DETAILED ACTION Preliminary Amendment fi l ed on 03/25/2024 is acknowledged. Claims 1-21 are pending in the application and are considered on merits . 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. 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. Claim 1 - 10, 12-14, 16 and 18-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. STEP 2A – Prong One Claim Recites a Judicial Exception Claim 1 recites a method comprising: preparing a biological sample, digesting proteins with a protease, detecting a proteolytic peptide from at least one listed protein using mass spectrometry with reference peptide, for assessing efficacy of treatment for a neurodegenerative disease. The claim is directed to detecting naturally occurring peptides in a biological sample and correlating their presence/level with treatment efficacy. Naturally occurring peptides and their relationship to disease or treatment response constitute natural phenomena and laws of nature. The Federal Circuit has consistently held that diagnostic methods based on detecting naturally occurring biomarkers are directed to judicial exceptions. See: Mayo Collaborative Servs. v. Prometheus Labs., 566 U.S. 66 (2012) Cleveland Clinic Found. v. True Health Diagnostics, 859 F.3d 1352 (Fed. Cir. 2017) Athena Diagnostics, Inc. v. Mayo Collaborative Servs., 915 F.3d 743 (Fed. Cir. 2019) Accordingly, Claim 1 recites a judicial exception. STEP 2A – Prong Two No Integration Into a Practical Application The additional claim elements include: incubating the sample with a protease to form a proteolytic digest; assaying the digest using mass spectrometry; using a labeled or unlabeled reference peptide. These are routine and conventional laboratory techniques for peptide detection and quantification. The claim does not: require a new or improved mass spectrometry technique, require a specific technological improvement, require a specific treatment step based on the result, alter the natural relationship being observed. The protease digestion and mass spectrometry steps merely gather data about the natural phenomenon and do not impose any meaningful limit beyond the judicial exception itself. Similar diagnostic claims were found ineligible in: Mayo (measuring metabolite levels via routine techniques) Athena (detecting antibodies using conventional assays) Cleveland Clinic (measuring MPO levels via standard detection methods) Accordingly, the claim does not integrate the judicial exception into a practical application. STEP 2B – No Inventive Concept The additional elements—protease digestion, mass spectrometry detection, and use of reference peptides—are well-understood, routine, and conventional techniques in the field of proteomics prior to the filing date. The claim merely applies conventional techniques to observe a natural relationship between peptide levels and treatment efficacy as evidenced by Van Eyke et al. below . As held in Mayo, appending routine, conventional steps to a law of nature does not provide an inventive concept. Therefore, the claim does not include significantly more than the judicial exception. Claim 2 -10, 12-14, 16 and 18-20 do not add significantly more than the judicial exception either. Claim Rejections - 35 USC § 102 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. 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. Claim(s) 1 -11 and 13-18 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Van Eyk et al. (US 2015/0212098) (Eyk) . Regarding claim 1, Eyk teaches a method for assessing the efficacy of a treatment for a neurodegenerative disease (AD) in a subject (par [0028]), the method comprising: (i) preparing a biological sample from the subject for assay by incubating the sample with a protease to form a proteolytic digest of proteins in the sample ( Fig. 2, par [0077]) ; and (ii) assaying the proteolytic digest of proteins of step (i) for the presence of a proteolytic peptide of at least one protein selected from the group of proteins consisting of Matrix metalloproteinase-9, Chitinase-3-like protein 1, Protein S1 OO-A8, Protein S100-A9, Neutrophil collagenase (MMP8), Complement C3, Galectin-3-binding protein, Catalase, Extracellular superoxide dismutase, Prosaposin, Beta-hexosaminidase subunit beta, Cathepsin D, Beclin-1, Lysosome-associated membrane glycoprotein 1, Autophagy protein 13, E3 ubiquitinprotein-protein ligase RNF26, E3 ubiquitin-protein ligase TRIM33, FAST kinase domain-containing protein 5, mitochondrial, Apoptosis-inducing factor 1 mitochondrial, Transmembrane protein 126A, Neurofilament light polypeptide, Chromogranin-A, Contactin-1, Neurexin-1-beta, Protein MTSS 1 (Metastasis suppressor YGL-1 ), Synaptotagmin-3, Apolipoprotein E ( Table 3, par [0006]), Apolipoprotein D, Clusterin ( Table 3, par [0006]), Flotillin-2, Cadherin-2, Neural cell adhesion molecule 2, Amyloid-beta precursor protein ( Table 3, par [0006] [0014] ) , Amyloid-like protein 1, Peptidyl-prolyl cis-trans isomerase FKBP3, Peptidyl-prolyl cis-trans isomerase FKBP4, Kallikrein-6, Neutrophil gelatinase-associated lipocalin, Protein disulfide-isomerase A1 (PDIA1 ), Limbic system-associated membrane protein (Fragment), Ceruloplasmin, Serotransferrin, Vacuolar protein sorting-associated protein 16 homolog (hVPS16), Peptidyl-prolyl cis-trans isomerase (PPlase; HEL-S-39), Lymphocyte cytosolic protein 2, Lactadherin, 72 kDa type IV collagenase, Transforming growth factor-beta-induced protein ig-h3, Neural proliferation differentiation and control protein 1, Ganglioside GM2 activator, wherein the presence of said proteolytic peptide is assayed for using mass spectrometry with reference to a corresponding labelled (known to be free of AD or a reference level) and/or unlabelled reference proteolytic peptide ( Fig. 2, par [0041] [0077] ) . Regarding claim 2, Eyk teaches stratifying the subject according to the relative concentration of a peptide measured in the sample (par [0027] [0041] ). Regarding claim 3, Eyk teaches diagnosing the neurodegenerative disease of the subject according to the relative concentration of a peptide measured in the sample (par [0028] [0041]). Regarding claim 4, Eyk teaches administering a pharmaceutical composition to the subject for the treatment of the neurodegenerative disease (par [0060]) . Regarding claim 5, Eyk teaches treating the subject with a pharmaceutical composition for a second-line treatment of the neurodegenerative disease (par [0060]) . Regarding claim 6, Eyk teaches that wherein the protease is a serine protease (trypsin) , a cysteine protease, a threonine protease, an aspartic protease, a glutamic protease or a metalloprotease (par [0077]). Regarding claim 7, Eyk teaches that wherein the protease is trypsin (par [ 0077]) . Regarding claim 8, Eyk discloses a kit for assessing the efficacy of a first-line treatment for a neurodegenerative disease in a subject (par [0028]), comprising: a plurality of sample preparation media for analysis of a sample by mass spectrometry for the presence of a proteolytic peptide (Table 2, par [0077]) of at least one protein selected from the group of proteins consisting of Matrix metalloproteinase-9, Chitinase-3-like protein 1, Protein S1 00-A8, Protein S1 00-A9, Neutrophil collagenase (MMP8). Complement C3, Galectin-3-binding protein, Catalase, Extracellular superoxide dismutase, Prosaposin, Beta-hexosaminidase subunit beta, Cathepsin D, Beclin-1, Lysosome-associated membrane glycoprotein 1, Autophagy protein 13, E3 ubiquitin-protein ligase RNF26, E3 ubiquitin-protein ligase TRIM33, FAST kinase domain-containing protein 5, mitochondrial, Apoptosisinducing factor 1 mitochondrial, Transmembrane protein 126A, Neurofilament light polypeptide, Chromogranin-A, Contactin-1, Neurexin-1-beta, Protein MTSS 1 (Metastasis suppressor YGL-1 ), Synaptotagmin-3, Apolipoprotein E, Apolipoprotein D, Clusterin, Flotillin-2, Cadherin-2, Neural cell adhesion molecule 2, Amyloid-beta precursor protein, Amyloid-like protein 1, Peptidyl-prolyl cis-trans isomerase FKBP3, Peptidyl-prolyl cis-trans isomerase FKBP4, Kallikrein-6, Neutrophil gelatinaseassociated lipocalin, Protein disulfide-isomerase A 1 (PDIA 1 ), Limbic systemassociated membrane protein (Fragment), Ceruloplasmin, Serotransferrin, Vacuolar protein sorting-associated protein 16 homolog (hVPS 16), Peptidyl-prolyl cis-trans isomerase (PPlase; HEL-S-39), Lymphocyte cytosolic protein 2, Lactadherin, 72 kDa type IV collagenase, Transforming growth factor-beta-induced protein ig-h3, Neural proliferation differentiation and control protein 1, Ganglioside GM2 activator (Table 3, par [0006]). Regarding claim 9, Eyk discloses that wherein the sample preparation media comprises a protease, optionally wherein the protease is a serine protease , a cysteine protease, a threonine protease, an aspartic protease, a glutamic protease or a metalloprotease (par [0077]). Regarding claim 10, Eyk discloses that wherein the protease is trypsin (par [0077]) Regarding claim 11, Eyk teaches that wherein the neurodegenerative disease is selected from the group consisting of Parkinson's Disease, Alzheimer's disease , Huntington's disease, Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Batten disease or a transmissible spongiform encephalopathy (e.g. scrapie, bovine spongiform encephalopathy (BSE) or Creutzfeldt-Jakob disease (CJD), (including iatrogenic, variant, familial or sporadic forms of CJD), or a lysosomal neurodegenerative disorder (e.g. Gaucher's disease) (par [0028]). Regarding claim 13, Eyk teaches that wherein the sample is selected from the group consisting of