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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3rd of June 3 has been entered.
Priority
This application is a 371 application of PCT/US21/15879 filed on January 29, 2021, which claims benefit to the provisional application 62/967,257 filed on January 29, 2020.
Claim Status
In the response filed on the 3rd of June 2026, Applicant has amended claims 1, and canceled claim 9 and 21-26.
Applicant elected without traverse of Group I (claims 1-8 and 10-17), and species election of cartilage disease is arthritis, filed on the 8th of July 2025.
Claims 18-20 and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Currently, claims 1-8 and 10-17 are under examination.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objections
Claim 1 is objected to because of the following informalities: typo and clarity. Claim 1 recites “chondroprogentior”, which appears to be a typo and should be corrected to “chondroprogenitor”.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 8, 10-13, and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Keller, Gordon and Craft, April (US2016/0038544 A1, 2016; hereinafter as “Keller”), in view of Adkar et al., (Stem Cells 37.1: 65-76,2018, cited IDS 10/4/2023; prior art of record), Gustafson, Carl T., et al. (Front Biosci (Landmark Ed) 22.1: 137-156, 2017; hereinafter as “Gustafson”), and Narcisi, Roberto, et al. (Stem cell reports 4.3: 459-472, 2015; hereinafter as “Narcisi”).
This rejection is a new rejection necessitated by amendments to the claims, any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Claim Interpretation: With regard to the recited "chondrocyte-like cell”, the specification defines that “chondrocyte-like cells mean cells that have a proliferative ability and the properties of the chondrocytes, with the capabilities to form or regenerate cartilage tissue (in other words, cartilage stem cells). Further, the chondrocyte and/or chondrocyte-like cells are transcriptionally and functionally similar to primary chondrocytes, including cartilage matrix deposition potential.” (See Spec. para. 35). Accordingly, the term “chondrocyte-like cell” embraces any population of stem cells that cells are transcriptionally and functionally similar to primary chondrocytes, including cartilage matrix deposition potential.
Regarding claims 1, 10, and 13, Keller discloses a method of generating a population of chondrocyte or chondrocyte-like cells (i.e. stem cells)(see e.g. abstract, para. 141, claims 1-13, fig. 1-2, 5-6 and 9).
Keller discloses culturing a population of pluripotent stem cells in a mesoderm differentiation medium with a WNT signaling inhibitor (e.g. IWP-2) to produce a population of chondroprogentior cells (see e.g. abstract, para. 141, claims 1-13, fig. 1-2, 5-6 and 9). Further, Keller discloses culturing the population of chondroprogenitor cells obtained from step (i) in a chondrogenic medium comprising the transforming growth factor-beta 3 (TGF-β3) to generate the population of chondrocyte or chondrocyte-like cells (see e.g. abstract, para. 141, claims 1-13, fig. 1-2, 5-6 and 9).
Keller is silent regarding the WNT signaling inhibitor as being WNT-C59, and wherein the cells exhibit increased homogeneity and off-target cells comprising neural cells and melanocytes compared to a population of cells without WNT-C59.
However, the prior art of Adkar discloses culturing a population of pluripotent stem cells in a mesoderm differentiation medium where the WNT signaling inhibitor is WNT-C59 to produce a population of chondroprogentior cells (see e.g. page 66-67, fig. 1). Further, Adkar discloses wherein the WNT-C59 is present at a concentration of about 1μM (see e.g. page 66-67). Additionally, the prior art Gustafson discloses that IWP-2 and Wnt-C59 are a small molecules known as inhibitors of Wnt Production (i.e. PPN or IWPs) and that (see e.g. page 140-141).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to use the Wnt signaling inhibitor of WNT-C59, as taught by Adkar, in the method of culturing chondrocyte-like cells with a Wnt signaling inhibitor, as taught by Keller, with a reasonable expectation of success because one of ordinary skill in the art would want to use a Wnt inhibitor that has been developed for use in clinical trials (as taught by Gustafson, page 140-141). Further, Adkar teaches that a person of ordinary skill in the art would know that Wnt inhibition can improve the efficiency of chondrocyte potential to generate cartilage-like tissues in vitro (i.e. via expression CD73 and CD105)(as taught by Keller, see page 4). Moreover, one of ordinary skill in the art would know that IWP-2 and Wnt-C59 are art recognized equivalents that known for the same purpose, and it is prima facie obvious to substitute equivalents known for the same purpose (as taught by Gustafson, page 140-141)(see MPEP 2144.06). In the instant case, both Keller and Adkar disclose culturing chondrocyte-like cells with a WNT signaling inhibitor (see e.g. claims 1-13, and pages 66-68, respectively). Therefore, lack of evidence to the contrary, one of ordinary skill in the art could have easily substituted one Wnt-inhibitor for another with predictable results, since both are readily available and are used with similar techniques.
