DETAILED ACTION
The Examiner for this application has changed. Please address all future correspondence to Examiner Kimberly Aron, Art Unit 1633. Additional Contact information can be found at the end of this paper.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/16/25 has been entered.
Claims 10-17 are pending. Claims 14-17 are withdrawn. Claim 10 is amended. Prosecution on the merits continues for claims 10-13.
PRIORITY
The instant application, filed 03/04/2022, is a 371 of PCT/KR2020/012045, filed 09/07/2020, which claims priority to KR10-2019-0110968, filed 09/06/2019. A certified copy of the Korean priority document has been filed in the instant application. As such, the earliest possible priority for the instant application is 09/06/2019.
STATUS OF REJECTIONS
103 Rejection of claims 10-13 as obvious over WO 2018116732 A1, as evidenced by 'Machine Translation of WO 2018116732 A1', in view of Moon et al. 2008, and Lee et al., 2017:
Applicant’s amendment to claim 10, directed to a method for preventing or treating obesity newly requires “inducing weight loss in a subject in need thereof” comprising administering dental tissue-derived mesenchymal stem cells to “the subject under conditions such that weight loss is induced in the subject”, is sufficient to overcome the rejection of record.
Although the rejection has been withdrawn, the Examiner is addressing Applicant’s arguments for clarity of record. Applicant argues that support for the amendment is found in the Abstract, paragraphs [0013], [0037], [0057] and FIG. 1A of the published specification. Applicant argues that there would be no expectation of success in arriving at the claimed invention resulting in weight loss because Lee, of record, showed that administration of undifferentiated MSCs showed no effect on body weight compared to controls. The Examiner agrees the cited prior art does not show weight loss following the administration of the MSCs, and thus the rejection is withdrawn.
At pages 5-6 of the Reply, Applicant further argues the claimed invention is unexpected in light of the failure of Lee, where results of
“the present disclosure demonstrate that administering dental tissue-derived MSCs results in a statistically significant reduction in body weight. As disclosed in the present application, the therapeutic effect on obesity via weight reduction is clearly demonstrated:
‘The pharmaceutical composition … of the present invention, reduces body weight...’
‘The body weight of the MSCi group was significantly lower (p<0.05) compared to the HFD group…’
This result, clearly illustrated in FIG. 1A of the application, is unexpected in view of Lee, which used MSCs from a different source (adipose tissue) and found them ineffective for this purpose. This surprising discovery underscores that the therapeutic utility for inducing weight loss is not a general property of all MSCs. Rather, the origin of the MSCs -from dental tissue- is critical for achieving this unexpected therapeutic outcome. This demonstrates a clear and unexpected difference compared to the cited prior art.”
The Examiner is not persuaded by Applicant’s arguments of unexpected results. When considering evidence of non-obviousness, “the applicant should establish a nexus between the rebuttal evidence and the claimed invention, i.e., objective evidence of nonobviousness must be attributable to the claimed invention. Additionally, the evidence must be reasonably commensurate in scope with the claimed invention. MPEP 2145. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. MPEP 716.02. Further, the burden is on Applicant to establish that the evidence provided are unexpected and significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." MPEP 716.02(b).
The claims require following administration of the dental tissue-derived MSCs, weight loss is induced in the subject. The Examiner notes the term “weight loss” is not defined in the specification, but one would understand that “weight loss” means that an individual subject had a starting body weight, and then that individual had a reduction in body weight. The “loss” of weight is in comparison to that same individual’s previous body weight. Absent an articulated definition in the specification.
FIG. 1A shows body weight measurements of 2 groups of MSC-treated mice (MSCi and MSCs) compared to a control (CON) group (normal diet) and a high fat diet (HFD) group (Example 2). The HFD, MSCi and MSCs groups were each fed a high fat diet for 10 weeks. The MSCi group (n=10) was administered 1 x 106 MSCs intraperitoneally after week 5, week 7, and week 9 during the 10-week high fat diet (paragraph [0054]). The MSCs group (n=10) was administered 1 x 106 MSCs intraperitoneally for 5 consecutive days after week 8 during the 10-week high fat diet (paragraph [0055]).
