DETAILED ACTION
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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
This application is the U.S. National Stage (371) application of PCT/US20/46224 filed on 08/13/2020 which claims priority to U.S. Provisional Application No. 63/044,836 filed on 06/26/2020, U.S. Provisional Application No. 62/970,950 filed on 02/06/2020 and U.S. Provisional Application No. 62/886,165 filed on 08/13/2019.
Claim Status
Claims 1-2, 4-6, 8-9 and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/03/2025.
Claims 3, 7, 10-15, 17-34 and 40-75 are cancelled. Claims 35-39 are currently amended, and the Applicant notes that no new matter is added. Claims 76-78 and 80-84 are new, and the Applicant notes that no new matter is added.
Newly submitted claim 79 is directed to non-elected species as noted in the Office action of 12/10/2025. Election of species was made without traverse in the reply filed on 11/03/2025.
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 Accordingly, claim 79 is withdrawn from consideration as being directed to non-elected species. See 37 CFR 1.142(b) and MPEP § 821.02.
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.
Thus, claims 35-39, 76-78 and 80-84 are under examination.
Withdrawn Rejections
The previous rejection of claim 35 under 35 U.S.C. 112(b), regarding indefiniteness, is withdrawn in light of Applicant’s amendments of the claim.
The previous rejection of claim 39 under 35 U.S.C. 102, regarding anticipation, is withdrawn in light of Applicant’s amendments of the claim.
New Objections & Rejections Necessitated by Applicant’s Amendments of Claims
Claim Objections
Claim 35 is objected to because of the following informalities: the claim recites two prepositions in a row “determining a level of microtubule-binding region (MTBR) tau that is indicative of Alzheimer disease (AD)-related tau deposition and/or and amyloid beta deposition”. To move prosecution, the Examiner will interpret the claim as “determining a level of microtubule-binding region (MTBR) tau that is indicative of Alzheimer disease (AD)-related tau deposition and/or amyloid beta deposition”. Appropriate correction is required.
Also, the amendments to the claims are not proper since they do not comply with 37 C.F.R. § 1.121(c)(2), which states, "All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of 'currently amended,' and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted
matter must be shown by strike-through except that double brackets placed before and after the
deleted characters may be used to show deletion of five or fewer consecutive characters. The text of
any deleted subject matter must be shown by being placed within double brackets if strike-through
cannot be easily perceived." See also, 37 C.F.R. § 1.121(c)(4)(ii), which states, “Cancellation of a
claim shall be effected by an instruction to cancel a particular claim number. Identifying the status of
a claim in the claim listing as 'canceled' will constitute an instruction to cancel the claim.” In the
instance case, claims 38-39 are submitted with markings to indicate that changes have been made relative to the immediate prior version of the claims, but the status of the presented claims is submitted as “Previously presented”. Thus, the status of submitted claims 38-39 is incorrect.
To move prosecution, the Examiner is treating claims 38-39 as currently amended.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 77 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Regarding claim 77, the new claim recites “The method of claim 35, wherein step (c) further comprises classifying the subject as having preclinical Alzheimer's disease when the subject is amyloid positive and has no dementia”. However, the inventive concept of “classifying the subject as having preclinical Alzheimer's disease when …” is not supported in the specification because the specification does not support nor discusses classifying the subject as having preclinical Alzheimer's disease. Thus, the claim does not have support for “classifying the subject as having preclinical Alzheimer's disease when the subject is amyloid positive and has no dementia”.
Also, none of the previous sets of claims recite “classifying the subject as having preclinical Alzheimer's disease when the subject is amyloid positive and has no dementia”.
MPEP2163.02 recites “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. This conclusion will result in the rejection of the claims affected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph - description requirement, or denial of the benefit of the filing date of a previously filed application, as appropriate”. In the instant case, the inventive concept of “classifying the subject as having preclinical Alzheimer's disease when the subject is amyloid positive and has no dementia” was introduced into the claims without proper support from the specification.
MPEP2163.06 further recites “Lack of written description is an issue that generally arises with respect to the subject matter of a claim. If an applicant amends or attempts to amend the abstract, specification or drawings of an application, an issue of new matter will arise if the content of the amendment is not described in the application as filed… If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981)… When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not "new matter" is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure”. In the instant case, the subject matter of “classifying the subject as having preclinical Alzheimer's disease when the subject is amyloid positive and has no dementia” was not properly described in the instant application as filed, and consequently it raises doubt as to possession of the claimed invention at the time of filing as discussed above in MPEP2163.02 and MPEP2163.06.
