otice 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 .
This Office Action is in reply to Applicants’ correspondence of 07/16/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 12/19/2025 Applicants elected, without traverse, the invention of Group 1 (methods of treating), and the particular species that are: measuring SKP2 levels (e.g.: relevant to claim 43); the analyte type that is cancer DNA (e.g.: as relevant to claim 44); and the particular MDM2 antagonist that is (2S,3S)-3-(4-chlorophenyl)-3- [(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1 S)-1-hydroxy- 1-(oxan-4-yl)propyl]-1- methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid or a tautomer, pharmaceutically acceptable salt or solvate thereof.
As noted on page 2 of the Office Action of 03/16/2026, light of the Examiner’s search and analysis of the elected elements, the species election requirement as applied to claim 44 (i.e.: election of an analyte) as set forth in II on page 4 of the Requirement of 10/21/2025,was withdrawn.
Claims 50-52, 60 and 61 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as set forth on page 2 of the Office Action of 03/16/2026. Election was made without traverse in the reply filed on 12/19/2025.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejections of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on pages 3-5 of the Office Action of 03/16/2026, are withdrawn in light of the amendments to the claims.
New Claim Rejections - 35 USC § 112 – Indefiniteness
Necessitated by Claim Amendments
Claims 47, 48, 57 and 58 are 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.
Claims 47 and 48 are unclear over recitation of the limitation “based on the biomarker profile”, as recited in claim 47 from which claim 48 depends, because there is no antecedent basis for any “biomarker”, any “profile”, or any “biomarker profile”.
Claims 57 and 58 are unclear over recitation of the limitation “the agent to lower the levels of SKP2” because there is no antecedent basis for any “agent to lower the levels of SKP2”.
Withdrawn Claim Rejections - 35 USC § 103
The rejections of claims under 35 U.S.C. 103, as set forth on pages 5-11 of the Office Action of 03/16/2026, are withdrawn in light of the amendments to the claims.
New Claim Rejections - 35 USC § 103
Necessitated by Claim Amendments
Claim(s) 42-45, 47-48, 54, 56, 57 and 59 is/are rejected under 35 U.S.C. 103 as being unpatentable over Astex et al (WO 2018/178691) (cited on the IDS of 09/25/2023) in view of Totary-Jain et al (2012) and Kitagawa et al (2008) (cited on the IDS of 09/26/2023) including the Supplemental Data.
Relevant to the treatment steps of the rejected claims, Astex et al teaches a MDM2 antagonist with anticancer activity (e.g.: p.192) that is (2S,3S)-3-(4-chlorophenyl)-3- [(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1 S)-1-hydroxy- 1-(oxan-4-yl)propyl]-1- methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid or a tautomer, pharmaceutically acceptable salt or solvate thereof (e.g.: p.3). Astex et al teaches that the MDM2 antagonist can be administered at a dose of 2 to 800 mg daily (e.g.: p.200) (relevant to claim 42 and 56) for the treatment of human subjects (e.g.: p.199) (relevant to claim 47). Astex et al further teaches that the MDM2 antagonist may be used in combination with other agents (e.g.: p.14-15) including anticancer agents (e.g. p.201) (relevant to claims 54 and 59). Astex et al exemplifies the treatment of p53 wildtype cancer (e.g.: p.191; p.259), and teaches that treatment with the MDM2 inhibitor leads to apoptosis (e.g.: p.184) (relevant to claim 45). Further relevant to the instantly rejected claims, Astex et al suggests that circulating biomarkers may be used to identify patients suitable for treatment with the MDM2 antagonist (e.g.: p.191).
Astex et al does not specifically teach the consideration or analysis of SKP2 levels in a subject that is treated, or the administration of agents that lower the level of SKP2. However, the association between detected SKP2 levels and response to cancer treatment, including treatment with an MDM2 antagonist, as well as the modulation of SKP2 levels using agents that reduce the amount of SKP2, were known in the prior art and taught by Totary-Jain et al and Kitagawa et al.
Totary-Jain et al teaches methods of treating cancer in a patient, comprising administering a therapeutically effective amount of a compound, where the cancer is SKP2 depleted, and teaches that SKP2 level in a responder sample is lower than the level in a sample with less of a response (e.g.: Figure 6D; p.1837 – Tumor xenografts; p.1839 - Skp2 determines tumor xenograft sensitivity to Rapamycin) (relevant to the limitations of claims 42, 47 and 56).
Relevant to claim 43, 44 and 48, Totary-Jain et al teaches that SKP2 depletion can be detected by determination of SKP2 levels directly using protein detection.