Dosing Regimens:
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FIG. 1A:
Reviewing FIG. 1A, there is no identifiable MSC-treated group that clearly shows the body weight of the mice at a starting point is higher than a weight at a later time point, and thus exemplifying “weight loss” with any noted statistical significance. There may be weight loss between week 8 and week 10 for the MSCs mice (the only negative slope), but one cannot determine from the graph or the specification whether this change represents a statistically significant weight loss. There does not appear to be any weight loss observed in the MSCi mice. Thus, FIG. 1A does not show that the administration of dental tissue-derived MSCs results in “weight loss” as claimed.
There is also no disclosure or explanation within the specification or working examples why only the MSCs mice exhibited “weight loss” but the MSCi mice did not. As noted above, the two MSC-treated groups were administered different regimens of MSCs, with different total amounts of MSCs administered. The MSCi mice received 3 separate doses of 1 x106 MSC at weeks 5, 7, and 9, thus receiving a total of 3 x106 MSC. The MSCs mice received a daily dose of 1 x106 MSC for 5 consecutive days in week 8, thus receiving a total of 5 x 106 MSC. Is the supposed weight loss in the MSCs mice a result of receiving more MSCs? Or due to the timing of the administrations?
The Examiner disagrees with Applicant’s assertion that because the body weight of a MSC- treated group is less than the body weight of the HFD group as shown in FIG. 1A provides evidence that the test group experienced “weight loss” as a result of dental tissue-derived MSCs administration. Looking at FIG. 1A, all mice (HFD, MSCi, MSCs and CON) gained weight (positive slope) over the 10 week time course, with the exception of MSCs mice from weeks 8 to 10 (negative slope). Thus, the reduced body weight of the MSCi/MSCs mice, when compared to the HFD mice, may be due to reduced weight gain in the treated mice, as the HFD, MSCi and MSCs all consumed the same diet. The physiological response of reduced weight gain compared to controls is not equivalent to “weight loss” of a treated subject. Thus, the Examiner does not agree that the specification exemplifies administration of dental-derived MSCs to treat obesity results in “weight loss” as claimed.
Even if the MSC-treated group exhibits reduced body weight when compared to the body weight of the control HFD group, and the reduction is considered evidence of “weight loss”-- which the Examiner does not concede –the specification and FIG 1A only identify that the MSCi mice had a reduced body weight compared to the HFD mice with statistical significance (shown by # in FIG 1 A, paragraphs [0014], [0057]). (The asterisks represent statistically significant increased body weight (of HFD and MSCs) relative to the CON mice (paragraph [0014])). The MSCi mice do not appear to have a reduced body weight compared to the HFD mice with any statistical significance.
There is also no disclosure or explanation within the specification or working examples why only the MSCi mice exhibited a reduced body weight compared to the HFD mice, but the MSCs mice did not. As noted above, the two MSC-treated groups were administered different regimens of MSCs, with different total amounts of MSCs administered. The MSCi mice received 3 separate doses of 1 x106 MSC at weeks 5, 7, and 9, thus receiving a total of 3 x106 MSC. The MSCs mice received a daily dose of 1 x106 MSC for 5 consecutive days in week 8, thus receiving a total of 5 x 106 MSC. Is the reduced body weight seen in the MSCi mice a result of receiving fewer MSCs? Or due to the timing of the administrations?
Even if the MSCi group exhibits reduced body weight when compared to the body weight of the HFD group, and the reduction is considered evidence of “weight loss”-- which the Examiner does not concede -- the difference/reduction in body weight would need to be the direct result of MSC administration. Indeed, Applicant quotes the specification as reciting “The body weight of the MSCi group was significantly lower (p<0.05) compared to the HFD group…” (page 5 of the Reply dated 10/16/25), to support the assertion that the claimed methodology results in weight loss. The Examiner notes that Applicant does not point to the source of this passage in the text. However, the apparent source of the passage is paragraph [0057] of the published specification, reproduced below:
As shown in A of FIG. 1, the body weight of the HDF group was significantly higher than that of the control group from the 3rd week of the high-fat diet (p<0.05). The body weight of the MSCi group was significantly lower (p<0.05) compared to the HFD group at the time of the first administration of MSC. (Emphasis added).
