DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment and response filed on 7/29/2026 has been received and entered into the case.
Claims 6, 10 and 19-20 have been canceled, and claims 1-5, 7-9 and 11-18 have been considered on the merits. All arguments have been considered.
Claim Interpretation
Claim 1 is interpreted as a method comprising 1) preparing MSC-secretome by culturing bone marrow-derived MSCs (BM-MSCs) at 0.1-5% oxygen and an acidic pH of 6.2-6.4; and 2) administering the MSC secretome preparation to a subject having a periodontal disease.
The “secretome” is interpreted based on the definition given in the instant specification. Paragraph [0059] (PGPub) discloses “MSC secretome composition” refers to a composition comprising acellular MSC growth factors, MSC exosomes (which are, by definition, acellular), extracellular vesicles, or acellular extracts of MSCs or MSC lysates obtained from human MSCs, fibroblast-like cells, and non-human animal MSCs including, but not limited to MSCs from horses, cows, pigs, sheep, non-human primates, dogs, cats, rabbits, rats, and mice.
Thus, the term “secretome” is broadly interpreted as a conditioned medium or a composition comprising MSC exosomes; or a composition comprising MSC lysates.
The conditioned medium or the composition comprising MSC exosomes would inherently meet the new limitation of “acellular MSC secretome preparation” as the conditioned medium is obtained after isolating the supernatant from the culture medium removing the cells, or the exosomes are isolated from the conditioned medium.
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.
Claim(s) 1-4, 7-9 and 11-18 are rejected under 35 U.S.C. 103 as being unpatentable over Kawai et al. (2015, Cytotherapy; of record) in view of Tamama et al. (2012, Advances in Wound Care; of record), Brodie (WO2018/083700; of record), Hazehara-Kunitomo et al. (2019, Int. J. Mol. Sci.; published on 3/4/2019; of record), Javidi et al. (2013, European Journal of Dentistry; of record) and Chew et al. (2019, Acta Biomaterialia; IDS ref.), and as evidenced by Gabrielyan et al. (2020, Stem Cell Research; of record), Polacek et al. (2011, Cell Transplantation; of record) and Howell et al. (1997, J. Periodontol.; of record).
Kawai et al. teach that secretomes from human bone marrow-derived mesenchymal stem cells enhance periodontal tissue regeneration (see entire document). The secretomes of Kawai et al. are prepared by collecting conditioned medium of the human MSC (MSC-CM) (Abstract; p.371, 1st col., Preparation of CM). The secretomes of Kawai et al. are considered as “acellular” as they are prepared from the CM of MSCs as the CM is separated from the MSCs after culturing. Kawai et al. teach that the MSC-CM is implanted to the periodontal tissue defect in rat model (Abstract).
Kawai et al. do not teach the BM-MSCs are cultured at 0.1-5% oxygen and an acidic pH of 6.2-6.4 (claim 1).
Regarding the low oxygen at 0.1-5% (claim 1) or 0.1-2% (claim 9), Tamama et al. teach that MSCs secrete numerous growth factors and cytokines to accelerate wound healing and tissue regeneration, and MSCs increase the secretion of various growth factors and cytokines under the hypoxic condition (entire document; Take-home message at p.179). Particularly production of VEGF and bFGF is upregulated in an HIF-dependent manner in the hypoxic condition (p.179). It is noted that Tamama et al. do not particularly disclose the percentage of oxygen level in the hypoxic condition, however, Tamama et al. teach that the wound hypoxia is a key limiting factor in wound healing and it is imperative to study the behavior of MSCs in a hypoxic condition, and the hypoxic condition of wound is pO2 at 0-10 mmHg. The pO2 at 10 mmHg is well known in the art that the hypoxic condition is about 1.3% under a standard atmospheric pressure of 760 mmHg: (10 mmHg/760 mmHg)*100=1.3%. Thus, the range of pO2 at 0-10 mmHg is 0-1.3% of oxygen, which overlaps with the claimed 0.1-5%.
It would have been obvious to a person skilled in the art to culture the BM-MSCs of Kawai et al. as discussed above under the hypoxic condition in order to obtain the secretomes with a reasonable expectation of success. A person of ordinary skilled in the art would have been motivated to do so because the hypoxic condition would increase the secretion of the growth factors and cytokines useful in tissue regeneration including bFGF and VEGF taught by Tamama et al. It is noted that the teaching of bFGF and VEGF by Tamama et al. would meet claims 12 and 15.
Furthermore, Brodie teaches that the MSCs grown in hypoxic conditions and incubated in medium with low pH increase exosome secretion and yield (para. 120). Thus, it would have been obvious to a person skilled in the art to use a hypoxic condition in order to increase exosome secretion and yield taught by Brodie in addition to the teaching of Tamama et al.
Regarding the acidic pH of 6.2-6.4 for the culturing BM-MSCs (claim 1), Kawai et al. in view of Tamama et al. do not teach the limitation.
