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 .
Claims 1-2, 4, and 6-7 are currently pending and under examination. Claims 3, 5, and 8-9 are cancelled. Claims 1-2, 4, and 6-7 are amended.
Response to Amendment
The Amendment filed 1/21/26 has been entered. Claims 1-2, 4, and 6-7 are pending.
Applicant’s amendments to the specification and claims 1-2, 4, and 6-7 have overcome the objections and 112(b) rejection previously set forth in the Non-Final Office Action mailed 10/21/25.
The 1/21/26 submission of the certified English translation of foreign priority document CN202010760263.8 is acknowledged. The priority date is determined to be 7/31/20.
Response to Arguments
Applicant’s arguments, see pages 8-11, filed 1/21/26, with respect to the rejections of claims 1-2, 4, and 6-7 under 35 USC 101 and 103 have been fully considered and are found persuasive. Therefore, the rejections documented in the Non-Final mailed 10/21/25 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments are made in this Final Office Action.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification (Table 1) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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.
Claim 6 is 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.
This new 112(b) rejection is necessitated by claim amendments filed 1/21/26.
Claim 6 recites the limitation "the kit" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim. For purposes of compact prosecution, claim 6 will be interpreted as dependent upon 1/21/26 claim 2, which is the first claim to introduce “a [diagnostic] kit”.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2, 4, and 6-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4 Monday, January 7, 2019).
This new 103 rejection is necessitated by claim amendments filed 1/21/26.
Step 1: The claims are directed to the statutory categories of a process.
Step 2A, prong one: The claim recites a judicial exception.
Claim 1 recites a correlation of long non-coding RNA expression and mild cognitive impairment. This phenotype-genotype correlation is a law of nature and natural phenomena (see MPEP 2106.04(b)).
Claims 6-7 recite mathematical formulae (abstract idea judicial exception– mathematical concepts, see MPEP 2106.04(a)(2), subsection I).
Step 2A, prong two: The judicial exception is not integrated into a practical application.
Claims 1-2, 4, and 6-7 recite extra-solution and data-gathering limitations for the judicial exceptions of law of nature/natural phenomena and mathematical formulae. These limitations generate the input data of the judicial exceptions, with no specification of a particular treatment or prophylaxis (see MPEP 2106.04(d)(2)).
Step 2B: The claim does not provide an inventive concept.
MPEP 2106.05(d)):
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. Ltd. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs. Ltd., 818 F.3d at 1377, 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
The claims are directed to well-understood, routine, and conventional activities in the life science arts recited at a high-level of generality. Additionally, plasma lncRNA diagnostic markers are not inventive (see Xiangdong et al. (2018; CN108866182 A; FOR citation 4 in IDS filed on 1/23/23), and Moussaoui et al. (2020; WO 2020/049135 A1; FOR citation 3 in IDS filed on 1/23/23). Using 18S as an internal control is also not inventive (see Penna et al. (2011; NPL citation U in PTO-892 filed 10/21/25; “Selection of Candidate Housekeeping Genes for Normalization in Human Postmortem Brain Samples”; Int. J. Mol. Sci. 2011, 12(9), 5461-5470; https://doi.org/10.3390/ijms12095461).
For the reasons set forth above, claims 1-2, 4, and 6-7 are not directed to patent eligible subject matter.
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.
Claims 1-2, 4, and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Moussaoui et al. (2020; WO 2020/049135 A1; FOR citation 3 in IDS filed on 1/23/23) in view of Penna et al. (2011; NPL citation U in PTO-892 filed 10/21/25; “Selection of Candidate Housekeeping Genes for Normalization in Human Postmortem Brain Samples”; Int. J. Mol. Sci. 2011, 12(9), 5461-5470; https://doi.org/10.3390/ijms12095461).
This new 103 rejection is necessitated by claim amendments filed 1/21/25.
(i) Moussaoui et al. teaches limitations relevant to claims 1-2, 4, and 6-7.
Relevant to claim 1, Moussaoui et al. Abstract teaches “The present invention describes a method for the therapeutic treatment and/or for the diagnosis of a brain disorder including but not limited to cognitive disorders such as mild cognitive impairment, Alzheimer disease, frontotemporal dementia, dementia with Lowy body in a subject at risk of having or developing a brain disorder such as cognitive disorder, using long non-coding RNA (IncRNA).”
Further relevant to claim 1, Moussaoui et al. teaches “This invention relates to a biomarker for brain disorders, such as cognitive disorders, consisting in long non-coding RNAs (IncRNAs) in a peripheral circulating body fluid such as plasma or blood and/or expressed in brain tissue and/or whole blood and representing a therapeutic target for brain disorders, or non-invasive method for diagnosing brain disorders such as cognitive disorders, in particular Alzheimer's disease or for monitoring its development or progression using this biomarker. It further relates to associated kits, methods, protocols and transmittable forms of information for diagnosis purposes and/or for other human medicine applications” (page 1, “Field of the Invention” section).
