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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/22/2025 has been entered.
Status
Claims 1-16 are pending. Claims 5-10 and 13-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Claims 9-10) or species (Claims 5-8 and 13-15). Therefore, Claims 1-4, 11, 12, and 16 are presented for examination.
Election/Restrictions
Applicant elected Group I (a method for treating arthritis) and tankyrase inhibitor including IWR-1 or XAV-939, without traverse in the reply filed on 12/19/2023.
Information Disclosure Statement
No Information Disclosure Statement was filed with Applicant’s current reply.
Withdrawn Objections/Rejections
Claim 16 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the problem of indefiniteness due to lack of antecedent basis made of record in the previous Office Action, specifically, the addition of “adult stem cells” in line 2 of the claim. Therefore, the objection is hereby withdrawn.
Declaration Under 37 C.F.R. 1.130
The declaration under 37 CFR 1.130a filed on 9/22/2025 is sufficient to overcome the rejection of claims 1-4, 11, 12 and 16 based on Kim et al. (Nat. Commun. 2019 Oct 25;10(1):4898. doi: 10.1038/s41467-019-12910-2. PMID: 31653858; PMCID: PMC6814715). The 9/22/2025 37 C.F.R. 1.130 declaration of Inventor Yongsik Cho established that the Kim et al. reference qualifies as a disclosure made by an inventor one year or less before the effective filing date of the claimed invention. Therefore, Kim et al. is excluded from consideration as a prior art reference under the exception set forth in 35 U.S.C. 102(b)(1)(A).
Withdrawn Rejection
Claims 1-4, 11, 12, and 16 were rejected under 35 U.S.C. 102a1 as being anticipated by Kim et al. (Nat Commun. 2019 Oct 25;10(1):4898. doi: 10.1038/s41467-019-12910-2. PMID: 31653858; PMCID: PMC6814715). The Kim et al. reference is excluded from consideration as a prior art reference under the exception set forth in 35 U.S.C. 102(b)(1)(A). Therefore, the rejection is hereby withdrawn.
Claim Rejections - 35 USC § 102
Rejection maintained
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 11, 12, and 16 are rejected under 35 U.S.C. 102a1 as being anticipated by Lietman et al. (“Inhibition of Wnt/β-catenin signaling ameliorates osteoarthritis in a murine model of experimental osteoarthritis." JCI Insight. 2018; 3(3):e96308. https://doi.org/10.1172/jci.insight.96308 - cited previously by Examiner) as evidenced by Kim et al. (Nat Commun. 2019 Oct 25;10(1):4898. doi: 10.1038/s41467-019-12910-2. PMID: 31653858; PMCID: PMC6814715.).
Claimed invention
Claim 1 is drawn to a method of regenerating cartilage in a subject having arthritis comprising the step of administering to the subject an effective amount of an inhibitor of Tankyrase,
wherein the inhibitor of Tankyrase stabilizes the Sox9 protein or increases the concentration of the Sox9 protein by inhibiting the Tankyrase activity.
Prior art
Lietman teaches mice underwent destabilization of the medial meniscus surgery by intra-articular injection with the tankyrase inhibitor, XAV-939, a small-molecule inhibitor of Wnt/β-catenin signaling. Wnt/β-catenin signaling was highly activated in murine synovial fibroblasts as well as in osteoarthritis (OA)-derived human synovial fibroblasts. XAV-939 ameliorated OA severity associated with reduced cartilage degeneration and synovitis in vivo. See abstract. Lietman concluded that therapeutic Wnt inhibition reduced disease severity in a model of traumatic OA via promoting anticatabolic effects on chondrocytes and antifibrotic effects on synovial fibroblasts and may be a promising class of drugs for the treatment of OA. See Id. Lietman teaches that the tankyrase inhibitor improved histological scores (OARSI) indicating reduction in cartilage damage or degradation in the improvement of OA. See p. 5, second full para.
While Lietman does not expressly recognize the tankyrase inhibition by XAV939 leads to regeneration of cartilage or the stabilization or increase levels of SOX9, Lietman does teach that XAV939 acts as a tankyrase inhibitor to stabilize AXIN2 and promotes the degradation of β-catenin, which is strongly upregulated in OA. See p. 2. Because XAV939 acts as a tankyrase inhibitor, it would, mechanistically, induce regeneration of cartilage and the stabilization or increase levels of SOX9 as evidenced by Kim. Kim teaches, “[m]echanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway”. See abstract.
