DETAILED ACTION
Acknowledgements
This office action is in response to the claims filed October 27, 2025.
Claims 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 16, 18, 22, 25, 40, and 44 are pending.
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 .
Information Disclosure Statement(s)
The information disclosure statement (IDS) submitted on 05/23//2025 was considered by the examiner.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/27//2025 has been entered.
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 1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 16, 18, 22, 25, 40, and 44 are rejected to under 35 U.S.C 101 as not being directed to eligible subject matter based on the grounds set out in detail below:
Independent Claims 1 and 10:
Eligibility Step 1 (does the subject matter fall within a statutory category?):
Independent claims 1 and 10 fall within the statutory category of method.
Eligibility Step 2A-1 (does the claim recite an abstract idea, law of nature, or natural phenomenon?): Independent claims 1 and 10 (claim 1 being representative) claimed invention is directed to an abstract idea without significantly more.
The claim elements which set forth the abstract idea in the independent claims (claim 1 being representative) is:
A method for diagnosing the presence of Parkinson's disease or the stage of Parkinson's disease in a subject, the method comprising:
(a) detecting the level of one or more Parkinson's Disease biomarkers in a biological sample from the subject, wherein the first marker is N-acetyl putrescine (NAP) or ethyl malonic acid (EMA); and
(b) comparing the level of the first marker in the biological sample with a first predetermined threshold value, wherein an increased or decreased level of the first marker as compared to the first predetermined threshold value indicates the presence of Parkinson's disease in the subject.
This abstract idea is “certain methods of organizing human activity” as it is following rules and instructions to find an indication of Parkinson’s disease in a subject (MPEP § 2106.04(a)(2), subsection II)
Eligibility Step 2A-2 (does the claim recite additional elements that integrate the judicial exception into a practical application?): For Independent claims 1 and 10 judicial exception is not integrated into a practical application.
Independent claims 1 and 10 recite no additional elements therefore are purely considered the abstract idea.
Eligibility Step 2B (Does the claim amount to significantly more?): The independent claims do not include additional elements therefore purely the abstract idea and therefore do not provide significantly more. The claims are patent ineligible.
Dependent Claims 2, 3, 4, 7, 8, 9, 11, 12, 13, 16, 18, 22, 25, 40, and 44:
Eligibility Step 1 (does the subject matter fall within a statutory category?):The dependent claims 2, 3, 4, 7, 8, 9, 11, 12, 13, 16, 18, 22, 25, 40, and 44 fall within the statutory category of method.
Eligibility Step 2A-1 (does the claim recite an abstract idea, law of nature, or natural phenomenon?): Dependent claims 2, 3, 4, 7, 8, 9, 11, 12, 13, 16, 18, 22, 25, 40, and 44 claimed invention is directed to an abstract idea without significantly more. The claims continue to limit the independent claim 1 and 10 abstract idea by (1) further limiting the types of data and how the data is collected and (2) further limiting a generic administration of treatment. Therefore, the dependent claims inherit the same abstract idea which is This abstract idea is “certain methods of organizing human activity” as it is following rules and instructions to find an indication of Parkinson’s disease in a subject (MPEP § 2106.04(a)(2), subsection II)
Eligibility Step 2A-2 (does the claim recite additional elements that integrate the judicial exception into a practical application?): For claims 2, 3, 4, 7, 8, 9, 11, 12, 13, 16, 18, 22, 25, 40, and 44 this judicial exception is not integrated into a practical application.
The dependent claims recite no additional elements and thus are purely considered the abstract idea.
Accordingly, the dependent claims as a whole do not integrate the recited abstract idea into a practical application (MPEP 2106.05(f) and 2106.04(d)(1).
Eligibility Step 2B (Does the claim amount to significantly more?): The dependent claims do not include additional elements therefore are purely considered the abstract idea and do not provide significantly more. The claims are patent ineligible.
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.
(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.
Claims 1, 8, 9, 10, 25, 40, and 44 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by HATTORI et. al (hereinafter HATTORI) (JP6820545B2)
As per claim 1, HATTORI teaches:
A method for diagnosing the presence of Parkinson's disease or the stage of Parkinson's disease in a subject, the method comprising: (page 1 paragraph 1 discloses, “The present invention relates to a method for determining the severity of Parkinson's disease and a determination reagent.”)
