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 08/05/2026.
Claims 1-13 have been cancelled.
Claims 14-32 have been newly added.
Claims 14-15, 18, 20-27 have been elected by original presentation and therefore examined.
Claims 16-17,19 & 28-32 have been withdrawn.
Election/Restrictions
Newly submitted claims 16-17, 19 & 28-32 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
The original invention claimed a method for treatment, and a multiplex assay panel, however the multiplex assay panel was just as claimed 3 natural biomarkers (sTNFR1, sTNFR2 and sVCAM1), which were already searched for the claimed method of treatment. As instantly amended, 08/05/2026, all prior claims were cancelled and now there is a set of claims drawn towards a method of treatment, and another set drawn towards a multiplex assay panel--- however in the new claims the panel is clear a device/structure wherein there is a plate and the plate itself is in some way structurally “configured to,” measure protein concentration levels and provide a score. Therefore, since the new claims 16-17,19 & 28-32 are now drawn to a system/device and not the claimed method, and do not contain all parts already examined in the claimed method they are restricted from the treatment claims, and the treatment claims14-15, 18, 20-27, are elected by original presentation.
Restriction between the treatment claims 14-15, 18, 20-27, and the device/system 16-17,19 & 28-32 claims is appropriate because the device/system as claimed can be practiced by a materially different method, such as one which does not require the claimed treatment.
Further, search would be burdensome if the examiner were to search both inventions since the inventions are classified in different classes/subclasses, with the treatment claims14-15, 18, 20-27 being classified in USPC 436/86 and the system/device 16-17,19 & 28-32 claims being classified in 422/407. Further, the inventions are drawn towards different statutory categories and therefore different types of limitations carry different weights and therefor search would be burdensome if the examiners were to search both inventions.
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 16-17,19 & 28-32 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 § 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 14-15, 18, 20-27 are rejected under 35 U.S.C. 103 as being obvious over ZHAO in TNF receptors are associate with tau pathology and conversion to Alzheimer’s dementia in subjects with mild cognitive impairment in view of TODD in US 20130316468 and further in view of JANELIDZE in CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer’s disease and in further view of FU in US 20190015480.
With respect to Claim 14, ZHAO teaches of a method of detection of conversion of mild cognitive impairment (MCI) into Alzheimer’s, which uses TNF receptors and their determines their association with Alzheimer’s disease and mild cognitive impairment (abstract). Specifically, ZHAO teaches of TNFR receptors being associated with likelihood of development of Alzheimer’s (abstract).
ZHAO teaches of detecting TNFR1, TNFR2 and VCAM1 (Page 2, column 2, 3.2). ZHAO teaches of measuring the levels of the biomarkers in CSF (Page 2, column 1, paragraph 1 & Page 2, column 2, paragraph 1 & 3.1 & 3.2, and abstract, results section).
ZHAO further teaches that while all three biomarkers of TNFR1, TNFR2 and VCAM1 are used, that mild cognitive impairment (MCI) patients with high CSF levels of TNFR1 And low levels of TNFR2 are more likely to develop into Alzheimer’s disease (Page 1, abstract, results section). ZHAO also teaches that higher levels of VCAM-1 increased risk of progression in AD dementia in patients without any cognitive impairment (Page 1, column 1, last two lines- column 2, first two lines).
Therefore ZHAO teaches that an increase in both TNFR1 and VCAM1 and a decrease in TNFR2 are all associated with Alzheimer’s progression from MCI. This makes the instantly claimed calculating of a score, which is actually only a sum of 3 values for TNFR1, VCAM1 and TNF2, in Claim 14, step (b) obvious as all the claimed values are taught, and summing and subtracting is just performing simple math on these values.
ZHAO also teaches of the measured values of these compounds in MCI patients and AD patients being compared to those of healthy controls (Page 2,left column 2.1). ZHAO further teaches of determining threshold values for the biomarkers (Page 2, column 1, last paragraph). ZHAO also teaches of the biomarkers correlation with various tau pathologies including MCI and Alzheimer’s disease (AD)(Table 2).
ZHAO even further teaches of monitoring the levels of the biomarkers over 72 months (Figure 1) and of specifically TNFR1 and TNFR2 levels relating to MCI-AD conversion/progression (Figure 1 A-F and associated key, but particularly A & B).
ZHAO shows in Figures 1 A & B, that by using the biomarkers TNFR1 and TNFR2, that by 12-18 months some patients have progressed to AD, while around 36 months more people have progressed to AD (Figure 1).
This, in combination with the thresholds for the individual biomarkers already taught, makes the claimed combined score/sum obvious, and also the claimed determination of progression based on the claimed biomarkers and thresholds of them ( a score/sum) obvious.
Though it is obvious from the teachings of ZHAO, since ZHAO does not call out calculation of a specific score from measured biomarkers, TODD is used to remedy this.
