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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-4, 11-13, 17-19, 22, 24-25, 27-29, 33 and 38 and species of tau phosphosite in CSF, one or more pT111, pT153, pT175 and semorinemab in the reply filed on 11/16/2025 is acknowledged. Upon further consideration, the species requirements are withdrawn.
Claim 16 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/6/2025.
Claims 12, 17-19, 22, 24, 27-29, 38 and new claim 48 are under consideration in the instant Office Action.
Withdrawn Objections and Rejections
The objection to claims 1, 12, 19 and 33 is moot due to the cancellation of claims 1 and 33 and claim amendments.
The objection to 3, 25, 27-28 is moot due to the cancellation of claims 3 and 25 and claim amendments.
The rejection of claims 3, 25 and 28 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is moot due to the cancellation of claims 3 and 25 and claim amendments.
The rejection of claims 1-4, 19, 24-25, 28-29 and 38 under 35 U.S.C. 102(a)(1) as being anticipated by Wildsmith et al., 2018 of claim 1 and claim amendments.
Modified and New Rejection Necessitated by Amendment
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (www), see page 44. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code (www). See MPEP § 608.01.
Response to Arguments
Applicant's arguments filed 6/16/2026 have been fully considered but they are not persuasive. Applicant asks Examiner to remove the objection the specification in view of their amendments. While applicant clearly attempted to address the issue they still failed to remove the www from page 45 as required.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”. The instant specification set forth amino acid sequences without sequence identifiers, see page 29, lines 28-30, and no CRF has been filed in the instant application.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
Specific deficiency - This application contains a “Sequence Listing as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)), but fails to comply with the requirements of 37 CFR 1.821 - 1.825 because a copy of the "Sequence Listing" in computer readable form (CRF) has not been submitted as required by 37 CFR 1.821(e)(1)(i) or 1.821(e)(2)(i) as indicated in item 2) above.
Required response - Applicant must provide:
A new CRF of the “Sequence Listing” in accordance with 37 CFR 1.821(e)(1)(i) or 1.821(e)(2)(i) and
A statement that the content of the CRF is identical of the “Sequence Listing” part of the disclosure, submitted as a PDF file (37 CFR 1.821(c)(2)) or on physical sheets of paper (37 CFR 1.821(c)(3)), as required by 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii).
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 12, 17-19, 22, 24, 27-29, 38 and new claim 48 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The claim(s) recite(s) a natural correlation and abstract ideas. This judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Step 1
This part of the eligibility analysis evaluates whether the claim falls within any statutory category per MPEP 2106.03
Regarding instant claim 12, Example 43 of “2019 PEG” is particularly enlightening because the fact pattern of claim 1 of example 43 is most similar to the instant application claims.
Regarding claim 1 of example 43 of the “2019 PEG” and per Step 1, the claim is directed to a process, which is one of the statutory categories of invention as the claim recites “A treatment method comprising: (a) calculating a ratio of C11 to C13 levels measured in a blood sample from a patient diagnosed with Nephritic Autoimmune Syndrome Type 3 (NAS-3) to identify the patient as having a non-responder phenotype; (b) administering a treatment to the patient having a non-responder phenotype.” (Step 1: YES).
Similarly, instant claim 12 is directed to a statutory method that detects one or more phospho-tau species in a CSF sample from a subject, then using that measurement to discriminate an Alzheimer’s disease subject from a healthy state and administer a generic anti-tau therapy. (Step 1: YES).
Step 2A, Prong 1: Does the claim recite a judicial exception?
This part of the eligibility analysis evaluates whether the claim recites a judicial
exception. As explained in MPEP 2106.04(II), 2019 Revised Patent Subject MatterEligibility Guidance, PEG and the October 2019 Update, a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim.
Regarding instant claims 12, 17-19, 22, 24, 27-29, 38 and 48, Example 43 of the “2019 PEG” shows a similar fact pattern.
