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 .
Detailed Action
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/20/2026 has been entered.
Summary
This is the Non-Final Office Action based on application 16/978959 RCE filed 01/20/2026.
Claims 1, 4, 6, & 17 have been elected, and fully considered.
Claims 2-3 & 5 are cancelled.
Claims 7-16 are withdrawn.
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 ofmatter, or any new and useful improvement thereof, may obtain a patent therefor, subject to theconditions and requirements of this title.
The claimed invention of Claims 1, 4, 6, & 7 are directed to non-statutory subject matter.
The invention of instant claims is drawn towards a method of detecting a neurodegenerative condition selected from the group of FTLD, and ALS. However, as instantly considered as a whole the claim is drawn towards the judicial exceptions which are a combination of a natural correlation and abstract idea without significantly more to make the claims move past these judicial exceptions.
Through 101, inquiry:
Inquiry: Is the claim directed to a statutory category of invention?
Yes, the claim is drawn towards a statutory category (a method).
Step 2A, Prong 1: Does the claim involve a Judicial Exception?
Independent claim 1 and those that depend therefrom require and heavily revolve around the calculation of a of “DO value”. As instantly clamed- “calculating,” of the DO value, including the claimed formula for the DO value is an abstract idea/mental process/math as instantly claimed which can be performed by the human mind.
The claim also is directed to a natural correlation, which is a law of nature judicial exception. The method is actually drawn towards this itself--- “detecting a neurodegenerative disease,” and even though the word “diagnosing,” is not use, that is what is being done in the instant claims, and the natural correlation (disease diagnosis of neurodegenerative disease correlation with the DO/measured pSer46 and MARCKS measured amounts, is still implicitly in the claim).
Step 2A, Prong: Has the abstract idea or natural correlation been integrated into a particular practical application?
In Claim 1, there is no particular practical application.
In addition to the claimed judicial exceptions the additional steps are required:
Preparing a sample comprising CSF and a buffer comprising Tris-HCL, SDS, DTT, wherein the preparing comprises denaturing proteins in the sample by heating the sample;
Measuring the pSer46 and MARCKS by mass spectrometry
Detecting/determining a distance by using a formula to determine DO (even though the word calculating is no longer used, this is still calculating), and comparing the value to that of a cutoff value DO known/determined from a healthy subject.
For step i), the use of a buffer comprising Tris-HCL, SDS, and DTT is
insignificant extra solution activity, and therefore does not integrate the judicial exception into a practical application. Buffers, as instantly claimed and in general are compounds or solutions that help maintain a stable pH level by neutralizing added acids or bases, crucial for biological systems like blood. Buffers are not meant to react, so there is no derivatization of the CSF that happens with a buffer, especially as generally claimed. Also, “denaturing proteins in the sample by heating the sample,” also does nothing to practically apply and is something that can/could happen naturally if said proteins are left in a heated room. Therefore, as generally claimed, both of these things are considered extra-solution activity and do nothing to practically apply the claimed judicial exceptions. See MPEP 2106.04 (d) I. & MPEP 2106.05 (g).
For step ii)—mass spectrometry is used merely to gather data in conjunction with/for the claimed law of nature and abstract idea. Therefore, this does not practically apply the judicial exceptions. Data gathered/gathering to use the judicial exception is considered extra-solution activity and therefore does not practically apply. See MPEP 2106.05 (g).
With respect to the step which was priorly claimed as step iii, with, “iii,” being instantly crossed out--- the claimed distance from origin (DO) formula and using it to determine whether the DO is higher or lower than a cutoff off to determine if a subject has neurodegenerative disease are natural correlation and abstract idea judicial exceptions (DO is calculated by a mathematical formula for DO--- this is an abstract idea, and neurodegenerative disease presence or not depends on if DO, based on pSer46-MARCKs and non phosphorylated MARCKS is above or below a threshold, which is a natural correlation). Therefore, these steps are part of the judicial exception/s themselves, they do nothing to practically apply.
Therefore, particularly at the level of generality claimed—there is not integration into a practical application.
Step 2B: Do the claims recite any elements which are significantly more than the abstract idea or natural correlation?
In addition to the claimed judicial exceptions the additional steps are required:
Preparing a sample comprising CSF and a buffer comprising Tris-HCL, SDS, DTT, wherein the preparing comprises denaturing proteins in the sample by heating the sample;
Measuring the pSer46 and MARCKS by mass spectrometry
“Detecting,” by comparing calculated DO value to that of a cutoff value DO known/determined from a healthy subject.