Hazehara-Kunitomo et al. teach the short-term (48 h) treatment of BM-MSCs under acidic pH at 6.8 enhances the phenotype of BM-MSCs particularly during the initial states of bone healing (abstract). The pre-conditioning taught by Hazehara-Kunitomo et al. at pH 6.8 is based on the measurement of pH at the tooth extraction socket (Fig. 1 and 2). In other words, the pH measured at the periodontal tissue defects would be used for pre-conditioning BM-MSCs. As the pH at the pulp dentin and periodontal ligament of necrotic teeth is known to be in a pH range of 6.0-7.4 according to Javidi et al. (p.70, 1st col.), one skilled in the art would use the pH of the periodontal tissue defect for pre-conditioning of MSCs for the culturing MSCs in order to obtain secretome taught by Kawai et al. as the purpose of the secretome of Kawai et al. is to treat periodontal tissue defects with reasonable expectation of success.
Thus, it would have been obvious to a person skilled in the art to measure the pH of the periodontal defect and use the pH for pre-conditioning MSCs as taught by Hazehara-Kunitomo et al. for the method of Kawai et al. As the pH of the pulp dentin and ligament would be in a range of pH 6.0-7.4, the measured pH is expected to fall within this range including the claimed pH 6.2-6.4.
Furthermore, Hazehara-Kunitomo et al. teach that the short-term (48 h) treatment of pH 6.4 on BM-MSCs induces much more marked increase in the stem cell phenotype of hBMSCs (p.7, last para.). Thus, one skilled in the art would utilize pH 6.4 for the method of preparing conditioned medium taught by Kawai et al. with a reasonable expectation of success.
Regarding the new limitation of claim 1 directed to FGF-2, it is considered that the combined teachings of Kawai et al. in view of Tamama et al. would meet the limitation. This is because Tamama et al. teach that the hypoxic condition would increase the secretion of the growth factors and cytokines useful in tissue regeneration including bFGF and VEGF (see above).
Regarding the limitation directed to the MSC secretome preparation comprising IGF (claim 1), VEGF (claim 12), TGF-b1 (claim 13), HGF, PDGF (claim 14), Kawai et al. teach that the MSC-CM comprises IGF-1, VEGF, PDGF, and TGF-b1 (Table II).
While the rest of the factors as claimed are not taught by Kawai et al., however, it is considered that these factors are inherently secreted from the BM-MSCs. The following references are cited to support the inherent presence of these factors in the conditioned medium of BM-MSCs.
Regarding BMP1 (claim 1), Kawai et al. do not particularly teach BMP1. However, BMP1 is inherently secreted by human BM-MSCs according to Polacek et al. Polacek et al. teach that BMP-1 is only detected in human BM-MSC supernatant (Abstract; p.1389, 2nd col.), i.e. conditioned medium. Figure 2 of Polacek et al. disclose that growth factors present in the MSC secretome, and Figure 3 shows presence of BMP1 in the secretome of BM-MSC.
Regarding M-CSF (claim 1), Gabrielyan et al. teach that BMSCs cultured under hypoxic condition produce M-CSF (Table 1; p.4, 2nd col.).
Regarding the limitation directed to the MSC secretome comprising an effective amount of IGF, M-CSF and BMP1, the claims do not require any particular amount or concentration but disclose a functional limitation. As the BM-MSC secretomes (or conditioned medium) taught by Kawai et al. inherently contain the claimed growth factors, and they are effective in regenerating the periodontal tissue defect, the growth factors secreted from the BM-MSCs into the MSC-CM are considered to be effective in regenerating the periodontal tissue defect.
However, it would have been obvious to a person skilled in the art to use the method of Kawai et al. in view of Tamama et al., Hazehara-Kunitomo et al., Javidi et al. and Chew et al. for a human subject. A person of ordinary skill in the art would have been motivated to do so because Howell et al. teach PDGF and IGF can improve human patients with periodontal disease (see entire document). As PDGF and IGF are secreted and present in the MSC-CM taught by Kawai et al., one skilled in the art would recognize that the MSC-CM derived from human BM-MSC taught by Kawai et al. would be used for treating human periodontal tissue defects with a reasonable expectation of success.
Regarding claim 2, the MSC-CM of Kawai et al. is administered (implanted) to the periodontal tissue where the defect was created as discussed above, and thus, this teaching would meet the limitation of claim 2.
Regarding claims 3 and 12-15, the MSC-CM of Kawai et al. would inherently comprise exosomes or extracellular vesicles along with various secreted factors including growth factors as discussed above.
Furthermore, Chew et al. teach that MSC exosomes are isolated from MSC conditioned medium (p.253, Materials and methods), and the MSC exosome cargo is highly diverse and complex and contain growth factors such as TGF-b, IGF and FGF (p.263, 1st col.).
Regarding claim 4, Kawai et al. teach the use of collagen sponge (i.e. biocompatible scaffold) as a scaffold (p.372, 2nd col.). Furthermore, Chew et al. teach that the administration/treatment is via using a collagen scaffold (CS), and the CS is loaded with human MSC exosomes.
Regarding claim 5 directed to the administration being an injection, Kawai et al. do not particularly teach the injection.