Regarding claim 1 of Example 43, Limitation (a) in the claim recites several nature-based product limitations including C11, C13, and the blood sample, which raises the question of whether the markedly different characteristics analysis should be used to determine if the nature-based product limitations are product of nature exceptions. For a process claim, the general rule is that the claim is not subject to the markedly different analysis for nature-based products used in the process. MPEP 2106.04(c)(I)(C). While there is an exception to this general rule for process claims that are drafted in such a way that they are no different in substance than a product claim, claim 1 does not invoke this exception because review of this claim indicates that it is focused on a process of determining how much C11 and C13 is present in the blood sample and then treating a patient in accordance with that determination, and is not focused on the products per se. Thus, the general rule expressed in the MPEP applies, meaning that the markedly different characteristics analysis is not performed on the recited nature-based product limitations, and the claim is not considered to “recite” any products of nature for purposes of further eligibility analysis.
Similarly, instant 12 recites several nature-based product limitations including CSF, and one or more phospho-tau and Aβ species. While there is an exception to this general rule for process claims that are drafted in such a way that they are no different in substance than a product claim, instant claim 12 does not invoke an exception because review of this claims indicates that it is focused on a process of determining the presence/levels of phosphor-tau as present in a CSF and then using those values to discriminate an Alzheimer’s subject by comparing it to tau PET SUVT as a positive correlation and further compare it to a healthy state and administer a generic anti-tau therapy. Thus, the general rule expressed in the MPEP applies, meaning that the markedly different characteristics analysis is not performed on the recited nature-based product limitations, and the claim is not considered to “recite” any products of nature for purposes of further eligibility analysis. However, like claim 1 in Example 43, the instant claim 12 must then be further reviewed for any other type of judicial exception.
Example 43 of “2019 PEG” continues the analysis to determine whether it recites any other type of judicial exception, per Step 2A, prong 1, the claim recites the judicial exception of “calculating a ratio of C11 to C13 levels measured in a blood sample from a patient diagnosed with Nephritic Autoimmune Syndrome Type 3 (NAS-3) to identify the patient as having a non-responder phenotype,” and according to broadest reasonable interpretation (BRI), an arithmetic calculation of a division is required to obtain the ratio of C11 to C13 that can be used to identify whether the patient has the non-respondent phenotype.
Specifically, limitation (a) in claim 1 of Example 43 of the “2019 PEG” recites “calculating a ratio of C11 to C13 levels measured in a blood sample from a patient diagnosed with Nephritic Autoimmune Syndrome Type 3 (NAS-3) to identify the patient as having a non-responder phenotype,” which has a BRI that requires performing an arithmetic calculation in order to obtain the ratio of C11 to C13 levels, and then using this ratio to identify whether the patient has the non-responder phenotype (i.e., the patient has a calculated ratio of 3:1 or greater and thus is not responding, or will not respond, to glucocorticoids). This limitation therefore recites a mathematical calculation. The grouping of “mathematical concepts” in the 2019 PEG includes “mathematical calculations” as an exemplar of an abstract idea. 2019 PEG Section I, 84 Fed. Reg. at 52. Thus, limitation (a) falls into the “mathematical concept” grouping
of abstract ideas. In addition, this type of simple arithmetic calculation (division) can be
practically performed in the human mind, and is in fact performed in the human mind on a daily basis, for instance by school-aged children studying mathematics. Note that even if most humans would use a physical aid (e.g., pen and paper, a slide rule, or a calculator) to help them complete the recited calculation, the use of such physical aid does not negate the mental nature of this limitation. Thus, limitation (a) also falls into the “mental process” groupings of abstract ideas.
In addition, limitation (a) describes a naturally occurring relationship between the ratio of C11 to C13 and the non-responder phenotype, and thus may also be considered to recite a law of nature. Accordingly, limitation (a) recites a judicial exception (an abstract idea that falls within the mathematical concept and mental process groupings in the “2019 PEG”, and a law of nature), and the analysis must therefore proceed to Step 2A Prong Two.
