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 .
Priority
This application was filed August 14, 2020, and is a 371 application of PCT/EP2020/072918 filed on August 14, 2020, which claims benefit to the foreign application SE 1950933-0 filed on August 15, 2019.
Claim Status
In the response filed on Dec. 22, 2025, Applicants have amended claim 1, and cancelled claims 13 and 22. Currently, claims 1-12 and 14-21 and 23 pending.
Applicant's election with traverse of Group I, Claim 1-7, in the reply filed on April 14, 2025, is acknowledged. Currently, claims 8-12, 14-21 and 23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable linking claim.
Claims 1-7 have been considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 16th of Dec. 2025, 22nd of Dec. 2025 and 29th of Jan. 2026, is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The rejection of claims 1, and 4-7, under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more is withdrawn because the claim has been amended to “combining a therapeutically effective amount of the isolated, pooled allogeneic MSC population and at least one pharmaceutically acceptable excipient or carrier to make a pharmaceutical composition” which results in an active step.
Claim Objections
Claim 1 objected to because of the following informalities: grammar. Claim 1, line 2, appears to be missing a comma between the words: “population” and “pharmaceutical”. Claim 1, line 3, appears to be missing a subject-verb pairing, e.g. MSC’s that are derived from at least 3 individual donors. It is suggested for claim 1, lines 4-5, be amended to recite “MSCs have at most been subjected to ten passages”. Claim 1, line 6, recites “more than said at least 3 individual donors.” It is suggested for the claim to be amended to “greater than or equal to three individual donors,” which would be clearer to one of ordinary skill in the art.
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 1-7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on August 20, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Claim 1 recites the limitation "more desirable assay result" in lines 13-14 and 17, and “more desirable population properties” in lines 18-20 and 20-22, and “desirable population properties based on their total score values” in line 22. The phrase “desirable” and “more desirable” are relative terms and therefore undefined. It is unclear what the difference is between a “desirable” and “more desirable” especially when they are dependent on the assay and the results of the assays. Further, Claim 1 recites limitation “wherein said desirable population properties, and thus said desirable assay results, correspond to the isolated, pooled allogenic MSC population exhibits enhanced immunosuppressive and/or immune-modulatory potential compared to the single donor cells of which the pooled product is comprised” (See Claims page 2-3). However, the claim has not recited what “the desirable population properties” are, for example proliferation or do they relate to a specific cell marker. Therefore, it is unclear to a person of ordinary skill in the art how the desirable population properties are related to the desirable assay results, because the claim indicates that they are assay dependent. Further, the claim limitation of “exhibits enhanced immunosuppressive and/or immune-modulatory potential” does not actually relate to the population actually performing the action, but that the cells have the “potential.” As discussed above, it is unclear how a person of ordinary skill in the art is to interpret the relative phrase of “desirable assay results” and “desirable population properties.”
Claim 1 recites “wherein a higher ranking score value is indicative of more desirable assay result; or wherein a lower ranking score value is indicative of more desirable assay result; allocating a total score value to each individual donor derived MSC population based on said at least 3 individual ranking score values”. Thus, it is not apparent to one of ordinary skill in the art as to what is the structure of the scores is and as to what comparison is being made to obtain a “desirable” or “more desirable” result, especially when the claim is directed to “at least three assays’ results” meaning that there could be infinite number of results. Therefore, a person of skill in the art would not know the result that is desirable versus “more desirable”. Thus, the phrase “desirable” and “more desirable” renders the claim indefinite, since it is unclear as to what are the metes and bounds of the claim. Furthermore, the dependent claims are rejected because they depend from claim 1 and does not remedy its deficiencies. Appropriate correction is required.
Claim 1 recites the limitation "the modulatory effect" in lines 30-33, but the claim does not establish what the structure and function is of “a modulatory effect”. Further, the claim recites where “one assay measuring the modulatory effect of said MSCs on the proliferation of peripheral blood mononuclear cells (PBMCs ); and wherein at least 1 of said at least 3 assays is selected from the group consisting of one assay measuring the modulatory effect of said MSCs on the capacity of T cells to suppress an immune response,” which it is unclear if both cases are referring to the same “modulatory effect”. Thus, it is unclear that a person of ordinary skill in the art would know what “the modulatory effect” there is insufficient antecedent basis for the limitation of “the effect” in the claim because the “the effect” has not been defined.
