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
Summary
This is the Final Office Action based on application 17/842433 response filed 09/12/2025.
Claims 1-3 & 5-13 have been examined and fully considered.
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.
For Claims 12-13, the claimed invention is directed to a product of nature which is a judicial exception without significantly more. The 101 analysis is shown below:
Step 1, Are the claims directed to a statutory category of invention?
Yes, independent Claim 12 is directed to a composition or product.
Step 2A, Prong One: Identify the judicial exception.
Independent Claim 12 recites a “multiplex assay panel of biomarkers,” and through broadest reasonable interpretation, biomarkers. These are natural products of nature, which is a judicial exception. As claimed, there is nothing that makes them markedly different from how they are found in nature.
Step 2A Prong Two: Has the judicial exception-- been integrated into a particular practical application?
For both Claims 12, the answer is no. Nothing in addition to the product of nature is claimed, so nothing to practically apply. Further, nothing is claimed to make the biomarkers markedly different from what is found in nature.
Step 2B: Does the claim recite any elements which are significantly more than the judicial exception?
Nothing is claimed in addition to the product of nature. Nothing is claimed which makes the biomarkers significantly more from what is found in nature, nor which makes them markedly different. Therefore, the answer is no.
The dependent claims undergo a similar analysis.
Claim 13 indicates that another biomarker/s is used in addition to the ones required by Claim 12. Again though, nothing is added which makes the biomarkers markedly different from what is found in nature. Also nothing is added which practically applies at Step 2A, 2, nor which adds significantly more at step 2B.
All pending claims are rejected under 101.
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 1-3 & 5-13 are rejected under 35 U.S.C. 103 as being obvious over O’BRYANT in US 20190234967 in view of TODD in US 20130316468 and further in view of ZHAO in TNF receptors are associate with tau pathology and conversion to Alzheimer’s dementia in subjects with mild cognitive impairment.
With respect to Claims 1, O’BRYANT teaches of a method for detecting Alzheimer’s disease in patients and excluding them from further analysis is they don’t need it comprising: obtaining a blood or serum sample from a patient in a primary care setting; determining the expression levels of at least 4 of the following proteins: FABP, beta 2 microglobulin, PPY, soluble tumor necrosis factor receptor 1 (sTNFR1), CRP, VCAM-1, thrombopoietin, α2 macroglobulin, eotaxin 3, tumor necrosis factor-alpha (TNF-α) (VCAM-1 and sTNFR1- read on two of the required 3 biomarkers) (abstract). A multiplex biomarker assay is used for the detection involving electrochemiluminescence (paragraph 0031) and statistical analysis was performed to determine which biomarkers were predictive of the condition and which are not (paragraph 0032). O’BRYANT teaches of determination of expression level (level is the amount or concentration) of the measured proteins (Abstract)
O’BRYANT teaches that the treatment is delayed if the initial screen is negative for Alzheimer’s (this reads on treatment dependent on progression), and that the treatment is amyloid disease modifying therapies, tau therapies, cholinesterase inhibitors, NMDA receptor blockers, which read on the claimed treatments (paragraph 0007). This makes it obvious to determine to treat, as claimed dependent on progression of the diagnosis as claimed, however in case there is any question about treating and determining not treating being treating, TODD is used to remedy this. O’BRYANT also does not indicate treating with a therapeutically effective amount.
O’BRYANT also do not specifically call out the 3rd claimed biomarker sTNFR2 or the calculation of a score.
TODD is used to remedy this and teaches of a method for diagnosing Alzheimer’s disease. This includes detecting biomarkers such as sTNFR2, which is also known as TNFR1-B (paragraph 0046), so sTNFR2 reads on sTNFR1Bs, in addition to other biomarkers (abstract) and of determining MMSE score as biomarkers including sTNFR2 are sequentially added to the algorithm/score (paragraph 0020). The MMSE score is a method for diagnosing Alzheimer’s disease severity (paragraph 0052).
TODD even further teaches that the method is specifically for treating Alzheimer’s disease and specifically treating based on diagnosis and severity or prognosis (paragraph 0010, 0056). TODD further teaches of evaluating therapeutic effectiveness (paragraph 0058-0059) and that cholinesterase inhibitors can bs used for the treatment/preventative therapy (paragraph 0055).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to treat with a therapeutically effective amount of cholinesterase inhibitor based on diagnosis as is done in TODD in the method of O’BRYANT due to that advantage that detection and treating based on stage offers with respect to preventing years of delayed progression with preventive therapy and due to the advantage cholinesterase inhibitors have for slowing down disease activity(TODD, paragraph 0003, 0055).