For step i), the use of a buffer comprising Tris-HCL, SDS, and DTT use as a buffer is well understood, routine and conventional (WURC). Buffers main functions are to resist changes in pH and maintain a stable environment for analytes when analyzed. This also applies to the claims, preparing comprising denaturing proteins in the sample by heating the sample as this is something that can happen naturally if a sample is left out in the open on a hot day. Therefore, as claimed, this is WURC. Therefore, both of these things are standard laboratory technique and are not sufficient to show an improvement in technology or add significantly more. See MPEP 2106.05 (a) & MPEP 2106.05 (d).
For step ii) measuring pSer46 and MARCKs by mass spectrometry, is just measurement by a WURC laboratory technique, and therefor is not enough to be significantly more. MPEP 2106.05 (d).
For step formally claimed as iii), with “iii,” now being crossed out, again the claimed determining DO through a calculation is a mental process/math itself, which is an abstract idea. Step “iii,” as newly amended 01/20/2026, the claimed “Detecting,” though the word “detecting,” is used, it is clear that the “Detecting,” is done merely through mental comparison of the calculated DO value to the cutoff DO value. Therefore, the claimed “detecting,” in step “iii,” is a mental process/abstract idea itself and therefore does not add significantly more. which as claimed can read on a mental comparison so an abstract idea/mental process itself. Further- comparison to a control is WURC in the art and therefore does not add significantly more.
Though part of the claimed judicial exception the examiner also notes that the claimed formula for DO is a Euclidean distance/distance from origin calculation. This a routine calculation and known formula, which is shown by the prior art below, and is used to determine the distance between two points.
Further, as claimed, measurement of protein markers in CSF, especially at the level of generality claimed is well understood, routine and conventional method for measurement in the art, and therefore this is not considered significantly more than the claimed judicial exceptions. Applicant also does not specify how exactly they are able to measure both phosphorylated 46 and the non-phosphorylated MARCKs compounds. See MPEP 2106.05 (d).
So, particularly at the level of generality claimed—this is not considered significantly more than the claimed judicial exceptions, nor is it considered an improvement in the technological field.
The dependent claims are reviewed as the independent claim above.
Claim 4, specifies that numerical values are normalized. This is a type of mathematical manipulation so is part of the claimed judicial exception/abstract idea and one that is routine in the art, so does not change any of the matters above.
Claim 6, specifies what the DO cutoff value is. This also doesn’t change anything, because is part of the natural correlation.
Claim 17, is claiming how a control from a healthy sample /patient is analyzed. The control is analyzed the same way as the sample in Claim 1—therefore, holds the same analysis as shown for Claim 1 above.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, 6, & 17 are rejected under 35 U.S.C. 103 as being unpatentable over PIKE in US 20180067133 in view of FUJITA in “HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer’s disease” (as cited on IDS dated 09/08/2020) in view of HU in Assessment of gene order computing methods for Alzheimer’s disease, and further in view of SCIENCING in How to Find Euclidean Distance.
With respect to Claims 1 & 17, PIKE teaches of a method for detection of alzheimer’s disease and alzheimer’s disease with fronto-temporal dementia combination (abstract, paragraph 0031, 0186). PIKE further teaches of detecting MARCKs- related proteins for this detection (paragraph 0018, 0060, 0149-0150, 0156, Table 1) and of determining if the measured biomarker is increased in relation to a reference/control (paragraph 0070-0071). PIKE also teaches that the biomarkers detected can be in phosphorylated form (paragraph 0064).
PIKE also teaches of processing the CSF samples by denaturation (paragraph 0356), and also of heating to 55 degrees Celsius from room temperature (25 degrees Celsius) (paragraph 0356).
PIKE does not teach of the detection of pSer46-MARCKS detection or of processing with the claimed buffer solution.
FUJITA is used to remedy this and more specifically teach of detecting a serine residue at position 46 of MARCKS is phosphorylated in Alzheimer’s Disease patients. Specifically, FUJITA teaches that HMGB1 triggers Ser46-phosphorylation of MARCKS, which is the protein that regulates stability in the actin network--- and that this phosphorylation at position 46 is sustained throughout Alzheimer’s disease. FUJITA further teaches that HMGB1 triggers the specific Ser46 phosphorylation of MARCKS (Abstract). FUJITA et al. teach of detecting/measuring Ser46-phosphorylated MARCKS signals--- after addition of HMGB1, by detecting HMGB1 in a sample prepared from CSF specimen/sample (Page 6, Figure 4, description (f) &(g), Page 7, second paragraph, page 12, 3rd paragraph from bottom). FUJITA teaches that the sample is mixed with Tris-HCl and SDS and DTT (Page 10, last paragraph, lines 1-4 & 7 lines from bottom).