As stated supra, Keller et al., does not explicitly state wherein the cells exhibit increased homogeneity and decreased off-target cells comprising neural stem cells and melanocytes compared to a population of cells obtained with a chondrogenic medium without WNT-C59.
However, the prior art of Narcisi discloses that treatment with a Wnt signaling inhibitor (e.g. IWP2) increased chondrogenic potential of mesenchymal stem cells (i.e. type II collagen, COL2) and increased glycosaminoglycan production compared to a population of cells obtained with a chondrogenic medium without a Wnt signaling inhibitor (see e.g. page 462-468, fig. 4, and Supplemental Fig. 3-4).
MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.” Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims." In the instant case, the claims are drawn to an invention employing the same process steps, but the product(s) is(are) alleged to be different. Applicant is required to recite the missing steps to form the alleged different product(s) in view of the above-cited decision. If this is the case, Applicant is required to recite the missing steps.
The instant claim recites the following active steps: (i) culturing a population of pluripotent stem (PS) cells in a mesoderm differentiation medium to generate a population of chondroprogentior cells; and (ii) culturing the population of chondroprogentior cells obtained from step (i) in a chondrogenic medium comprising a combination of a transforming growth factor beta-3 (TGF-133) and a WNT signaling inhibitor, wherein the WNT signaling inhibitor comprises WNT-C59 to generate the population of chondrocyte or chondrocyte-like cells”(see claim 1, lines 3-9). The “wherein” clause following the active steps in claim 1 describes the qualities of the resulting cell method but does not require active steps or define structural limitations and is therefore not considered to be limiting to the claim.
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have had the methods of generating chondrocytes or chondrocyte-like cells, as taught by Keller and Adkar, and have the cells exhibit increased homogeneity and decreased off-target cells, comprising neural stem cells and melanocytes, compared to a population of cells obtained with a chondrogenic medium without WNT-C59, as suggested by Narcisi, with a reasonable expectation of success because one of ordinary skill in the art would know that treatment with a Wnt signaling inhibitor would have increased chondrogenic potential of mesenchymal stem cells, as taught by Narcisi, see e.g. page 462-468). Thus, the methods of generating chondrocytes or chondrocyte-like cells with a Wnt signaling inhibitor, like WNT-C59, would have naturally exhibit increased homogeneity and decreased off-target cells comprising neural stem cells and melanocytes compared to a population of cells obtained with a chondrogenic medium without a Wnt signaling inhibitor like WNT-C59. Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 2 and 17, Keller discloses the pluripotent stem cells are induced pluripotent stem cells (iPS) and that the pluripotent stem (PS) cells are genetically modified (see e.g. para. 98-101 and 271, page 15).
Regarding claim 3, Keller discloses the pluripotent stem cells are embryonic stem cells (see e.g. para. 4, 98-101, 179, claims 1-8).
Regarding claim 4, Keller discloses wherein the population of chondroprogenitor cells in step (ii) is prepared in a 3D culture (see e.g. para. 76-79, 250-259).
Regarding claim 5, 8 and 15, Keller discloses a bone morphogenic protein is BMP-4 at a concentration of about 20ng/mL (i.e. 10 to 100 ng/mL)(see e.g. para. 242-243, 308, page 14, 18-19, Examples 1-5,and claim 1).
Regarding claim 10, Keller does not explicitly disclose that the method require sorting but discloses that chondrocyte like cells that expressing CD73 are able to be identified as articular chondrocyte like cells and able to quantitative measure that cell size to indicate hypertrophy by flow cytometry (see e.g. para. 272-274, 297, 314-316, pg. 15, fig. 4, claim 61, Example 1, 4, and 6). Further, Keller discloses that a loss in collagen 10 (i.e. type X collagen) may indicate a loss of hypertrophy (see e.g. fig. 5, Examples 1-2, and 5-6).
