DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group III (claims 19-26) in the reply filed on 9/22/2025 is acknowledged.
Claims 1-18 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 19-26 have been considered on the merits.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 19-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea, a judicial exception, without significantly more.
The claim(s) recite(s) a method of obtaining an isolated, pooled allogeneic MSC population pharmaceutical composition, and the method requires a step of 1) allocating an individual ranking score value obtained from measuring immunosuppressive properties, 2) allocating a total score value to each individual donor derived MSC population, and 3) selecting a subset of individual donor derived MSC populations with desirable population properties based on their total score values. These steps of assaying, allocating and selecting are directed to the analysis of data obtained from the cultured MSC populations from at least 3 individual donors by using a generic assay to measure the immunosuppressive properties of the populations. As these steps can be carried out mentally by looking at the data obtained from the assaying and measuring immunosuppressive properties, i.e. mental process, the instant claims recite an abstract idea which is a judicial exception. MPEP2106.04(a)(2)(III) states that if a claim recites a limitation that can practically be performed in the human mind, with or without the use of a physical aid such as pen and paper, the limitation falls within the mental processes grouping, and the claim recites an abstract idea.
The method steps of allocating the scores and selecting a subset of the populations are disclosed such that higher ranking score values being indicative of more desirable assay results. This is considered as the claims are directed to a method of using a naturally occurring correlation, i.e. laws of nature. In other words, higher immunosuppressive properties of MSC populations are more desirable for the therapeutic application, and the score value given to the individual MSC population and selecting the population having higher ranking score value is based on naturally occurring correlation between higher immunosuppressive properties and higher therapeutic outcome.
Thus, based on the above analysis, it is concluded that the instant claims recite a judicial exception (STEP 2A, Prong One: YES).
The claim then requires further analysis in Step 2A Prong Two, to determine whether any additional elements in the claim integrate the abstract idea into a practical application. This judicial exception is not integrated into a practical application because the additional element, i.e. step of culturing MSCs from at least 3 individual donors; measuring the immunosuppressive properties; pooling the individual donor derived MSC populations; combining the pooled MSCs with a pharmaceutically acceptable excipient; and cryopreserving the pooled MSC population. These additional elements are directed to an insignificant extra-solution activity to obtain the data to carry out the judicial exception of comparing the data and allocating a ranking score value and a total score value (see MPEP2106.04(d)(2)). The pooling the individual MSC population based on the scores determined by the judicial exception, combining the MSC population with an excipient or carrier, and cryopreserving the cells as claimed are considered not more than generally linking the use of a judicial exception to a particular technological environment or filed of use (MPEP2106.05(h)). Therefore, the judicial exception is not integrated into a practical application (STEP 2A, Prong Two: NO).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements directed to the steps of culturing the individual MSC population, pooling the MSC populations, combining the pooled populations with an excipient or carrier, and cryopreserving the pooled MSC population are well-understood, routine, conventional activity in the field. Thus, the additional elements do not add significantly more to the judicial exception.
Regarding the limitations of claims 20-26 directed to the specific limitation to the assay or types of MSCs, or number of passages, they are not considered to be enough to qualify as significantly more to the judicial exception.
Based on the above discussion, it is the Examiner’s position that the claims of the instant application do not disclose subject matter eligible under 35 U.S.C. 101.
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) 19 and 21-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ta et al. (WO2012/131618) in view of Ardanaz et al. (2016, BMC Veterinary Research), Deskins et al. (2013, Stem Cells Translational Medicine) in further view of Francois et al. (2011, Molecular Therapy), Solchaga et al. (2012, Am. J. Stem Cell), Killer et al. (2017, Stem Cell Research & Therapy), Solomon et al. (2018, Biol. Blood Marrow Transplant.; published on 1/17/2018), and Klinker et al. (2017, PNAS)
It is noted that the references cited in the instant claim rejection were of record in the parent application except those underlined.
Regarding claim 19 and 25-26, 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 culturing 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). Ta et al. exemplified 5 individual samples (Fig. 1), which would meet the limitation of claim 26.