Instant claim 12 recites “detecting the level of pT217 and other specific biomarkers in a cerebrospinal fluid (CSF) sample from the subject and correlating the level of pT217 in the sample with a tau PET SUVR for a subject and determining whether the subject is likely to have AD based on the level of the pT217compared to the tau PET SUVR, wherein the level of pT217 positively correlates with tau PET SUVR.” which describes a naturally occurring relationship between the one or more phosphor-tau and correlating it to AD, and thus is considered to recite a law of nature. Further, instant claim 12 and recite using the obtained phosphor-tau values from CSF and compare them to PET SUVR data to discriminate between an Alzheimer’s subject and a healthy state, which is directed towards an abstract idea that falls under the mental process grouping (i.e., concepts performed in the human mind (including an observation, evaluation, judgement, opinion)). Comparing collected information to a predetermined threshold, which is an act of evaluating information that can be practically performed in the human mind. Consequently, like example 43, instant claim 12 recite the judicial exception of applying and using a law of nature and an abstract idea. Claim 12 now requires a method of treating Alzheimer’s disease and do not add significantly more to the natural correlation; the method is solely directed to performing the steps to determine the natural correlation in the patient population and then to “apply it.” by treating with a generic anti-tau therapy. Moreover, a claimed treatment step or agent must be “particular”, i.e., specifically identified, so that it does not encompass all applications of a judicial exception(s) in order to integrate it into a practical application. The instant treatment limitation is not considered a “particular” treatment and is instead considered merely instructions to apply the judicial exception or is merely indicating a field of use. See MPEP § 2106.05(h). While new claim 48 also calls out specific anti-tau therapy agents, there is still no guidance beyond a diagnosis and apply well-known treatments with no further guidance or specificity of when to administer these treatments.
Dependent instant claims 17-19, 22, 24, 27-29, 38 and new claim 48 contain limitations that fall under a judicial exception. The dependent claims recite measurements of biomarkers and/or natural correlations of the presence and levels of biomarkers with a disease. Further, instant claims 12, 17-19, 22, 24, 27-29, 38 and 48 have a BRI that requires a comparison between a subject’s biomarker levels to a healthy subject’s biomarker level, which is directed towards an abstract idea that falls under the mental process grouping (i.e., concepts performed in the human mind (including an observation, evaluation, judgement, opinion). Comparing collected information to a predetermined threshold, which is an act of evaluating information that can be practically performed in the human mind. Lastly, Instant claims recite “determining whether the subject is likely to have AD based on the level of the pT217 compared to the tau PET SUVR, wherein the level of pT217 positively correlates with tau PET SUVR.”, which has a BRI that requires performing an arithmetic calculation in order to obtain a value relative to a healthy control in order to indicate the subject as being at risk for AD or a non-AD subject. This limitation therefore recites a mathematical calculation. The grouping of “mathematical concepts” in the 2019 PEG includes “mathematical calculations” as an exemplar of an abstract idea. 2019 PEG Section I, 84 Fed. Reg. at 52. Thus, limitation (a) falls into the “mathematical concept” grouping of abstract ideas. In addition, this type of simple arithmetic calculation (division) can be practically performed in the human mind, and is in fact performed in the human mind on a daily basis, for instance by school-aged children studying mathematics. Note that even if most humans would use a physical aid (e.g., pen and paper, a slide rule, or a calculator) to help them complete the recited calculation, the use of such physical aid does not negate the mental nature of this limitation. Thus, limitation (a) also falls into the “mental process” groupings of abstract ideas.
Accordingly, instant claims 12, 17-19, 22, 24, 27-29, 38 and new claim 48 recite a judicial exception (a law of nature, a natural correlation, and an abstract idea that falls within the mental process groupings) and the analysis must therefore proceed to Step 2A Prong Two.
Step 2A Prong 2: Does the claim recite additional elements that integrate the exception into a practical application?
Regarding instant claim 12, Example 43 of “2019 PEG” shows a similar fact pattern.
In claim 1 of example 43 of the “2019 PEG” and per Step 2A, prong 2, the claim as a whole does not integrate the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. Besides the abstract idea, the claim 1 of example 43 of the “2019 PEG” recites the additional element of “(b) administering a treatment to the patient having a non-responder phenotype”. Although this limitation indicates that a treatment is to be administered, it does not provide any information as to how the patient is to be treated, or what the treatment is, but instead covers any possible treatment that a doctor decides to administer to the patient. In fact, this limitation is recited at such a high level of generality that it does not even require a doctor to take the calculation step’s outcome (the patient’s phenotype) into account when deciding which treatment to administer, making the limitation’s inclusion in this claim at best nominal. Thus, limitation (b) of example 43 of the “2019 PEG” fails to meaningfully limit the claim because it does not require any particular application of the recited calculation, and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, limitation (b) of example 43 of the “2019 PEG” does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception.