Therefore, claim 77 does not comply with the written description requirement, and the claim is rejected under 35 U.S.C. 112(a) for lack of written description.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 39 and 82 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 39, the phrase "wherein step (c) is based on both the quantified MTBR tau species and the Aβ42/40 ratio" renders the claim indefinite because it is not clear from the claim language how will the Aβ42/40 ratio be used with the quantified MTBR tau species for the comparison step of claim 35. The specification does not provide a standard for making the comparison with both Aβ42/40 ratio and quantified MTBR tau species, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the language of claim 39 is not clear and claim 39 is deemed indefinite.
Regarding claim 82, the claim recites that “determining the level indicative of AD-related tau deposition and/or amyloid beta deposition is based on a ratio of the quantified MTBR tau species to a mid-domain tau species measured in the same processed CSF or blood sample”. And claim 35, onto which claim 82 depends, recites depleting the processed sample of mid-domain tau species before measuring MTBR tau species, and thus it is not clear how will mid-domain tau species be measured in claim 82 if they have been depleted from the sample. Thus, the language of claim 82 is not clear and is vague, and the claim is rejected as being indefinite under 35 U.S.C. 112(b).
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 39 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 39 is expanding the comparison criteria of claim 35 which recites “(c) comparing the quantified amount of the MTBR tau species to a reference level determined from a control population that is amyloid negative, wherein an increased level of the MTBR tau species relative to the reference level is indicative of AD-related tau deposition and/or amyloid beta deposition in the subject” by further adding Aβ42/40 ratio to the comparison criteria as claim 39 recites “The method of claim 35, further comprising determining an amyloid beta Aβ42/40 ratio, wherein step (c) is based on both the quantified MTBR tau species and the Aβ42/40 ratio”. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Maintained Rejections
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 35-39, 76-78, 80-84 are rejected under 35 U.S.C. 101 because the claimed invention is for a process or a method that is directed to at least one judicial exception without significantly more. The claims recite a mere collection of information in the form of data that is compared to a reference value from which the applicant or doctor will be able to predict the possibility of a subject having Alzheimer disease (AD)-related tau deposition and/or amyloid beta deposition. Such an inference is not sufficient to transform the abstract idea of a mental process of comparison, and a law of nature (correlation of MTBR amounts to AD-related tau deposition and/or amyloid beta deposition in a subject) into a patentable application.
The claims are ineligible because the claims recite at least one judicial exception, i.e., abstract idea of a mental process (comparing the quantified amount of the MTBR tau species to a reference level) and a law of nature (correlation of MTBR amounts to AD-related tau deposition and/or amyloid beta deposition in a subject. Moreover, the claims as a whole do not integrate the judicial exceptions into a practical application nor do they provide an inventive concept.
Step 1: Is the claim to a process, machine, manufacture or composition of matter?)
This part of the eligibility analysis evaluates whether the claim falls within any statutory category per MPEP 2106.03.
Example 43 of 2019 Revised Patent Subject Matter Eligibility Guidance (PEG) is particularly enlightening because the fact pattern of claim 1 of example 43 is most similar to the instant application claims (Subject matter eligibility | USPTO)
Regarding claim 1 of example 43 of the 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, claim 35 of the instant application is also directed to a statutory class of a method for determining a level of microtubule-binding region (MTBR) tau that is indicative of Alzheimer disease (AD)-related tau deposition and/or amyloid beta deposition by quantifying one or more MTBR tau species from a processed cerebrospinal fluid (CSF) sample or blood sample that is depleted of mid-domain tau and enriched for microtubule-binding region (MTBR) tau. And comparing the quantified amount of the MTBR tau species to a reference level. (Step 1: YES).
(Step 2A, Prong 1: Does the claim recite an abstract idea, law of nature or natural phenomenon?)
Regarding claim 1 of example 43 of PEG and 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 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 (division) 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 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 PEG, and a law of nature), and the analysis must therefore proceed to Step 2A Prong Two.
Similarly, claim 35 of the instant application recites a judicial exception of an abstract idea of a mental process of “comparing the quantified amount of the MTBR tau species to a reference level
determined from a control population that is amyloid negative”.
