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 .
This Office Action is in reply to Applicants’ correspondence of 11/20/2025.
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 Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.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.
Declaration of Eran Hornstein made under 37 CFR 1.132
The Declaration of Eran Hornstein, made under 37 CFR 1.132 filed 11/20/2025 is sufficient to overcome the rejection of claims made under 35 USC 112(a) (i.e.: enablement of the claimed methods), as set forth in the previous Office Action of 07/22/2025.
Election/Restrictions
Withdrawal of Amended/Newly Presented Claims
In the reply filed on 06/03/2025 Applicants elected the invention of Group I (claims directed to methods comprising treatment), and the species that are the particular micro RNA that is hsa-miR-361-5p, with the additional particular micro RNA that is hsa-miR-423-5p. The election has been treated as an election without traverse (MPEP § 818.01(a)), as set forth on page 2 of the Office Action of 07/22/2025.
In light of the amendments to the claims, claim 4 and 16 (specifically requiring non-elected miRNA combinations) is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/03/2025.
Information Disclosure Statement
The listing of references in the specification (see pages 27-29 of the specification, as well as within the text of the specification such as p.19 ln.33 – p.20 ln.23) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness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 3-4 of the Office Action of 07/22/2025, as withdrawn in light of the amendments to the claims.
Here it is noted that the claims recite (i.e.: step (i)(c) of claim 1) a step of “diagnosing the subject as having FTD when said levels of said miRs are higher than that in said control sample”. While the limitation includes the term “when”, the limitation is recited as part of step (i) of claim 1, which is a step of “diagnosing the subject as having FTD by a method …”, and the method is recited as (as stated in the preamble of claim 1) “a method of diagnosing and treating Frontotemporal dementia (FTD)”. As such the claims are directed to methods where the recited higher level of miR-361-5p and miR-423-5p are present and detected in the sample of the subject.
Withdrawn Claim Rejections – Improper Markush Group
The rejection of claims for including an improper Markush grouping of alternatives, as set forth on pages 4-6 of the Office Action of 07/22/2025, is withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112 – Failure to properly limit
The rejection of claims under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as set forth on pages 6-7 of the Office Action of 07/22/2025, is withdrawn in light of the amendments to the claims.
Withdrawn Claim Rejections - 35 USC § 112 - Enablement
The rejection of claims under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as set forth on pages 7-11 of the Office Action of 07/22/2025, is withdrawn in light of the amendments to the claims and in view of the Declaration of Eran Hornstein, made under 37 CFR 1.132 filed 11/20/2025. The Declaration provides evidence that detection of the combination of miR-361-5p and miR-423-5p provides for distinguishing FTD subjects from healthy controls.
New Claim Rejections - 35 USC § 103
Necessitated by Claim Amendments
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) 1, 6, 9, 12, 13, 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Grasso et al (2019) including the Supplementary data, in view of Kimura et al (2010).
Relevant to the methods of the rejected claims, Grasso et al teaches the analysis of miRNA levels that may discriminate between FTD patients and healthy controls (HCs). Grasso teaches obtaining plasma samples (e.g.: p.e2 - 2.2. - RNA isolation from plasma) (relevant to claim 6) and detecting levels of miRNA species in the samples from FTD patients and healthy controls (e.g.: p.e2 - 2.1. - Subject recruitment and assessment) using RT-PCR (e.g.: p.e2 - 2.3. MicroRNA reverse transcription and quantitative real-time PCR (qPCR)) (relevant to claim 9). Grasso et al teaches that specific biomarkers that can help in diagnosing early FTD, teaches that combinations of biomarkers may have improved sensitivity and specificity (e.g.: .: p.e2 - 2.4. Statistical analysis; Fig 4), and teaches that both hsa-miR-423-5p and hsa-miR-361-5p are expressed at higher levels in the plasma of FTD subjects as compared to the plasma of healthy controls (e.g.: Table A.1, where the cycle threshold average in FTD is lower as compared to the cycle threshold average in HC in each case).
