CTFR 18/296,652 CTFR 88820 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. This office action is in response to the claimed filed on March 23, 2026, amending claims 1, 3, 5,6, 10, 11, 13, 15, 16 and 19 and canceling claims 2 and 12. Claims 11 Claims 11 and 13-19 are withdrawn. Claims 1, and 3-10 are examined below. Election/Restrictions Applicant’s election without traverse of Group I (claims 1-10) in the reply filed on Oct. 23, 2025 is acknowledged. Claims 11-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-10 are pending and examined on their merits below. Priority Acknowledgment is made of applicant's claim for foreign priority based on applications filed in Japan on Oct. 7, 2020 and Jan. 28, 2021. The non-final Office Action dated Dec. 23, 2025 mistakenly asserted that certified copies of the 2020-169712 and 2021-011736 applications had not been filed. Those copies have, as the response dated March 23, 2026 asserts, been filed and the priority is acknowledged. Information Disclosure Statement The information disclosure statement filed April 8, 2026 complies with the provisions of 37 CFR 1.17(v) with the assertion that no IDS size fee is required at this time. Accordingly, the IDSs has been considered by the examiner and the corresponding 1449 is attached herewith. Withdrawn Rejections The rejection of claims 1, 4, 7, and 9 under 35 U.S.C. 102 as being anticipated by Ikeya et al. is withdrawn in view of the claim amendments in the Response of March 23, 2026. The rejection of claim 10 under 35 U.S.C. 102(a)(2) as being anticipated by, or in the alternative, under 35 U.S.C. 103(a) as obvious over Ikeya et al. in view of Stultz et al., if necessary, is withdrawn in view of the claim amendments in the Response of March 23, 2026. The rejection of claims 3 and 8 under 35 U.S.C. 103 as being unpatentable over Ikeya et al. as applied to claims 1, 4, 7, and 9 above, and further in view of Lamo-Espinosa et al. is withdrawn in view of the claim amendments in the Response of March 23, 2026. The rejection of claim 5 under 35 U.S.C. 103 as being unpatentable over Ikeya et al. in view of Capelli et al. is withdrawn in view of the claim amendments in the Response of March 23, 2026. The rejection of claims 1, 3, 4, 6, 7 and 9 under 35 U.S.C. 103 as being unpatentable over the combination of Fujisawa et al. and Sotiropoulou et al. is withdrawn in view of the claim amendments in the Response of March 23, 2026. The rejection of claim 5 under 35 U.S.C. 103 as being unpatentable over Fujisawa et al. and Sotiropoulou et al . in view of Capelli et al. is withdrawn in view of the claim amendments in the Response of March 23, 2026. The rejection of claim 8 under 35 U.S.C. 103 as being unpatentable over Fujisawa et al. and Sotiropoulou et al. further in view of Lamo-Espinosa et al. is withdrawn in view of the claim amendments in the Response of March 23, 2026. The rejection of claim 10 under 35 U.S.C. 103 as being unpatentable over Fujisawa et al. and Sotiropoulou et al. further in view of Stultz et al. is withdrawn in view of the claim amendments in the Response of March 23, 2026. Claim Rejections - 35 USC § 101 07-04-01 AIA 07-04 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 7-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring product without significantly more. The claim(s) recite(s) a cell preparation that includes a cultured mesenchymal stem cell (MSC). This judicial exception is not integrated into a practical application because the product (a therapeutic product that consists of mesenchymal stem cells) does not differ from its naturally occurring counterpart. Even though the MSC is cultured in a culture medium that includes an ascorbic acid derivative, alanyl glutamine and pyridoxine (claim 7), does not contain extracellular substrate or a scaffold (claim 8); is a meniscus curing agent or an osteoarthritis curing agent (claim 9) or is a human MSC with 46 chromosomes, with 1-22 pairs of chromosomes and an XY or XX chromosome (claim10), none of these limitations differentiate the claimed cells from their naturally occurring counterpart. More specifically, the mesenchymal stem cells claimed, while claimed as being produced by a method that includes ex vivo culture in a culture medium including an ascorbic acid derivative, alanyl glutamine and pyridoxine, are substantially similar (and not distinguishable) from their naturally-occurring counterparts because therapeutically useful non-recombinant cells are fundamentally intended to mimic their naturally-occurring counterpart. That is, therapeutic MSCs, through the use of improved isolation protocols and optimized culture and storage conditions, are intended to mimic the healthiest, most robust MSCs that are naturally occurring. ( See entire document, esp. p. 2519, “Isolation Efficiency and Origin-Dependent