Regarding “at least 3 individual donors” of claim 19, Ta et al. exemplified 5 individual samples and pooled (Fig. 1) and Example 1 shows 3 individual donors. Regarding the MSCs having at most been subject to eight passages, Ta et al. teach that MCB is established at P1 (p.19, lines 21-23).
Regarding the number of MSCs derived from any one donor does not exceed 50% of the total cell number (claim 19), Ta et al. teach that equal number of MSCs from each cord is pooled to form a single working cell bank (p.20, lines 1-2). Considering that the pooled MSCs of Ta et al. are from “multiple” donors including 3 individual donors or 5 individual donors as discussed above, the number of cells from each donor would not inherently exceed 50% of the total cell number when pooled.
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, Ta et al. do not teach the limitation.
Ardanaz et al. teach a method of preparing pooled allogeneic BM-MSCs for treating musculoskeletal injuries (Abstract; Method at p.6, 2nd col. “Study design”), and Ardanaz et al. teach a step of characterizing BM-MSCs prior to pooling to optimize the treatment (Fig. 1). Ardanaz et al. teach that allogeneic MSCs provide the possibility to be selected according to their characteristics to optimize the treatment (higher immunomodulatory capacity, rate of growth in culture, etc.) (p.2, Background, 1st col., 3rd para.).
Deskins et al. teach that in order 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 prior to pooling the allogeneic MSCs from multiple donors taught by Ardanaz et al. and Deskins et al. for the method of Ta et al. This is because Ardanaz et al. teach a step of characterizing BM-MSCs prior to pooling to optimize the treatment and 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.
Ta et al. in view of Ardanaz et al. and Deskins et al. do not particularly teach the characterization includes the assay measuring IDO, PGE2 and the effect of the MSCs on proliferation of PBMCs.
Francois et al. teach that there are discrepancies in the immunosuppressive capacity of MSCs, and such variability in the immunosuppressive potential of each MSC donor source can be measured by IFN-mediated IDS upregulation, and IDO activity is correlated with the immunosuppressive capacity of MSCs (seen entire document).
Solchaga et al. teach that PGE2 measured from a conditioned medium of hMSCs is a putative potency indicator of the immunosuppressive activity of hMSCs (see entire document).
Killer et al. teach that co-culture of MSCs with PBMC in an allogeneic T-cell proliferation assay would measure the potency of immunosuppressive function of the MSCs (Abstract; Conclusion).
It would have been obvious to a person skilled in the art to carry out the assays measuring IDO, PGE2 and proliferation of PBMC as taught by Francois et al., Solchaga et al., and Killer et al., respectively, to determine the immunosuppressive capacity of the MSCs from each donors to select the optimal MSCs for the therapeutic application with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because it is known in the art that there are variabilities in MSC’s immunosuppressive properties as taught by Francois et al., and the assay determining immunosuppressive capacity would allow one skilled in the art to choose the best MSCs as intended by Deskins et al.
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 19), Ta et al. in view of Ardanaz et al. and Deskins et al. do not particularly teach the limitation.
However, the use of scoring system to identify and select the best candidate as such system is extremely well known in the art.
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).
Klinker et al. teach a method of determining immunosuppression scores for various sources of MSC for stimulated and unstimulated condition (Fig. 6). Klinker et al. developed their own method of scoring immunosuppression utilizing AUC value based on morphology of MSCs, and higher AUC values represent weaker immunosuppression (p. E2600).
Thus, it would have been obvious to one skilled in the art to generate a donor selection scoring system similar to that of Solomon et al. or Klinker et al. for selecting the best donor MSCs having the higher immunosuppressive capacity using the assay results from determining immunosuppressive capacity of MSCs by measuring IDO, PGE2 and proliferation of PBMS taught by Francois et al., Solchaga et al. and Killer et al. for each donor with a reasonable expectation of success.
Regarding the MSCs having at most been subject to eight passages (claim 19) or 2-6 passages (claim 24), 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). Furthermore, Ardanaz et al. teach that approximately 106 cells from passage three were thawed and plated in a flask for three days and used on the different injections (p.7, 1st col., 1st para.). These teachings would meet the limitations of claims 19 and 24.