Similarly, instant claim 12 does not have additional elements that would integrate the judicial exception cited above into a practical application. In comparison, claim 1 of Example 43 did not pass step 2A prong 2 with step of general treatment, instant claim 12 only recites the vague idea of treating with a generic anti-tau therapy and it dependent claim 48 calls for well-known therapies that would be applied whether one uses or does not use the instantly claimed method of claim 12. Example 43 failed with the step of general treatment, instant claim 12 only calls for treating the subject with ant anti-tau therapy which reads as a general suggestion to “apply it”.
Therefore, instant claim 12 does not integrate the judicial exception into a practical application.
Step 2B: Does the claim recite significantly more?
Regarding claim 1 of example 43 of the “2019 PEG” and per Step 2B, this part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. As explained with respect to Step 2A Prong Two, the claim recites a single additional element in limitation (b), which does not require any particular application of the recited calculation and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept (Step 2B: NO). The claim is not eligible.
Similarly, instant claim 12 recite the additional limitation of (a) providing a processed CSF obtained from a subject that is enriched for one or more phosphor-tau and Aβ species which recites measuring naturally occurring biomarkers in a sample from a subject which are mere instructions of obtaining a judicial exception and cannot be considered an inventive concept. Accordingly, instant claim 12 is not eligible (STEP 2B: NO).
Instant claims 12, 17-19, 22, 24, 27-29, 38 and new claim 48 are rejected as ineligible under 35 USC 101.
Response to Arguments
Applicant's arguments filed 6/16/2026 have been fully considered but they are not persuasive. Applicant argues that the newly cancelled and amended claims overcome the 101 judicial rejection since the newly amended claim 12 now requires treatment in conjunction with the instantly claimed natural correlation. This is not found persuasive because the new amendment is vague and not specific and reads as “apply it”. Newly amended claim calls for treating a subject with any anti-tau therapy. This is very broad and generic and is not a markedly significant change from what one would do with a patient with Alzheimer’s disease. New claim 48 does recite a narrower scope of treatment by calling out 4 specific anti-tau therapies but this is still vague and not dependent on only specifically being able to administer this treatment when you perform the claimed method based on the natural correlation. Therefore, for the reasons set forth above, the new amendments are not sufficient to overcome the 101 rejection of record.
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 nonobviousness.
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 12, 17-19, 22, 24, 27-29 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Wildsmith et al., 2018 (1/16/2026 PTO-892) as applied to claims 1-4, 19, 24-25, 28-29 and 38 above, and further in view of Barthelemy et al., WO 2019213612A1 (IDS filed on 9/27/2022).
The instant claims are towards methods of determining whether a human subject is likely to have Alzheimer’s disease (AD) by detecting the level of phosphorylated tau including pT111, pT153, pT175 , pT181, pS199, pS202, pT205, pS208, pS214, pT217 and pT231, in a cerebrospinal fluid (CSF) sample from a subject, and correlating the level of pT217 in the sample with a tau PET SUVR obtained with 18F GTP1 and determining whether the subject has AD based on the level of the pT217 compared to the tau PET SUVR, wherein the level of pT217 positively correlates with tau PET SUVR.