Grasso et al does not teach methods that include treating a subject with a drug that ameliorates symptoms associated with FTD. However, such treatments were known in the prior art and are taught by Kimura et al.
Kimura et al teaches that Yokukansan is a drug used in Kampo, traditional Japanese herbal medicine, and has been used to treat behavioral and psychological symptoms of dementia. Kimura et al teaches methods that include treating with a dose of 7.5 g/day Yokukansan. The reference teaches Yokukansan can alleviate the behavioral symptoms of frontotemporal dementia (Table 1).
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 diagnosed a subject with FTD when the levels of hsa-miR-423-5p and hsa-miR-361-5p are higher in a plasma sample of a subjects as compared to the level in a healthy control. The skilled artisan would have been motivated to diagnose FTD based on the expression levels of miRNA based on the expressed teachings of Grasso et al that clinical diagnostic evaluation of FTD is difficult because of the overlap of the clinical manifestation with other types of dementia, and that miRNAs may offer simple, noninvasive, cost-efficient, and specific biomarkers to help in diagnose early FTD. The skilled artisan would have a reasonable expectation of success in diagnosing FTD in a subject with increased levels of hsa-miR-423-5p and hsa-miR-361-5p in a plasma sample based on the expressed teachings of Grasso et al that these particular miRNAs are found at increased levels in FTD subject as compared to controls. The skilled artisan would be motivated to provide a drug treatment to a subject diagnosed with FTD based on the expressed teachings of Kimura et al that Yokukansan treatment decreased the NPI score in 18 (90.0%) of20 patients and overall significantly decreased the NPI (Neuropsychiatric Inventory score and SRI (Stereotypy Rating Inventory) scores of treated FTD subject.
With regard to the instant rejection of claims 12-14, Grasso et al teaches that different miRNAs are associated with FTD with different levels of sensitivity and specificity, and that different miRNAs can be combined with provide improved sensitivity and specificity in the discrimination between FTD subjects and healthy controls (p.e.3 – 3.3 Validation study). The Grasso et al recognizes the selection of different miRNAs as a results effective variable. Thus, in regard to the limitations of the claims, where the increased expression of hsa-miR-423-5p and hsa-miR-361-5p in FTD is provided in the cited prior art, and the selection of different miRNAs is recognized as a results-effective variable, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the methods suggested by the prior art. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. It would have been prima facie obvious to one of ordinary skill in the art before the effective date of the methods of the instantly rejected claims to detect a number of miRNAs that provide a desired sensitivity or specific of discrimination, such as 100 or less miRNAs, 50 or less miRNAs, or 30 or less miRNAs, in the samples of the methods rendered obvious by Grasso et al to provide a diagnosis of FTD with a desired level of sensitivity or specificity.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Grasso et al (2019) including the Supplementary data, in view of Kimura et al (2010) as applied to claims 1, 6, 9, 12, 13, 14 above, and further in view of Coene-Stass et al (2018).
Grasso et al in view of Kimura et al renders obvious the methods of claim 1, including the detection of increased amounts of hsa-miR-423-5p and hsa-miR-361-5p in a plasma sample, diagnosis of FTD, and treatment with a drug to alleviate FTD symptoms.
Grasso et al in view of Kimura et al does not provide for detecting miRNA levels using NGS.
However, NGS methods to detect miRNA were known in the prior art and are taught by Coenen-Stass et al (e.g.: Figure 1).
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 NGS-based methods of miRNA detection, as taught by Coenen-Stass et al, in the methods of FTD diagnosis by miRNA detection as rendered obvious by Grasso et al in view of Kimura et al. The skilled artisan would have been motivated to use NGS-based methods based on the expressed teachings of Coenen-Stass et al that such methods provide for sensitive and accurate miRNA quantification with a convenient workflow with potential for automation.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683