Regarding the pooled allogeneic MSC population being not further cultured after the pooling step, Ta et al. teach that a Working Cell Bank (WCB) established from polling MSCs from plurality of established Master Cell Bank (MCB), and the WCB is cryopreserved in a cryopreservation medium to obtain WCB composition (p.8, lines 25-31). Thus, the cryopreserved WCB composition of Ta et al. would meet the limitation directed to the pooling and cryopreserving steps without further culturing.
Regarding the limitation directed to the step of cryopreserving the isolated, pooled allogeneic MSC population (claim 19), as discussed above, Ta et al. teach that the pooled MCBs forming the WCB composition and then cryopreserved.
Regarding the step of combining the therapeutically effective amount of isolated, pooled allogeneic MSC population and a pharmaceutically acceptable excipient or carrier to make a pharmaceutical composition, Ardanaz et al. teach that the injection of pooled allogeneic BM-MSCs is diluted in 3 ml of lactated ringer’s solution (LRS) (Method at p.6, 2nd col. “Study design”). The injection, i.e. pharmaceutical composition, of Ardanaz et al. is considered to be made by combining the pooled allogeneic MSCs with LRS, a pharmaceutically acceptable carrier/excipient.
Regarding the therapeutically effective amount of the isolated, pooled allogeneic MSC population, this limitation is interpreted as any amount of MSCs as the claims do not disclose any particular purpose or use of the cell population. Thus, the WCB composition of Ta et al. would meet the limitation.
Furthermore, the amount of injected in the method of Ardanaz et al., i.e. 25x106 MSCs, is considered as a therapeutically effective amount for treating joint-related disorders such as osteoarthritis (OA) (p.2, Background).
Regarding claim 21, the limitation is directed to the number of assayed MSCs from individual donors being at least one more than those pooled in the pooling step. While the combined teachings of the cited reference above do not particularly teach the limitation, however, it would have been obvious to a person skilled in the art that the screening assays of IDO, PGE2, and PBMC proliferation inhibition leading to the ranking of each individual MSCs would result in either all of the MSCs would meet the criteria (number of assayed = number of pooled), some of the tested/assayed MSCs would meet the criteria (number of assayed > number of pooled), or none of the tested/assayed MSCs would meet the criteria (number of pooled = 0). Based on these possibilities, the last one would not be considered as the method requires pooling MSCs. Then, the possibilities from the selection would be either the numbers are the same or the number of pooled would be smaller than the number of assayed. Considering the variability of MSCs from different donors, it is expected that the number of pooled would be smaller than the number of MSCs assayed.
Regarding claim 22 directed to the number of assayed donor MSCs being at least 2-4 times as many as the number of pooled, the same analysis can be applicable as above. The number of pooled donors would be determined by how stringent the threshold for the results to select MSCs for pooling of Ta et al. in view of Ardanaz et al. and Deskins et al. Therefore, the ratio of assayed vs. pooled would be routinely optimizable by changing the stringency of the selecting candidates from the assays.
Regarding claim 23 directed to the number of MSCs (cell concentration) of each donor not being exceed 4 times of the number of cells of other donors in the pool, while the combined teachings of the references do not particularly teach the limitation, however, the number of cells from each donor in the pool of the pooled MSCs of Ta et al. would be modified based on the amount of cells obtained from each donor. For example, if the MSCs from each donor are combined at the equal number per donor, then the claimed limitation would be met. As the pooling of MSCs taught by Ta et al. is intended to reduce variability of the cells from different donors (p.25, lines 20-22), one skilled in the art would not use MSCs from a single donor dominate the whole pooled population in their number, and by doing so, the claimed limitation would be met. This would also meet the requirement of the claims directed to any one donor does not exceed 50% of the total cell number.