(a) detecting the level of one or more Parkinson's Disease biomarkers in a biological sample from the subject, wherein the first marker is N-acetyl putrescine (NAP) or ethyl malonic acid (EMA); and (page 1 para. 3 and 4 discloses, “An object of the present invention is to provide a biomarker capable of diagnosing the severity from an early stage by a simple test. Therefore, the present inventor focused on polyamines and their biotransforms among the components in blood, and searched for components that can be differentiated between PD and other neurodegenerative diseases. In the PD group, N8-acetylspermidine was used. Was found to be significantly higher. Furthermore, the relationship between PD severity and N8-acetylspermidine, the relationship between acetylase activation by mutations at the genomic DNA level and PD severity, and demyelinating changes and N8-acetyl in PD diseased brains. As a result of examining the relationship with markers such as spermidine, it was found that the concentration of a component selected from N8-acetylspermidine, N1-acetylspermidine and N-acetylputrecin in blood has a correlation with PD severity, and the present invention has been developed.”)
(b) comparing the level of the first marker in the biological sample with a first predetermined threshold value, wherein an increased or decreased level of the first marker as compared to the first predetermined threshold value indicates the presence of Parkinson's disease in the subject. (page 2 paras. 8 and 9 and page 3 para. 1 discloses, “Concentrations of N8-acetylspermidine, N1-acetylspermidine or N-acetylputrescine in blood samples are significantly higher in PD patients and higher in proportion to the severity of PD patients. Here, the severity of PD is determined by the Hoehn and Yahr stage, which is widely known as the severity classification of PD, and UPDRS (Unified Palladium's Disease Racing Scale), which is a quantitative evaluation of PD movement disorders. (UPDRS-III), but the marker of the present invention can evaluate the severity of both Yar stage and UPDRS-III. The PD severity classification of the Yar stage is shown below.The blood concentration of the marker used in the present invention is significantly increased in II to IV among Yar stages I to IV with non-PD patients, and further increases as the severity of the Yar stage progresses. .. The blood concentration of the marker used in the present invention also correlates with the severity of UPDRS-III. Therefore, by measuring the blood concentration of the marker of the present invention, it is possible to diagnose PD from Yar stage II in PD, and early treatment can be started. Here, in order to determine the severity of PD based on the blood concentration of the marker of the present invention, the determination may be made based on the blood concentration of the marker of a healthy subject.”)
As per claim 8, HATTORI teaches:
The method of claim 1, wherein the subject is suspected of having or being at risk of having Parkinson's disease. (page 2 para. 2 discloses, “According to the present invention, the severity of Parkinson's disease can be easily determined from stage II of the Yar stage by simply measuring the concentrations of N8-acetylspermidine, N1-acetylspermidine and N-acetylputrescine in the blood. In addition, cerebral demyelinating changes in Parkinson's disease patients can also be determined.”/ examiner notes that the severity of the Parkinson’s disease is disclosed as being reviewed therefore the subject necessarily has PD.”)
As per claim 9, HATTORI teaches:
The method of claim 1, further comprising comparing the level of the first marker and/or the level of the second marker in the biological sample with that in a control sample, wherein the biological sample is a sample obtained at a later time point than the control sample, the control sample being an earlier-in-time biological sample obtained from the subject, or wherein the control sample is a Parkinson's disease-positive biological sample that is obtained from a subject with Parkinson's disease. (page 3 para. 7 and para. 9 discloses, “The patient group shown in Table 2 (control group: 45, PD: 145), Parkinson's disease with dementia (PDD): 12, Alzheimer's disease (AD): 24, progressive supranuclear Capillary electrophoresis in paralysis (PSP): 9, multiple system atrophy (MSA): 10, amyotrophic lateral sclerosis (ALS): 10) (this cohort is referred to as "cohort 1") -Comprehensive analysis of plasma metabolites was performed using both a mass analyzer and a liquid chromatography / mass analyzer, and an attempt was made to identify a biomarker (BM) that contributes to early diagnosis of PD. To evaluate the universality of this change, control: 25 people, PD: 50 people (Hoehn and Yahr stage (see Table 1, hereinafter Yar stage) I degree: 13 people, II degree: 12 people, III degree: 13 people , IV degree: 12 people) (This cohort (Table 4) is referred to as "cohort 2") evaluated polyamine metabolites, and N8-AcSPD was significantly increased in the PD group (according to Wilcoxon test). It was confirmed that it was present (Table 5).”)