TODD And O’BRYANT do not teach of slow progression to dementia being 36 months and fast progression being 12-18 months.
ZHAO is used to remedy this and teaches of a method of comparing predictors of conversion and decline in mild cognitive impairment. Specifically ZHAO teaches of TNFR receptors being associated with likelihood of development of lower impariments into Alzheimers(abstract). ZHAO further teaches of detecting TNFR1,TNFR2 and VCAM1 (Page 2, column 2, 3.2). ZHAO even further teaches of monitoring the levels of the biomarkers over 72 months (Figure 1) and that by 12-18 months some patients have progressed to AD, while around 36 months more people have progressed to AD (Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to monitor over 36 or so months with respect to slow or fast progression to Alzheimers disease as is done in ZHAO in the methods of TODD and O’BRYANT due to the advantage TNF1 and TNF2 offer for prediction of MCI to AD conversion (Page 5, column 1, 2nd paragraph).
With respect to Claim 2, O’BRYANT teaches of the instant invention as shown above for Claim 1. O’BRYANT further teaches of using the method to monitor progression and that treatment is delayed if the initial screen is negative for Alzheimer’s (this reads on treatment dependent on progression) (paragraph 0007). O’BRYANT further teaches of assessing the patients for cognitive impairment (paragraph 0005) and that some patients have mild cognitive impairment that that the method is specifically monitors if it is this or Alzheimer’s (paragraph 0006), and even further teaches of the method has a negative predictive value of greater that .9 for MCI and greater than .8 for Alzheimer’s disease (paragraph 0006).
O’BRYANT does not teach of the claimed development of a biomarker score.
TODD is used to remedy this and teaches of calculating an Alzheimer’s Disease Severity Score (paragraph 0052) and also of using the detected biomarkers to calculate a score (paragraph 0200, 0204). TODD even further teaches of using logistic regression and a discrimination score and an algorithm to generate models for the biomarkers with respect to Alzheimer’s Disease (paragraph 0207, 0209).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a score to calculate the disease state of Alzheimer’s as is done in TODD in the method of O’BRYANT due the advantage a multiple biomarker score has for not misclassifying people as much as for a single biomarker (TODD, paragraph 0207). It is noted that neither O’BRYANT of TODD teach of the claimed progression being specifically 36 months or 12-18 months, however it would have been obvious to one of ordinary skill to predict Alzheimer’s disease state as claimed from the teaching above. The month timeline for the claimed diagnosis, is part of the mental diagnostic and is also what is expected for each specific disease state, and the score is just a result effective variable which is it obvious to adjust as is done in TODD (paragraph 0020, 0119).
O’BRYAN and TODD do not teach of the claimed score of .435, however this is a number that results from the calculation of a score. Since O’BRYANT and TODD however teach of calculation of a score and of using the claimed three biomarkers, it would be obvious to one of ordinary skill in the art to arrive at this score of a predetermined threshold through routine optimization. See MPEP 2144.05, routine optimization.
With respect to Claim 3, O’BRYANT teaches of a method for detecting Alzheimer’s disease in patients and excluding them from further analysis is they don’t need it comprising: obtaining a blood or serum sample from a patient in a primary care setting; determining the expression levels of at least 4 of the following proteins: FABP, beta 2 microglobulin, PPY, soluble tumor necrosis factor receptor 1 (sTNFR1), CRP, VCAM-1, thrombopoietin, α2 macroglobulin, eotaxin 3, tumor necrosis factor-alpha (TNF-α) (VCAM-1 and sTNFR1- read on the claimed required two biomarkers in claim 1 and TNF-α is the third required) (abstract).
O’BRYANT and TODD do not teach of the claimed score of predetermined threshold of 0, however this is a number that results from the calculation of a score. Since O’BRYANT and TODD however teach of calculation of a score and of using the claimed three biomarkers, it would be obvious to one of ordinary skill in the art to arrive at this score of a predetermined threshold through routine optimization. See MPEP 2144.05, routine optimization.
With respect to Claim 5, O’BRYANT and TODD teach of the claimed invention as shown for Claims 4 & 2 above.
TODD further teaches of calculating an Alzheimer’s Disease Severity Score (paragraph 0052) and also of using the detected biomarkers to calculate a score (paragraph 0200, 0204).
TODD even further teaches of using logistic regression and a discrimination score and an algorithm to generate models for the biomarkers with respect to Alzheimer’s Disease (paragraph 0207, 0209).