Claim 1 recites the limitation “therapeutically effective amount.” The term “effective” in claim 1 is a relative term which renders the claim indefinite. The term “effective ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus, it is unclear to one of ordinary skill in the art what amount would successfully produce a desirable or intended result.
Claim 7 recites “an assay measuring the effect of said MSCs on microglia cells.” Therefore, it is unclear if “the effect” is “the modulatory effect” because claims have not established the structure (i.e. assay) or function that results in “the modulatory effect”. Thus, it is unclear that a person of ordinary skill in the art would know not know what “the effect” is related or to what “the modulatory effect”. Thus, there is insufficient antecedent basis for the limitation of “the effect” in the claim because the “the effect” has not been defined.
Additionally, it is unclear what is being measured to obtain “the effect” and renders the claim indefinite, since it is not understood by a person of skill in the art as to what has given the effect. Therefore, it is unclear as to what are the metes and bounds of the claimed effect. For compact prosecution “the effect” will be interpreted as any result of the claimed assay. Furthermore, the dependent claims are rejected because they depend from claim 1 and does not remedy its deficiencies. Appropriate correction is required.
Response to Traversal:
Applicant argues that the “Amendments to claim 1 define "desirable" and "more desirable" as "said desirable population properties, and thus said desirable assay results, correspond to that the isolated, pooled allogeneic MSC population exhibits enhanced immunosuppressive and/or immune-modulatory potential compared to the single donor cells of which the pooled product is comprised" ( e.g., specification paragraphs [0020], [0105]-[0108], fig. 2, examples 5-6 showing 2: 5-15% enhancement in IDO/PGE2, example 10)(Remarks, page 8-9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Contrary to Applicants belief the amendments to claim 1 do not clearly define “desirable”, “more desirable” or “enhanced immunosuppressive and/or immune-modulatory potential”. As discussed above, “desirable” and “more desirable” are relative terms and are not clearly defined in the claim, especially when the claim recites “wherein a higher ranking score value is indicative of more desirable assay result; or wherein a lower ranking score value is indicative of more desirable assay result”, which shows the “desirable” results depends on the assay or even the person’s opinion. It is noted that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, the claims should recite the what are the desirable population properties that the cells are exhibiting and what is the structure/function of the MSC population that pooled allogeneic MSC population exhibits the enhanced immunosuppressive and/or immune-modulatory potential. Further, it is not obvious to one of ordinary skill in the art how the stability of an undiluted drug substance exhibits the enhanced immunosuppressive and/or immune-modulatory potential. It is noted that Applicant cites “examples 5-6 showing 2: 5-15% enhancement in IDO/PGE2”. However, this is not recited in the claim. Therefore, the claim is rendered indefinite. Because the claim has not described the terms “desirable, “more desirable,” and “desirable population properties.”
Applicant argues that “the effect of the MSC that is measured in the recited assays has now also been defined as a "modulatory" effect”. Applicant assets that a skilled artisan that “the assays measure immunomodulatory ability of the MSCs such that is indicative of desirable properties of the cells, and thus, is indicative of selecting the given donor MSC population for pooling”(Remarks, page 8-9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicant’s argument, the structure/functions have not been clearly defined that a person of ordinary skill in the art would not know what “the effect” is because it has not been defined in the clam. It is noted that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, Further, “the modulatory effect” is a relative term because the claim does not actually describe the assays that measure the “immunomodulatory ability” of the MSCs, such that there is an indicative structure/function relationship present in the claim that one of ordinary skill in the art would know the “desirable properties” of the MSCs. Further, a person of ordinary skill in the art would understand that measuring the “immunomodulatory ability” of MSCs may be interpreted based on a variety of factors. It is noted that Applicant argues that “it is evident from the application was filed, said modulatory effect involves enhancing, suppressing, and other modulatory functions. However, the “other modulatory functions” have not been defined in the claim, as discussed above.