Applicant provided a truncated portion of the full sentence. The sentence discloses that the MSCi mice already had a significantly lower body weight “at the time of the first administration of MSC” - which would mean the initial reduced body weight in the MSC treated group cannot be attributable to the administered MSCs. The specification provides to explanation as to why the body weights of the MSCi mice were already significantly lower than the HFD mice at the time of initial MSC administration -as it would be expected the body weight would be the same between the MSCs, MSCi, and HFD mice until after dental tissue-derived MSC administration.
Applicant argues the reduction of body weight of the dental tissue-derived MSC treated mice compared to HFD mice was unexpected because Lee shows that there was no reduction of body weight in mice treated with adipose-derived MSCs. However, the results seen in Lee and those of the present application are not comparable because the experiments were not similar enough such that changing only the source of MSC (from adipose derived MSC to dental tissue-derived MSCs) is source of any success seen in the present Application.
The experimental designs between those of the instant specification and those used in Lee are very different. For example, the obesity models used are different. Lee establishes mouse models exhibiting obesity, metabolic syndrome and nonalcoholic fatty acid liver disease (NAFLD) with a 30 week high fat diet, and then administering the MSCs every other week for 10 weeks (pages 63-64, supplemental FIGs. S2, S5). The obesity produced in the MSCi, MSCs and HFD of the present invention is the result of starting the high fat diet at the beginning of the entire 10 week test period, where the mice on the high fat diet showed significantly increased body weight compared to controls at week 3 of the high fat diet (paragraph [0057]). Thus, in Lee, the obesity of the mice began 30 weeks prior to being treated with MSCs. The obesity of the mice of the present application began 5 weeks prior (MSCi) or 8 weeks prior (MSCs) to being treated with MSCs. The mice of Lee will have had much longer physiological changes due to obesity than the mice of the present application. In addition, in the obesity model of Lee, at 30 weeks on the high fat diet, the body weight of the obese mice was stable, or had little increase, prior to MSC treatment (FIG S2), whereas the body weight of the mice of the present application continued to increase throughout the test period (FIG 1A). Applicant makes no remarks on how the differences in mouse models are comparable when asserting the unexpected results of the claimed invention.
In addition, the dosing regimens are different. Lee administers 5 separate doses of 1 x 106/kg body weight via intraperitoneal injection to mice (n=6) on weeks 0, 2, 4, 6, and 8 (page 63, supplemental FIG. S5). The MSCi mice (n=10) of the present application receive 3 separate doses of 1 x 106 MSCs in a 200 μL volume at week 5, 7 and 9 (paragraph [0054]. The MSCs mice (n=10) of the present application receive 5 separate consecutive daily doses of 1 x 106 MSCs in a 200 μL volume in week 8 (paragraph
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[0054].
As noted above, only the MSCi mice showed reduced body weight compared to HFD mice with statistical significance (paragraph [0057]). Applicant makes no remarks on how the differences in dosing or administration regimens between Lee and the present application are comparable when asserting the unexpected results of the claimed invention.
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Applicant points to Lee’s statement of “The administration of MSC and M-L did not affect body weight and serum lipid profile in HFD mice” showing the failure of Lee’s MSCs to result in weight loss in treated mice, and evidence as the alleged unexpected success from administering the dental tissue-derived weight loss of the present invention. Figure 1A of Lee shows the body weight data of the tested mice:
The figure confirms only the M-BA mice showed reduced body weight compared to the HFD mice with statistical significance. Although one could argue the body weight of MSC mice was also less than the HFD mice, although not statistically significant. Lee only tests 6 mice, compared to 10 mice in each group of the present invention. Had the cohort size increased in Lee, would the differences in body weight in the MSC mice reached statistical significance? Lee acknowledges the study had limitations. The study used doses of MSC cells that were relatively lower than previously used studies, and cell dose is a critical determinant of the effects of cell-based therapies. Thus, Lee suggests increasing the dose and number of injections to improve therapeutic effect (page 72).