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) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ta et al. in view of Ardanaz et al. and Deskins et al. in further view of Francois et al., Solchaga et al., Killer et al., Solomon et al., and Klinker et al. as applied to claim 19 above, and further in view of Rizzo et al. (2008, Cytotherapy; of record)
Regarding claim 20 directed to an assay measuring HLA-G expression in the MSCs in response to IL-10, the cited references do not teach an assay measuring HLA-G expression in MSCs in response to IFN- or IL-10.
However, it is known in the art that soluble HLA-G antigens play a role in immune modulation mediated by MSCs according to Rizzo et al. Rizzo et al. teach that IL-10 is one of the main up-modulators of soluble HLA-G, and exogenous IL-10 induced sHLA-G molecule secretion by MSC along (Abstract: Results).
It would have been obvious to a person skilled in the art to assay the secretion of sHLA-G by MSCs by IL-10 as one way to determine immunomodulatory property of MSCs along with IDO and PGE2 discussed above. One skilled in the art would recognize that the determining the value of the sHLA-G secreted by MSCs would be in addition to IDO, PGE2, PBMC proliferation inhibition of MSCs to determine that the MSCs from individual donors to select the best candidate for pooling in the method of Ta et al. in view of Ardanaz et al. and Deskins et al. with a reasonable expectation of success. These factors are all known parameters of immunomodulatory properties of MSCs, and thus, it would have been obvious to combine them together to determine the immunosuppressive property of the MSCs.
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 Rejection
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.
Claims 19-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-7, 14, 21, 23 of copending Application No. 17/634,436 (reference application) in view of Ta et al. (supra) and Rizzo et al. (supra). 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, etc., 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 cryopreserving the isolated, pooled allogeneic MSC population of the instant application (claim 19), the claims of the ‘436 application do not teach the limitation. However, it would have been obvious to a person skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘436 application for the future use with a reasonable expectation of success. One skilled in the art would recognize that cryopreservation is a well-known option for storing cells regardless they are pooled or not, and thus, it is considered a well-known option to a person skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘436 application after pooling for the storage purpose with a reasonable expectation of success. For example, cryopreserving pooled allogeneic MSCs is known in the art as taught by Ta et al. Ta et al. teach that Master Cell Bank (MCB) of individual MSCs is optionally cryopreserving the MCB, and then pooling the [thawed] MCB to establish Working Cell Bank (WCB), and optionally cryopreserving the WCB (p.8, lines 24-31). Thus, it would have been obvious to one skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘436 application.
Regarding HLA-G expression of claim 20 of the instant application, the claims of the ‘436 application do not teach the limitation. However, it is well known in the art that soluble HLA-G antigens play a role in immune modulation mediated by MSCs according to Rizzo et al. Rizzo et al. teach that IL-10 is one of the main up-modulators of soluble HLA-G, and exogenous IL-10 induced sHLA-G molecule secretion by MSC along (Abstract: Results). As the assays of the ‘436 application are directed to measuring the immunosuppressive properties/potentials of MSCs, and Rizzo et al. teach that HLA-G secreted by MSCs upon IL-10 is involved in the immunomodulatory potential of MSCs, one skilled in the art would try to measure HLA-G expression/secretion by MSCs as additional property of MSCs having immunosuppressive properties for the pooling.
Regarding the combining step of the isolated, pooled, allogeneic MSC population with a pharmaceutically acceptable carrier to make a pharmaceutical composition, claims 21 and 23 of the ‘436 application disclose that the isolated, pooled allogeneic MSC population is a part of the pharmaceutical composition and further contains a pharmaceutically acceptable carrier. Regarding the therapeutically effective amount, claim 14 of the ‘436 application discloses a method of using the isolated, pooled, allogeneic MSC population being administered at a therapeutically effective amount. Thus, it would have been obvious to a person skilled in the art to use a therapeutically effective amount of the isolated, pooled, allogeneic MSC population in the pharmaceutical composition with a reasonable expectation of success.