Relevant to limitations of claims 47 and 48, Totary-Jain et al teaches that RNA interference (RNAi)–mediated silencing of Skp2 in human tumor cells increased their sensitivity to rapamycin (e.g.: - Abstract), and that Skp2 levels could serve as a marker for predicting the response of tumors to anti-cancer compounds that require the presence of the SKP2 protein for their therapeutic activity (e.g.: p,1842 – left col). Relevnat to claims 56 and 57, the vector expression Skp2-shRNA is an agent that lowers the level of SKP2 in a cell.
Kitagawa et al teaches treatment of a SKP2 depleted cancer in a patient with a therapeutically effective amount of an MDM2 antagonist. Kitagawa et al teaches treating HCT116 (human colon cancer cells which are wild type for P53) with Nutlin-3, a selective small-molecule antagonist of Mdm2 (e.g.: p.217 – right col; Fig. 1). Kitagawa et al teaches depleting cells of Skp2 by expression of siRNA, and treating cells that are depleted of Skp2, and demonstrates a greater response as measured by apoptosis when Nutlin-3 is administered to cells with reduced expression of Skp2 (e.g.: Fig 1E). Furthermore, Kitagawa et al teaches that overexpression of Skp2 suppresses Nutlin-3 induced apoptosis (e.g.: Fig S2).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used the MDM2 antagonist in the treatment of cancer in a subject, as taught by Astex et al, to treat a cancer that is SKP2 depleted, as taught by both Totary-Jain et al and Kitagawa et al. The skilled artisan would have been motivated to treat a cancer with depleted SKP2 based on the expressed teachings of Astex et al that circulating biomarkers may also be used to identify patients suitable for treatment with the MDM2 antagonist (e.g.: p.191), and that the MDM2 antagonist inhibits the interaction of p53 with MDM2 leading p53 activation, cell proliferative arrest and apoptosis (e.g.: p.184), and the expressed teachings of Kitagawa et al that Skp2 is an important factor controlling p53-dependent signaling pathways, and that Skp2 suppresses p53-dependent apoptosis. Thus detecting a level of Skp2 in a subject would provide an indication of the likelihood of response to treatment with the MDM2 antagonist of Astex et al, where a higher level of Skp2 would be indicative of a suppressed response to treatment, and a depleted level of Skp2 would be indicate of a comparatively enhanced response to treatment. The prior art teaches that SKP2 is part of a molecular mechanism related to P53-dependent apoptosis in response to therapeutic treatment with an MDM2 antagonist. With regard to the limitations of claim 47 (i.e.: prognosing response to treatment with an assessment of SKP2 in a sample from the patient), such a method would have been obvious to the skilled artisan based on the expressed teachings of Totary-Jain et al which provide that malignant tumors may have different levels of Skp2 expression (p.1836 – left col), and that Skp2 expression levels could serve as a marker for predicting the response of tumors to therapeutic treatments which target the molecular mechanism related to Skp2 expression (e.g.: p.1842 – left col), and the expressed teachings of Kitagawa et al that a further induction of apoptosis by an MDM2 antagonist is provided upon reduced expression of Skp2. With regard to the claims as they include administering an agent to lower the level of SKP2 in a treated subject (e.g.: claims 56 and 57) both Totary-Jain et al teaches the modulation of SKP2 levels using shRNA, and Kitagawa et al teaches the modulation of SKP2 levels using siRNA, thus providing for the application of an agent to lower the level of SKP2. Where the prior art teaches that a depleted level of Skp2 provides an enhanced response to treatment with an MDM2 antagonist, the skilled artisan would be motivated to treat a subject, such as a subject with a normal or high level of SKP2, with an agent, such as shRNA or siRNA, to lower the level of SKP2 to achieve the enhanced response to treatment.
Claim(s) 55 and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Astex et al (WO 2018/178691) (cited on the IDS of 09/25/2023) in view of Totary-Jain et al (2012) in view of Kitagawa et al (2008) (cited on the IDS of 09/26/2023) including the Supplemental Data as applied to claims 42-45, 47-48, 54, 56, 57 and 59 above, and further in view of Xiao et al (2019).
Astex et al in view of Totary-Jain et al and Kitagawa et al including the Supplemental Data renders obvious methods of treating cancer in a subject using the MDM2 antagonist treatments of the claims, including the administration of additional therapeutic agents and additional agents to lower the level of SKP2. Further relevant to the instantly rejected claims, Astex et al teaches that the additional agent may be an IAP (inhibitor of apoptosis proteins) antagonist (e.g.: p.205).
Astex et al in view of Totary-Jain et al and Kitagawa et al including the Supplemental Data does not provide for the particular additional agent that is ASTX660 (relevant to claims 55 and 58).