Regardless, if one accepts Lee’s statement that administration of MSC did not affect body weight, based on the statistical significance of weight data generated, then only data that achieves statistical significance in the present application can fairly be compared to Lee, or used as evidence of any alleged unexpected results. In the present application, the data of body weight in MSCs mice from weeks 8 to 10, which appears to demonstrate weight loss, does not appear to be statistically significant. The data of body weight in MSCi mice compared to body weight of HFD mice was already statistically significantly reduced at the time of the first MSC administration, and thus that data cannot be conclusively tied to the MSC administration.
Contrary to Applicant’s assertion that weight loss is unexpected following administration of MSCs in light of Lee’s failure to demonstrate any reduction, weight loss following administration of MSCs was known in the art at the time of the invention. For example, where Lee discloses his study utilized lower doses of MSCs than previous studies (page 72) and cites to Ji, 2015. Ji shows the administration of MSCs to obese type II diabetes mice fed a high fat diet (Abstract, page 927). Ji shows the obese mice fed a high-fat diet, administered 2 systemic doses of 4.2 x 107 cells/kg in 200 uL, resulted in a statistically significant reduction in weight loss (FIG. 1B):
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See, Ji et al. Niche-Dependent Regulations of Metabolic Balance in High-Fat Diet-Induced Diabetic Mice by Mesenchymal Stromal Cells. Diabetes, 2015. 64:926-936.
Additional evidence is provided by Salah et al, 2018. Saleh provides a review of preclinical use of adipose-derived mesenchymal stem cells in animal models for the treatment of obesity. Salah shows 7 studies which have been published where undifferentiated adipose-derived MSCs were administered in obese animal models and specifically assessed body weight in treated mice (Table 1). Of the 7 studies, only 2 did not demonstrate a reduction in body weight following administration of MSCs: Silva, 2014 and Lee, 2017 (of record). The remaining studies showed weight loss in animal models following administration of MSCs. See, Saleh, et al. Adipose-Derived Mesenchymal Stem cells in the Treatment of Obesity: A Systematic Review of Longitudinal Studies on Preclinical Evidence. Current Stem Cell Research, 2018. 13:000-000. 10 pages.
Nagaishi shows the administration of bone-marrow derived MSCs to obese type II diabetes mice fed a high fat diet (Abstract, page 1818). Nagaishi shows the obese mice fed a high-fat diet, are administered 4 systemic doses of 1 x 104 cells/kg (HFD-MSC, FIG 1A), resulted in a statistically significant reduction in weight loss compared to HFD mice (FIG. 1B, presented in modified form below):
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Nagaishi et al. Mesenchymal Stem Cell Therapy Ameliorates Diabetic Hepatocyte Damage in Mice by Inhibiting Infiltration of Bone Marrow-Derived Cells. Hepatology, 2014. 59(5):1816-1829.
In addition, claim 1 is drawn to, “A method for preventing or treating obesity by inducing weight loss in a subject in need thereof, the method comprising administering dental tissue-derived mesenchymal stem cells to the subject under conditions such that weight loss is induced in the subject.” The scope of the claim encompasses administering any type of dental-tissue derived MSCs, in any amount, using any route of administration, “under conditions such that weight loss is induced in the subject.”