Growth of hMSC”; Motaln et al., Cancer, 2010). This is whether just a cell or a cell + extracellular matrix is administered (claim 8) and also when the therapeutic cell is intended for a specific purpose, such as use as a meniscus or a osteoarthritis curing agents (claim 9). As demonstrated by Stultz et al. naturally occurring, healthy MSCs have 22 pairs of chromosomes and a pair of XX or XY chromosomes. (Abstract, Stultz et al., Cytotherapy, 2016). The claim(s) do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the only element the claims require is MSCs, so they are not additional elements claimed that need to be assessed to determine if they amount to significantly more. Response to Arguments - 35 USC § 101 07-37 AIA Applicant's arguments filed March 23, 2026 have been fully considered but they are not persuasive. Applicants assert that the therapeutic MSCs are not necessarily intended to mimic their naturally occurring counterparts, citing Motaln, which indicates that proliferation and expansion of cells in vitro can result in changed cell morphology; and para [0084] of the specification, which are the results of the MSCs cultured in Basal medium A (where ascorbic acid, glutamine and pyridoxal have been replaced with ascorbic acid-2-phosphate trisodium salt, alanyl glutamine and pyridoxine), as compared with culture medium where this replacement had not been undertaken. Applicants assert that the proliferation ability of the cells is increased in the Basal medium A and that “it is likely that the MSCs cultured in medium A have a different proliferation ability from that of their naturally occurring counterparts and thus are not substantially equivalent to their naturally occurring counterparts.” This is not found persuasive because the cell claimed is not the cell in the example. The cell in the example is a bone-marrow derived MSC that has been subjected to 9 passages in the claimed media; the claimed cell is a synovium-derived MSC that only require culturing (perhaps not even to a first passage?) in a medium containing an ascorbic acid derivative, alanyl glutamine and pyridoxine. Additionally, the comparison being made is between two cultured cells, with applicants concluding that the naturally occurring cell behaves as the cell that is cultured in standard medium? Applicants assert that the working examples also demonstrate that medium A results in fewer karyotype abnormalities than that observed for cells cultured in standard medium. “The fact that this slight difference in culture medium composition alters the occurrence of karyotype abnormalities strongly suggests that the properties of MSCs in vivo are those of the MSCs and those of the present invention are significantly different…” This is not found persuasive because karyotype abnormalities are a problem that is seen when culturing cells in vitro , a problem those skilled in the art are aware of and are trying to overcome. Producing an in vitro cells that isn’t prone to karyotype abnormality would make it more similar to its in vivo counterpart which also have a low rate of karyotype abnormalities . Claim Rejections - 35 USC § 103 07-103 AIA The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. 07-21-aia AIA Claim (s) 1, 3, 4, 6, 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Fujisawa et al. (Stem Cell Res & Ther, 2018) in view of Sotiropoulou et al. (Stem Cells, 2006) and Fan et al. (Tissue Engineering Part B Rev, 2009) . The amended claims are directed to methods for producing a cell preparation through culturing a synovium-derived mesenchymal stem cell in a medium that includes an ascorbic acid derivative, alanyl glutamine and pyridoxine. Claim 1 recites “…culturing a mesenchymal stem cell in a culture medium containing an ascorbic acid derivative, alanyl glutamine, and pyridoxine.” (emphasis added). Containing is being interpreted as open-ended and synonymous with comprising. ( See MPEP 2111.03). With respect to independent claim 1 (process) and product-by-process claim 7, which uses the process of claim 1, Fujisawa et al. teach that since mesenchymal stem cells (MSCs) are capable of differentiating into fat, bone and cartilage cells, they are well suited for regenerative medicine applications. (pg. 1, “Background”). To increase this therapeutic potential, there is a need to optimize the culturing conditions for MSCs. (para. bridging pgs. 1-2, “Background”). Fujisawa et al. investigated the effect of ascorbic acid on proliferation and differentiation in culture for MSCs, using L-ascorbic acid 2-phosphate (AAP) (“ascorbic acid derivative), added to DMEM. (Title, Abstract, pg. 2, para. bridging 1 st and 2 nd cols.). Fujisawa et al. used AAP, as ascorbic acid rapidly degrades in cell culture conditions (in DMEM at 37 o C), determining that addition of AAP at 0.1, 1.0 and 3.0 mM