TODD 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, which reads on the claimed treating “based on the determined progression,” obvious (paragraph 0010, 0056). TODD further teaches of evaluating therapeutic effectiveness, so this makes it obvious to treat with an effective amount of these therapies (paragraph 0058-0059) and that cholinesterase inhibitors can be 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 calculate a score for severity or progression of Alzheimer’s and to treat with a therapeutically effective amount of cholinesterase inhibitor based on diagnosis as is done in TODD in the method of ZHAO due to the 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) and it would have been obvious to detect through scoring due to the need in the art to enable a more sensitive and specific detection and diagnosis for AD including the risk, onset, and severity of AD (TODD, paragraph 0005).
Though ZHAO teaches of VCAM1 increase being associated with progression of impairment to alzheimers disease, since this was not the focus of ZHAO, JANELIDZE is used to remedy this.
JANELIDZE teaches of a method of measuring in CSF in unimpaired and mild cognitively impaired, and patients with AD the levels of biomarkers including VCAM1 and that increased levels of this compound is associated with cognitive deterioration (Page e867, results section and methods). JANELIDZE also teaches of comparison to a control group(Page e868, column 2, 13 lines from bottom).
It would have been obvious to one of ordinary skill in the art to include VCAM1 as is done in JANELIDZE in the methods of ZHAO and TODD, in the score for determining progression to Alzheimers due to the advantage VCAM1 shows for being associated with AB alzheimers pathology (JANELIDZE, page e874, column 1, last paragraph).
Though TODD teaches of the treatment as claimed, if this is not clear to one of ordinary skill that an effective amount is used, FU is used to remedy this and more specifically teaches of methods of treating neurodegenerative conditions (abstract), which can be alzheimers disease (paragraph 0003). FU further teaches of treating with a combined composition including an effective amount of a composition including IL-33 and also aducanumab, donepezil, rivastigmine, or galantamine (paragraphs 0021-0022).
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 an effective amount as is done in FU in the methods of ZHAO, TODD, and JANELIDZE due to the advantage this would have in being and effective treatment ( FU, paragraph 0021).
Further with respect to the claimed score, which as instantly claimed is only a simple sum since ZHAO specifically teaches of detection of all three claimed biomarkers and each biomarkers specific association and comparison to a control with progressive alzheimers- it makes the instantly claimed score which is just relying of summing these detected values which are all individually taught in comparison to controls to be predictive of alzheimers-obvious. See MPEP 2144.05 II Routine optimization
[“W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235.”
With respect to Claim 15, ZHAO teaches of a method of detection of conversion of mild cognitive impairment (MCI) into Alzheimer’s, which uses TNF receptors and their determines their association with Alzheimer’s disease and mild cognitive impairment (abstract). ZHAO also teaches of the first stage being healthy or normal cognition (Page 2, column 1, paragraph 2).
With respect to Claim 18, ZHAO further teaches of using TNF-alpha(TNF-α) as a biomarker (abstract, background & Table 2).
With respect to Claim 20, TODD further teaches that the method is specifically for treating Alzheimer’s disease and specifically treating based on diagnosis and severity or prognosis, which reads on the claimed treating “based on the determined progression,” obvious (paragraph 0010, 0056). TODD further teaches of evaluating therapeutic effectiveness, so this makes it obvious to treat with an effective amount of these therapies (paragraph 0058-0059) and that cholinesterase inhibitors can be used for the treatment/preventative therapy and more specifically that galantamine and rivastigmine are used (paragraph 0055).
With respect to Claim 21, TODD further teaches that the method is specifically for treating Alzheimer’s disease and specifically treating based on diagnosis and severity or prognosis, which reads on the claimed treating “based on the determined progression,” obvious (paragraph 0010, 0056). TODD further teaches of evaluating therapeutic effectiveness, so this makes it obvious to treat with an effective amount of these therapies (paragraph 0058-0059) and that rivastigmine and donepezil are used (which are inhibitors of acetylcholine breakdown) (paragraph 0055).
With respect to Claim 22, TODD further teaches that the method is specifically for treating Alzheimer’s disease and specifically treating based on diagnosis and severity or prognosis, which reads on the claimed treating “based on the determined progression,” obvious (paragraph 0010, 0056). TODD further teaches of evaluating therapeutic effectiveness, so this makes it obvious to treat with an effective amount of these therapies (paragraph 0058-0059) and that memamine is used (paragraph 0055).
With respect to Claim 23, TODD further teaches that the method is specifically for treating Alzheimer’s disease and specifically treating based on diagnosis and severity or prognosis, which reads on the claimed treating “based on the determined progression,” obvious (paragraph 0010, 0056). TODD further teaches of evaluating therapeutic effectiveness, so this makes it obvious to treat with an effective amount of these therapies (paragraph 0058-0059) and that galantamine are used (which are inhibitors of acetylcholine breakdown) (paragraph 0055).
With respect to Claim 24, ZHAO and TODD and JUNELIDZE teach of the invention as shown above, however do not teach of treating with aducanumab. FU is used to remedy this and more specifically teaches of methods of treating neurodegenerative conditions (abstract), which can be alzheimers disease (paragraph 0003). FU further teaches of treating with a combined composition including an effective amount of a composition including IL-33 and also aducanumab, donepezil, rivastigmine, or galantamine (paragraphs 0021-0022).