As noted above, the “working examples” in the specification comprise administering dental-derived MSCs to mice (MSCi and MSCs) in Example 2. FIG 1A shows body weight measurements of the MSC-treated mice (MSCi and MSCs) compared to a control (CON) group (normal diet) and a high fat diet (HFD) group. The HFD, MSCi and MSCs groups were each fed a high fat diet for 10 weeks. The MSCi group was administered 1 x 106 MSCs intraperitoneally after week 5, week 7, and week 9 during the 10-week high fat diet (paragraph [0054]). The MSCs group was administered 1 x 106 MSCs intraperitoneally for 5 consecutive days after week 8 during the 10-week high fat diet (paragraph [0055]).
These conditions utilized the same subject mice, and administered the MSCs via the same intraperitoneal route, and each individual dosed administration was the same amount of MSCs (1 x 106 MSCs), although the total amount of MSCs administered differed. There were 2 different regimens administered, every other week x3 (MSCi) and 5 consecutive days (MSCs). These conditions are significantly narrower in scope than the pending claims. And, as noted above, the working examples do not show the administration of dental-tissue derived MSCs resulted in a statistically significant weight loss in treated mice.
Taken together, Applicant’s arguments of unexpected results is not persuasive at least because 1) the working examples do not demonstrate “weight loss” of the treated mice; 2) even if, for the sake of argument, reduced body weight of MSCi and MSCs mice compared to HFD mice is considered “weight loss,” the reduced body weight of the MSCi mice cannot be attributable to the administered MSCs because their body weights were already statistically less than HFD mice before MSC administration (paragraph [0057]); 3) weight loss following administration of MSCs is not unexpected; and 4) the evidence provided is not commensurate in scope with the claimed invention.
CLAIMS
Claim 10 is drawn to “A method for preventing or treating obesity by inducing weight loss in a subject in need thereof, the method comprising administering dental tissue-derived mesenchymal stem cells to the subject under conditions such that weight loss is induced in the subject.”
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.
Claim 13 is 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.
Claim 13, dependent upon claim 10, recites, “wherein the dental tissue is cryopreserved by vitrification” which is unclear and lacks antecedent basis. Claim 10 is directed to a method of administering “dental tissue-derived mesenchymal stem cells.” Thus it is unclear whether the claim is attempting to recite “wherein the dental tissue-derived mesenchymal stem cells are cryopreserved by vitrification” or if the claim is referring to the process in which the stem cells were produced, and the dental tissue source is cryopreserved?
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 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over WO2009/046346 to Riordan, further in view of Nagaishi et al. Mesenchymal Stem Cell Therapy Ameliorates Diabetic Hepatocyte Damage in Mice by Inhibiting Infiltration of Bone Marrow-Derived Cells. Hepatology, 2014. 59(5):1816-1829, Rao, et al. Stem Cells from Human Exfoliated Deciduous Teeth Ameliorate Type II Diabetic Mellitus in Goto-Kakizaki Rats. Diabetic & Metabolic Syndrome, February 28, 2019. 11:22, 11 pages, and Botelho et al. Dental Stem Cells: Recent Progesses in Tissue Engineering and Regenerative Medicine. Annals of Medicine, 2017. 489(8):644-651.
With regard to claim 10, Riordan discloses methods of treating or prevention of obesity comprising the administration of stem cells resulting in weight loss (Abstract, paragraphs [0002], [0006], [0025]-[0027], [0036]-[0037], [0056]-[0057], [0068]-[0073], [0075], Examples 1-2). Treatment includes treating obesity in general, or for individuals in which weight loss is desired, and treats secondary complications which result from obesity, including insulin resistance and fatty liver disease (paragraph [0006], [0023]-[0024]).
Riordan discloses the stem cells are provided as pharmaceutically acceptable formulations, administered via routes known in the art, and in therapeutically effective quantities (paragraphs [0049], [0080]-[0085]). Riordan discloses the stem cells include mesenchymal stem cells and dental-derived stem cells, including stem cells from human exfoliated deciduous teeth (SHED) (paragraphs [0068]-[0073], [0075]). Riordan states, “One of the embodiments of the current invention involves utilization of this novel source of stem cells for the treatment of obesity or for preventing secondary complications associated with obesity. In one embodiment of the invention, SHED cells are administered systemically or locally into a patient with obesity at a concentration and frequency sufficient for induction of therapeutic effect. SHED cells can be purified and used directly, certain sub-populations may be concentrated, or cells may be expanded ex vivo under distinct culture conditions in order to generate phenotypes desired for maximum therapeutic effect” (paragraph [0075]).