concentrations to DMEM all promoted proliferation to the same degree, and concluding that the addition of ascorbic acid (in the form of a stable derivative) enables faster MSC expansion. (pgs. 8-9, 1 st para. of “Discussion”). It is noted that DMEM contains pyridoxine hydrochloride. Fujisawa et al. does not teach the inclusion of alanyl-L-glutamine in their culture medium. Sotiropoulou et al. teach that clinical scale production of human mesenchymal stem cells is enhanced with the inclusion of GlutaMax (L-alanyl-L-glutamine). Abstract. More specifically, Sotiropoulou et al. teach: “Low glucose concentration in DMEM-based media and Glutamax instead of L-glutamine in all different basal media consistently supported MSC growth. Greater proliferation in media with Glutamax has been observed in various cell types and has been attributed to the greater stability of L-alaynyl-L-glutamine contained in media with Glutamax, in contrast to L-glutamine, which is chemically unstable, even at 4 o C, and its chemical breakdown and cellular metabolism lead to ammonia formation and subsequent inhibition of cell growth.” (pg. 469, “Discussion, 2 nd col, 2 nd full para.). It would have been obvious for one of ordinary skill in the art at the time of the invention to have modified the MSC culturing process of Fujisawa et al. to incorporate adding Glutamax to the culture medium because it would have been obvious to combine prior art elements according to known methods to yield predictable results. Incorporating Glutamax in the media taught by Fujisawa et al. would have led to predictable results with a reasonable expectation of success because both Fujisawa et al. and Sotiropoulou et al. teach improved methods of proliferating MSCs using DMEM media. “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven , 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). MPEP 2144.06, I. With respect to the preamble “a cell preparation for a joint medical treatment,” Fujisawa et al. teach that since mesenchymal stem cells (MSCs) are capable of differentiating into fat, bone and cartilage cells, they are well suited for regenerative medicine applications (pg. 1, “Background”). Further, Sotiroopoulou et al. teach that their cells are capable of differentiating in vitro and in vivo along multiple pathways including bone, cartilage, cardiac and skeletal muscle, neural cells, tendon, adipose, and connective tissue (pg. 462, “Introduction, 1 st para.), which would make the cell preparation suited for its intended use of joint medical treatment. The limitation that " a cell preparation for a joint medical treatment,” is intended use, as the claims do not require actual treatment of joints; rather they recite steps to form a product which can be used in this manner. The prior art structure taught by Fujisawa et al. is capable of performing the recited intended use and, therefore, this limitation is met. See e.g. In re Schreiber , 128 F.3d 1473, 1477; 44 USPQ2d 1429, 1431 (Fed. Cir. 1997); MPEP 2114 (Apparatus Claims Must Be Structurally Distinguishable From the Prior Art). Fujisawa et al. teach MSCs that are derived from bone marrow (pg. 2, “Methods: Cells and cell culture”), not from synovium. Fan et al. teach that synovium-derived MSCs are a promising source of MSCs for musculoskeletal regeneration, especially for reconstruction of cartilage, bones, tendons and muscles, as they have a higher proliferation ability and higher chondrogenesis. (Abstract). It would have been obvious for one of ordinary skill in the art at the time of the invention to have modified the method of culturing MSCs of Fujisawa et al. to substitute synovium-derived MSCs for the bone marrow MSCs because it would have been obvious to substitute one known element for another to obtain predictable results. Substituting the synovium-derived MSCs as taught by Fan et al. would have led to predictable results with a reasonable expectation of success because Fan et al. teach that synovium-derived cells are an excellent source of MSC for the therapeutic uses (muscuskeletal regeneration) envisioned by Fujisawa et al.; as such it would have been obvious for one of ordinary skill to expect that such a substitution would be successful and might produce superior results. With respect to claim 3, Sotiropoulou et al. teach that administration of autologous or allogeneic MSCs in injury models enable migration of the MSCs to the site of damage where they undergo tissue-specific differentiation. (pg. 462 “Introduction”, para. bridging 1 st and 2 nd cols.). It would have been obvious for one of ordinary skill in the art at the time of the invention to employ autologous MSCs in the method taught by Fujisawa et al. because it would have been obvious to try autologous MSCs as the person of ordinary skill would be choosing from a finite number of