As per claim 10, HATTORI teaches:
A method for monitoring Parkinson's disease in a subject, the method comprising: (a) detecting the level of a first marker in a first biological sample obtained at a first time from a subject having Parkinson's disease, wherein the first marker is NAP or EMA; (b) detecting the level of the first marker in a second biological sample obtained from the subject at a second time, wherein the second time is later in time than the first time; and ( c) comparing the level of the first marker in the first biological sample with that in the second biological sample, wherein a change in the level of the first marker indicates a change in Parkinson's disease status or stage in the subject. (see Fig. 1 and see fig. 3 and see page 1 para. 3 and 4 discloses, “An object of the present invention is to provide a biomarker capable of diagnosing the severity from an early stage by a simple test. Therefore, the present inventor focused on polyamines and their biotransforms among the components in blood, and searched for components that can be differentiated between PD and other neurodegenerative diseases. In the PD group, N8-acetylspermidine was used. Was found to be significantly higher. Furthermore, the relationship between PD severity and N8-acetylspermidine, the relationship between acetylase activation by mutations at the genomic DNA level and PD severity, and demyelinating changes and N8-acetyl in PD diseased brains. As a result of examining the relationship with markers such as spermidine, it was found that the concentration of a component selected from N8-acetylspermidine, N1-acetylspermidine and N-acetylputrecin in blood has a correlation with PD severity, and the present invention has been developed.” And see page 4 para. 2 discloses, “Example 3 The position of N8-AcSPD in the polyamine metabolic pathway is shown in FIG. As shown in the figure in both cohorts 1 and 2, N8-AcSPD increased in the PD group, but the concentrations of putrescine, spermidine (SPD), and spermine (SPM) did not change. Therefore, these compounds due to acetylation were not observed. We speculated that modification would play an important role, and examined changes in N-Acetylputrescine (measurable in cohort 1) and N1-AcSPD (measurable in cohort 2) in each disease, as well as their correlation with PD severity. As shown in FIG. 6, both acetylase compound concentrations correlate with PD severity (by analysis of variance) and also positively correlate with N8-AcSPD concentration, indicating that changes in acetylase activity are involved in disease progression. Was suggested.”)
As per claim 25, HATTORI teaches:
The method of claim 10, wherein the stage of Parkinson's disease is based on the Hoehn-Yahr scale 0, scale 1, scale 1.5, scale 2, scale 2.5, scale 3, scale 4, or scale 5. (page 2 paras. 8 and 9 discloses, “Concentrations of N8-acetylspermidine, N1-acetylspermidine or N-acetylputrescine in blood samples are significantly higher in PD patients and higher in proportion to the severity of PD patients. Here, the severity of PD is determined by the Hoehn and Yahr stage, which is widely known as the severity classification of PD, and UPDRS (Unified Palladium's Disease Racing Scale), which is a quantitative evaluation of PD movement disorders. (UPDRS-III), but the marker of the present invention can evaluate the severity of both Yar stage and UPDRS-III. The PD severity classification of the Yar stage is shown below. The blood concentration of the marker used in the present invention is significantly increased in II to IV among Yar stages I to IV with non-PD patients, and further increases as the severity of the Yar stage progresses. .. The blood concentration of the marker used in the present invention also correlates with the severity of UPDRS-III. Therefore, by measuring the blood concentration of the marker of the present invention, it is possible to diagnose PD from Yar stage II in PD, and early treatment can be started.”)
As per claim 40, HATTORI teaches:
The method of claim 1, wherein the level of the first marker and/or the level of the second marker are determined using immunoassay, ELISA, mass spectrometry, or liquid chromatography with tandem mass spectrometry. (page 2 para. 6 and 7 discloses, “The blood sample may be any blood sample collected from the subject, but plasma is preferable from the viewpoint of convenience. Examples of means for measuring the concentration of N8-acetylspermidine, N1-acetylspermidine or N-acetylptresin in a blood sample include capillary electrophoresis / mass spectrometry, liquid chromatography / mass spectrometry, and other known means. Of these, capillary electrophoresis / mass spectrometry and liquid chromatography / mass spectrometry are more preferable because they are quantitative and can be measured by a general-purpose device.”)