Furthermore, claim 35 is also reciting a law of nature of correlating the amount of measured MTRB-tau species to AD-related tau deposition and/or amyloid beta deposition in the subject “wherein an increased level of the MTBR tau species relative to the reference level is indicative of AD-related tau deposition and/or amyloid beta deposition in the subject”.
Last, while example 43 of the PEG is drawn to the calculation of a ratio of C11 to C13 levels in limitation (a), claim 35 of the instant application is just merely measuring the amount of MTRB-tau species and associating such an amount with AD-related tau deposition and/or amyloid beta deposition in the subject. Thus, claim 35 of the instant application also describes a naturally occurring relationship between the amount of the measured MTRB-tau species and AD--related tau deposition and/or amyloid beta deposition in the subject, and thus is considered to recite a law of nature.
Accordingly, claim 35 of the instant application recites two judicial exceptions of an abstract idea of a mental process and a law of nature, and the analysis must therefore proceed to Step 2A Prong Two.
(Step 2A, Prong 2: Does the claim recite additional elements that integrate the judicial exception into a practical application?)
Regarding claim 1 of example 43 of 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 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 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 PEG does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception.
Similarly, claim 35 of the instant application does not have additional elements that would integrate the judicial exceptions cited above into a practical application. The claim has steps of measuring MTBR tau species in a CSF or blood sample of a subject to correlate the presence of MTBR tau species to AD-related tau deposition and/or amyloid beta deposition in the subject, and these steps do not integrate the judicial exception into a practical application because they are data gathering steps to use in the calculation and correlation, which do not add a meaningful limitation to the method as they are insignificant extra-solution activity. These steps do not integrate the judicial exceptions into a practical application because they do not amount to more than the judicial exceptions themselves, analogous to Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 80, 84, 101 USPQ2d 1961, 1968-69, 1970 (2012). Furthermore, the claims do not act on or use the judicial exceptions in any further steps as required by MPEP 2106.04(d). Furthermore, unlike claim 1 of example 43 of PEG, claim 1 of the instant application does not have a treatment step.
Therefore, claim 35 does not integrate the judicial exception into a practical application.
(Step 2B: Does the claim recite additional elements that amount to significantly more than the judicial exception?)
Regarding claim 1 of example 43 of 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, claim 35 of the instant application simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, such as measuring MTBR tau species with a commercially available assay such as by liquid chromatography - mass spectrometry (LC-MS) (Specification, page 46, [0147-0148] and Table A, “Tryptic peptides of tau that indicate the presence of MTBR tau”). Furthermore, the claim itself is recited at a high level of generality in which any assay can be used as the measurement method for claim 35.
Thus, claim 35 is not eligible and is rejected under 35 USC 101.
Regarding claims 36-37 and 76, the claims are attempting to specify the subject’s condition which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claims 38-39, the claims recite what to quantify or identify in the biological or CSF sample which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 77, the claim attempts to classify the patient which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 78, the claim teaches that method to use for quantification which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 80, the claim further defines the processing of the sample which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 81, the claim describes how to monitor a disease which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 82, the claim is still calculating a ratio which is an abstract idea of a mathematical calculation which is a judicial exception without significantly more and is not integrated into a practical application. Claim 82 is also reciting a judicial exception of a natural law (natural correlation between AD-related tau deposition and/or amyloid beta deposition and the ratio of MTBR tau species to a mid-domain tau species) without significantly more and is not integrated into a practical application
Regarding claim 83, the claim correlates the increased level of MTBR tau species with Tau PET imaging which does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Regarding claim 84, although the claim provides a treatment, it is too general and thus it does not integrate the judicial exception into a practical application, nor does it amount to significantly more.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 35-36 and 38, 78, 80-81 and 84 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Steen et al. (US 11,698,378 B2, priority to Sep. 25, 2015).
Claims 78, 80-81 and 84 are new and are included in this rejection.
Regarding claim 35, the claim recites:
“A method for determining a level of microtubule-binding region (MTBR) tau that is indicative of Alzheimer disease (AD)-related tau deposition and/or and amyloid beta deposition in a subject, the method comprising:
(a) providing a processed cerebrospinal fluid (CSF) sample or blood sample obtained
from the subject, wherein the processed CSF or blood sample is depleted of mid-domain tau and
enriched for microtubule-binding region (MTBR) tau;
(b) quantifying, in the processed sample, one or more MTBR tau species comprising the
amino acid sequence of SEO ID NO:3; and
(c) comparing the quantified amount of the MTBR tau species to a reference level
determined from a control population that is amyloid negative, wherein an increased level of the MTBR tau species relative to the reference level is indicative of AD-related tau deposition and/or amyloid beta deposition in the subject”.