identified, predictable solutions with a reasonable expectation of success. Substituting autologous cells for the cells taught by Fujisawa et al. would have led to a reasonable expectation of success because Sotiropolou et al. indicate both types of human MSCs, autologous or allogeneic, work for therapeutic applications. With respect to claim 4, Fujisawa et al. teach that the culture medium does not contain ascorbic acid, as it is not stable for cell culture and can inhibit proliferation. (pgs. 8-9, 1 st para. of “Discussion”). With respect to claim 6, Sotiropoulou et al. teach that bone marrow (BM) aspirates were diluted 1:2 in Hanks’ balanced salt solution (“a suspension of a tissue containing MSCs”), then BM mononuclear cells (which will become MSCs) were isolated using standard Ficoll-Hypaque centrifugation (“separating the suspension into two layers” and “collecting the lower layer” which contains MSCs). It would have been obvious to adjust this isolation procedure substituting synovium-derived cells in place of the BM aspirates, as is known in the art. With respect to claim 9, Sotiropoulou et al. teach that their cells are capable of differentiating in vitro and in vivo along multiple pathways including bone, cartilage, cardiac and skeletal muscle, neural cells, tendon, adipose, and connective tissue (pg. 462, “Introduction, 1 st para.), which would make the cell preparation suited for its intended use of a meniscus curing agent or osteoarthritis curing agent. The limitation "wherein the cell preparation for a joint medical treatment is a meniscus curing agent or an osteoarthritis curing agent,” is intended use, as the claims do require actual treatment of joints; rather they recite steps to form a product which is capable of being used in this manner. The prior art structure taught by Fujisawa et al. in view of Sotiropoulou et al. is capable of performing the recited intended use and, therefore, this limitation is met. See e.g. In re Schreiber , 128 F.3d 1473, 1477; 44 USPQ2d 1429, 1431 (Fed. Cir. 1997); MPEP 2114 (Apparatus Claims Must Be Structurally Distinguishable From the Prior Art) . 07-22-aia AIA Claim (s) 5 is rejected under 35 U.S.C. 103 as being unpatentable over Fujisawa et al . (Stem Cell Res & Ther, 2018), Sotiropoulou et al. (Stem Cells, 2006), and Fan et al. (Tissue Engineering Part B Rev, 2009) , as applied to claim s 1, 3, 4, 6 and 9 above, and further in view of Capelli et al . (Immunology Letters, 2015) . Fujisawa et al. does not teach that the MSCs are cultured in a multilayer flask that has at least five layers. Capelli et al. teach production of MSCs for therapeutic purposes using 5-layer flasks (pg. 223, “3. MSC Manufacture in our GMP-facility”). It would have been obvious for one of ordinary skill in the art at the time of the invention to have modified the MSC culturing process of Ikeya to incorporate using a 5-layer flask because it would have been obvious to substitute one known element for another to obtain predictable results. Making these substitutions as taught by Capelli et al. would have led to predictable results with a reasonable expectation of success because Capelli et al. teach that these modifications are useful for production of a GMP compliant therapeutic product. (pg. 223, “3. MSC Manufacture in our GMP-facility”) . 07-22-aia AIA Claim (s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Fujisawa et al . (Stem Cell Res & Ther, 2018), Sotiropoulou et al. (Stem Cells, 2006) ), and Fan et al. (Tissue Engineering Part B Rev, 2009) , as applied to claim s 1, 3, 4, 6 and 9 above, and further in view of Lamo-Espinosa et al. (J Translational Med, 2016) Fujisawa et al. is silent on whether a MSC composition would include extracellular matrix (claim 8). Lamo-Espinosa et al. teach administration of autologous MSCs for knee osteoarthritis which does not include extracellular matrix. (entire doc, esp. pg. 3, “Treatment Groups”). It would have been obvious for one of ordinary skill in the art at the time of the invention to have modified the MSC culturing process of Fujisawa et al. to incorporate producing a product that does not include extraceullar matrix products because it would have been obvious to substitute one known element for another to obtain predictable results. Making these substitutions as taught by Lamo-Espinosa et al. would have led to predictable results with a reasonable expectation of success because Lamo-Espinosa et al. teach that a composition that does not include an extracellular matrix is useful for treating osteoarthritis . 