DETAILED ACTION
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 response to the communication filed 11-10-25.
Claims 1-6 are pending in the instant application.
Claims 1, 4-6 are withdrawn from further consideration as being drawn to a nonelected species or invention.
Claims 2 and 3 have been examined on their merits as set forth below.
Response to Arguments and Amendments
Withdrawn Rejections
Any rejections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2 and 3 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the in vitro transfection of miR-32533 and miR-32533 inhibitor in APPswe cells, does not reasonably provide enablement for treating Alzheimer's disease or increasing viability or reducing apoptosis in any cell in vivo for the reasons of record set forth in the Office action mailed 8-13-25 and as set forth below.
Applicant’s Arguments
Applicant argues the following:
In response, the applicant has amended subject matter of claim 2 to “a method for increasing viability and reducing apoptosis in Alzheimer's disease model cells”. Correspondingly, claim 3 is amended to “the method according to claim 2, wherein increasing viability and reducing apoptosis in Alzheimer's disease model cells is achieved by one or more selected from the group consisting of I) to IV): I increasing an expression level of ADAM10 in a non-amyloid metabolic pathway of B-amyloid (AB); ID reducing expression levels of BACE1 and PS1 in an amyloid metabolic pathway of the Af; IID) inhibiting generation of the AB; and IV) reducing an expression level of CREBS”. According to the description in Examples 3 and 5, it can be seen that the overexpression of miR- 32533 significantly increases the viability of Alzheimer's disease model cells and reduces apoptosis in Alzheimer's disease model cells; the overexpression of miR-32533 increases an expression level of ADAM10 in a non-amyloid metabolic pathway of B-amyloid (AB) and reduces expression levels of BACE1 and PS1 in an amyloid metabolic pathway of the AB; and the overexpression of miR-32533 inhibits generation of the AB. It is evident that the specification explicitly discloses the subject-matter recited in the amended claims 2 and 3.
Response to Applicant’s Arguments
Applicant's arguments filed 11-10-25 have been fully considered but they are not persuasive. Applicant is correct that increasing viability and reducing apoptosis in Alzheimer's disease model cells (APPswe) have been observed upon overexpression of miR-32533 in vitro. However, in vitro effects are not necessarily representative or correlative of the ability to provide the same effects in target cells in a subject.
As stated previously, the following factors have been considered in determining that the specification does not enable the skilled artisan to make and/or use the invention over the broad scope claimed.
The breadth of the claims:
The claims are drawn to methods of increasing viability and reducing apoptosis in Alzheimer’s disease model cells comprising administering the biomarker miR-32533 to a subject in need, which biomarker has SEQ ID No. 1, which increasing viability and reducing apoptosis is achieved by one or more functions selected from the group consisting of increasing an expression level of ADAM10 in a non-amyloid metabolic pathway of B-amyloid (Aβ), reducing expression levels of BACE1 and PS1 in an amyloid metabolic pathway of the Aβ, inhibiting generation of the Aβ, and reducing an expression level of CREB5.
The teachings in the specification:
As stated previously, the instant specification teaches the following in vitro results:
[0033] FIG. | is a heat map showing the expression level of miR-32533 in the cerebral cortex of APP/PS1 mice and WT wild-type control mice detected by RNA high-throughput sequencing.
[0034] FIG. 2 shows the expression level of miR-32533 detected by RT-PCR in APP/PS1 mice and WT wild-type control mice.
[0035] FIG. 3 shows the results of the ROC curve analysis of the diagnostic predictive value of miR-32533 in APP/PS1 mice.
[0036] FIG. 4 shows the expression level of miR-32533 detected by RT-PCR in 5xFAD mice.
[0037] FIG. 5 shows the expression level of miR-32533 in APPswe cells at different time points after copper ion treatment detected by RT-PCR.
[0038] FIG. 6 is the results of MTS assay showing the effect of miR-32533 on the cell viability of APPswe cells induced by copper ions.
[0039] FIG. 7 shows the quantitative results of the miR-32533 on copper ion-induced APPswe cell apoptosis detected by flow cytometry.
[0040] FIG. 8 shows representative images of flow cytometry analysis of the effect of the miR-32533 on copper ion-induced APPswe cell apoptosis.
[0041] FIG. 9 shows representative Western blotting images of ADAM10, BACE1, PS1, APP, Afi-42, and Bax in APPswe cells after transfection
with miR-32533, miR-32533 inhibitor, and negative sequence control (NC/NCI).
[0042] FIG. 10 shows the representative protein relative expression levels of ADAM 10, BACE1, PS1, APP, ABi-42, and Bax in APPswe cells after transfection with miR-32533, miR- 32533 inhibitor, and negative sequence control (NC/NCD).
[0043] FIG. 11 shows the expression level changes of miR-32533 in the plasma of AD patients and age-matched healthy adult volunteers (HAV) (n=10, HAV; n=11, AD patients).
[0044] FIG. 12 shows the correlation between the expression level of miR-32533 and MMSE score.
[0045] FIG. 13 shows the ROC curve analysis for the diagnostic predictive value of miR- 32533 in AD patients and HAV controls.
[0046] FIG. 14 shows the expression levels of CREBS in the cortex of APP/PS1 mice at 1, 3, 6, and 9 months of age detected by RT-PCR.
[0047] FIG. 15 shows the expression level of CREBS5 in the cortex of 5xFAD mice detected by RT-PCR.
[0048] FIG. 16 shows the correlation between the miR-32533 and CREBS expression level in the cerebral cortex of APP/PS1 mice.
[0049] FIG. 17 shows the expression of CREB5 mRNA in APPswe cells after transfection with miR-32533 mimics and miR-32533 inhibitor.
[0050] FIG. 18 shows representative images of the effect of miR-32533 overexpression and miR-32533 silencing on CREBS protein expression level in APPswe cells.
[0051] FIG. 19 shows quantitative results of CREB5 protein expression level in APPswe cells with miR-32533 overexpression and miR-32533 silencing.
[0052] FIG. 20 shows a schematic diagram of the construction of the dual luciferase reporter gene plasmids with wild-type pmirGLO-CREBS5-3'UTR-WT and mutant pmirGLO-CREB5-3'UTR-MUT.
[0053] FIG. 21 shows the effect of co-transfection of the miR-32533 (or negative sequence control NC) and pmirGLO-CREB5-3'UTR-WT (or pmirGLO-CREB5-3'UTR-MUT) on a luciferase activity of HEK293 cells detected by dual luciferase reporter gene assay.
The teachings in the instant specification, of the in vitro effects of transfection of miR-32533 and miR-32533 inhibitor in APPswe cells, are not representative or correlative of the ability to treat Alzheimer’s disease or provide the same effects in a subject that are observed in target cells in vitro. Since the specification fails to provide the guidance for providing treatment in a subject, and since determination of the factors required for treating Alzheimer’s is highly unpredictable, whereby treatment is provided in a subject, it would require undue experimentation to practice the invention over the full scope claimed.
For these and the aforementioned reasons, the instant rejection is properly maintained.
Allowable Subject Matter
SEQ ID No. 1 appears free of the prior art searched and of record.
Conclusion
THIS ACTION IS MADE FINAL. 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.
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
11-25-25
/JANE J ZARA/Primary Examiner, Art Unit 1637