Although Keller does not explicitly state the method does not require sorting or expansion of the isolated population of chondrocytes or chondrocyte-like cells.
However, the prior art of Adkar discloses wherein the method does not require prospective sorting of the isolated population of chondrocyte or chondrocyte-like cells (i.e. unsorted)(see e.g. page 67). Further, Adkar discloses that type X collagen was not observed in unsorted and unsorted chondroprogenitors indicating that hypertrophy was reduced (see e.g. pages 67-69, 72-73, fig. 2, 6). Further, it is noted that the specification teaches that a hypertrophic chondrocyte marker is type X collagen (i.e. COL10 or COL10A1)(see Spec. e.g. para. 150, fig. 2). Therefore, Adkar discloses three population of chondrocyte or chondrocyte-like cells (i.e. BJFF, ATCC, and RVR) wherein chondrocyte hypertrophy (i.e. COL10) is reduced in a population of chondrocyte-like cells (i.e. ATCC or RVR) relative to a population of chondrocyte or chondrocyte-like cells (i.e. BJFF) produced by a method which does not inhibit WNT and/or MITF signaling in step (ii) as recited in the claims.
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the method of generating a population of chondrocyte or chondrocyte-like cells, as taught by Keller, in a method that does not require prospective sorting or expansion of the isolated chondrocyte or chondrocyte-like cell population wherein off-target cells and/or chondrocyte hypertrophy is reduced in the population relative to a population of chondrocyte or chondrocyte-like cell produced by a method which does not inhibit WNT signaling and/or MITF signaling, a taught by Adkar, with a reasonable expectation of success because one of ordinary skill in the art would want to improve methods of obtaining the chondrocyte or chondrocyte-like populations that are used to generate general models of cartilage diseases, such as osteoarthritis (as taught by Keller, see e.g. page 15). Further, both Keller and Adkar disclose using type X collagen as a hypertrophic chondrocyte marker (see e.g. page 15, and 73, respectively). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 11, Keller discloses wherein the base chondrogenic medium media is a mix of DMEM and F12 (i.e. Ham’s F-12)(see e.g. para. 198, page 12).
Regarding claim 12, as discussed above, Keller discloses wherein the transforming growth factor beta is TGF-β3, and wherein TGF-β3 is present at a concentration of about 10ng/ml (see e.g. para. 206, page 13, 18-19, fig. 6, Examples 1-5, claims 1-28).
Regarding claim 16, Keller discloses wherein the chondroprogenitor cells are cultured in the chondrogenic differentiation medium for about 25 days which reads on the claim limitation of about 1 to about 56 days (see e.g. Fig. 1, page 3, 17-19).
Thus, the claimed invention as a whole was anticipated by Adkar in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that Adkar does not teach or suggest culturing a population of chondroprogenitor cells in a medium comprising a combination of TGF-beta and WNTC59 to produce a population of chondrocyte or chondrocyte-like cells, and the additional prior art does not cure the deficiencies of Adkar (Remarks, page 6-8).
Applicant’s arguments, filed June 3, 2026, with respect to the previous rejection of the claims as being obvious over Adkar et al., Lietman, et al., Zhou, Wang, et al., Faloon et al., and Diederichs, et al., have been fully considered and are persuasive in view of the amendments to the claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of Keller, Gordon and Craft, April; Adkar et al.; Gustafson, Carl T., et al.; Narcisi, Roberto, et al; Faloon et al.; Hartman, Mariusz L., and Malgorzata Czyz; and Schepsky, Alexander, et al., as discussed above.
Applicant argues that Adkar is fundamentally different from the instant claims, i.e., achieving enhanced homogeneity and reduced off target differentiation through stage-specific signaling modulation (Remarks, page 7). Applicant argues that the prior art of Adkar employs WNT-C59 and TGF-β3 at entirely different stages (Remarks, page 7).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, it is acknowledged that Adkar employs WNT-C59 and TGF-β3 at different times (i.e. different stages) when culturing (see e.g. fig. 1). As discussed above, Adkar is cited for WNT-C59, and Keller is cited for employing a chondrogenic medium with a WNT-inhibitor and TGF-β3. However, it is noted that the claims read on “comprising” which does not exclude other embodiments, such as the addition of WNT-C59 and TGF-β3 at different times as long as they are I the same chondrogenic medium as claimed (see MPEP 2111.03). Furthermore, it is noted that claim 1 does not recite the stage or time to employ the chondrogenic medium comprising WNT-C59 and TGF-β3.