07-22-aia AIA Claim (s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Fujisawa et al . (Stem Cell Res & Ther, 2018), Sotiropoulou et al. (Stem Cells, 2006) ), and Fan et al. (Tissue Engineering Part B Rev, 2009) , as applied to claim s 1, 3, 4, 6 and 9 above, and further in view of Stultz et al . (Cytotherapy, 2016) . Fujisawa et al. is silent on the chromosomal make-up of a human MSC within their cultured composition. As evidenced by Stultz et al., most healthy human MSCs do not have chromosomal aberrations associated with culturing. (“…reported low levels of chromosomal aberrations among donor samples and during culture expansion. “Introduction,” 3 rd para.). It is therefore likely that the cells taught by Fujisawa et al. have a karyotype of 1-22 chromosomal pairs and XX or XY chromosomes. However, even if the cells taught by Fujisawa et al. do not possess this karyotype, it would have been obvious, based on the teachings of Stultz et al. to have performed a karyotyping on the cells and to have isolated only the cells whose karyotype matched a normal karyotype, using routine techniques such as Giemsa banding, FISH, SKY or CGH. (“Introduction”, 4 th para.), as Stultz et al. teach that these techniques are routine and karyotyping analysis is useful for monitoring the genetic stability of MSCs during in vitro expansion. (Abstract). Response to Arguments - 35 USC § 103 Applicant's arguments filed March 23, 2026 have been fully considered but they are moot with respect to the rejection that used Ikeya et al. as prior art (this reference is not used in the current rejections) and not persuasive for the other rejections above, as explained below. Applicant assert that Fujisawa et al. teaches culturing MSCs derived from bone marrow, not from synovium, that the examiner’s argument that substituting the synovium-derived MSCs taught by Fan et al. would not have been obvious. Applicants assert that Fan teaches that longtime culture decreases chondrogenic potential of synovium-derived MSCs (SMSCs). This is not found persuasive because while Fan et al. does indicate that the chondrogenic potential gradually decreases with culturing of SMSCs (“Genotype and Phenotype”), Fan et al. clearly state that SMSCs are valued for the multipotency and high proliferation: “As a new member of the MSC family, SMSCs have been revealed to be a multipotent cell source similar to BMSCs. Under lineage-specific culture medium, SMSCs are capable of differentiating into several mesenchymal lineages, including chondrocytes, osteoblasts, adipocytes, and myocytes; they are particularly efficient in undergoing chondrogenic differentiation (Fig. 1). Further, their multipotent capacity is not influenced by donor age, cell passages, or cryopreservation.” (pg. 77, “Multipotency and high proliferation”, emphasis added). Applicants appear to assert that Fan et al. teach that longtime culture decreases the chondrogenic potential of SMSCs. As seen in the quote above, Fan et al. teaches that the chondrogenic differentiation potential of SMSCs is strong and specifically states that their multipotent capacity is not influenced by cell passage. Applicants assert that their results are unexpected, citing their meniscus regeneration after SMSC transplantation after long culturing in basal medium A (paras. [0120]-[0127]), pg. 34, Table 11. This is not persuasive because the results are not comparing the closest prior art with the invention, but rather comparing the invention with a negative control; as such “expected” and “unexpected” cannot be determined. ( See MPEP 716.02(a)). Additionally, the claims do not require any “longtime” culturing (8 passages, in the application). The claims only requiring “culturing”. To assess any unexpected results, the claims would need to be commensurate in scope with the results presented as inventive ( see MPEP 716.02(d)) and the results would need to be compared with the closest prior art. For at least these reasons, applicants’ arguments are not persuasive. Conclusion No claims are allowed. 07-40 AIA 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. /TERESA E KNIGHT/Primary Examiner, Art Unit 1634 Application/Control Number: 18/296,652 Page 2 Art Unit: 1634 Application/Control Number: 18/296,652 Page 3 Art Unit: 1634 Application/Control Number: 18/296,652 Page 4 Art Unit: 1634 Application/Control Number: 18/296,652 Page 5 Art Unit: 1634 Application/Control Number: 18/296,652 Page 6 Art Unit: 1634 Application/Control Number: 18/296,652 Page 7 Art Unit: 1634 Application/Control Number: 18/296,652 Page 8 Art Unit: 1634 Application/Control Number: 18/296,652 Page 9 Art Unit: 1634 Application/Control Number: 18/296,652 Page 10 Art Unit: 1634 Application/Control Number: 18/296,652 Page 11 Art Unit: 1634 Application/Control Number: 18/296,652 Page 12 Art Unit: 1634 Application/Control Number: 18/296,652 Page 13 Art Unit: 1634 Application/Control Number: 18/296,652 Page 14 Art Unit: 1634 Application/Control Number: 18/296,652 Page 15 Art Unit: 1634 Application/Control Number: 18/296,652 Page 16 Art Unit: 1634
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