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 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Ta et al. (WO2012/131618, hereinafter as “Ta” cited on 2/10/2022 IDS, previously presented) in view of Aggarwal et al., (Blood 105, 1815–1822, published 2005, previously presented), Deskins et al. (Stem Cells Translational Medicine, published 2013, previously presented), and Solomon et al. (Biol. Blood Marrow Transplant.; published 2018, previously presented).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on August 20, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 1 and 4-6, Ta discloses a method for obtaining an isolated, pooled allogeneic Wharton’s jelly-derived mesenchymal stem cell (MSC) population comprising MSCs derived from multiple donors, e.g. five (see fig. 1), which reads on the claim limitation of at least 3 individual donors(see e.g. abstract, fig. 1, 3, 6). Further, Ta discloses 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 (see e.g. page 8 and 15), corresponding to the claim limitation of the isolated pooled allogenic MSC population is not further after the pooling step. Further, Ta discloses “a composition comprising pooled Wharton's Jelly derived Mesenchymal stem cells, optionally along with pharmaceutically acceptable carrier,” which reads on the claimed pharmaceutical composition (see e.g. claim 1). Additionally, Ta discloses that the “human WJ-MSCs do not stimulate proliferation of allogeneic or xenogeneic immune cells and also, produce an immunosuppressive isoform of human leukocyte antigen (HLA)(i.e. HLA-DR)(see page 3, 6-7 and Fig. 3), which reads on the claim limitation of MSC population exhibit enhanced immunosuppressive potential compared to a single donor of cells.
Regarding claim 1, Ta discloses wherein the number of cells derived from any one donor does not exceed 50% of the total cell number (see e.g. page 6-7, Fig. 1).
Regarding claim 1, Ta discloses that MCB is established at P1 (see e.g. page 19) and WJ-MSCs at passage 2 (P2/P3) can be used for as therapeutic composition (see e.g. page 20). Further, Ta discloses at least 6 passages (see e.g. fig. 7), which would meet the limitation of wherein said MSCs have at most have been subject to ten passages.
Regarding claim 1, the step of assaying each individual donor derived MSC population, Ta discloses an assay each individual donor derived MSC population measuring the effect of said MSCs on the proliferation of peripheral blood mononuclear cells (PBMCs)(see e.g. fig. 2), corresponding to the claim limitation of at least one of the three assays.
Ta does not explicitly disclose assaying at least 3 assays to obtain at least 3 assay results for said each individual donor derived MSC population.
However, the prior art of Aggarwal discloses assays for measuring the effect of MSCs on the proliferation of peripheral blood mononuclear cells (PBMCs) (see e.g. page 1817), the prostaglandin E2 secreted by MSCs (see e.g. page 1817, fig. 5), and the effect of MSCs on the capacity of T cells to suppress an immune response (see e.g. abstract, page 1817-1820, fig. 1-2), corresponding to the claim limitation of at least three assays and one assay measuring a modulatory effect (i.e. suppression).
Accordingly, it would have been obvious to a person skilled in the art to have assays for MSC populations from each donor in the method as taught by Ta et al. for measuring three assays e.g. proliferation, allogeneic T-cell responses, and PGE2 secretion as taught by Aggarwal because both Ta and Aggarwal discloses methods for avoiding allogenic transplantation complications with MSCs populations (see e.g. page 17 and abstract, respectively). Further, Ta discloses that MSCs populations are useful for preparing therapeutic composition for managing diseases (see e.g. page 16). Aggarwal discloses that it was known that MSCs produced elevated prostaglandin E2 (PGE2) in co-cultures, and that the addition of inhibitors of PGE2 production mitigated MSC-mediated immune modulation (see e.g. abstract, page 1817). Thus, a person of ordinary skill in the art would assess the MSC populations by the three assays as suggested by Aggarwal in the method of obtaining the optimal MSC populations as taught by Ta because Aggarwal teaches a reduction of transplantation complications such as rejection and graft versus host disease (GVHD)(see e.g. abstract, respectively). Therefore, it would have been obvious to a person of ordinary skill in the art to perform the three assays as suggested by Aggarwal in the method of Ta in order to obtain the optimal MSC population. Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 1, Ta et al. does not explicitly teach the limitation of 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.
Nevertheless, it is extremely well known in the art that grading MSCs from individual donor based on their properties and selecting those with highest desirable properties in the application. For example, for clinical application, particularly for cell therapy, the cells from donors would be analyzed for best possible donor cells for the application. Further, the prior art of Deskins et al. teaches 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 (see e.g. page 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 e.g. Fig. 5).
Accordingly, it would have been obvious to a person skilled in the art to modify the method of Ta by using the scoring system for the MSC properties as suggested by Deskins because both Ta and Deskins disclose that MSC’s immunomodulatory properties have therapeutic potential (see e.g. page 17 and abstract, respectively). A person of ordinary skill in the art would use the in vitro assays that show higher engraftment and vascularity of MSC populations (see e.g. Fig. 5) as taught by Deskins in the method of Ta because Ta et al. teaches that due to MSCs potent immunomodulatory properties they are useful as therapeutic composition for managing a variety of immune-mediated disease including autoimmune diseases (see e.g. page 17 of Ta). Thus, a person of ordinary skill in the art would have had predictable results and a reasonable expectation of success because both Ta and Deskins recognize that the MSC populations have immunomodulatory properties, as discussed above.