Regarding claim 35, Steen teaches a method for determining a level of microtubule-binding region (MTBR) tau that is indicative of Alzheimer disease (AD)-related tau deposition in a subject (Columns 9-10, “This disclosure also provides a highly sensitive, robust tau-specific assay that can measure tau peptides down to amol quantities”; column 64, lines 42-46, “Importantly, in our study, the majority of the peptides selected as discriminating features are located in the MT-binding repeat region of tau, including exon 10, indicating that this region harbors molecular characteristics that are unique to each tauopathy”). And Steen further teaches providing a processed cerebrospinal fluid (CSF) sample or blood sample obtained from the subject (Column 15, lines 3-13). Also, Steen teaches that the processed CSF or blood sample is depleted of mid-domain tau and enriched for microtubule-binding region (MTBR) tau (Sheet 1 of 26, Fig 1A, “Fractionation/Enrichment”; column 64, lines 42-46, “Importantly, in our study, the majority of the peptides selected as discriminating features are located in the MT-binding repeat region of tau, including exon 10, indicating that this region harbors molecular characteristics that are unique to each tauopathy”). And Steen teaches providing a processed cerebrospinal fluid (CSF) sample or blood sample obtained from the subject, wherein the processed CSF or blood sample is depleted of mid-domain tau and enriched for microtubule-binding region (MTBR) tau (MTBR) tau (Sheet 1 of 26, Fig 1A, “Fractionation/Enrichment”; Column 15, lines 3-13; column 64, lines 42-46, “Importantly, in our study, the majority of the peptides selected as discriminating features are located in the MT-binding repeat region of tau, including exon 10, indicating that this region harbors molecular characteristics that are unique to each tauopathy”). Also Steen teaches quantifying, in the processed sample, one or more MTBR tau species comprising the amino acid sequence of SEO ID NO:3 of the instant application and teaches that the presence of SEQ ID No.10 (LQTAPVPMPDLK) with post translation modifications (PTM) in a biological sample indicates that the patient has Alzheimer’s disease AD (Sheet 12 of 26, Fig. 5B, “LQTAPVPMPDLK”; column 2, lines 33-35; column 3, lines 47-57; column 24, lines 59-63; Sequence alignment of SEQ ID10 of Reference Steen to SEQ ID 3 of instant application). Steen further teaches comparing the quantified amount of the MTBR tau species to a reference level determined from a control population that is amyloid negative, wherein an increased level of the MTBR tau species relative to the reference level is indicative of AD-related tau deposition and/or amyloid beta deposition in the subject (Column 2, lines 42-48; column 5, lines 1-3; column 15, lines 30-31).
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Sequence Alignment of SEQ_ID03 of instant application to SEQ_ID10 of Steen et al.
Regarding claim 36, Steen teaches that the subject has mild cognitive impairment (Colum 13, line 40; column 33, line 42-43).
Regarding claim 38, Steen teaches quantifying post-translational modifications of tau protein (Colum 2, lines 20-48, “… identifying the patient as having a tauopathy if the level of PTM associated with one or more tau peptide fragments in the patient sample is altered relative to the reference level for the tau peptide fragments …”). And Steen further teaches quantifying a post-translationally modified tau species comprising phospho-tau217 that is based on both the quantified MTBR tau species and the quantified phospho-tau217 (Table 2, “Summary of phosphorylated tau peptide species and phosphorylation sites detected in deP-tau, P-tau and PP-tau”, “PTM site”, “T 217”).
Regarding claim 78, Steen teaches that the quantifying comprises liquid chromatography-tandem mass spectrometry (LC-MS/MS) (Column 42, lines 21-26).
Regarding claim 80, Steen teaches that the processed sample is depleted of N-terminal tau and mid-domain tau prior to quantifying the MTBR tau species (Sheet 1 of 26, Fig 1A, “Fractionation/Enrichment”; column 64, lines 42-46, “Importantly, in our study, the majority of the peptides selected as discriminating features are located in the MT-binding repeat region of tau, including exon 10, indicating that this region harbors molecular characteristics that are unique to each tauopathy”).