Regarding claim 21, the limitation is directed to the number of assayed MSCs from individual donors being at least one more than those pooled in the pooling step. While the combined teachings of the cited reference above do not particularly teach the limitation, however, it would have been obvious to a person skilled in the art that the screening assays of IDO, PGE2, PBMC proliferation inhibition, and HLA-G leading to the ranking of each individual MSCs would result in either all of the MSCs would meet the criteria (number of assayed = number of pooled), some of the tested/assayed MSCs would meet the criteria (number of assayed > number of pooled), or none of the tested/assayed MSCs would meet the criteria (number of pooled = 0). Based on these possibilities, the last one would not be considered as the method requires pooling MSCs. Then, the possibilities from the selection would be either the numbers are the same or the number of pooled would be smaller than the number of assayed.
Regarding claim 22 directed to the number of assayed donor MSCs being at least 2-4 times as many as the number of pooled, the same analysis can be applicable as above. One skilled in the art would expect that the number of pooled donors selected from the total number of assayed donors would be determined by the desired stringency or threshold of the selection of MSCs for pooling. Therefore, the ratio of assayed vs. pooled would be routinely optimizable by changing the stringency/threshold of the selection resulted from the assays.
Regarding claim 23 directed to the number of MSCs (cell concentration) of each donor not being exceed 4 times of the number of cells of other donors in the pool, while the combined teachings of the references do not particularly teach the limitation, however, the number of cells from each donor in the pool of the pooled MSCs of the ‘436 application would be modified based on the amount of cells obtained from each donor. For example, if the MSCs from each donor are combined at the equal number per donor, then the claimed limitation would be met.
Thus, the claims of the ‘436 application in view of Ta et al. and Rizzo et al. 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 19-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 7, 10-11, 20 of copending Application No. 18/041,507 (reference application) in view of Ta et al. (supra) and Rizzo et al. (supra).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘507 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 ‘507 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. Claim 1 also discloses the isolated pooled allogeneic MSC population is not further cultured after the pooling step. The claims of the ‘507 application teach the type of MSCs being WJ-MSCs or UC-MSCs (claim 6).
Regarding the pharmaceutical composition made by combining the isolated, pooled allogeneic MSC population and a pharmaceutically acceptable carrier/excipient, the claims of the ‘507 application do not disclose the limitation. However, it is well known in the art that isolated, pooled, allogeneic MSC population is combined with a pharmaceutically acceptable carrier/excipient according to Ta et al. (p.8, lines 16-19).
Regarding the step of cryopreserving the isolated, pooled allogeneic MSC population of the instant application (claim 19), the claims of the ‘507 application do not teach the limitation. However, it would have been obvious to a person skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘507 application for the future use with a reasonable expectation of success. One skilled in the art would recognize that cryopreservation is a well-known option for storing cells regardless they are pooled or not, and thus, it is considered a well-known option to a person skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘507 application after pooling for the storage purpose with a reasonable expectation of success. For example, cryopreserving pooled allogeneic MSCs is known in the art as taught by Ta et al. Ta et al. teach that Master Cell Bank (MCB) of individual MSCs is optionally cryopreserving the MCB, and then pooling the [thawed] MCB to establish Working Cell Bank (WCB), and optionally cryopreserving the WCB (p.8, lines 24-31). Thus, it would have been obvious to one skilled in the art to cryopreserve the isolated, pooled allogeneic MSC population of the ‘507 application.
Regarding HLA-G expression of claim 20 of the instant application, the claims of the ‘507 application do not teach the limitation. However, it is well known in the art that soluble HLA-G antigens play a role in immune modulation mediated by MSCs according to Rizzo et al. Rizzo et al. teach that IL-10 is one of the main up-modulators of soluble HLA-G, and exogenous IL-10 induced sHLA-G molecule secretion by MSC along (Abstract: Results). As the assays of the ‘507 application are directed to measuring the immunosuppressive properties/potentials of MSCs, and Rizzo et al. teach that HLA-G secreted by MSCs upon IL-10 is involved in the immunomodulatory potential of MSCs, one skilled in the art would try to measure HLA-G expression/secretion by MSCs as additional property of MSCs having immunosuppressive properties for the pooling.