Applicant argues that the Examiner is speculating that increased homogeneity would naturally result from WNT inhibition and that none of the cited publications report increased cellular homogeneity resulting from administration of WNT-C59 during chondrogenic differentiation (Remarks, page 8).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive. In response to applicant's argument regarding speculation, the MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.” Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) provides "that since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims." In the instant case, the claims are drawn to an invention employing the same process steps, but the products is/are alleged to be different. Applicant is required to recite the missing steps to form the alleged different product(s) in view of the above-cited decision. If this is the case, Applicant is required to recite the missing steps. As discussed above, in the instant case, the claim recites the following active steps: (i) culturing a population of pluripotent stem (PS) cells in a mesoderm differentiation medium to generate a population of chondroprogentior cells; and (ii) culturing the population of chondroprogentior cells obtained from step (i) in a chondrogenic medium comprising a combination of a transforming growth factor beta-3 (TGF-133) and a WNT signaling inhibitor, wherein the WNT signaling inhibitor comprises WNT-C59 to generate the population of chondrocyte or chondrocyte-like cells”(see claim 1, lines 3-9). The “wherein” clause following the active steps in claim 1 describes the qualities of the resulting cell method but does not require active steps or define structural limitations and is therefore not considered to be limiting to the claim. Thus, the methods of generating chondrocytes or chondrocyte-like cells with a Wnt signaling inhibitor, as taught by Keller, like WNT-C59, as taught by Adkar, would have naturally exhibit increased homogeneity and decreased off-target cells comprising neural stem cells and melanocytes compared to a population of cells obtained with a chondrogenic medium without a Wnt signaling inhibitor like WNT-C59 as recited in the instant claims. Moreover, if the prior art structure is capable of performing the intended use, then it meets the claim.
Applicant argues that the results of Applicants invention are unexpected (i.e. figures 4A-4B and 6) and outweigh any prima facie obviousness of the claims (Remarks, page 8-9). Applicant argues that the timing of the administration of WNT-C59, and the effects of WNT inhibition are highly stage-dependent (Remarks, page 9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to the argument that Applicant has unexpected results, it is noted that 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). 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). In the instant case, the specification discloses that “Fig. 4A-4E show WNT inhibition during pellet culture enhanced homogeneity of hiPSC chondrogenesis”(para. 13) and “that FIG. 4C shows pellets treated with WNT-C59 in only pellet culture exhibited an increased glycosaminoglycans (GAG)/DNA ratio compared to pellets treated with other culture regiments”(para.13). Further, the specification discloses that WNT-C59 treatment during pellet culture enhanced Saf-0 staining and decreased off-target cells (yellow arrowheads) as compared to other WNT inhibition culture regiments (fig. 4b)(Spec. para. 13). It is noted that figure 4b shows increased homogeneity with BMP4, WNT-C59, and TGF-β3 cells and discloses an increased glycosaminoglycans (GAG)/DNA ratio. Thus, Applicants arguments are not commensurate in scope with the claims (i.e. not reciting BMP4). Further, it is unclear how figure 4a or 4b shows decrease off-target cells. It appears that Figure 6C discloses the same amount of mesenchyme and chondrocytes obtained with WNT-C59, and TGF-β3 (spec. para. 15). Further, it appears that fig. 6D shows the decrease of off-target cells showing that TGF-β3 and WNT-C59-treated cells had higher expression of chondrogenic markers SOX9 and COL2A1, and lower expression of neurogenic markers SOX2, OTX1 and PAX6, and low expression of melanocyte marker MITF. However, it is unclear if the expression of the neurogenic and melanocyte markers in the TGF-β3 treated cells are statistically significant compared to the WNT-C59 and TGF-β3 teared cells, since the results are based on the expressions and are not quantitative results. Additionally, Applicants response of unexpected results is not comparing the claims to the cited/closest prior art showing that the results of the instant application are unexpected.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., stage of employing inhibitors) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).As discussed above, it is noted that the claims read on “comprising” which does not exclude other embodiments, such as the addition of WNT-C59 and TGF-β3 at different times as long as they are in the same chondrogenic medium as claimed (see MPEP 2111.03). In the instant case, independent claim 1 does not recite a stage and/or time to employ WNT-C59 and TGF-β3 in the chondrogenic medium.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claims 6-7, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Keller, Gordon and Craft, April (US2016/0038544 A1, 2016; hereinafter as “Keller”), in view of Adkar et al., (Stem Cells 37.1: 65-76,2018, cited IDS 10/4/2023; prior art of record), Gustafson, Carl T., et al. (Front Biosci (Landmark Ed) 22.1: 137-156, 2017; hereinafter as “Gustafson”), and Narcisi, Roberto, et al. (Stem cell reports 4.3: 459-472, 2015; hereinafter as “Narcisi”), as applied to claims 1-5, 8, 10-13, and 15-17 above, and further in view of Faloon et al., (Probe Reports from the NIH Molecular Libraries Program, 2014; cited IDS 10/4/2023, prior art of record), Hartman, Mariusz L., and Malgorzata Czyz. (Cellular and Molecular Life Sciences 72.7: 1249-1260, 2015; hereinafter as “Hartman”), and Schepsky, Alexander, et al. (Molecular and cellular biology 26.23: 8914-8927, 2006; hereinafter as “Schepsky”).