Regarding claim 1, Ta et al. does not explicitly teach ranking a 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, and 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 as such system is extremely well known in the art. For example, a scoring system is known in the art being utilized for donor selection for a cell therapy (e.g. transplantation). Further, the prior art of Solomon et al. teaches the use of a donor selection scoring system based on the various donor characteristics, variables on a certain outcome (see e.g. page 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. Furthermore, an artisan of ordinary skill in the art of (i.e. cell culture methods for obtaining mesenchymal stem cell populations) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 2, Ta et al. discloses incubation MSCs with bFGF (basic fibroblast growth factor), which is not directly a proinflammatory molecule, but it can potentiate the effects of inflammation and inflammatory mediators. Therefore, Ta does not explicitly teach the presence of proinflammatory factors.
However, the prior art of Aggarwal discloses that MSCs interact with each of the isolated cells of the immune system and are capable of altering the outcome of the immune cell response by inhibiting 2 of the most important proinflammatory cytokines (i.e. TNF-α and IFN-γ)(See e.g. page 1819).
Regarding claim 2-3, Aggarwal discloses comprising a step of exposing the isolated pooled allogenic MSC population to the presence of proinflammatory factors (e.g. TNF-α and IFN-γ)(see e.g. page 1818, fig. 4), wherein said exposure is for a period for between about 1 to about 24 hours before administration (i.e. 16 hours)(see e.g. page 1816-1817).
Accordingly, it would have been obvious to a person skilled in the art to modify the methods of obtaining MSCs populations from each donor as taught by Ta et al. with the proinflammatory factors as taught by Aggarwal because both Ta and Aggarwal disclose methods regarding MSC-mediated immunomodulation regarding reduction of transplantation complications, which would create the optimal MSCs populations for therapeutic applications that would reduce transplant rejections (i.e. graft versus host disease (GVHD))(see Aggarwal e.g. page 1819-1820 and e.g. page 17 of Ta). A person of ordinary skill in the art would have predictable results with a reasonable expectation of success because both Ta and Aggarwal disclose that MSCs properties were known in the prior art as being useful for preparing therapeutic compositions for managing diseases, as discussed above.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues “that the combination fails to teach or suggest the claimed method, lacks motivation, and involves impermissible hindsight. Applicant argues None of the cited prior art documents discloses a method for obtaining a pharmaceutical composition comprising an isolated, pooled allogeneic MSC population without further culturing after pooling.
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
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). In the instant case, Ta discloses 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 (see e.g. page 8 and 15), corresponding to the claim limitation of the isolated pooled allogenic MSC population is not further after the pooling step. Further, Ta discloses “a composition comprising pooled Wharton's Jelly derived Mesenchymal stem cells, optionally along with pharmaceutically acceptable carrier,” which reads on the claimed pharmaceutical composition (see e.g. claim 1 of Ta). Further, Ta discloses that these cells are useful for preparing medicament or therapeutic or pharmaceutical composition, which are all interchangeable terms(see e.g. page 16). Further, the prior art of Deskins et al. teaches 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 (see e.g. page abstract). Therefore, it is well known that a person of ordinary skill in the art would grade MSCs from individual donor based on their properties and selecting those with highest desirable properties in the assay or application.
Applicant argues that Ta is silent on any relevant teachings with respect to assaying donor MSC populations for desired characteristics and selection of a subset of donor MSC populations for pooling based on these assay results. Further, Applicant argues he disclosure of Ta, wherein only further cultured pooled MSC populations (WCB) can be understood as a therapeutic MSC composition, i.e. a pharmaceutical composition. Applicant argues the number of cells in the MCB and the WCB is disclosed to be substantially different from the number of cells in the final therapeutic composition, thus these cannot be interpreted as interchangeable cell populations for the disclosed therapeutic use (Remarks, page 15-16).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the prior art of Ta, it is noted that arguing against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Ta is not cited for teaching assay results, the prior art of Aggarwal is cited for discloses assays for measuring the effect of MSCs on the proliferation of peripheral blood mononuclear cells (PBMCs) (see e.g. page 1817), the prostaglandin E2 secreted by MSCs (see e.g. page 1817, fig. 5), and the effect of MSCs on the capacity of T cells to suppress an immune response (see e.g. abstract, page 1817-1820, fig. 1-2), corresponding to the claim limitation of at least three assays and one assay measuring a modulatory effect (i.e. suppression), as discussed above. In response to applicant's argument that that Ta does not teach a pharmaceutical composition, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In the instant case, the prior art of Ta discloses that these cells are useful for preparing medicament or therapeutic or pharmaceutical composition (all interchangeable terms)(see e.g. page 16). Contrary to Applicant argument again the number of cells in the MCB and the WCB is disclosed to be substantially different from the number of cells in the final therapeutic composition, it is noted that there is not a claim limitation directed to the number of cells in the final therapeutic composition.