Kim teaches that tankyrase inhibition with XAV939 stimulates cartilage-specific anabolism. See title; ‘Results’ section at pp. 2-3. Tankyrase inhibition enhances SOX9 transcriptional activity. See p. 7. Kim also teaches tankyrase inhibition enhances SOX9 transcriptional activity and showed that nine different tankyrase inhibitors, specifically increased the transcriptional activity of SOX9 in chondrocytes. See p. 7 and Figure 5a-c. Thus, the regeneration of cartilage or the stabilization or increase levels of SOX9 are features present in the method explicitly taught by Lietman, i.e., treatment of OA by administration of the tankyrase inhibitor, XAV939.
Claim 2 limits claim 1, wherein the cartilage is articular cartilage. Lietman and Kim concern treatment of joints and arthritis. Thus, the cartilage disclosed is articular cartilage.
Claim 3 limits claim 1, wherein the inhibitor of Tankyrase is an agent that binds to a nicotinamide sub-domain of ARTD domain which is a catalytic domain of a Tankyrase protein. Claim 4 limits claim 3, wherein the agent that binds to a nicotinamide sub-domain of ARTD domain is XAV-939. Lietman teaches XAV-939. This meets the limitations of Claim 11 and Claim 12.
Claim 16 depends from claim 2, wherein the adult stem cell is a mesenchymal stem cell. Mesenchymal stem cells are naturally present in subjects and are stimulated to chondrogenesis by tankyrase inhibition. See Kim, p. 2 and Figure 6.
Response to arguments
Applicant argues that the Kim reference is excluded as prior art and therefore cannot be used as a teaching reference. However, in this case, the Kim reference is used as an evidentiary reference. Exclusion of the reference under the exception set forth in 35 U.S.C. 102(b)(1)(A) only removes the reference from consideration as a prior art reference. In this case, Kim is not being considered as prior art. Kim still can be considered for purposes of establishing known biological effect of XAV939 and tankyrase inhibition – specifically, to demonstrate that administration of XAV939 results in increased SOX9 transcription activity.
Applicant further argues that Lietman, when analyzed alone, is fundamentally
deficient for three reasons:
It teaches cartilage preservation, a starkly different concept from the cartilage regeneration taught by the present invention.
Its findings rely on XAV939, a broad-spectrum inhibitor of PARP family members whose effects cannot be attributed solely to tankyrase inhibition, thus providing no reliable teaching on the specific function of tankyrase.
It explicitly teaches away from the core concept of the invention, stating its observed effects are not due to regeneration.
Applicant's arguments have been fully considered but have not been found to be persuasive. Regarding 1) Lietman teaching cartilage preservation which is different from cartilage regeneration, one would understand that Lietman’s identification of other factors of treatment with tankyrase inhibitor, XAV939, does not remove the explicit teaching of a method of treating OA by administering XAV939. With regard to 2) XAV939’s effects cannot be attributed solely to tankyrase inhibition because it is a broad spectrum of PARP, the fact that XAV939 may possess other features does not then remove its known tankyrase inhibitory-activity which is explicitly mentioned by Lietman as outlined above. See ‘Introduction’ section of Lietman p. 2.
Applicant argues that Lietman teaches away from regenerating cartilage because Lietman states that the cartilage-sparing effects of XAV9369 are not due to cartilage regeneration. This is not persuasive because chondrocyte regeneration is not synonymous to cartilage regeneration and Lietman does not discourage the use of XAV939 or criticize its utility in treating osteoarthritis. To the contrary , the reference confirms that XAV939 exerts disease-modifying effects, preserves cartilage structure, and improves histological outcomes, which a person of ordinary skill would understand as beneficial and compatible with regenerative intent. As further evidence by Kim, XAV939 functions through tankyrase inhibition, resulting in SOX9 protein increase and restoration of cartilage in vivo. This supports the interpretation that the therapeutic effect observed by Lietman includes regenerative activity and SOX9 modulation. Further, Lietman teaches XAV939 showed regeneration of auricular cartilage. See ‘Introduction’ section of Lietman p. 2. Additionally, the language of Lietman is not a definitive and unequivocal exclusion of regeneration as an outcome as Lietman states “[c]ollectively, the cartilage-sparing effects of XAV-939 and C113 were not likely due to spurring chondrocyte/cartilage regeneration;” Emphasis added. While Lietman may not have recognized and unequivocally concluded and explicitly stated that the regeneration of cartilage is an inherent feature of XAV939 administration to OA patients, Lietman’s teaching of a method of administering the same agent (tankyrase inhibitor) to the same patient population (OA patients) and the Kim’s evidence that XAV939 acts as a tankyrase inhibitor and, therefore, mechanistically induce regeneration of cartilage and the stabilization or increase levels of SOX9, provide that the regeneration of cartilage is an intrinsic feature of XAV939 administration.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRIS E SIMMONS/Examiner, Art Unit 1629
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622