Regarding claim 81, Steen teaches that step (c) of claim 35 further comprises monitoring disease progression by repeating the quantifying step at two or more time points and detecting an increase in the MTBR tau species over time (Column 54, lines 60-62; column 64, lines 42-46, “Importantly, in our study, the majority of the peptides selected as discriminating features are located in the MT-binding repeat region of tau, including exon 10, indicating that this region harbors molecular characteristics that are unique to each tauopathy”).
Regarding claim 84, Steen teaches administering to the subject a therapeutic agent for treating or preventing Alzheimer's disease when the increased level of the MTBR tau species indicates AD-related tau deposition and/or amyloid beta deposition (Column 2, lines 45-48; column 3, lines 39-46; column 30, lines 31-57).
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 (PHOSITA) 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.
Claims 37, 76 and 83 are rejected under 35 U.S.C. 103 as being unpatentable over Steen et al. (US 11,698,378 B2, priority to Sep. 25, 2015) as applied to claim 35 above, and further in view of Blennow et al. (Trends in Pharmacological Sciences, May 2015, Vol. 36, No. 5).
Claims 76 and 83 are new and are included in this rejection.
Regarding claim 37, the claim recites:
“The method of claim 35, wherein step (c) further comprises classifying the subject as having Alzheimer's disease when the increased level of the MTBR tau species indicates AD-related tau deposition and/or amyloid beta deposition.”
Regarding claims 37 and 76, the teachings of Steen are previously discussed.
Moreover, regarding claim 83, Steen teaches correlating the increased level of the MTBR tau species with tauopathy and tau deposition in the subject’s brain (Column 12, lines 15-42).
Regarding claim 37, Steen does not teach the presence of amyloid beta deposition in a subject’s brain or brain arteries as a sign of Alzheimer’s disease.
Regarding claim 76, Steen does not teach that the subject is amyloid positive as determined by PET imaging or CSF Aβ42/40 measurement.
Regarding claim 83, Steen does not teach PET imaging signal.
Regarding claim 37, Blennow teaches the presence of amyloid beta deposition in a subject’s brain as a sign of AD (Abstract).
Regarding claim 76, Blennow teaches that the subject is amyloid positive as determined by PET imaging or CSF Aβ42/40 measurement (Page 300, left column, fifth paragraph, “The first study on amyloid PET used an 11C-labeled modified derivative of the amyloid-binding histological dye Thioflavin-T called Pittsburgh Compound-B (PiB) and showed increased ligand retention in cortical brain regions in AD dementia cases as compared with controls, using cerebellum as a reference region”)
Regarding claim 83, Blennow teaches PET imaging signal that is indicative of tau deposition in the subject’s brain (Page 300, left column, fifth paragraph).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the amyloid beta deposition marker of Blennow with the posttranslational modifications (PTM) of tau species to improve the diagnosis of Alzheimer’s disease in a patient because Blennow noted that amyloid deposition is central in the molecular pathogenesis of Alzheimer’s disease (Abstract). A skilled artisan would succeed in combining the methods of Blennow and Steen because the methods are in the field of neurodegenerative diseases and Alzheimer’s disease.
A skilled artisan is motivated to use the amyloid marker of Blennow with the PTM markers of tau species of Steen to produce a diagnostic test with high sensitivity and specificity for Alzheimer’s disease.
Response to Arguments
Applicant's arguments filed 03/10/2026 have been fully considered but they are not persuasive.
Rejection of claims 35-39 under 35 U.S.C. 101:
The Applicant argued that the amended claim 35 is directed to a specific method (e.g., laboratory method) involving concrete biochemical processing and measurement step, and therefore the claim is not directed merely to an abstract idea or to a law of nature.
This argument is not persuasive because the amended claim 35 is still directed at least one judicial exception without significantly more i.e., abstract idea of a mental process (comparing the quantified amount of the MTBR tau species to a reference level) and a law of nature (correlation of MTBR amounts to AD-related tau deposition and/or amyloid beta deposition in a subject. Moreover, the claims as a whole do not integrate the judicial exceptions into a practical application nor do they provide an inventive concept.
The Applicant introduced a treatment step to dependent claim that is too general to integrate the judicial exceptions into a practical application.
The Applicant is advised to include a specific treatment step in claim 35 and to avoid conditionality of treatment to overcome the 101 rejection of claims.