Applicant argues that Aggarwal describes assays performed on individual MSC-DCl pairs, wherein each one of the MSC samples originated from a different individual donor (Table 1) and is tested individually without the aim for pooling (Remarks, page 16-17).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Contrary to Applicants argument the claim recites “at least three assay results for said each individual donor derived MSC population. Furthermore, in response to applicant's argument that Aggarwal tested individually without the aim for pooling, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant argues that although higher levels of PGE2 and VEGF in co-cultures of MSCs and PBMCs were measured, it is stated in Aggarwal that the exact contributions of each cell source to the increased levels of secreted factors are not known (pl 821, left column, second paragraph and Fig. 4). Further, Applicant argues that “it cannot be considered that Aggarwal teaches usefulness of assays measuring PGE2 in a method for selecting donor cells for pooling”.
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Contrary to Applicants assertion, Aggarwal also states that “our preliminary experiments in which human VEGF secretion was measured following rat MSCs (rMSCs)–human PBMCs (hPBMCs) coculture, and vice versa, showed that the hPBMCs, following coculture with rMSCs, increased secretion of human VEGF (data not shown)” (page 1821).
In response to Applicant argument regarding “usefulness,” a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In the instant case, Aggarwal is cited for showing that hMSCs, when cocultured with immune cells resulted in increased PGE2 and VEGF secretion (page 1821). Contrary to Applicant assertion Aggarwal also discloses that this increase in PGE2 and VEGF could also be explained “by a synergistic rather than an additive effect, suggesting MSC–immune cell cooperation at sites of inflammation” (page 1821).
Applicant argues that the prior art of Deskins cannot be considered relevant for a pharmaceutical composition, and that the disclosure of Solomon is only considered relevant for a selection scoring system for obtaining proper matching of donors and recipients for transplantation (Remarks, page 17-18). Applicant argues that the method according to the present invention is directed towards a selection "system" to obtain a pooled MSC population which can be administered to any recipients without the need to perform substantive evaluation of donor-recipient compatibility on a case-by-case basis. Applicant argues that the two selection "systems" serve entirely different purposes, and thus Solomon does not provide relevant teachings for the present inventive concept (Remarks, page 17-18).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, the prior art of Deskin is not cited for teaching the pharmaceutical composition, the prior art of Ta is discussed above. Further, the prior art of Solomon et al. teaches the use of a donor selection scoring system based on the various donor characteristics, variables on a certain outcome and that 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) (see e.g. page 792, 2nd col., last para.; Table 4). In response to applicant's argument that the scoring system of Solomon would be contrary to the intended purpose, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant argues that the inventor’s composition has no significant batch-to-batch variability, low allosensitization risk (human leukocyte antigen-based risk), a known formulation (% composition of each donor) and suitability for "off-the-shelf' use with fixed dosing (no need to change cellular concentration to the individual patient) in treating conditions like CNS disorders” (Remarks, page 18-19). Applicant asserts that “with no further culturing of the pooled population, there is no risk of change in product formulation, issues with change in cellular phenotype or functionality, or a sub-selection through preferential growth of one particular donor in the composition”(Remarks, page 18-19).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicant's arguments do not comply with 37 CFR 1.111(c) because they do not clearly point out the patentable novelty which he or she thinks the claims present in view of the state of the art disclosed by the references cited or the objections made. Further, they do not show how the amendments avoid such references or objections. In response to applicant's argument that that the inventor’s composition has suitability for "off-the-shelf' use with fixed dosing (no need to change cellular concentration to the individual patient) in treating conditions like CNS disorders, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In the instant case, the claims are not directed to central nervous system disorders (CNS).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., that the inventor’s composition has no significant batch-to-batch variability, low allosensitization risk (human leukocyte antigen-based risk), a known formulation (% composition of each donor) and suitability for "off-the-shelf' use with fixed dosing (no need to change cellular concentration to the individual patient) in treating conditions like CNS disorders) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, the Applicant has not disclosed the structure nor the function of a “more desirable assay result” or the “more desirable assay properties”. Therefore, it is unclear what batch-to-batch variability, low allosensitization risk (human leukocyte antigen-based risk), a known formulation (% composition of each donor), and suitability for "off-the-shelf' use with fixed dosing that the applicant is referring to in the claims and how it is not obvious over the prior art.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claims 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ta et al. (WO2012/131618, hereinafter as “Ta” cited on 2/10/2022 IDS, previously presented) in view of Aggarwal et al., (Blood 105, 1815–1822, published 2005, previously presented), Deskins et al. (Stem Cells Translational Medicine, published 2013, previously presented), and Solomon et al. (Biol. Blood Marrow Transplant.; published 2018, previously presented), as applied to claims 1, and 4-6 above, and further in view of Xu, Chao, et al. (International journal of neuroscience 127.12: 1124-1135, published 2017, previously presented), and Lin, Willie, et al. (Cell Transplantation 26.11: 1798-1810, published 2017, previously presented).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on August 20, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Ta et al., apply here as indicated above.