As per claim 44, HATTORI teaches:
The method of claim 1, wherein the biological sample comprises blood, serum, urine, cerebrospinal fluid, organ tissue, feces, skin, hair, or cheek tissue. (page 2 para. 6 and 7 discloses, “The blood sample may be any blood sample collected from the subject, but plasma is preferable from the viewpoint of convenience. Examples of means for measuring the concentration of N8-acetylspermidine, N1-acetylspermidine or N-acetylptresin in a blood sample include capillary electrophoresis / mass spectrometry, liquid chromatography / mass spectrometry, and other known means. Of these, capillary electrophoresis / mass spectrometry and liquid chromatography / mass spectrometry are more preferable because they are quantitative and can be measured by a general-purpose device.”)
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.
Claims 2 and 11 are rejected to under 35 U.S.C. 103 as being unpatentable over HATTORI et. al (hereinafter HATTORI) (JP6820545B2) in view of Juárez-Flores et. al (hereinafter Juárez-Flores) (Juárez-Flores DL, Ezquerra M, Gonzàlez-Casacuberta Ï, Ormazabal A, Morén C, Tolosa E, Fucho R, Guitart-Mampel M, Casado M, Valldeoriola F, de la Torre-Lara J, Muñoz E, Tobías E, Compta Y, García-García FJ, García-Ruiz C, Fernandez-Checa JC, Martí MJ, Grau JM, Cardellach F, Artuch R, Fernández-Santiago R, Garrabou G. Disrupted Mitochondrial and Metabolic Plasticity Underlie Comorbidity between Age-Related and Degenerative Disorders as Parkinson Disease and Type 2 Diabetes Mellitus. Antioxidants (Basel). 2020 Oct 30;9(11):1063. doi: 10.3390/antiox9111063. PMID: 33143119; PMCID: PMC7693963.)
As per claim 2, HATTORI does not teach:
The method of claim 1, further comprising detecting the level of a second marker in the biological sample from the subject, wherein the second marker is EMA or NAP, and wherein the first marker and the second marker are different markers; and comparing the level of the second marker in the biological sample with a second predetermined threshold value, wherein an increased or decreased level of the second marker as compared to the second predetermined threshold value indicates the presence of Parkinson's disease in the subject.
However, Juárez-Flores teaches:
The method of claim 1, further comprising detecting the level of a second marker in the biological sample from the subject, wherein the second marker is EMA or NAP, and wherein the first marker and the second marker are different markers; and comparing the level of the second marker in the biological sample with a second predetermined threshold value, wherein an increased or decreased level of the second marker as compared to the second predetermined threshold value indicates the presence of Parkinson's disease in the subject. (page 5 para. 3 discloses, “Measurement of organic acid and amino acid levels in iPD-fibroblasts showed unbalanced metabolic fluxes related to mitochondrial function. Organic acids related to mitochondrial energetic metabolism were increased in iPD patients, suggesting the deregulation of the intermediary metabolism (Figure 1). At standard glucose concentration (5 mM), classical biomarkers of mitochondrial diseases such as lactic acid, and the main components of the Krebs’s cycle (citric, malic, succinic, and 2OH-glutaric acid), tended to increase in iPD samples. Similar trends were observed in the metabolites derived from Kreb’s cycle related to amino acid or fatty acid metabolism (as ethylmalonic or glutaric acid) and the biomarkers from free fatty acid β-oxidation (including adipic, suberic, and sebacic dicarboxylic acids). The accumulation of all these metabolites is frequently associated with MRC dysfunction and, specifically the increase in lactic acid levels, with the activation of anaerobic glycolysis in detriment of MRC function. A high glucose concentration (25 mM) further accentuated such trends, as observed by the significant increase of citric, suberic, and sebacic acids (p = 0.01, p = 0.03, and p = 0.03, respectively). Such an increment suggests a worsened phenotype for iPD-fibroblasts in high-glucose conditions. The accumulation of all these metabolites feeding mitochondrial metabolism is frequently associated with mitochondrial dysfunction, specifically the increase in lactic acid levels, with the activation of anaerobic glycolysis in detriment of mitochondrial function.”)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with Juárez-Flores’ teachings, the motivation being HATTORI discloses, all the markers of the present invention are acetylated metabolites of polyamines, and these polyamine acetylated metabolites correlate with PD severity, suggesting that acetylase activity is involved in PD disease progression (see page 3 para. 3 for example), therefore Juárez-Flores’ ethylmalonic acid could have been combined with the method of to provide additional metabolic markers for the diagnosis of PD as high levels of this metabolite can indicate a metabolic disorder and metabolic disorder is strongly linked with PD patients and HATTORI already discloses in order to investigate the significance of changes in polyamine metabolism in PD, the autophagy-inducing effects of putrescine, spermidine, spermine and their acetylated derivatives belonging to the polyamine metabolic pathway can be examined improving the quality data to indicate severity or individualized care for patients.