Further relevant to claim 1, Moussaoui et al. teaches “(a) isolating a biological sample from the subject; (b) detecting a level of expression in a lncRNA signature… in the biological sample from said subject; (c) comparing the level of expression of lncRNA in the sample to a level of expression in a reference, wherein an increased or decreased level of expression in the sample compared to the level in the reference identifies the subject having a cognitive disorder or being at risk of developing a cognitive disorder” (page 14).
Further relevant to claim 1, Moussaoui et al. teaches “In some embodiments, the expression level of lncRNAs may be determined using quantitative PCR. Quantitative, or real-time, PCR is a well known and easily available technology for those skilled in the art and does not need a precise description… The number of template transcript molecules in a sample is determined by recording the amplification cycle in the exponential phase (cycle threshold or Co or CT), at which time the fluorescence signal can be detected above background fluorescence. Thus, the starting number of template transcript molecules is inversely related to CT” (page 27).
Further relevant to claim 1, Moussaoui et al. teaches the lncRNA associated with KCNC2 to be differentially expressed in MCI (page 139, Table 10). The instantly claimed ENST00000549762 is the antisense transcript to KCNC2 (see RNA central excerpt below). Moussaoui et al. teaches “In some embodiments, the lncRNA signature comprises or consist of at least one lncRNA selected from… 2847 lncRNAs listed in Table 10” (page 15).
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These teachings read on claim 1 A method of detecting Mild Cognitive Impairment (MCI) in a subject, the method comprising: isolating a biological sample from the subject; detecting the level of expression of at least one long non-coding RNA (lncRNA) in the biological sample of ENST00000549762… and using… as an internal control gene, wherein the detection of MCI is when a detected amount, ΔCt, is the level of expression less a detected amount.
Relevant to claim 2, Moussaoui et al. teaches “In an aspect, the invention also provides a kit for diagnosing and/or monitoring a brain disorder including but not limited to cognitive disorders such as MCI, AD, FTD, DLB, comprising at least one reagent for the determination of a lncRNA expression profile comprising or consisting of at least one lncRNA” (page 23).
Relevant to claims 4 and 6, Moussaoui et al. teaches “By ‘reagent’ is also meant a reagent which specifically allows the determination of the lncRNA expression profile, i.e. a reagent specifically intended for the specific determination of the expression level of the lncRNA present in the lncRNA expression profile. Examples include e.g. amplification primer pairs (forward and reward) and/or probes specific for the lncRNA present in the lncRNA expression profile” (page 24).
Relevant to claim 7, Moussaoui et al. teaches “lncRNAs were also measured by qPCR using specific primers. For this, total RNA was first extracted, reverse transcription and real time PCR using specific primers were performed” (page 171).
Further relevant to claim 7, Moussaoui et al. teaches “In some embodiments, the expression level of lncRNAs may be determined using quantitative PCR. Quantitative, or real-time, PCR is a well known and easily available technology for those skilled in the art and does not need a precise description… The number of template transcript molecules in a sample is determined by recording the amplification cycle in the exponential phase (cycle threshold or Co or CT), at which time the fluorescence signal can be detected above background fluorescence. Thus, the starting number of template transcript molecules is inversely related to CT” (page 27).
(ii) Moussaoui et al. is silent to specifics regarding using 18S as an internal control gene relevant to claims 1 and 7. However, these limitations were known in the prior art and taught by Penna et al.
Relevant to claims 1 and 7, Penna et al. Table 2 teaches that the 18S ribosomal RNA subunit was used as a reference gene (or internal control gene) within the quantitative real-time RT-PCR assays within Alzheimer’s disease tissues.
(iii) Although Moussaoui et al. in view of Penna et al. is silent to 18S internal controls in RT-qPCR, it would have been prima facie obvious to the skilled artisan. It is noted that Moussaoui et al. and Penna et al. are analogous disclosures to the instant measuring of diagnostic markers.
The skilled artisan would have been motivated to combine the analogous art. Penna et al. Abstract teaches “The most frequently used technique to study the expression profile of genes involved in common neurological disorders is quantitative real-time RT-PCR… Expression analysis by RT-qPCR requires an appropriate normalization to the expression level of genes characterized by a stable, constitutive transcription… The aim of this study is to identify the most stable genes in postmortem human brain samples of patients affected by Alzheimer’s disease (AD) suitable as reference genes. The experiments analyzed 12 commonly used reference genes in brain samples from eight individuals with AD and seven controls.” As discussed above, Penna et al. includes 18S as one of those reference genes.
Thus, the skilled artisan would have been motivated to include the Penna et al. 18S internal control gene within the methodology rendered obvious by Moussaoui et al. The skilled artisan would recognize that the 18S gene is one of the most commonly used reference genes, and would thus be motivated to follow convention and use it as an internal control gene. The skilled artisan would have a reasonable expectation of success based on the disclosures of Moussaoui et al. in view of Penna et al., as discussed in preceding paragraphs.
Conclusion
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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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682