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 .
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 Nov. 24, 2025, the Applicant has amended claims 1, 5-8, 11, 14-15 and 27, and canceled claim 9 and 21-26.
Applicant’s election without traverse of Group I (claims 1-8 and 10-17), and species election of cartilage disease is arthritis. Claims 18-20 and 27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-8 and 10-17 are under examination in this application.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment.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.
The previous objection due disclosure because it contains an embedded hyperlinks (i.e. Tool (http://david.abcc.ncifcrf.gov; version 6.8), located on page 49, para. 131) is withdrawn. The substitute specification filed Nov.24, 2025 is acknowledged.
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 1-2, 4-8, and 10-17 are rejected under 35 U.S.C. 103 as being unpatentable over Adkar et al., (Stem Cells 37.1: 65-76, published Oct. 2018, cited IDS 10/4/2023, previously presented), Lietman, et al. (JCI insight 3.3: e96308, published 2018, previously presented), Zhou, Shuanhu, Karim Eid, and Julie Glowacki. (Journal of Bone and Mineral Research 19.3: 463-470, published 2004; hereinafter as “Zhou”), Wang, et al. (Cell Communication and Signaling 17.1: 97, published 2019, previously presented), Faloon et al., (Probe Reports from the NIH Molecular Libraries Program [Internet], published 2014, cited IDS 10/4/2023, previously presented), and Diederichs, et al. (Cellular and Molecular Life Sciences 76.19: 3875-3889, published 2019, cited IDS 10/4/2023, previously presented).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on Sept. 3, 2025, therefore 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 claim 1, Adkar discloses a method of generating a population of chondrocyte or chondrocyte-like cells (see e.g. abstract, fig. 1A, page 68-69).
Regarding claim 1(i), Adkar discloses culturing a population of pluripotent stem cells in a mesoderm differentiation medium with a WNT signaling inhibitor (WNT-C59) to produce a population of chondroprogentior cells (see e.g. page 66-67, fig. 1A).
Regarding claim 1(ii), Adkar 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. page 66-67, fig. 1A).
Adkar is silent regarding culturing the population of chondroprogenitor cells in a combination medium comprising a WNT signaling inhibitor (WNT-C59) and wherein the cells exhibit increased homogeneity compared to a population of cells without WNT-C59.
However, the prior art of Lietman discloses WNT signaling inhibitors (e.g. XAV-939 and C113) acted to restore a chondrocyte-protective profile and reverse the catabolic profile following Wnt activation (see e.g. abstract, page 9, and fig. 1-6). Further, the prior art of Zhou discloses that Wnt-mediated signaling is one of the mechanisms of controlling TGF- beta’s effects on chondrocytes (see e.g. abstract).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Adkar and incorporate a Wnt signaling inhibitor as taught by Lietman because Lietman discloses that the WNT inhibition promotes anticatabolic effects on chondrocytes (see e.g., page 1). Further, Adkar already cultures with Wnt-C59 (see e.g. page 66-67, fig. 1A), as discussed above. Therefore, a person of ordinary skill in the art would have predictable results with a reasonable expectation of success of incorporating a Wnt signaling inhibitor. Additionally, he prior art of Wang discloses that it was known in the prior art that inhibiting Wnt/β-catenin signaling resulted in improved cartilage tissue production in 3D cultures in vitro (see e.g. page 9). Moreover, the prior art of Zho suggest that culturing the population of chondroprogenitor cells in a combination medium (i.e. transforming growth factor-beta 3 (TGF-β3) and a WNT signaling inhibitor (WNT-C59)) would naturally have cells that exhibit increased homogeneity compared to a population of cells without WNT-C59. Moreover, an artisan of ordinary skill in the art of (i.e. chondrocytes or chondrocyte-like cultures) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 2, Adkar discloses the pluripotent stem cells are induced pluripotent stem cells (iPS)(see e.g. page 68-69).
Regarding claim 4, Adkar discloses wherein the population of chondroprogenitor cells in step (ii) is prepared in a 3D culture (see e.g. page 66-67).
Regarding claim 5, 8 and 15, Adkar discloses a bone morphogenic protein (i.e. BMP-4 at a concentration of about 20ng/mL)(see e.g. Example 1) to produce a population of chondrocyte or chondrocyte-like cells from chondroprogentior cells (see e.g. page 66, Fig. 1 and 3-6).
Regarding claim 6-7, and 14, Adkar is silent regarding an inhibitor of the microphthalmia-associated transcription factor (MITF) pathway and wherein the MITF inhibitor is ML329 and is present at a concentration of about 1μM.
However, the prior art of Faloon is in the field of small molecule inhibitors of the MITF pathway (see e.g. Title) and teaches the MITF inhibitor of ML329 (see e.g. pages 1-5).