As per claim 11, HATTORI does not teach:
The method of claim 10, further comprising detecting the level of a second marker in the first biological sample, wherein the second marker is EMA or NAP, and wherein the first marker and the second marker are different markers; detecting the level of the second marker in the second biological sample; and comparing the level of the second marker in the first biological sample with that in the second biological sample, wherein a change in the level of the second marker indicates a change in Parkinson's disease status or stage in the subject.
However, Juárez-Flores does teach:
The method of claim 10, further comprising detecting the level of a second marker in the first biological sample, wherein the second marker is EMA or NAP, and wherein the first marker and the second marker are different markers; detecting the level of the second marker in the second biological sample; and comparing the level of the second marker in the first biological sample with that in the second biological sample, wherein a change in the level of the second marker indicates a change in Parkinson's disease status or stage in the subject. (page 5 para. 3 discloses, “Measurement of organic acid and amino acid levels in iPD-fibroblasts showed unbalanced metabolic fluxes related to mitochondrial function. Organic acids related to mitochondrial energetic metabolism were increased in iPD patients, suggesting the deregulation of the intermediary metabolism (Figure 1). At standard glucose concentration (5 mM), classical biomarkers of mitochondrial diseases such as lactic acid, and the main components of the Krebs’s cycle (citric, malic, succinic, and 2OH-glutaric acid), tended to increase in iPD samples. Similar trends were observed in the metabolites derived from Kreb’s cycle related to amino acid or fatty acid metabolism (as ethylmalonic or glutaric acid) and the biomarkers from free fatty acid β-oxidation (including adipic, suberic, and sebacic dicarboxylic acids). The accumulation of all these metabolites is frequently associated with MRC dysfunction and, specifically the increase in lactic acid levels, with the activation of anaerobic glycolysis in detriment of MRC function. A high glucose concentration (25 mM) further accentuated such trends, as observed by the significant increase of citric, suberic, and sebacic acids (p = 0.01, p = 0.03, and p = 0.03, respectively). Such an increment suggests a worsened phenotype for iPD-fibroblasts in high-glucose conditions. The accumulation of all these metabolites feeding mitochondrial metabolism is frequently associated with mitochondrial dysfunction, specifically the increase in lactic acid levels, with the activation of anaerobic glycolysis in detriment of mitochondrial function.”)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with Juárez-Flores’ teachings for the same reasons given for claim 2.
Claims 3, 4, 7, 12, 13, 16, 18, and 22 are rejected to under 35 U.S.C. 103 as being unpatentable over HATTORI et. al (hereinafter HATTORI) (JP6820545B2) in view of MIDDLETON et. al (hereinafter MIDDLETON) (US20220042099A1)
As per claim 3, HATTORI does not teach:
The method of claim 1, further comprising determining the subject's performance on an anxiety test, a sleep test, a smell test, or any combination thereof, wherein an impaired performance on the anxiety test, the sleep test, the smell test, or any combination thereof indicates the presence of Parkinson's disease in the subject.
