DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 30, 2026 has been entered. Applicant’s 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 Any rejections or objections not reiterated herein have been withdrawn.
Applicants election of miR-5100 (SEQ ID NO: 87) and miR-1228-5p (SEQ ID NO: 110) is reiterated for the record.
Claims 1-10, 19-24, and 26-30 are currently pending.
Claims 1-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on July 24, 2025.
Claim Rejections - 35 USC § 101
3. 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 19-24, and 26-30 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).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The claims recite abstract ideas. The claims recite the following limitations:
-determining that the measured expression level of miR-5100 in the sample from the subject is decreased in comparison to the expression level of miR-5100 in control blood, serum or plasma samples (clm 19)
-determining that the human subject has hippocampal atrophy (clm 19)
-stratifying the subject for dementia type based on pathological findings and initiating a medical intervention in accordance with the symptoms of the subject.
-wherein the expression level of miR-5100 is further used to evaluate therapeutic sensitivity of hippocampal atrophy or to screen for a candidate substance useful in the prevention, amelioration, or treatment of hippocampal atrophy.
- using the expression level of miR- 5100 to evaluate or diagnose the presence or absence of amelioration of hippocampal atrophy in a subject administered a therapeutic drug selected from the group consisting of donepezil, memantine, galantamine, rivastigmine, and combinations thereof.
The broadest reasonable interpretation of these steps is that they fall within the mental process groupings of abstract ideas because they cover concepts performed in the human mind, including observation, evaluation, judgment, and opinion.
For example, one may “determine” that the measured expression level is decreased in comparison to a control by thinking about the level of miRNA-5100 that was detected in the sample and the control level of miRNA-5100.
One may “determine” a subject has hippocampal atrophy by thinking about the results of the comparison.
One may “stratify” a subject for dementia type by thinking about the pathological findings and “initiate” a medical intervention by verbally giving instructions to the subject.
One may “evaluate” therapeutic sensitivity of hippocampal atrophy by thinking about the level miR-5100 and “screen” for a candidate substance by reading a list of substances known to modulate the level of miR-5100.
Finally, one may “evaluate or diagnose” the presence or absence of amelioration o hippocampal atrophy by thinking about the level of miRNA-5100 that was detected in the sample.
The instant claims recite a law of nature. Thus the claims recite a correlation between miR-5100 and hippocampal atrophy. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
The claims recite a final step of administering to the subject, upon being classified as having hippocampal atrophy in step (c), a therapeutic drug selected from the group consisting of donepezil, memantine, galantamine, rivastigmine, and combinations thereof, for the treatment or amelioration of hippocampal atrophy or a disease accompanied thereby, OR performing a further diagnostic procedure on the human subject determined to have the hippocampal atrophy in step (c), wherein the diagnostic procedure is an imaging test selected from the group consisting of MRI, CT, SPECT, PET, MIBG myocardial scintigraphy, and neuropsychological examination or test of MMSE. It is noted that a claim limitation can integrate a judicial exception by applying or using the judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. In the instant case the claims recite particular drugs for treating hippocampal atrophy, or a disease accompanied thereby. However the administering step is not a required step. In view of the recitation of the word “or” the claims encompass performing further diagnostic procedures instead of the “administering”. The further diagnostic procedures do not provide integration because they merely recite additional data gathering steps.
In addition to the judicial exceptions the claims require measuring, by a hybridization technique, the expression level of miRNA using a probe complementary to the miRNA. The claims optionally require performing a further diagnostic procedure. These steps do NOT integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims require measuring, by a hybridization technique, the expression level of miRNA using a probe complementary to the miRNA. The claims optionally require performing a further diagnostic procedure. These steps do NOT amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art to the judicial exceptions.
The steps are recited at a high level of generality. Obtaining a sample in order to perform tests is well understood, routine, and conventional activity for those in the field of diagnostics. Measuring, by a hybridization technique an expression level merely instructs a scientist to use any nucleic acid hybridization technique. The recitation that measuring, uses a probe complementary to the target miRNA is general and non-specific and would encompass a large genus of probes having any level of complementarity to the target miRNA. The claim does not require the use of any particular non-conventional reagents. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities engaged in by scientists prior to applicants invention and at the time the application was filed.
Additionally the teachings in the specification demonstrate the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available. For example the specification teaches the following:
[1243] For example, various hybridization techniques can be used for measuring the expression levels in the present invention. Examples of hybridization techniques include, but are not limited to, Northern blot (Northern hybridization), Southern blot (Southern hybridization), nucleic acid array methods such as DNA chip analysis, and in situ hybridization. PCR such as quantitative RT-PCR, nucleic acid amplification techniques such as LAMP, or next-generation sequencing can be used in combination with the hybridization technique or as an alternative thereto.
[1246] The nucleic acid array methods use, for example, an nucleic acid array in which the nucleic acid(s) for detection of hippocampal atrophy of the present invention, such as nucleic acid probe(s) (single-stranded or double-stranded probe(s)) in the kit or device of the present invention are immobilized on a solid phase (substrate). Regions of the array on which the nucleic acid probe(s) are immobilized are referred to as “probe spots”, and regions on which no nucleic acid probe(s) are immobilized are referred to as “blank spots”. An array in which a set of nucleic acids are immobilized on a solid-phase (substrate) is generally called a nucleic acid chip (a DNA chip or an RNA chip), a nucleic acid array (a DNA array or an RNA array), a microarray (a DNA microarray or an RNA microarray), or the like. In the context of the present invention, the term “nucleic acid array” includes all of such chips and arrays. The DNA or RNA array includes a DNA or RNA microarray and a DNA or RNA microarray. The nucleic acid array methods can use, for example, but not limited to, 3D-Gene® Human miRNA Oligo chip (Toray Industries, Inc., Japan) as a DNA chip.