TODD further teaches of diagnosis, that is part of the mental diagnostic and is also what is expected for each specific disease state, and the score is just a result effective variable which is it obvious to adjust as is done in TODD (paragraph 0020, 0119).
They do not teach of the specifically claimed formula/mathematical equation.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a score to calculate the disease state of Alzheimer’s as is done in TODD in the method of O’BRYANT due the advantage a multiple biomarker score has for not misclassifying people as much as for a single biomarker (TODD, paragraph 0207).
O’BRYANT and TODD do not teach of the claimed score of predetermined threshold of 0, however this is a number that results from the calculation of a score. Since O’BRYANT and TODD however teach of calculation of a score and of using the claimed three biomarkers, it would be obvious to one of ordinary skill in the art to arrive at this score of a predetermined threshold through routine optimization. See MPEP 2144.05, routine optimization.
With respect to Claim 6, O’BRYANT teaches of the instant invention as shown above for Claim 1. O’BRYANT does not teach of detecting sTNFR2. TODD teaches of a method for diagnosing Alzheimer’s disease. This includes detecting biomarkers such as sTNFR2 in addition to other biomarkers (abstract). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a multi-biomarker score to calculate the disease state of Alzheimer’s as is done in TODD in the method of O’BRYANT due the advantage a multiple biomarker score has for not misclassifying people as much as for a single biomarker (TODD, paragraph 0207).
With respect to Claim 7, O’BRYANT and TODD teach of the claimed invention as shown for Claim 1 above.
TODD further teaches of calculating an Alzheimer’s Disease Severity Score (paragraph 0052) and also of using the detected biomarkers to calculate a score (paragraph 0200, 0204).
TODD even further teaches of using logistic regression and a discrimination score and an algorithm to generate models for the biomarkers with respect to Alzheimer’s Disease (paragraph 0207, 0209).
TODD and OBRYANT do not teach of the specifically claimed formula/mathematical equation with -.435 being the threshold.
TODD further teaches of diagnosis, that is part of the mental diagnostic and is also what is expected for each specific disease state, and the score is just a result effective variable which is it obvious to adjust as is done in TODD (paragraph 0020, 0119).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a score to calculate the disease state of Alzheimer’s as is done in TODD in the method of O’BRYANT due the advantage a multiple biomarker score has for not misclassifying people as much as for a single biomarker (TODD, paragraph 0207).
O’BRYANT and TODD do not teach of the claimed score of predetermined threshold of -.435, however this is a number that results from the calculation of a score. Since O’BRYANT and TODD however teach of calculation of a score and of using the claimed three biomarkers, it would be obvious to one of ordinary skill in the art to arrive at this score of a predetermined threshold through routine optimization. See MPEP 2144.05, routine optimization.
With respect to Claim 8, O’BRYANT teaches of a method for detecting Alzheimer’s disease in patients and excluding them from further analysis is they don’t need it comprising: obtaining a blood or serum sample from a patient in a primary care setting; determining the expression levels of at least 4 of the following proteins: FABP, beta 2 microglobulin, PPY, soluble tumor necrosis factor receptor 1 (sTNFR1), CRP, VCAM-1, thrombopoietin, α2 macroglobulin, eotaxin 3, tumor necrosis factor-alpha (TNF-α) (VCAM-1 and sTNFR1- read on the claimed required two biomarkers in claim 1 and TNF-α is the third required) (abstract).
O’BRYANT and TODD do not teach of the claimed score of predetermined threshold of 0, however this is a number that results from the calculation of a score. Since O’BRYANT and TODD however teach of calculation of a score and of using the claimed three biomarkers, it would be obvious to one of ordinary skill in the art to arrive at this score of a predetermined threshold through routine optimization. See MPEP 2144.05, routine optimization.
With respect to Claim 9, O’BRYANT and TODD teach of the claimed invention as shown for Claim 7 above.
TODD further teaches of calculating an Alzheimer’s Disease Severity Score (paragraph 0052) and also of using the detected biomarkers to calculate a score (paragraph 0200, 0204).
TODD even further teaches of using logistic regression and a discrimination score and an algorithm to generate models for the biomarkers with respect to Alzheimer’s Disease (paragraph 0207, 0209).
TODD further teaches of diagnosis, that is part of the mental diagnostic and is also what is expected for each specific disease state, and the score is just a result effective variable which is it obvious to adjust as is done in TODD (paragraph 0020, 0119).
They do not teach of the specifically claimed formula/mathematical equation.