FUJITA et al. teach of detection by mass spectrometry (Page 2, Figure 1 description, Page 5, first paragraph).
FUJITA et al. further teach of detecting disease and other neurodegenerative diseases by looking for/detecting phosphorylation of MARCKS, a submembrane protein that regulates the stability of the actin network that occurs at Ser46 (MARCKS protein phosphorylated at position 46) prior to aggregation of Aβ and is sustained throughout the course of AD in human (abstract, also see Figure 1, 2, and page 7, first paragraph). FUJITA et al. further teach of detecting/ measuring non- phosphorylated MARCKS molecules (Page 4, Figure 3 & Figure 3 description).
FUJITA teaches that the measurements are compared to that of a healthy control and that if there is an increase compared to healthy control that is indicative of disease (Page 6, second paragraph, line 2 and lines 1-5, and Page 10, paragraph 6, 2 & 5 lines from bottom) (which makes the instantly claimed calculation of DO compared to healthy control obvious since the DO is just a calculation from the claimed measurements).
FUJITA et al. further teach of using statistics to perform analysis of the phopspho-proteome.
Specifically, FUJITA teach that peptide ratios followed log-normal distribution. For biological analyses, the data were considered to follow a normal distribution and are represented as the mean± standard error. Student’s t-test was applied for two group comparisons. Further, non-parametric Wilcoxon’s rank-sum test was employed for this analysis. (Page 13, last paragraph, page 14, first paragraph).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to detect pSer46 MARCKs and non-phosphorylated versions as is done in the method of FUJITA for detection of Alzheimer’s disease in the method of PIKE for detecting Alzheimer’s with fronto-temporal dementia disease due to the advantage MARCKs phosphorylation at Ser46 show for being a hallmark of neurite degeneration (Page 2, title of bottom paragraph & bottom paragraph). Further, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use the buffer of FUJITA in the method of PIKE due to the advantage the three part buffer of Tri-HCl, SDS, and DTT as a lysis buffer to assisting in sample lysis operations (FUJITA, page 10, last paragraph).
With respect to the instantly claimed formula FUJITA et al. does not teach of this. In the instant claims and in applicant’s instant specification PGPUB paragraph 0183 it is shown that DO in the formula stands for “distance from origin,” --- In applicants instant PGPub, they also teach that Wilcoxon test is also used (see paragraph 0183 of instant PGPub).
FUJITA does not call out the specifically claimed DO formula and the method including a step for calculating the DO value specified by formula 1 of claim 1—which as claimed is a Euclidean distance formula.
HU et al. teach of a method for assessment of genes in Alzheimer’s disease using computational genetics (abstract). Specifically, HU uses different distance formulas including Euclidean distance, squared Euclidean distance, and Pearson distance to do the analysis of the Alzheimer’s markers (abstract, methods). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use Euclidean distance analyses as is done in HU in the methods of FUJITA and PIKE to analyze the MARCKS phosphorylated pos 46 markers and the non phosphorylated markers, due to the advantage that these analyses are known to have superiority when data is not normalized (HU, abstract, conclusion, page 6, second column, 2nd-last paragraph).
If it is not clear to one of ordinary skill in the art that what is claimed in the instant invention is Euclidean distance, SCIECING is used to remedy this.
SCIENCING et al. teach the Euclidean distance refers to the distance between two points in space (Page 1, first paragraph, Page 2, first paragraph). SCIENCING et al. further teach that to calculate the Euclidean distance in two- dimensional space (Such as on a graph with x and y axes to mark to variables), the difference in the x coordinates (on variable on graph, which could be the phosphorylated MARCKS), and the calculating the difference in the y coordinates (could be the non- phosphorylated variable), and then take the square root of the sum to find the distance (Page 3). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to calculate the calculate the Euclidean distance as is done in in HU and SCIENCING in the method of FUJITA and PIKE due to the advantage this offers in finding the distance or difference between two points or variables (even ones including multiple points) (Sciencing, paragraph 1).
With respect to Claim 4, HU et al. teach that if vector components are normalized that one must pay attention to which distance calculation they use an weigh issues/concerns (Page 6, column 2, last paragraph and Page 7, column 1, first paragraph).