cerebrospinal fluid (CSF ), blood (serum, whole blood (venous blood or peripheral blood), plasma, urine, tear, saliva, interstitial fluid, lymph fluid or tissue samples (par [0077]) . Regarding claim 14, Eyk teaches that wherein the sample is cerebrospinal fluid (CSF) (par [0077]) . Regarding claim 15, Eyk teaches that wherein the proteolytic peptide of at least one protein is selected from the group consisting of: AATVGSLAGQPLQER (SEQ ID No. 64) (Table 3) LGPLVEQGR (SEQ ID No. 66) (Table 3) ASSIIDELFQDR (SEQ ID No. 70) (Table 3) LVFFAEDVGSNK (SEQ ID No. 81) (Table 3) WYFDVTEGK (SEQ ID No. 82) (Table 3). Regarding claim 16, Eyk teaches that wherein the at least one protein is selected from the group consisting of Chromogranin-A, Amyloid-beta Precursor Protein , Amyloid- like Protein 1, Transforming Growth Factor-Beta-Induced Protein IG-H3, Prosaposin and Apolipoprotein E ( Table 3, par [0006] [0014] ) . Regarding claim 17, Eyk teaches that wherein the proteolytic peptide of at least one protein is selected from the group consisting of: ASSIIDELFQDR (SEQ ID No. 70) (Table 3). Regarding claim 18, Eyk teaches that wherein the at least one protein is selected from the group consisting of: Apolipoprotein E Clusterin Amyloid-beta precursor protein (Table 3, par [0006]). Claim Rejections - 35 USC § 103 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. 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. Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Eyk et al. (US 2015/0212098) (Eyk) in view of Bibl et al. (Brain, 2006) (Bibl). Regarding claim 12, Eyk teaches a method comprising protease digestion of a biological sample, generation of proteolytic peptides, and quantitation of biomarker peptides using mass spectrometry with labeled reference peptides for neurodegenerative disease biomarker assessment (par [0077]) . Claim 12 differs from Eyk in that the neurodegenerative disease is Parkinson’s disease. C erebrospinal fluid biomarker detection methods used for one neurodegenerative disease are routinely applied to other neurodegenerative diseases, including Parkinson’s disease, because such diseases share overlapping molecular pathology and biomarker profiles. For example, Bibl teaches C erebrospinal fluid biomarker detection methods used for one neurodegenerative disease are routinely applied to other neurodegenerative diseases, including Parkinson’s disease (abstract). It would have been obvious to apply the Eyk biomarker detection method to Parkinson’s disease as a predictable use of a known diagnostic technique. Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Eyk et al. (US 2015/0212098) (Eyk) . Regarding claim 19 , CSF contains thousands of proteins detectable by proteomics : large-scale CSF proteomics studies identify numerous biomarker candidates biomarker panels are routinely expanded to improve diagnostic performance targeted MS assays routinely allow multiplex detection of many peptides Thus, it would have been obvious to one of ordinary skill in the art to expand the biomarker panel to include more proteins , in order to confirm the diagnose. Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Eyk et al. (US 2015/0212098) (Eyk) in view of Catalano et al. (WO 2019/089988) (Catalano). Regarding claim 20, Eyk teaches biomarker for diagnosing AD (par [0006][0041]). Eyk coes not specifically teach that wherein the at least one protein is selected from the consisting of E3 Ubiquitin - Protein Ligase TRIM33, Fast Kinase Domain-Containing Protein 5, Mitochondrial and Contactin-1. However, Catalano teaches Contactin-1 as the biomarker for diagnosing AD (par [0005][0008]). It would have been obvious to one of ordinary skill in the art to include Contactin-1 as the biomarker in Eyk’s method for diagnosing AD, in order to confirm the diagnose . Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Eyk in view of Catalano as applied to claim 20, and further in view of Rohlff et al. (US 2009/0208507) (Rohlff ). Regarding claim 21, Catalano does not teach that wherein the proteolytic peptide of Contactin-1 is IVESYQIR (SEQ ID No. 54). However, Rohlff teaches IVESYQIR proteolytic peptide for diagnosing AD (abstract, Figure 1(b)). It would have been obvious to one of ordinary skill in the art to include IVESYQIR proteolytic peptide for diagnosing AD, in order to confirm the diagnose. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT XIAOYUN R XU, Ph. D. whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)270-5560 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT M-F 8am-5pm . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Lyle Alexander can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-272-1254 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /XIAOYUN R XU, Ph.D./ Primary Examiner, Art Unit 1797