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 an aducunumab as is done in FU in the methods of ZHAO, TODD, and JANELIDZE due to the advantage this has shown in being therapeutically active for alzheimers ( FU, paragraph 0021).
With respect to Claim 25, ZHAO teaches that all of the samples are run in duplicate along with six CSF standards on each plate (Page 2, column 1, paragraph 3).
With respect to Claim 26, ZHAO teaches that all of the samples are run in duplicate along with six CSF standards on each plate, meaning that more than one plate, so multiple plates are used (Page 2, column 1, paragraph 3).
With respect to Claim 27, ZHAO teaches that all of the samples are run in duplicate along with six CSF standards on each plate, meaning that more than one plate, so multiple plates are used. Further ZHAO teaches that all TNF-alpha related proteins are measured using ELISA kits, which read on the claimed one assay (Page 2, column 1, paragraph 3). ZHAO does not specifically call the assay used to measure VCAM1.
JANELIDZE is used to remedy this and teaches of measuring VCAM1 by an assay (Page e869, column 1, paragraph).
It would have been obvious to one of ordinary skill in the art to include VCAM1 as is done in JANELIDZE in the methods of ZHAO and TODD, in the score for determining progression to Alzheimers due to the advantage VCAM1 shows for being associated with AB alzheimers pathology (JANELIDZE, page e874, column 1, last paragraph 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to measure VCAM1 with a different assay as is done in JANELIDZE in the method of ZHAO and TODD due to the advantage this VCAM1 detection has in detecting Ab pathology, which would be advantageous for combination with an assay that can detection tau pathology (like those in ZHAO) since those together are the core pathologies for alzheimer’s disease (e870, column 2, paragraphs 4-5).
Response to Arguments
Applicant's arguments filed 08/05/2026 have been fully considered but they are not persuasive.
The prior 112b and 101 rejection are overcome due to the cancellation of the prior claims these rejections were made for.
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 combination of references applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Also, the instant claims were completely rewritten into new claims on 08/05/2026, so a new grounds or rejection/combination of references is permitted.
Though this is the case, with respect to the 103 rejection, the examiner responds to some relevant sections of applicants arguments. First, applicant argues that the claimed thresholds and “score architecture,” could not be obtainable through routine optimization. With respect to this, the examiner adamantly disagrees, especially at the level of generality the claimed thresholds are claimed at. In fact, no actual number or units for measurement or the threshold are give. Therefore, since the prior art ZHAO teaches of detecting all these compounds and that their levels are associated with conversion of cognitive impairment into alzheimers, these thresholds as claimed can absolutely be found through optimization, since they have no number.
Applicant argues that the ZHAO reference does not disclose the prognostic AD model and specifically of incorporation of VCAM1 into a model or score, and therefore it is not obvious to do so. The examiner disagrees, as shown in the above art rejection--- even if it is not used in the score or model in ZHAO, ZHAO clearly shows VCAM1 has association with progression of Alzheimers.
Applicant argues that ZHAO does not teach of using VCAM1 as a weighted contributor to the score. The examiner notes that this argument is not commensurate in scope with the claims as nothing is claimed about VCAM1 being a weighted contributor.
Further, with respect to this, the examiner notes that ZHAO teaches, as shown in the rejection above of measuring the 3 claimed biomarkers together. Applicant argues that TNF1 and TNF2 together are measured separately from VCAM1. The examiner agrees that this is the case, however maintains that this makes the instant score which is just a simple sum/subtraction score obvious.
.
Applicant even further argues that the prior art does not show “administering a therapeutically effective amount of Alzheimer’s therapy based on the score derived progression determination.” Again--- with respect to this, applicant seems to be arguing that one single reference does not teach of the whole claim and the examiner again reminds applicant that a 103 rejection was made. As shown in the 103 rejection above, the treatment, which appears to be somewhat treatment for Alzheimer’s as claimed is made obvious by the combination of references. Even further, though applicant seems to be administering “ based on the progression of AD in the subject,” the treatment as claimed do not appear to be any different from treatments for Alzheimer’s without progression monitoring. Further--- the treatments as claimed are not even different from one another if the progression is determined to be slow or fast. Therefore, applicants arguments are not convincing.
Applicant argues about what the TODD reference is used for, and notes that the reliance on TODD has changed somewhat, so applicant’s arguments do not apply here. The examiner notes that TODD teaches of using therapeutically effective amounts of the claimed treatments, as shown in the above 103 rejection.
Applicant argues about the OBRYANT reference, however that is no longer used.
Applicant further argues that the rejection relies on routine optimization does not teach or make obvious the claimed thresholds, recited formulas, coefficients, and biomarker assignments. With respect to the thresholds, the examiner notes that there are no numerical thresholds claimed. As claimed, simple sum equations and thresholds thought they have meaning, do not have a great amount of meaning as thresholds are very commonly used in the art.
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).
O’BRYANT in US 20190234967
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). It would have been obvious to one of ordinary skill in the art to monitor and treat as is done in O’BRYANT in the methods of ZHAO and TODD due to the problems in the field associated with delayed treatment of Alzheimer’s (O’BRYANT, paragraph 0005).
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.
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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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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