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 .
Election/Restrictions
Applicant’s election without traverse of the invention of Group 1 (methods of treating), and the particular species that are: measuring SKP2 levels (e.g.: relevant to claims 44); the analyte type that is cancer DNA (e.g.: as relavant 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 relevant to claims 46 and 49), in the reply filed on 12/19/2025 is acknowledged.
In 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as applied to claim 44 (i.e.: election of an analyte) as set forth in II on page 4 of the Requirement of 10/21/2025, is withdrawn.
Claims 50-52, 60 and 61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/2025.
Claim Rejections - 35 USC § 112 - Indefiniteness
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.
Claims 42-49 and 53-59 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 42-49 and 53-59 are unclear over recitation of the limitations requiring “the cancer is SKP2 depleted”, as recited in claim 42 from which claims 43-49 and 53-59 depends. With regard to the requirement for SKP2 to be “depleted”, the specification (para 0015 of the PG Pub) teaches:
The term depletion may mean loss or complete loss of the SKP2 gene, mutation of the SKP2 gene and loss of function, or it may mean low gene expression and low protein expression and function, which result from the loss or mutation of the gene or otherwise. All of these depletions are encompassed by the term “depleted”.
The term “depleted” thus encompasses a laminating that is relative in nature (e.g.: low gene expression), but this element is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is, for example, what level of expression would be required or encompassed for that expression to be “low”.
Claims 43, 44, 45, 47, 48, and 49 are unclear over the recitation of limitations as “optionally”, as recited in claims 43, 44, 45, 47, and 48, which render the required and encompassed limitations of the claims unclear.
Claims 47-49 are unclear over the recitation of the limitation “prognosing or assessing the responsiveness of a human cancer patient to treatment with an MDM2 antagonist”, because the recitation of the indefinite article “a” in the phrase “of a human cancer patient” makes it unlcear as to how the limitations of claims 47-49 are intended or required to be related to the steps of claim 42, form which the rejected claims depend. It is unclear if the SKP2 depleted cancer that is treated in claim 42 is required to be the same cancer that is the subject of the analysis of claim 47-49.
Claim 53 is unclear over the limitation “the cancer shows SKP2 loss”, because it is unclear what the “loss” is required to be in relation to. It is further unclear how the “SKP2 loss” is intended to be a further limitation with regard to “SKP2 depleted” as recited in claim 42 from which claim 53 depends.
Claims 54 and 55 are unclear over recitation of the limitation “a second therapeutic agent”, as recited in claim 54 from which claim 55 depends. The limitation is unclear because there is no recitation in claim 54, or in claim 42 from which claim 54 depends, for any “therapeutic agent” or any “first therapeutic agent” such that the agent in claim 54 is clearly “a second therapeutic agent”.
Claim 56 is unclear over recitation of the limitation “the cancer has normal or high SKP2 expression”. The terms “normal” and “high” are relative terms which are not defined in the claims, the specification, or the related art; and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Additionally, where claim 56 depends from claim 42, and claim 42 requires that “the cancer is SKP2 depleted”, it is unclear how the cancer can have normal or high SKP2 expression and still be consonant with the requirements of claim 42.
Claim 57 is unclear over recitation of the limitation “selecting a patient … having normal or high levels of SKP2 within a biological sample obtained from said patient”, for the same reason as addressed in the limitations above in claim 56. Claim 57 is further unclear over recitation of the limitations presented as “the steps of selecting a patient: (a) ….. and (b)” because the limitation recited in (b) is not a step related to “selecting” (i.e.: step (b) is a treatment step of administering a treatment), so the recitation of the plural “steps” in “the steps of selecting a patient” is unclear because there are not a plurality of steps related to selecting a patient.
Claim 59 is unclear over recitation of the limitation “additionally comprising administering another anticancer agent to the patient”, because there is no antecedent basis for any initial “anticancer agent” such that it is clear what is required or encompassed by “another anticancer agent”.
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.
Claim(s) 42-45, 47-48 and 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Totary-Jain et al (2012) in view of Kitagawa et al (2008) (cited on the IDS of 09/26/2023).
Relevant to instantly rejected claim 42, 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 (relevant to claim 53) (e.g.: Figure 6D; p.1837 – Tumor xenografts; p.1839 - Skp2 determines tumor xenograft sensitivity to Rapamycin).
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).