This rejection is a new rejection necessitated by amendments to the claims, any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Keller et al., apply here as indicated above.
Regarding claim 6-7, and 14, as stated supra, Keller discloses Wnt inhibitors and that inhibition of the Wnt pathway resulted in an increased for chondrocyte or chondrocyte-like cells (see e.g. para. 312, page 16, Example 1). Further, Keller discloses using any Wnt agonist that stimulates wnt/beta-catenin receptor signaling in a chondrocyte lineage cell (see e.g. page 6, para. 91).
Keller is silent regarding an inhibitor of the microphthalmia-associated transcription factor (MITF) pathway, and where the MITF is ML329, and is present at a concentration of about 1μM.
However, the prior art of Faloon discloses using the micropthalmia-associated transcription factor (MITF) inhibitor of ML329 at a concentration of about 1μM, and discloses that it was a well-known small molecule inhibitor of MITF (see e.g. pages 1-5, 12-14, 35-37, 41, and 44). Furthermore, the prior art of Hartman discloses that MITF is a key regulator in melanocyte development and is involved with Wnt/β-catenin signaling pathways (see e.g. page 8914-8915). Additionally, the prior art of Schepsky discloses that MITF expression is activated in epithelial-mesenchymal transitions (see e.g. page 1251).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modify the chondrocyte or chondrocyte-like cell method, as taught by Keller, and include an Wnt agonist like the MITF inhibitor, ML329, as suggested by Faloon, Hartman, and Schipske, because one of ordinary skill in the art would know that inhibiting the expression of MITF with ML329 in a method of culturing pluripotent stem cells for obtaining chondrocytes or chondrocyte-like cells which would thereby further prevent undesired cell populations (as suggested by Hartman and Schepsky, pages 8914 and 1251, respectively). Further, the prior art of Faloon discloses that ML329 would be an optimal small molecule inhibitor for understanding MITF’s function in biological process instead of just studying its role in the development of osteoclasts (i.e. damaged bone cells)(see e.g. page 3). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the cited prior art Faloon does not cure the deficiencies of Adkar (see Remarks, page 8). Applicant asserts that Faloon only describes MITF inhibitors in the context of melanocytes (Remarks, page 8).
Applicant’s arguments with respect to the previous rejection of the claims as rejected as being obvious over Adkar et al., Lietman, et al., Zhou, Wang, et al., Faloon et al., and Diederichs, et al., have been fully considered and are persuasive in view of the amendments to the claims. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection is made in view of Keller, Gordon and Craft, April; Adkar et al.; Gustafson, Carl T., et al.; Narcisi, Roberto, et al; Faloon et al.; Hartman, Mariusz L., and Malgorzata Czyz; and Schepsky, Alexander, et al., as discussed above.
In response to applicant's arguments against the references individually (i.e. Faloon), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In response to the argument Faloon is no longer the only prior art cited for inhibiting MITF. As discussed above, the prior art of Keller, Hartman, and Schepsky suggest employing MITF inhibitors to limit off-target cell population, such as melanocytes, when generating a population of chondrocytes or chondrocyte-like cells.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is allowed.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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