[1253] When using quantitative RT-PCR, a commercially available kit for measurement specially designed for quantitatively measuring miRNA, such as TaqMan® MicroRNA Assays (Life Technologies Corp.), LNA®-based MicroRNA PCR (Exiqon), or Ncode® miRNA qRT-PCT kit (Invitrogen Corp.), may be used.
[0004] The results of examination of an extent of atrophy in the hippocampal region are considered as one aspect of information for diagnosis of Alzheimer’s disease (N: Neurodegeneration). An example of a common method for examining the hippocampus is diagnostic imaging by brain MRI or the like.
[1364] The use of nucleic acids capable of specifically binding to the hippocampal atrophy markers of the present invention enables objective and quantitative detection of hippocampal atrophy in a simple manner without differences caused among physicians or medical institutions. For example, the measured expression levels of from one to several miRNAs in the blood, serum, and/or plasma sample from a subject, which can be obtained in a less invasive manner, may be used as an indicator to determine an extent of hippocampal atrophy of the subject in a simple manner. With the use of the kit, the device, and the method of the present invention, in addition, hippocampal atrophy can be detected less invasively and more easily, compared with conventional methods for detection of hippocampal atrophy, such as brain MRI imaging or brain PET imaging examination.
Further it is noted that 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.
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);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. 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);
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);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
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)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Response To Arguments
4. In the response the Applicants traversed the rejection under 35 USC 101. Regarding Step 2A, Prong 2, the Applicants argue that any recited judicial exceptions are integrated into a practical application. The Applicants argue that the claims as amended require actively responding to the classification by administering a therapeutic drug, such as donepezil, memantine, galantamine, rivastigmine, or combinations thereof, for the treatment or amelioration of hippocampal atrophy or a related disease, or by performing a defined clinical diagnostic procedure. They argue that administering a therapeutic agent based on the claimed classification constitutes a method of treatment, which is a recognized category of patent-eligible subject matter. They argue that even the alternative pathway of performing a diagnostic procedure is not a generic instruction to gather additional data. That step is expressly conditioned on the prior classification and is limited to specific clinically recognized procedures.
This argument has been fully considered. The claims as amended require doing one of two things (i) administering the specifically recited therapeutic drugs OR (ii) performing a further diagnostic procedure. If option (i) were required, it would be sufficient to provide integration of the judicial exceptions into a practical application. On the other hand, option (ii) is a mere data gathering step. The fact that specific diagnostic procedures are recited does not change the fact that this is extra solution activity. The step of performing further diagnostic procedures is insufficient to provide integration. Since the administering step is not required it is maintained that the claims fail to integrate the judicial exceptions into a practical application.
The Applicants argue that the specification further confirms that the claimed method provides concrete clinical benefits. As described, for example, in paragraph [0719], the method enables early detection of hippocampal atrophy, supports earlier diagnosis of dementia and related conditions, and facilitates timely medical intervention to suppress disease progression.
These benefits are not abstract or theoretical. The claimed method employs a defined biomarker framework to produce a clinically actionable classification, which in turn directly guides therapeutic intervention or targeted diagnostic follow-up. In this way, the claimed invention is directed to the treatment and management of a medical condition and reflects a practical application of any alleged exception, rather than a disembodied natural law or mental process.
This argument has been fully considered. In the instant case, the Applicants have identified a new natural phenomena, the relationship between miR-5100 and hippocampal atrophy, and applied routine and conventional technologies to perform data gathering steps required for application of the JE. While Applicants may have made a useful discovery of the natural correlation, there is no integration of the judicial exception into a system or process resulting in the improvement of the relevant technology. Rather, routine and conventional technologies to perform necessary data gathering for the general application of the judicial exceptions have been applied. The only “improvement” that appears to have been made is the discovery of the judicial exception itself, which the MPEP makes clear cannot be the basis of an eligible inventive concept.
Regarding Step 2B the Applicants argue that the claims provide an inventive concept. They argue that claim 19 sets forth a specific and integrated clinical workflow in which expression of a particular miRNA, miR-5100, is measured and compared to a defined control group characterized by a hippocampus-to-whole-brain volume ratio of 0.68% or more, leading to a determination that the subject has a volume ratio of 0.57% or less. The claim further requires linking that determination to a concrete clinical action, including administration of specific therapeutic agents or performance of defined diagnostic procedures. They argue that as demonstrated in Examples 1 and 2-(3), this framework provides superior diagnostic performance tied to specific quantitative thresholds and clinically actionable outcomes. The claim does not merely recite routine or conventional activity, but instead requires a particular biomarker, defined comparative thresholds grounded in imaging-based metrics, and a specific clinical response in the form of treatment or targeted diagnostics. This ordered combination of elements reflects more than a conventional application of a natural correlation and constitutes a non- conventional and clinically meaningful diagnostic and treatment protocol.
This argument has been fully considered but is not persuasive. In addition to the judicial exceptions the claims require measuring, by a hybridization technique, the expression level of miRNA using a probe complementary to the miRNA. The claims optionally require performing a further diagnostic procedure. Applicants have not identified anything in these steps that is not well understood, routine, or conventional other than the biomarker itself. The technology used to measure the biomarker and the technology used to perform the additional diagnostic procedures is well understood, routine, and conventional. The claims fail to provide an inventive concept and the claims are not eligible.
5. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached on 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1634
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