However, Brodie teaches that MSC exosomes can be injected to any desired site on the body (para. 170), and the other methods of administration can be also used such as transplantation or transfusion with or without specific scaffolds (par. 170). Thus, it would have been obvious to a person skilled in the art to inject the MSC-CM comprising exosomes taught by Kawai et al. in view of Tamama et al., Hazehara-Kunitomo et al., Javidi et al. and Chew et al. to the periodontal tissue as Brodie teaches that injection can be another route of administration to the transplantation (i.e. implantation) with a reasonable expectation of success.
Regarding claim 7 directed to the MSC secretome preparation comprising water or buffer, Kawai et al. teach that the CM is prepared using the serum-free medium, and the serum-free medium is considered to inherently comprise water as well as a buffer.
Regarding claim 8 directed to the extracellular vesicles and/or one or more growth factors are about 0.00001% to about 20% by weight of the secretome preparation, Kawai et al. in view of Tamama et al., Hazehara-Kunitomo et al., Javidi et al. and Chew et al. do not teach the limitation. However, the amount of extracellular vesicles/exosomes in the MSC-CM would be inherently within the claimed range of the weight of the MSC secretome because the MSC-CM of Kawai et al. in view of Tamama et al., Hazehara-Kunitomo et al., Javidi et al. and Chew et al. would be substantially similar, if not identical, to the claimed MSC secretome, and the combined teachings of the cited references meet the conditions for preparing the MSC-CM. Thus, the extracellular vesicles would be within the claimed range of the MSC-CM of the cited references.
Regarding claim 11 directed to the size of extracellular vesicles being about 35-150 nm, while Kawai et al. do not teach the limitation, however, the MSC-CM inherently contain extracellular vesicle or exosomes, and the size of exosomes is known to be about 50-200 nm according to Chew et al. (p.253, 1st col.).
Regarding claims 16-18, the limitation is directed to the results of the method and this does not require any other active step other than those in claim 1, thus, the wherein clauses of claim 16-18 do not limit the claimed method. As the combined teachings of the cited reference meet the subject matter of claim 1, the results obtainable from the combined teachings would be the same as the claimed method.
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.
Response to Arguments
Applicant's arguments filed 7/29/2026 have been fully considered but they are not persuasive. The claim rejection has been modified in order to address the instant amendment. The instant amendment does not introduce any new limitation, rather the limitations of claim 6 (human subject) and 15 (FGF-2) have been incorporated into claim 1. Thus, the claim rejections presented in the previous OA are rearranged/combined and maintained.
Applicant argued that one of skill in the art would have had no reasonable expectation of success in modifying the cited references to arrive at the claimed method. Applicant asserted that the “unique” BM-MSC secretome preparations comprise IGF, M-CSF, FGF2 and BMP1. Applicant pointed out that Kawai teaches that FGF-2 was not detected in a BM-MSC secretome. It is acknowledged that FGF-2 was not detected from the MSC-CM according to Kawai et al. The claim rejection for claim 15 in the previous claim rejection incorrectly identified the teaching of Kawai et al. However, the presence of bFGF or FGF2 in the CM of hBM-MSCs is already addressed by the combined teachings of Kawai et al. and Tamama et al. Tamama et al. teach that the hypoxic condition would upregulate bFGF in MSCs, and thus, the combined teaching of Kawai et al. in view of Tamam et al. would arrive to the FGF-2 secreted into the CM-MSCs. It is also noted that the growth factors presented in the condition medium of the bone-marrow mesenchymal stem cells are dependent on the culture condition as claimed. As the combined teachings of the cited references address the culturing conditions (i.e. hypoxic condition and acidic pH as claimed), the CM of the human BM-MSCs produced by the combined teachings would be inherently identical to the claimed CM of hBM-MSCs.
Applicant discussed that the instant invention is based on the unexpected finding such that other MSC populations were ineffective, less effective or even promote the diseased state.
In submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964).
The evidence relied upon should also be reasonably commensurate in scope with the subject matter claimed and illustrate the claimed subject matter “as a class” relative to the prior art subject matter “as a class.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971); In re Hostettler, 429 F.2d 464, 166 USPQ 558 (CCPA 1970). See, also, In re Lindner, 457 F.2d 506, 173 USPQ 356 (CCPA 1972).
It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D’Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
Applicant is advised to provide factual evidence to support the “unexpected” finding as alleged, preferably in the form of a declaration.
Applicant further asserted that the teaching of Howell and Kawai are in direct contradiction because Howell teaches at Table II that PDGF was not detected. It appears that applicant intended to point out Table II of Kawai et al. rather than Howell et al. Howell’s teaching is cited to address the human subject of claim 6 which is now incorporated into claim 1. As discussed above, FGF-2 is not detected in the CM of MSCs cultured under the normal condition as taught by Kawai et al., however, under the hypoxic condition as taught by Tamama et al., FGF-2 is upregulated and secreted from the MSCs.
Based on the above discussion, it is the Examiner’s position that the combined teachings of the cited references render the claimed invention obvious.
Conclusion
No claims are 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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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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