Wildsmith teaches determining the levels of phosphorylated tau in CSF samples to determine the diagnosis of subject to determine if they have AD. Wildsmith teaches using CSF samples analyzed by nano-LC-MS/MS and paired phosphorylated and unphosphorylated peptides at sites T181, S202, T205 and T217 were quantified as in instant claims 12, 18-19, 24, 28-29 and 38. Wildsmith teaches CSF tau levels, in particular the T181 phospho-variant, can support a diagnosis of AD when combined with CSF Ab42 levels as in instant claim 19. Wildsmith teaches using the tau PET tracer [18F]GTP1, and CSF measurements of different phosphorylated tau sites using a highly specific LC-MS/MS assay wherein the matched CSF samples, [18F]GTP1 and florbetapir images collected from cognitively normal (amyloid positive or negative), and amyloid positive cognitively impaired subjects (aged 50-85) who were sub-classified as prodromal, mild or moderate AD as in instant claims 12, 19, 24 and 28. Wildsmith teaches that this study provides insight into the relationship between tau PET imaging and CSF phospho-tau, and helps guide the usage and interpretation of biomarker data in the clinic and that CSF species containing phosphosites T217 and T205 are more closely reflective of tauopathy such as AD, as detected by tau PET. Wildsmith teaches the limitations of instant claims 12, 17-18 as set forth above since it teaches using CSF tau samples and comparing to tau PET SUVR. While Wildsmith teaches some of the target phosphorylated tau species, Wildsmith does not teach all of the claimed tau species or treatment.
Barthelemy teaches a method of discriminating a tauopathy, the method comprising providing a processed CSF or blood sample obtained from a subject with an isolated tau sample purified from cerebrospinal fluid (CSF) obtained from a subject, wherein the CSF is enriched for one or more phospho-tau (see [0060], [0139]). Barthelemy teaches a method to diagnose a subject's stage of AD comprising providing an isolated tau sample obtained from a subject and measuring, in the isolated tau sample, tau phosphorylation at one or more amino acid residue chosen from chosen from T111, S113, T181, S199, S202, S208, T153, T175, T205, S214, T217, and T231, and measuring total tau; and diagnosing the stage of the subject's AD when the measured phosphorylation level(s) significantly deviate from the mean in a control population without brain amyloid plaques as measured by PET imaging (see figure 13, see figure 15, see [0064], [0072]) and meets the tau species limitations of instant claims 12 18, 22, 24, 27-29 and 38. Barthelemy teaches measuring, in the isolated tau sample, tau phosphorylation at one or more amino acid residue chosen from T181 , T205 and T217 and measuring total tau; and diagnosing the subject as being a certain number of years after onset of MCI due to AD when the measured phosphorylation levels significantly deviate from the mean in a control population without brain amyloid plaques as measured by PET imaging (see [0010], [0271]) or a ratio calculated from the measured phosphorylation levels and total tau. Barthelemy teaches wherein the subject is diagnosed as having or at an increased risk of having AD when the detected pT153/T153 value is increased relative to a healthy control population and/or a non-AD tauopathy population (see [0072]); wherein the subject is diagnosed as having or at an increased risk of having AD when the detected pT111/T111 value is increased relative to a healthy control population and/or a non-AD tauopathy population (see figure 11, see [ 0025], [0071]) teaching measuring T111 in order to diagnose AD staging and where the pT111 levels are significantly deviated from the mean of the control population; wherein the subject is diagnosed as having or at an increased risk of having a tauopathy when the detected pT205/T205 value is increased relative to a healthy control population (see [0032] [0282]) teaching an increase in pT205 levels: wherein the subject is diagnosed as having or at an increased risk of having AD when the detected pS208/S208 value is increased relative to a healthy control population (see [0023] [0072]). Barthelemy teaches determining a composite pT217/T217 value wherein an increased composite value relative to a healthy control population indicates the subject as having or at an increased risk for AD or a non-AD tauopathy (see [0008] – [0009], [0070]). Barthelemy teaches providing an isolated tau sample obtained from a subject and measuring, in the isolated tau sample, tau phosphorylation at one or more amino acid residue chosen from chosen from T111, S113, T181, S199, S202, S208, T153, T175, T205, S214, T217, andT231, and measuring total tau; and determining if measured phosphorylation level(s) significantly deviate from the mean in a control population without brain amyloid plaques as measured by PET imaging and/or Al342/40 measurement in CSF and administering a tau therapy (see [0090], [0102], [0104], [0114]) as now required in instant claim 12.