However, Riordan does not reduce to practice the methodology comprising the use of dental tissue-derived mesenchymal stem cells, as required by claim 10.
Nagaishi discloses MSC-based methodologies to treat type II diabetes, which is associated with fatty liver disease and insulin resistance (abstract, page 1816). Nagaishi shows the administration of bone-marrow derived MSCs (BMSC) to obese type II diabetes mice (HFD-diabetic mice) fed a high fat diet (Abstract, page 1818). Nagaishi shows the obese mice fed a high-fat diet, are administered 4 systemic doses of 1 x 104 cells/kg (HFD-MSC, FIG 1A), resulted in a statistically significant reduction in weight loss compared to HFD mice (FIG. 1B, presented in modified form below):
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Thus, Nagaishi exemplifies a method of treating obesity in a subject by administering BMSC and inducing weight loss in the subject in an in vivo model of type II diabetes.
Rao compares the effect of human exfoliated deciduous teeth (SHED) cells (a population of dental tissue-derived mesenchymal stem cells) to bone-marrow derived mesenchymal stem cells (BMSC) when administered to a non-obese type II diabetic rat model (Abstract, page 2). In this non-obese type II diabetic rat, SHED treatment performed similarly as BMSC treatment to improve symptoms including blood glucose levels, liver histology, diabetic-induced increase of G-6-Pase and PK and diabetic-induced decrease of GSK3β, GLUT2 and PFKM (FIGs 2-5). Both SHED treatment and BMSC treatment increased body weight of the non-obese mice towards a normal weight (FIG 2a).
Rao discloses MSCs appear to be an ideal tool for treating diabetes and related secondary complications, whose therapeutic effects have been demonstrated in multiple studies and animal models with low toxicity. Further, MSCs can be easily isolated from bone marrow, adipose tissue, cord blood and dental pulp and rapidly produced. (pages 2, 8-9). Thus, Rao establishes dental tissue-derived mesenchymal stem cells perform similarly to BMSC across all experiments in an in vivo model of type II diabetes.
Botelho discloses mesenchymal stem cell populations have been isolated from numerous tissues, and are used to develop cell-based therapies (Abstract, page 645). Dental tissue-derived mesenchymal cells, represent a diverse tissue-derived population of MSC cells with therapeutic potential across many clinical fields (Abstract, page 644). Dental tissue-derived MSC are highly accessible and exist in the human body throughout life (page 644, 648). Individual populations of dental tissue-derived mesenchymal cells include Dental pulp stem cells (DPSCs), Stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), dental follicle precursor cells (DFPCs), and stem cells from apical papilla (SCAP) (page 645, FIG. 1). The diversity of the individual populations have demonstrated an extensive range of multipotency including osteogenic, odontogenic, dentinogenic, cementogenic, adipogenic, chondrogenic, myogenic and neurogenic differentiation, allowing for potential use in oro-facial, neurologic, corneal, cardiovascular, hepatic, diabetic, renal, muscular dystrophy and autoimmune diseases (page 645-647). Dental tissue-derived mesenchymal cells can maintain their multipotential properties after both short-term and long-term cryopreservation (page 645). In addition, populations of dental tissue-derived mesenchymal cells have been shown to have increased stem cell properties and increased proliferation rates compared to bone marrow-derived stem cells (BMSC) (page 645).
