvious to a person skilled in the art to use pooled MSCs without further culturing after pooling for the method of Zhang et al.
Regarding the applicant's allegation that there is unexpected results, as discussed in the previous OA, it is the Examiner’s position that applicant failed to provide clear evidence that there is unexpected results. Applicant alleged that the in vitro assays performed by the inventors demonstrate the surprisingly beneficial therapeutic potential of the claimed pooled MSC population (“ProTrans”) in the treatment of COVID-19.
Applicant asserted that the pooled MSC (ProTrans) exhibits a significantly elevated basal secretion of IL-6 compared to single-donor MSCs under unstimulated condition. Applicant alleged that this higher IL-6 elevation as an indicative of a “primed” immunomodulatory state. There is no evidence supporting this allegation. Merely the secretion of IL-6 under unstimulated state is elevated, this does not equate to the “primed” immunomodulatory state. Even if it is considered primed immunomodulatory state, however, there is no evidence that this is considered as unexpected considering that the level of secretion of IL-6 or other agents for that matter would be varying in different MSCs from different donors.
Applicant further argued that co-culture of PBMCs with ProTrans induces a significant increase in CD4+ central memory T cells and decrease in CD4+/CD8+ effector memory T-cells. As discussed in the previous OA, the presented data (in the response filed on 1/19/2026) were from the comparison between in the presence or absence of ProTrans in the co-culture with PBMC. There is no data showing the effect of single donor MSCs co-cultured with PBMC. The data merely show the effects of MSCs when co-cultured with PBMC but it does not support if this is only limited to ProTrans in the absence of any comparison to a single MSC population. Therefore, the data shown with regard to the increase or decrease of subset of T cells from the co-culture with PBMC do not provide evidence supporting any unexpected results of the pooled MSCs compared to a single donor MSCs.
Furthermore, there is no evidence supporting unexpected results from treating COVID-19 using ProTrans compared to a single donor MSCs. The unexpected results should be in commensurate with the claimed invention (MPEP716.02(d)). Mere difference between two (i.e. ProTrans vs. a single donor MSC) does not necessarily provide sufficient evidence to consider that the use of ProTrans in COVID-19 produces unexpected results compared to the method taught by Zhang et al. which utilizes a single donor of MSCs.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicant’s response with regarding to the double patenting rejection does not overcome the rejections and thus, they are maintained.
Conclusion
No claims are allowed.
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/TAEYOON KIM/ Primary Examiner, Art Unit 1631
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