While Barthelemy doesn’t explicitly teach the specific combination of phosphorylated tau combinations or increasing or decreasing ratios for all the species of tau it would have been prima facia obvious to one of ordinary skill in the art at the time of the instant application to consider measuring all of the disclosed species taught by Wildsmith and Barthelemy. One of ordinary skill in the art would be motivated to use the combined teachings of Wildsmith and Barthelemy to determine if someone has or is at risk for having AD since both Wildsmith and Barthelemy teach all of the required species and the methods taught by Wildsmith are capable of determining the ratios of tau species in the CSF and PET SUVR that predict the likely hood of diagnosing AD. One of ordinary skill in the art would have considered comparing the levels of the biomarkers from the subject to a healthy control to determine if the levels have increased, decreased, or stayed the same as already taught by Barthelemy. Using a healthy control sample when measuring biomarkers to compare values is a commonly used technique in the art.
One of ordinary skill in the art would have considered comparing the biomarker levels from the subject to a control (AD population) in order to discriminate AD and non-AD. It is a common technique in the diagnostic art to compare biomarker levels to a control population in order to differentiate/discriminate between diseases. It would have been prima facia obvious to one of ordinary skill in the art to exclude a subject from an AD diagnosis when they do not have the biomarker levels that are associated with AD disease.
Claims 12, 17-19, 22, 24, 27-29, 38 and new claim 48 are rejected under 35 U.S.C. 103 as being unpatentable over Wildsmith et al., 2018 (1/16/2026 PTO-892) and Barthelemy et al., WO 2019213612A1 (IDS filed on 9/27/2022) in view of Pinheiro et al., 2018 (instant PTO-892).
While Barthelemy teaches treating AD subjects with a tau therapy, Barthelemy and Wildsmith fail to teach treating with an anti-tau antibody which include gosuranemab and ABBV-8E12 as required in instant new claim 48.
Pinheiro teaches multiple types of drug treatments for AD and specific tau therapies for AD subjects and that tau has become one of the most actively pursued therapeutic targets for AD, recently (see abstract). Pinheiro teaches clinical trials involving tau-directed immunotherapeutic approaches of treating AD subjects with gosuranemab and ABBV-8E12 (see Table2, page 11 and page 9, bottom of 1st column) and that passive immunotherapy, involving direct administration of anti-tau antibodies, can be a more effective and safer alternative to active immunization with tau epitopes due to the weakened immune system of the elderly population (see page 8, “Passive Immunization”). Pinheiro does not teach the claimed method of AD diagnosis as in instant claim 12.
One of ordinary skill in the art would be motivated to use the teachings of treatment of AD by Pinheiro and administer these types of passive immunization that target tau since Pinheiro states that tau treatments are the new and the most actively pursued therapeutic targets for AD. One of ordinary skill would be motivated to use the treatments taught by Pinheiro in combination with tau derived diagnostic methods as taught by Wildsmith and Barthelemy with a reasonable expectation of success since the prior art teaches that AD subjects suffer from tau dysregulation also.
Response to Arguments
Applicant's arguments filed 6/16/2026 have been fully considered but they are not persuasive. Applicant argues that the references of record fail to teach or suggest detecting the level of at least one tau phosphosite in a cerebrospinal fluid (CSF) sample from the subject with the claimed phosphorylated tau biomarkers and that the examiner fails to explain why a person of skill in the art would measure these particular species in the context of a method of treatment as recited in claim 12.
These arguments are not found persuasive because the prior art teaches all of the required steps and all of the required biomarkers linked to AD diagnosis based on tau biomarkers. Wildsmith is depended upon to demonstrate that all of the required steps are known in the prior art in the use of phosphorylated tau site biomarkers and specially teach one of the required biomarkers pT217. As already set forth above, Wildsmith places these phosphorylated tau site biomarkers in the context of AD diagnosis while Barthelemy teaches all of the other required phosphorylated tau site biomarkers that are used in AD diagnosis and treatment. Therefore, there is a clear reason why these biomarkers would be suitable for use in the method of AD diagnosis using tau biomarkers and AD treatment. Therefore, there is clearly reasoning why one of ordinary skill in the art would be motivated to use all of the known phosphorylated tau site biomarkers in the Wildsmith method since they are both in the same field of endeavor, AD diagnosis and treatment, and one of ordinary skill in the art would have a reasonable expectation of success in combining the references and produce the same method of diagnosis.
Conclusion
No claims are allowed.
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.
Advisory Information
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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