It would have been obvious to combine the methodology of Riordan, directed to treating obesity comprising administering dental tissue-derived mesenchymal stem cells and inducing weight loss in the subject, further with the disclosures of Nagaishi, Rao and Botelho. A skilled artisan would have been motivated to select dental tissue-derived mesenchymal stem cells when practicing the claimed invention because Riordan expressly suggests using the cells to induce weight loss (paragraph [0075]). A skilled artisan would have had a reasonable expectation of success in achieving weight loss in the treated individual because Nagaishi discloses exemplifies treating obesity in a type II diabetes model by administering bone marrow derived MSC (BMSC) that results in weight loss, and Rao shows dental tissue-derived mesenchymal stem cells perform similarly to BMSC across all experiments in a non-obese in vivo model of type II diabetes, and Botelho discloses dental tissue-derived mesenchymal stem cells are an additional MSC population with diverse multipotential properties, and have been shown to have improved properties to BMSC.
With regard to claim 11, Riordan discloses the dental tissue includes deciduous teeth (paragraph [0057).
With regard to claim 12, Riordan does not disclose wherein the dental tissue includes a dental tissue of a wisdom tooth. However, Botelho discloses dental tissue-derived mesenchymal cells are sourced from premolar teeth and third molar teeth (i.e. wisdom teeth), and dental tissue-derived mesenchymal cells isolated from third molars have increased proliferation rates (page 645). Thus, it would have been obvious to use dental tissue from a wisdom tooth.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over WO2009/046346 to Riordan, further in view of Nagaishi et al. Mesenchymal Stem Cell Therapy Ameliorates Diabetic Hepatocyte Damage in Mice by Inhibiting Infiltration of Bone Marrow-Derived Cells. Hepatology, 2014. 59(5):1816-1829, Rao, et al. Stem Cells from Human Exfoliated Deciduous Teeth Ameliorate Type II Diabetic Mellitus in Goto-Kakizaki Rats. Diabetic & Metabolic Syndrome, February 28, 2019. 11:22, 11 pages, and Botelho et al. Dental Stem Cells: Recent Progesses in Tissue Engineering and Regenerative Medicine. Annals of Medicine, 2017. 489(8):644-651, as applied to claims 10-12 above, and further in view of Moon et al. Successful Vitrification of Human Amnion-Derived Mesenchymal Stem Cells, Human Reproduction, 2008. 23(8): 1760-1770, of record. Claim 13 is directed to an embodiment wherein the dental tissue is cryopreserved by vitrification.
The disclosures of Riordan, Nagaishi, Rao and Botelho are applied as in the rejection above, the content of which is incorporated herein in its entirety. Riordan, Nagaishi, Rao and Botelho combine to render obvious a method of treating obesity comprising administering dental tissue-derived mesenchymal stem cells according to claim 10. Riordan and Bothelho disclose stem cells used in the methods can be cryopreserved (Riordan, paragraph [0014]; Bothelho at page 645).
However, none of Riordan, Nagaishi, Rao or Botelho disclose the cells are cryopreserved by vitrification as required by the claim.
Moon et al. teaches the method of cryopreserving mesenchymal stem cells by vitrification (Abstract). Moon discloses vitrification provides a rapid cooling a high concentration of cryoprotectant which prevents ice crystal formation in the tissue during freezing (page 1761, 1766). Moon’s method utilized a two-step protocol using an equilibration solution and a vitrification solution, which was successful in the vitrification and survival of thawed MSC cells (pages 1761, 1763-1765).
It would have been obvious to combine the method of Riordan, Nagaishi, Rao and Botelho of using dental tissue-derived stem cells, wherein the stem cells can be cryopreserved, with the disclosure of Moon on a known method of cryopreservation for MSCs. It is prima facie obvious to combine prior art elements according to known methods to yield predictable results. In the instant case, the prior art included each element claimed, one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. MPEP 2143 (I)(A). A skilled artisan would have been motivated to use a vitrification method because the method prevents ice formation in frozen tissue. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as use of vitrification methods of cryopreserve MSCS were known at the time of the invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY A ARON whose telephone number is (571)272-2789. The examiner can normally be reached Monday-Friday 9AM-5PM.
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KAA
/CHRISTOPHER M BABIC/ Supervisory Patent Examiner, Art Unit 1633