Rejection of claims 35-36 and 38 under 35 U.S.C. 102:
The Applicant argued that Steen does not does not disclose providing a processed CSF or blood sample that is depleted of mid-domain tau and enriched for MTBR tau.
This argument is not persuasive because Steen teaches that the processed sample is depleted of N-terminal tau and mid-domain tau prior to quantifying the MTBR tau species (Sheet 1 of 26, Fig 1A, “Fractionation/Enrichment”; column 64, lines 42-46, “Importantly, in our study, the majority of the peptides selected as discriminating features are located in the MT-binding repeat region of tau, including exon 10, indicating that this region harbors molecular characteristics that are unique to each tauopathy”)
The Applicant argued that Steen also fails to disclose quantifying MTBR tau species comprising SEQ ID N0:3 in processed CSF or blood samples as a clinical biomarker.
This argument is not persuasive because Steen teaches quantifying, in the processed sample, one or more MTBR tau species comprising the amino acid sequence of SEO ID NO:3 of the instant application and teaches that the presence of SEQ ID No.10 (LQTAPVPMPDLK) with PTM in a biological sample indicates that the patient has Alzheimer’s disease AD (Sheet 12 of 26, Fig. 5B, “LQTAPVPMPDLK”; column 2, lines 33-35; column 3, lines 47-57; column 24, lines 59-63).
The Applicant argued that Steen fails to teach that a single MTBR peptide, such as SEQ ID NO:3 is quantified in an enriched CSF/blood sample and capable of being used as a standalone biomarker.
This argument is not persuasive because the instant application does not limit the method to only quantifying SEQ ID No. 3 and per part (b) of claim 35, the claim recites “quantifying in the processed sample, one or more MTBR comprising the amino acid sequence of SEQ ID NO:3”. Thus, the method of the instant is not confined to quantifying only SEQ ID No. 3.
The Applicant argued that Steen does not disclose comparing quantified MTBR tau levels to a reference level determined from an amyloid-negative control population and does not disclose determining that MTBR tau levels are indicative of AD-related tau deposition and/or amyloid beta deposition, as claimed.
This argument is not persuasive because Steen teaches comparing the quantified amount of the MTBR tau species to a reference level determined from a control population that is amyloid negative, wherein an increased level of the MTBR tau species relative to the reference level is indicative of AD-related tau deposition and/or amyloid beta deposition in the subject (Column 2, lines 42-48; column 5, lines 1-3; column 15, lines 30-31).
Thus, the previous rejection of claims 35-36 and 38 under 35 U.S.C. 102 is maintained and is made final.
Rejection of claim 37 under 35 U.S.C. 103:
The Applicant argued against the reference combination of Steen and Blennow because it fails to teach or suggest the presently claimed method.
This argument is moot as it has been shown above that Steen teaches the missing limitations that the Applicant argued about. Furthermore, Blennow is a secondary reference that is brought to teach any missing limitations in the dependent claims.
Thus, the previous rejection of claim 37 is maintained and is made final.
Conclusion
No claims are allowed.
Notwithstanding the 112(b) and 101 rejection, claim 82 is free of the prior art because there is no prior art that teaches or suggests a ratio of the quantified MTBR tau species to a mid-domain tau species measured in the same processed CSF or blood sample as being indicative of AD-related tau deposition and/or amyloid beta deposition.
And the closest prior art is discussed:
Steen et al. (US 11,698,378 B2, priority to Sep. 25, 2015) teaches a method for determining a level of microtubule-binding region (MTBR) tau that is indicative of Alzheimer disease (AD)-related tau deposition in a subject (Columns 9-10, “This disclosure also provides a highly sensitive, robust tau-specific assay that can measure tau peptides down to amol quantities”; column 64, lines 42-46, “Importantly, in our study, the majority of the peptides selected as discriminating features are located in the MT-binding repeat region of tau, including exon 10, indicating that this region harbors molecular characteristics that are unique to each tauopathy”). Steen does not teach nor suggest a ratio of the quantified MTBR tau species to a mid-domain tau species measured in the same processed CSF or blood sample as being indicative of AD-related tau deposition and/or amyloid beta deposition.
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 OMAR RAMADAN whose telephone number is (571)270-0754. The examiner can normally be reached Monday-Friday 8:30 am - 5:00 pm.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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