Totary-Jain et al does not teach treatment of a SKP2 depleted cancer in a patient with a therapeutically effective amount of an MDM2 antagonist (relevant to the limitations of claim 42), or treatment of a cancer that is P53 wildtype (relevant to claim 45). However, the use of MDM2 antagonist in the treatment of the cancer phenotype, including in cells that are P53 wildtype, and its association with SKP2 expression was known in the prior art and is taught by Kitagawa et al.
Relevant to the limitations of the claims, 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 treating cells that are depleted of Skp2 by expression of siRNA, 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).
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 treat the patients of Totary-Jain et al (i.e.: subjects with tumors with depleted SKP2) with the MDM2 antagonist (i.e.: Nutlin-3) of Kitagawa et al. The skilled artisan would have been motivated to treat SKP2 depleted tumors in a subject with Nulin-3 based on the expressed teachings of Kitagawa et al that cancer cells with reduced SKP2 have a greater response to Nutlin-3, and that SKP2 is part of a molecular mechanism related to apoptosis in response to therapeutic treatment. The skilled artisan would thus recognize that applying the teachings of Kitagawa et al to the xenograft model of Totary-Jain et al may supply a more comprehensive understanding of how the mechanism operated in a living organism. 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 the MDM2 antagonist Nutlin-3 is provided upon reduced expression of Skp2.
Claim(s) 46, 49, 54 and 59 are rejected under 35 U.S.C. 103 as being unpatentable over Totary-Jain et al (2012) in view of Kitagawa et al (2008) (cited on the IDS of 09/26/2023) as applied to claims 42-45, 47-48 and 53 above, and further in view of Astex et al (WO 2018/178691) (cited on the IDS of 09/25/2023).
Totary-Jain et al in view of Kitagawa et al renders obvious the treatment of SKP2 depleted cancer with an MDM2 antagonist (relevant to claim 42) and detecting SKP2 level in a tumor tissue sample to prognose treatment response to an MDM2 antagonist (relevant to claim 47).
Totary-Jain et al in view of Kitagawa et al does not provide for a 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 consonant with the Election, and recited in claims 46 and 49), or administering additional anticancer agents (relevant to claim 54 and 59).
However, the use of the required reagent as an MDM2 antagonist, and its use in combination with other compounds or agents for the treatment of cancer, was known in the prior art and is taught by Astex et al.
Astex et al provides the required compound (e.g.: p.3) and teaches that it is suitable for use as an MDM2 antagonist in the treatment of cancer (e.g.: p.192) and that the compound may be used in combination with other agents (e.g.: p.14).
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 of Astex et al, as well as the MDM2 antagonist of Astex et al in combination with other agents, in the methods of treatment rendered obvious by Totary-Jain et al in view of Kitagawa et al. The skilled artisan would have been motivated to use the MDM2 antagonist of Astex et al, and the antagonist in combination with other agents, based on the expressed teachings of Astex et al that such compounds have superior potency and in vivo efficacy, and when used in combination with other agents there may be a synergistically beneficial response (e.g.: p.201). Using the compounds of Astex et al in the methods of treatment rendered obvious by Totary-Jain et al in view of Kitagawa et al would have been the simple substitution of one known element for another with predictable results.
Claim(s) 55-58 are rejected under 35 U.S.C. 103 as being unpatentable over Totary-Jain et al (2012) in view of Kitagawa et al (2008) (cited on the IDS of 09/26/2023) and Astex et al (WO 2018/178691) (cited on the IDS of 09/25/2023) as applied to claims 46, 49, 54 and 59 above, and further in view of Xiao et al (2019).
Totary-Jain et al in view of Kitagawa et al and Astex et al renders obvious the treatment of SKP2 depleted cancer with an MDM2 antagonist, and treatment with additional agents. Further relevant to the instantly rejected claims, Kitagawa et al teaches treatment of control siRNA cells (i.e.: cells in which SKP2 is not down-regulated) with Nutlin-3 (e.g.: Fig 1). 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).
Totary-Jain et al in view of Kitagawa et al and Astex et al does not provide for the particular additional agent that is ASTX660 (relevant to claims 55 and 58), or the selection of a subject with normal or high SKP2 levels and administering to the subject an agent that induces sensitivity to an MDM2 antagonist (relevant to claims 56 and 57).
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 with normal or high SKP2 using the methods rendered obvious by Totary-Jain et al in view of Kitagawa et al and Astex et al. 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.
Conclusion
No claim is allowed.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/ Primary Examiner, Art Unit 1683