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 .
Status of the Application
The Amendment and Response filed July 3, 2025 is acknowledged.
Claims 1-2, 5-6, 11, 13, 17 and 23-25 were pending. All of the previously pending claims, except for claim 25, are canceled. Claims 25 and new claims 36-44 are currently pending. Claims 25 and 36-39 are being examined on the merits. Claims 40-44 are newly withdrawn.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 3, 2025 has been entered.
Response to Arguments
Applicant’s arguments filed July 3, 2025 have been fully considered.
All of the previously made rejections are WITHDRAWN in view of the instant claim amendments.
Withdrawal of Allowability
The indicated allowability of claim 25 is withdrawn in view of the newly discovered references to Le, Ouyang, Kang and Qin (citations provided below). Rejections based on the newly cited reference(s) follow.
Election/Restrictions
Newly submitted claims 40-44 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: The subject matter of claims 25 and claims 40-44 are directed to related methods. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, the inventions as claimed have a materially different design, mode of operation, function, or effect, in that the claim 25 method is directed to detecting and quantifying miRNA mutations, and the method of claims 40-44 is directed to analysis of mutations in genomic DNA. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants. Thus, the invention of claim 25 is a complete and distinct invention, and applicant has received an action on the merits for the that invention.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 40-44 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
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 25 and 36-39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
In considering whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue,” the factors set forth in In re Wands (858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) should be considered. These factors are:
The breadth of the claims,
The nature of the invention,
The state of the prior art,
The level of one of ordinary skill in the art,
The level of predictability in the art,
The amount of direction provided by the inventor,
The existence of working examples; and
The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Each of these will be discussed in turn below.
Nature of the Invention and the Breadth of the Claims
The invention of instant claim 25 is directed to a method of detecting and quantifying at least one nucleic acid mutation in a skin sample obtained from a subject by non-invasive sampling, where the at least one nucleic acid mutation is an miRNA mutation. Dependent claims 36-37 and 39 further describe the skin sampling technique, while claim 38 further describes the subject from which the sample is collected.
The State of the Prior Art
The prior art teaches that the quantification of mutations in miRNA requires the ability to distinguish between the mutated miRNA and its corresponding non-mutated counterpart. It was not known in the art how to do so prior to the effective filing date of the instant invention. For example …
Le (Innovative microRNA quantification by qPCR, Molecular Therapy Nucleic Acids, 31, 628-630, 2023) teaches that “[a]n effective miRNA quantification method should be capable of differentiating between the miRNA, its precursors, similar miRNAs, and isomiRs” (p. 628, left col., para. 2).
Ouyang (MicroRNA Detection Specificity: Recent Advances and Future Perspective, Anal. Chem., 91, 3179-3186, 2019) teaches that “[f]or small RNA, primer design of PCR is difficult because base pairing may be mismatched during amplification. When designing primers for the cDNA of miRNAs, the short length reduces the PCR efficiency because of low melting temperature, which means that if primer pairing area is consistent but the unpaired area is different, then false positives would occur. In clinical sample detection, it is more challenging and error-prone” (p. 3181, left col., para. 3).
Kang (miPrimer: an empirical-based qPCR primer design method for small noncoding microRNA, RNA, 24(3): 304-312, 2018) teaches that “[b]ecause of miRNAs’ short length, the design of miRNA primers for PCR amplification remains a significant challenge. Adding to the challenge are miRNAs similar in sequence and miRNA family members that often only differ in sequences by 1 nt” (abstract).
Qin (Quantitative analysis of miRNAs using SplintR ligase-mediated ligation of complementary-pairing probes enhanced by RNase H (SPLICER)-qPCR, Molecular Therapy Nucleic Acids, 31: 241-255, 2023) developed a modified qRT-PCR that can distinguish at least some miRNAs with mutations from those without mutations, but it could not successfully detect all miRNA targets (p. 251, left col., para. 2; also see Le: p. 628, right col., para. 2 through p. 629, middle col., para. 1).
Thus, as reported in at least these journal articles published within the last few years, to accurately quantify miRNAs you have to be able to distinguish the target miRNA from related miRNAs, including miRNAs that differ by 1 or a few nucleotides, perhaps due to mutations. Generally, qRT-PCR is used for quantification, but primer and probe design is very challenging because miRNAs are so short. Even now, the latest techniques can distinguish between closely related miRNAs in some cases, but not in others.
Level of One of Ordinary Skill in the Art
One of ordinary skill in the art would have the knowledge equivalent to a graduate-level degree in molecular biology.
Level of Predictability and Amount of Direction Provided by Inventor; Existence of Working Examples
The specification does not provide any working examples directed to quantifying miRNA mutations. As noted above, prior to the effective filing date of the instant invention, the prior art also does not provide any direction as to quantifying miRNA mutations, nor does it even provide direction as to reliable and reproducible methods for distinguishing mutated miRNAs from their non-mutated counterparts in a detection assay. Thus, the predictability in the art is low, and the inventor has not provided any direction as to these steps.
Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure
To make and use the invention of the instant claims, one of ordinary skill in the art would have to determine how to overcome at least the issues discussed above in the cited references. Given the time that has passed since the filing date of the invention, and given that even now these issues have not been resolved, one can conclude that undue experimentation would be required to make and use the recited invention, and that the instantly claimed method was not enabled at the time of filing.
For the above reasons, one of ordinary skill in the art would not be able to make and use the claimed invention without undue experimentation.
Claims 36-39 depend from claim 25, and consequently incorporate the lack of enablement issues of claim 25.
Appropriate correction is required.
Conclusion
Claims 25 and 36-39 are being examined, and are rejected. No claims are allowed.
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/CAROLYN L GREENE/Examiner, Art Unit 1681
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681