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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/4/2026 has been entered.
Claims 10 and 19-20 have been canceled, and claims 1-9 and 11-18 have been considered on the merits. All arguments have been considered.
Response to Amendment/Declaration
The declaration under 37 CFR 1.132 filed 2/4/2026 is insufficient to overcome the rejection of claims 1-9 and 11-18 as set forth in the last Office action.
The declaration alleges that there is an unexpected and surprising result from the claimed method in ameliorating a periodontal disease, and the evidence supporting the unexpected result is a photograph with a brief description. There is no indication how the data shown in the declaration are considered unexpected. MPEP716.02(a) states that the unexpected results can be shown by greater than expected results or superiority of a property shared with the prior art. The instant declaration did not establish what the expected results are, and why the alleged regeneration is considered unexpected. Merely showing that there is positive outcome is not considered unexpected in the absence of any basis what the expected results are. There is no comparison of the results obtainable from the claimed invention to the closest prior art to show any superiority. In the absence of showing how the data presented in the declaration is considered unexpected and/or any comparison to support the alleged superiority, it is the Examiner’s position that the declaration was not sufficient to overcome the 103 rejections.
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) 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) and Chew et al. (2019, Acta Biomaterialia; IDS ref.), and as evidenced by Gabrielyan et al. (2020, Stem Cell Research; of record) and Polacek et al. (2011, Cell Transplantation).
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 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 limitation directed to the MSC secretome preparation comprising IGF (claim 1), VEGF (claim 12), TGF-b1 (claim 13), HGF, PDGF (claim 14), FGF2 (claim 15), Kawai et al. teach that the MSC-CM comprises IGF-1, VEGF, PDGF, TGF-b1, HGF and FGF-2 (Table II).
While the rest of the factors as claimed, 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 BM-MSCs according to Polacek et al. Polacek et al. teach that BMP-1 is only detected in 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.
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.
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over Kawai et al. in view of Tamama et al., Hazehara-Kunitomo et al., Javidi et al. and Chew et al. as applied to claim 1 above, and further in view of Howell et al. (1997, J. Periodontol.; of record)
Regarding claim 6 directed to the subject being human, the cited references do not teach the subject being a human.
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 skilled in the art would have been motivated to do so because Howell et al. teach PDGF and IGF can improved 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.
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
It is noted that the claim rejections presented above have been changed from the claim rejections present in the OA mailed on 11/5/2025. The claim rejections cite Kawai et al. as a primary reference in order to address the claimed MSC secretome based on the conditioned medium of BM-MSC taught by Kawai et al. rather than exosomes taught by Chew et al. It is also noted that evidentiary references cited previously, i.e. Yang et al. and Lee et al. are removed from the rejection and a new evidentiary reference, i.e. Polacek et al., is added to address BMP1.
As discussed above, the declaration by Dr. Mosley (inventor) was not sufficient to overcome the 103 rejections in the previous OA. The declaration is insufficient to overcome the new 103 rejections for the same reason discussed above. Applicant is advised to provide a detailed explanation of the data instead of merely showing a photograph, and discuss how the data shown in the declaration are considered unexpected.
As Chew et al. is no longer a primary reference in the 103 rejection, the arguments directed to the teaching of Chew et al. are moot.
It is noted that applicant argued that the exosomes of Chew et al. do not inherently contain the claimed proteins of IGF, M-CSF and BMP1. It is acknowledged that Chew et al. is directed to exosomes and there is no indication that these proteins are present in the exosomes. The new reference, Kawai et al., in fact teaches that the CM contains various factors including IGF as well as those disclosed in claims 12-15. As discussed previously, Gabrielyan et al. teach that M-CSF is secreted from BMSCs under hypoxic condition. Regarding BMP1, Polacek et al. was cited as an evidentiary reference to address that BMP1 is secreted from BM-MSCs. Therefore, the newly cited references address the inherent presence of these factors in the secretome of BM-MSCs.
Regarding the use of pH 6.2-6.4 for the preparation of MSC secretome, the claim rejections above are no longer relied upon the teaching of Brodie. Rather, the rejection provides a new discussion based on Hazehara-Kunitomo et al. and a newly added reference, Javidi et al.
Applicant asserted that there would be a unique secretion profile of a MSC based on the culture condition, and there is no reasonable expectation of success to arrive at the claimed secretome. The Examiner respectfully disagrees with this assertion. The claim rejection above has established that the secretion of IGF, M-CSF and BMP1 by BM-MSC and their presence in the MSC-CM, and thus, the secretion of these factors are inherent for BM-MSCs. There is no evidence that the amount of these factors are different from the MSCs cultured in different conditions. There is no disclosure that the claimed acidic pH causes any difference in their secretion. Applicant is advised to provide any evidence that the claimed pH produces a unique composition of MSC secretome and/or such composition would produce unexpected results. However, as those claimed factors released from the BM-MSCs into the conditioned medium are known in the art as discussed in the claim rejection, it is the Examiner’s position that the combined teachings would be able to produce the claimed secretome.
It is noted that the instant amendment introduced “effective amount of IGF, M-CSF and BMP1”. Without any specific concentration, the inherent presence of IGF, M-CSF and BMP1 in the secretome of BM-MSC is considered to meet the limitation.
Applicant alleged that there is unpredictability in the field renders the claimed limitation unobvious. Applicant stated that the present claims require that the administration of the MSC secretome preparation to a subject ameliorates periodontal disease or symptom thereof in the subject, and other MSC populations were found to be ineffective, less effective or even promote the disease state.
First, there is no factual evidence that supports the applicant’s allegation. The instant specification does not provide any working example that only the BMSCs cultured under the claimed culture condition would produce a secretome that “ameliorate” any periodontal disease or symptoms thereof whereas other MSCs would not be able to ameliorate the condition. In order to further entertain this idea, applicant is advised to provide supporting evidence for the capability of the secretome produced by BMSCs cultured under the hypoxic condition and an acidic pH of 6.2-6.4. Without such evidence, it is considered that the combined teachings of the cited references would meet the claimed method with a reasonable expectation of success.
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.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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