However, it would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a score to calculate the disease state of Alzheimer’s as is done in TODD in the method of O’BRYANT due the advantage a multiple biomarker score has for not misclassifying people as much as for a single biomarker (TODD, paragraph 0207).
With respect to Claim 10, O’BRYANT teaches of the instant invention as shown above for Claim 1. O’BRYANT does not teach of detecting sTNFR2. TODD teaches of a method for diagnosing Alzheimer’s disease. This includes detecting biomarkers such as sTNFR2 in addition to other biomarkers (abstract). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a multi-biomarker score to calculate the disease state of Alzheimer’s as is done in TODD in the method of O’BRYANT due the advantage a multiple biomarker score has for not misclassifying people as much as for a single biomarker (TODD, paragraph 0207).
With respect to Claim 11, O’BRYANT teach of detecting normal cognition, or mild cognition (Table 2), or Alzheimer’s disease (paragraph 0006, 0021, table 2).
With respect to Claim 12, O’BRYANT teaches of a method for detecting Alzheimer’s disease in patients and excluding them from further analysis is they don’t need it comprising: obtaining a blood or serum sample from a patient in a primary care setting; determining the expression levels of (detecting a biomarker panel including) at least 4 of the following proteins: FABP, beta 2 microglobulin, PPY, soluble tumor necrosis factor receptor 1 (sTNFR1), CRP, VCAM-1, thrombopoietin, α2 macroglobulin, eotaxin 3, tumor necrosis factor-alpha (TNF-α) (VCAM-1 and sTNFR1- read on the claimed required two biomarkers) (abstract). A multiplex biomarker assay is used for the detection involving electrochemiluminescence (paragraph 0031).
O’BRYANT teaches of the instant invention as shown including that the sample is a CSF sample.
O’BRYANT does not teach of detecting sTNFR2/including on the biomarker panel. TODD teaches of a method for diagnosing Alzheimer’s disease. This includes detecting biomarkers such as sTNFR2 in addition to other biomarkers (abstract). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use a multi-biomarker score/use sTNFR2 to calculate the disease state of Alzheimer’s as is done in TODD in the method of O’BRYANT due the advantage a multiple biomarker score has for not misclassifying people as much as for a single biomarker and since it has good predictive ability (TODD, paragraph 0207).
Since O’BRYANT in view of TODD teach of detection of sTNFR1,sTNFR2, and sVCAM1, this reads on the claimed “multiplex assay panel,” through broadest reasonable interpretation.
ZHAO further teaches of detecting TNFR1,TNFR2 and VCAM1 (Page 2, column 2, 3.2).
With respect to Claim 13, O’BRYANT teaches of a method for detecting Alzheimer’s disease in patients and excluding them from further analysis is they don’t need it comprising: obtaining a blood or serum sample from a patient in a primary care setting; determining the expression levels of at least 4 of the following proteins: FABP, beta 2 microglobulin, PPY, soluble tumor necrosis factor receptor 1 (sTNFR1), CRP, VCAM-1, thrombopoietin, α2 macroglobulin, eotaxin 3, tumor necrosis factor-alpha (TNF-α) (VCAM-1 and sTNFR1- read on the claimed required two biomarkers in claim 1 and TNF-α is the third required) (abstract).
Response to Arguments
Applicant's arguments filed 09/12/2025 have been fully considered but they are not persuasive.
The prior 101 rejection is withdrawn for Claims 1-11 since the claims now are practically applied due to the claimed treatment. The instant claims 1-11 all now require particular and specific treatment, as the claims were amended 09/12/2025. For Claims 12-13, the 101 rejection is maintained, since all that is claimed is a product of nature.
Applicant’s arguments with respect to claim(s) have been considered but are moot because the new ground of rejection does not rely on the exact combination of references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Specifically, a new reference ZHAO is used as shown in the rejection above.
Applicant argues that neither TODD nor O’BRYANT teach of relation of all three claimed biomarkers to Alzheimer’s progression. ZHAO is used to teach of this as shown above and specifically teaches of TNFR1, TNFR2, and VCAM1.
Applicant argues that TODD and O’BRYANT do not teach of a “score,” using all three biomarkers. Again—the ZHAO Reference makes using all three biomarkers obvious. Especially, since applicant does not claim a concrete score/scoring system or equation in the independent claim.
All claims remain rejected at this time.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
JIANG in Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer’s disease. JIANG teaches of detection of all the claimed biomarkers, TNFR1, TNFR2 in CSF (abstract).
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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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758