Regarding claim 6-7, and 14, Faloon discloses a field of small molecule inhibitors of the MITF pathway (see e.g. Title and page 1) where the MITF inhibitor is ML329 (see e.g. 12-14, 35-37, 41, and 44). Further, Faloon discloses that the small molecule probe (i.e. ML329) that inhibits the expression of numerous micropthalmia-associated transcription factor (MITF) target genes and blocks the proliferation of numerous cell lines that require MITF for proliferation (see e.g. Title and page 1, 12-14, 35-37, 41, and 44).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modify the methods of Adkar and include an MITF inhibitor (i.e. ML329) as taught by Faloon because Faloon discloses that ML329 will benefit studies of melanogenesis by parsing out MITF’s function in this biological process away from its role in the development of osteoclasts (i.e. damaged bone cells)(see e.g. page 3). Additionally, the prior art of Diederichs provides evidence that a person of ordinary skill in the art would have modified the methods of Adkar and include an MITF inhibitor (i.e. ML329) as taught by Faloon for the purpose of inhibiting the expression of osteogenic markers during chondrocyte differentiation thereby preventing undesired characteristics (see e.g. page 3876, 3884-3885). Further, Diederichs discloses that the inhibition of WNT signaling during MSC in vitro chondrogenesis may have the potential to lower BMP signaling and repress prominent hypertrophic and osteogenic differentiation markers to levels as seen articular chondrocyte-(AC)-like phenotype. (see e.g. page 3876, 3884-3885). Therefore, a person of ordinary skill in the art would have combined similar cell species, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. chondrogenesis) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 10, 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 suggests that extended treatment of BMP-4 may promote a more hypertrophic phenotype (see e.g. page 74). Additionally, Adkar discloses a time course of the unpurified chondroprogenitors measuring COL10 (see e.g. page 67-69 and fig. 2E). The specification teaches that a hypertrophic chondrocyte marker is type X collagen (i.e. COL10 or COL10A1)(see e.g. para. 150, fig. 2D, 2E). 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 MITF signaling in step (ii).
Regarding claim 11, Adkar discloses wherein the base chondrogenic medium media is a mix of DMEM and F12 (see e.g. page 66-67).
Regarding claim 12, as discussed above, Adkar 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. page 66).
Regarding claim 13, as discussed above, Adkar discloses wherein the WNT signaling inhibitor is WNT-C59., and wherein the WNT-C59 is present at a concentration of about 1μM (see e.g. page 66-67).
Regarding claim 16, Adkar discloses wherein the chondroprogenitor cells are cultured in the chondrogenic differentiation medium for about 28 days which reads on the claim limitation of about 1 to about 56 days (see e.g. page 66-67).
Regarding claim 17, Adkar discloses wherein the pluripotent stem (PS) cells are genetically modified (See e.g. page 71).
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 prior art of Faloon, Diederichs, and West do not cure the deficiencies of Adkar (Remarks, page 9).
Applicant’s arguments, filed Nov. 24, 2025, with respect to the previous rejection of the claims as being anticipated over Adkar 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 ground(s) of obviousness rejection is made in view of Adkar et al., Lietman, et al., Zhou, Shuanhu, Karim Eid, and Julie Glowacki, Wang, et al. Faloon et al., and Diederichs, et al..
Applicant asserts that the results of Applicants invention are unexpected and outweigh any prima facie obviousness of the claims (Remarks, page 9-10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
As discussed above, a new ground(s) of obviousness rejection is made in view of Adkar et al., Lietman, et al., Zhou, Shuanhu, Karim Eid, and Julie Glowacki, Wang, et al. Faloon et al., and Diederichs, et al.. In response to the argument that the prior art is not teaching the combination of TGF-beta and WNT-C59 administered to chondroprogenitor cells significantly enhanced homogeneity of hiPSC chondrogenesis by decreasing off-target cells is not evidence that the results are unexpected. It is noted that the claims do not recite “decreasing off-target cells”. Thus, Applicants arguments are not commensurate in scope with the claims. Furthermore, Applicants response of unexpected results is not comparing the claims to the cited/closest prior art.
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 3 is rejected under 35 U.S.C. 103 as being unpatentable over Adkar et al., (Stem Cells 37.1: 65-76, published Oct. 2018, cited IDS 10/4/2023, previously presented), Lietman, et al. (JCI insight 3.3: e96308, published 2018, previously presented), Zhou, Shuanhu, Karim Eid, and Julie Glowacki. (Journal of Bone and Mineral Research 19.3: 463-470, published 2004; hereinafter as “Zhou”), Wang, et al. (Cell Communication and Signaling 17.1: 97, published 2019, previously presented), Faloon et al., (Probe Reports from the NIH Molecular Libraries Program [Internet], published 2014, cited IDS 10/4/2023, previously presented), and Diederichs, et al. (Cellular and Molecular Life Sciences 76.19: 3875-3889, published 2019, cited IDS 10/4/2023, previously presented), as applied to claims 1-2, 4-8, and 10-17 above, and further in view of West et al., (US2014/0234964A1, published 2014, cited IDS 10/4/2023).
The teachings of Adkar apply here as indicated above.
Regarding claim 3, Adkar does not specifically disclose the pluripotent stem cells are embryonic stem cells (see e.g. page 68-69).
However, the prior art of West et al. discloses pluripotent stem cells are embryonic stem cells (i.e. progenitor cells lines that were derived from NTH registered human embryonic stem (hES) cell line H9 and Progenitor cell lines so obtained were treated as described below to induce differentiation to chondrocytes or chondrocyte progenitors)(see e.g. para. 36, 52, 144, 162, and 172).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Adkar to incorporate stem cells (i.e. embryonic stem cells) as taught by West because West discloses utilizing easily obtained cell lines that are commercially available (see e.g. para. 38). Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods to yield predictable results. Additionally, the prior art of West et al. which is in the field of orthopedic cell therapy and other methods relating to the use of embryonic stem cells (see e.g. Title; Abstract). Therefore, incorporating pluripotent stem cells that are embryonic stem cells would have led to predictable results with a reasonable expectation of success because both Adkar and West describe chondrocyte-like cell methods. Therefore, a person of ordinary skill in the art would have combined similar cell species, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. chondrocytes) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
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 prior art does not cure the deficiencies of Adkar (Remarks, page 9).
As stated supra, Applicant’s arguments, filed Nov. 24, 2025, with respect to the previous rejection of the claims 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 ground(s) of obviousness rejection is made in view of Adkar et al., Lietman, et al., Zhou, Shuanhu, Karim Eid, and Julie Glowacki, Wang, et al. Faloon et al., and Diederichs, et al.. 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.
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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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631