Regarding claim 21, the limitation is directed to the number of assayed MSCs from individual donors being at least one more than those pooled in the pooling step. While the combined teachings of the cited reference above do not particularly teach the limitation, however, it would have been obvious to a person skilled in the art that the screening assays of IDO, PGE2, PBMC proliferation inhibition, and HLA-G leading to the ranking of each individual MSCs would result in either all of the MSCs would meet the criteria (number of assayed = number of pooled), some of the tested/assayed MSCs would meet the criteria (number of assayed > number of pooled), or none of the tested/assayed MSCs would meet the criteria (number of pooled = 0). Based on these possibilities, the last one would not be considered as the method requires pooling MSCs. Then, the possibilities from the selection would be either the numbers are the same or the number of pooled would be smaller than the number of assayed.
Regarding claim 22 directed to the number of assayed donor MSCs being at least 2-4 times as many as the number of pooled, the same analysis can be applicable as above. One skilled in the art would expect that the number of pooled donors selected from the total number of assayed donors would be determined by the desired stringency or threshold of the selection of MSCs for pooling. Therefore, the ratio of assayed vs. pooled would be routinely optimizable by changing the stringency/threshold of the selection resulted from the assays.
Regarding claim 23 directed to the number of MSCs (cell concentration) of each donor not being exceed 4 times of the number of cells of other donors in the pool, while the combined teachings of the references do not particularly teach the limitation, however, the number of cells from each donor in the pool of the pooled MSCs of the ‘507 application would be modified based on the amount of cells obtained from each donor. For example, if the MSCs from each donor are combined at the equal number per donor, then the claimed limitation would be met.
Thus, the claims of the ‘507 application in view of Ta et al. and Rizzo et al. 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.
The Examiner’s Comment
It is noted that applicant has presented a declaration under 1.132 based on the assumption that a claim rejection identical to the rejection presented in the parent case would be issued for the instant application. It is also noted that the interview held on 11/4/2025 was mainly to the claim rejection presented in the parent case. However, as the claim rejection under 35 U.S.C. 103 above cites a different set of references, the discussion of the declaration is moot. It is also noted that some of the references cited in the parent application were also cited in the instant claim rejection.
During the prosecution of the parent application, Ta et al. was initially cited in the 103 rejection and then replaced with Ardanaz et al. in the response to the limitation directed to the pooled MSCs being no further cultured. Upon the further consideration, the Examiner has determined that the teachings of Ta et al. would better serve as a primary reference and their teaching would meet the claimed limitation obvious with regard to the no-further culturing after pooling (see the claim rejection above).
It is also noted that applicant previously alleged in the parent application that the teaching of Ta et al. does not meet the limitation of no additional culturing step after pooling because Ta et al. teach an additional culturing after thawing the MCB (pooled MSCs) to form a “final” composition. However, the instant claims do not disclose that the product produced is a final product and utilized for the step of administering the pooled MSCs to a subject without further culturing after thawing. Rather, the method is merely to obtain the pooled MSCs and cryopreserving the pooled MSCs without further culturing and cryopreserving. Thus, it is the Examiner’s position that the WCB composition of Ta et al. would meet the limitation (see claim rejection above).
It is noted that during the pre-exam interview held on 11/4/2025, applicant has shown the data obtained from the use of the pooled MSC product. The data appear to show the comparison between the pooled MSCs vs. placebo, and it is the examiner’s position that this comparison does not necessarily show any unexpected results of the MSC product produced by the claimed method. Furthermore, the advantage of the reduced batch-to-batch variability is already expected by pooling the MSCs according to the teaching of Ta et al.
Applicant is advised to amend the claims to disclose an active step of using the MSC product prepared by the claimed method “directly” or without “post-thaw culturing” to clarify that the product produced by the claimed method being used for a thearpy. Furthermore, any supporting evidence that the pooled MSCs prepared by the claimed method produce unexpected results in the form of a declaration for advancing the prosecution.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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, JAMES SCHULTZ can be reached at 571-272-0763. 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.
/TAEYOON KIM/ Primary Examiner, Art Unit 1631