With respect to Claim 6, FUJITA et al. teach of comparison to compared control/cutoff values (Page 10, proteome analysis). FUJITA teaches that the measurements are to that of a healthy control and that if there is an increase compared to healthy control that is indicative of disease (Page 6, second paragraph, line 2 and lines 1-5, and Page 10, paragraph 6, 2 & 5 lines from bottom) (which makes the instantly claimed calculation of DO compared to healthy control obvious since the DO is just a calculation from the claimed measurements). HU et al. also teaches of comparison to control samples (Page 6, column 1, paragraph 4, Figure 1) and that the controls are for control (which can be interpreted as healthy), incipient, moderate, and severe data (Page 6, column 1, paragraph 1). Since severe is one data, the control can be interpreted as not affected by disease or healthy It could have been obvious to adjust the cutoff value dependent on the analysis performed.
Response to Arguments
Applicant's arguments filed 01/20/2026 have been fully considered but they are not persuasive.
Applicant argues with respect to the 101 rejection. The 101 rejection is maintained for the significantly amended claims as shown in the above rejection. As the claims were significantly amended, the examiners response to these amendments is found and can be reviewed in the rejection and is not repeated here.
Applicant argues that the addition of the claimed buffer and newly claimed denaturing of proteins by heat, “transforms,” the sample and that mass spectrometry and the addition of the three-part buffer cannot be performed in the human mind. While the examiner agrees that the addition of the buffer and mass spectrometry cannot be performed in the human mind, and that denaturing by heat “can,” be a physical step, the examiner reminds applicant that whether or not something is solely performed in the human mind or not is not the test for 101. The examiner has noted the steps in the 101 rejection, which are considered to be abstract ideas and that can, as claimed be performed in the human mind. The buffer addition, heating, and mass spectrometry steps are not performed in the human mind. The examiner agrees on this, however the examiner does not agree that these steps make the instant claims eligible, since they do not practically apply nor do they add significantly more to the claimed judicial exceptions. The reasons for this are shown in the above rejection. It is also noted that as claimed--- the claimed three-part buffer does not seem to “transform,” the sample as no derivatization or binding, nor the resulting compound thereof is claimed. So, even if transformation occurs, it is not clearly claimed.
Applicant further argues with respect to MPEP 2106.05 (c ) that the claimed steps transforms the claimed article “ to a different state or thing.” The examiner again, disagrees with applicant. If any transformation is present, it is not claimed, and it is certainly not claimed in a way which practically applies nor which adds significantly more to the claimed judicial exceptions.
Therefore, all examined claims remain rejected under 101.
With respect to the 103 prior art rejection, applicant notes that to move prosecution forward, they have deleted the mention of Alzheimer’s disease, and that that claims are now specific to fronto-temporal dementia and amyotrophic lateral sclerosis. The examiner notes, that due to applicant’s amendments, a new reference, PIKE is used as shown in the above rejection.
Applicant further argues that the FUJITA reference does not teach of detecting an increase in the MARCKS protein as an indicator for disease. With respect to this, the examiner points out that the PIKE further teaches of detecting MARCKs- related proteins for this detection (paragraph 0018, 0060, 0149-0150, 0156, Table 1) and of determining if the measured biomarker is increased in relation to a reference/control (paragraph 0070-0071). FUJITA teaches of the pSer46-MARCKS, with good reason for combination with PIKE.
Applicant argues with respect to “Exhibit A,” which they have submitted with this action. Though the examiner has reviewed the reference in Exhibit A, it is not found to be convincing with respect to overcoming FUJITA. This is due to the inclusion now of the PIKE reference in the rejection above, due to applicant’s amendments dated 01/20/2026. Due to what is shown in the PIKE reference, the examiner disagrees with applicant’s argument that “one would not envisage changes in MARCKS levels of FTLD and ALS patients would resemble those of AD patients.” Again, as shown above, PIKE does in fact teach of detecting both fronto-temporal lobe dementia and alzheimer’s together, using MARCKS protein.
All elected claims remain rejected.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Sarah Folkesson Hansson in, “Validation of a prefractionation method followed by two-dimensional electrophoresis – Applied to cerebrospinal fluid proteins from frontotemporal dementia patients.”
FOKELSSON teaches of a prefractionation method followed by analysis for detecting Alzheimer’s in CSF samples (abstract). FOKELSSON teaches that CSFT samples and used and DTT is used (Page 8, column 2, paragraph 5), DTT with Tris and SDS is used (page 9, column 1, first paragraph), or DTT, Tris-HCL, and SDS can be used together (Page 9, column 1, second paragraph). This/these buffers offer advantage for allowing prefractionation (Page 8, column 2, 2nd to last paragraph).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris Kessel can be reached on 571-270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758