Regarding 7, Ta is silent regarding the method comprises an assay measuring the effect of the said MSCs on microglia cells or microglia-like cells and an assay measuring expression of markers characteristic of the M2 phenotype in microglia.
However, the prior art of Xu discloses that MSCs induce the activation of macrophages/microglia and drive them polarize into the M2 phenotypes (see e.g. abstract).
Accordingly, it would have been obvious to a person skilled in the art to have assays for MSC populations from each donor in the method as taught by Ta et al. for measuring the effect of the said MSCs on microglia cells as taught by Xu because both Ta and Xu disclose methods where MSCs are useful for preparing therapeutic composition for managing injuries and promoting tissue repair (see e.g. page 17 and abstract, respectively). Additionally, the prior art of Lin discloses that treatment with hUC-MSCs preserved adult newborn neurons and reduced functional impairment after transient cerebral ischemia by reducing the number of hypertrophic microglia/macrophages (see e.g. abstract and fig. 1). Further, Xu discloses that MSCs induce the activation of macrophages/microglia and drive them polarize into the M2 phenotypes, which inhibits the release of pro-inflammatory cytokines and promotes tissue repair and nerve regeneration (see e.g. abstract). A person of ordinary skill in the art would have a reasonable expectation of success because both Ta, Xu and Lin disclose methods where MSCs are suggested for use in cell replacement therapies (see e.g. page 17, and abstract, respectively). Thus, one of ordinary skill in the art would obtain predictable results with a reasonable expectation of success.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that neither Xu nor Lin remedies the above deficiencies (i.e. pharmaceutical composition), or can make the subject matter of claim 7 obvious. Applicant asserts that Xu is a review article which relies on in vitro experiments or simple animal models for their conclusions on macrophage/microglia phenotype shifts. Applicant asserts that Lin is silent on the markers of M1 or M2 microglia phenotype. Applicant argues that the method as defined in claim 7 cannot be considered obvious over Ta in view of Aggarwal, Deskins, Solomon, Xu and Lin (Remarks, page 19-20).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, a person skilled in the art would modify the MSCs population methods as taught by Ta et al. with an assay measuring the effect of the said MSCs on microglia cells as taught by Xu because Xu discloses that MSCs inhibit the release of pro-inflammatory cytokines and promotes tissue repair and nerve regeneration (see e.g. abstract). Further, the prior art of Lin is cited for disclosing that treatment reduces functional impairment after transient cerebral ischemia by reducing the number of hypertrophic microglia/macrophages (see e.g. abstract and fig. 1). Therefore, a person of ordinary skill in the art would have a reasonable expectation of success because both Ta, Xu and Li disclose methods where MSCs are useful for preparing therapeutic composition for managing injuries. Furthermore, an artisan of ordinary skill in the art of (i.e. cell culture methods for obtaining mesenchymal stem cell populations) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
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 1, 2, 4-5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, and 19-22 of co-pending Application No. 18/041,507 (reference application) in view of Ta et al. (supra).
This rejection is a new rejection necessitated by amendments to the claims.
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 (claims 1 and 19-22).
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 pooled allogeneic MSC population of the instant application (claim 1-7), 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 claims 1-7, 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. Thus, the claims of the ‘507 application in view of Ta 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.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
Prosecution Insights