However, the use of ASTX660 to sensitize cancer cells to treatment, and the effect of ASTX660 in lowering levels of MDM2, were known in the prior art and are taught by Xiao et al.
Xiao et al teaches that ASTX660 is an antagonist targeting IAP (e.g.: 6464 left col.) and teaches that administration of ASTX660 decreases the TP53-negative regulator MDM2 and sensitizes cancer cells to treatment with therapeutics that target the apoptosis mechanism that includes MDM2 (e.g.: p.6468 - ASTX660 sensitization of HPV+ tumor cells to TNFα through TP53; Fig 4A).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used ASTX660 as an additional agent in the treatment of cancer in a subject, for example a subject with normal or high SKP2, using the methods rendered obvious by Astex et al in view of Totary-Jain et al and Kitagawa et al including the Supplemental Data. The skilled artisan would have been motivated to use ASTX660 in combination with the MDM2 antagonist based on the expressed teachings of Astex et al that the MDM2 antagonist can be used in combination with an IAP antagonist, and the expressed teachings of Xiao et al teaches that ASTX660 is an antagonist targeting IAP. The skilled artisan would be motivated to apply the combined treatment (i.e.: ASTX660 and the MDM2 antagonist) to a subject with high or normal SKP2 based on the expressed teachings of Xiao et al teaches that ASTX660 reduces MDM2; the skilled artisan would recognize that reduction of MDM2 by a secondary means (i.e.: administration of ASTX660) may improve the results of the MDM2 antagonist by addressing the same mechanistic pathway in a subject that is not expected to have superior results (i.e.: a subject without decreased SKP2, as taught by Kitagawa et al) to the treatment with MDM2 antagonist.
Response to Remarks
Applicants have traversed the rejection of claims made under 35 USC 103. The arguments (p.12-15 of the Remarks of 07/16/2026) have been fully considered but are not persuasive to withdraw the rejections as set forth above. A new rejection, as necessitated by claim amendments, is set forth above; in so far as Applicants’ arguments are germane to the new rejection, the arguments are addressed here.
Initially it is noted that Applicants’ traversal provides a piecemeal analysis of the individual references, and does not take into consideration the combination of the teachings of the references as applied to the limitations of rejected claims.
Applicants first address the teachings of Totary-Jain et al, and assert that the teachings of the reference are limited to the use of SKP2 as a biomarker for rapamycin and other inhibitors of the PI3K/mTOR pathway. This argument is not persuasive because Totary-Jain et al, is cited for the general use of SKP2 as a biomarker for the predication of response to treatment. While Totary-Jain et al exemplifies a particular treatment, the reference is clear that malignant tumors may have different levels of Skp2 expression (p.1836 – left col), and that Skp2 expression levels could serve as a marker for predicting the response of tumors to therapeutic treatments which target the molecular mechanism related to Skp2 expression (e.g.: p.1842 – left col).
Applicants next address the asserted shortcomings of Kitagawa et al as applied to the rejection of the instantly claimed methods. Applicants initially assert that the reference does not teach treating a patient having a naturally occurring biomarker defined cancer. This argument is not persuasive. Here it is noted that Totary-Jain et al is cited in the rejection for the teaching that tumors may have different levels of Skp2 expression. Applicants next argue that Kitagawa fails to teach: identifying an MDM2-antagonist non-responsive subject or a cancer sample from such a subject; establishing a SKP2 reference level; or selecting a cancer based on depletion relative to that reference level. These arguments are not persuasive. Kitagawa et al expressly teaches that Skp2 is an important factor controlling p53-dependent signaling pathways, provides experimental results demonstrating that Skp2 suppresses p53-dependent apoptosis, supporting the conclusion stated in the reference that SKP2 is part of a molecular mechanism related to P53-dependent apoptosis in response to therapeutic treatment with an MDM2 antagonist.
Where Applicants argue that Kitagawa et al fails to teach: the specifically recited MDM2 antagonist; or provide any oral treatment regimen, this argument is not persuasive because these aspects of the claims are clearly provided by Astex et al, as set forth in the rejections. Furthermore, as noted in the rejection, Astex et al clearly suggests the use of biomarker to identify subjects that may be suitable for treatment.
Applicants’ argument that “Kitagawa' s comparison of siRNA-treated and control cells is not the comparator required” by the claims is not persuasive. Kitagawa et al clearly teaches the detection of different levels of SKP2 in samples, and the associated levels of responsiveness (i.e.: higher SKP2 in less responsive samples; lower SKP2 in more responsive samples).
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Huang et al (2017) teaches that treatment with C25 (a SKP2 inhibitor) sensitizes cancer cells to treatments comprising an MDM2 antagonist.
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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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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