However, MIDDLETON does teach:
The method of claim 1, further comprising determining the subject's performance on an anxiety test, a sleep test, a smell test, or any combination thereof, wherein an impaired performance on the anxiety test, the sleep test, the smell test, or any combination thereof indicates the presence of Parkinson's disease in the subject. ([0061] discloses, “The final functional domain that we evaluated in our subjects was chemosensory in nature ( smell and taste ) , where our PD cohort scored much worse than the healthy control subjects ( Table 3 ) . While not considered pathognomonic , decreased olfaction and taste has been well - docu mented in PD , including early stages of the disease.” And see [0041] discloses, “ All PD subjects were evaluated using Part III of the MDS - UPDRS by a movement disorder specialist or trained Ph.D. - level evaluator …[…]… All subjects then completed a detailed sensory , motor , cognitive , and balance assessment that included : ( 1 ) 12 - item Modified Brief Smell Identification Test ( mBSIT ) ;”)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with MIDDLETON’s teachings, the motivation being HATTORI discloses, UPDRS-motor section and Yahr scale testing (see e.g. page 1 para. 7 and page 8 para. 1-3) which includes some behavior and mood questionnaire testing, therefore it would be obvious to combine with MIDDLETON’s additional BSIT testing as it would improve the pool of data to properly diagnose severity or presence of PD and properly treat the disease with a specific individualized care plan.
As per claim 4, HATTORI does not teach:
The method of claim 3, wherein impaired performance on the anxiety test is indicated where the anxiety test yields a HADsDTotal score of 8 or above, impaired performance on the sleep test is indicated where the sleep test indicates the presence of REM sleep behavior disorder or impaired performance on the smell test is indicated where the smell test yields a BsitTotal score of 6 or below.
However, MIDDLETON does teach:
The method of claim 3, wherein impaired performance on the anxiety test is indicated where the anxiety test yields a HADsDTotal score of 8 or above, impaired performance on the sleep test is indicated where the sleep test indicates the presence of REM sleep behavior disorder or impaired performance on the smell test is indicated where the smell test yields a BsitTotal score of 6 or below. (see table 3 and see [0061] discloses, “The final functional domain that we evaluated in our subjects was chemosensory in nature ( smell and taste ) , where our PD cohort scored much worse than the healthy control subjects ( Table 3 ) . While not considered pathognomonic , decreased olfaction and taste has been well - documented in PD , including early stages of the disease . Notably , similar decreases in chemosensory function have also been consistently found in subjects with Alzheimer's disease , or a history of mild traumatic brain injury ( MTBI ) . Thus , our findings are consistent with the literature on early stage PD and suggest that these measures may represent useful screening tools , when used in combination with other assessments , for identifying subjects at risk for neurodegenerative disease in general.” And see [0050] discloses, “Chemosensory Scores . PD subjects showed highly significant decreased performance in measures of both taste and smell ( Table 3 ).” / examiner notes it is obvious if the decreased performance is seen at the 7.42 scoring of smell than it is also decreased when below this number)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with MIDDLETON’s teachings, for the same reasons given above for claim 3.
As per claim 7, HATTORI does not teach:
The method of claim 1, further comprising administering a treatment for Parkinson's disease where the diagnosis indicates the presence of Parkinson's disease in the subject.
However, MIDDLETON does teach:
The method of claim 1, further comprising administering a treatment for Parkinson's disease where the diagnosis indicates the presence of Parkinson's disease in the subject. ([0037] discloses, “Thus , once a subject has been determined to be an at risk patient and / or having Parkinson's disease , the subject is treated to reduce and / or attenuate further progression of the disease . Various medications and treatments are known in the art and include Carbidopa levodopa , Dopamine ago nists such pramipexole , ropinirole , rotigotine , and apomor phine , MAO B inhibitors such as selegiline , rasagiline and safinamide , Catechol O - methyltransferase ( COMT ) inhibi tors such as entacapone , anticholinergic medications such as benztropine and trihexyphenidyl , Amantadine , deep brain stimulation , other surgical interventions , prescribed diet and exercise programs.”)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with MIDDLETON’s teachings, for the same reasons given above for claim 3.
As per claim 12, HATTORI does not teach:
The method of claim 10, further comprising determining the subject's performance on an anxiety test, a sleep test, a smell test, or any combination thereof at the first time point and at the second time point; and comparing the subject's performance on the anxiety test, the sleep test, the smell test or any combination thereof at the first time point with that at the second time point; wherein a change in performance on the anxiety test, the sleep test, the smell test, or any combination thereof between the first time point and the second time point indicates a change in Parkinson's disease status or stage in the subject.
However, MIDDLETON does teach:
The method of claim 10, further comprising determining the subject's performance on an anxiety test, a sleep test, a smell test, or any combination thereof at the first time point and at the second time point; and comparing the subject's performance on the anxiety test, the sleep test, the smell test or any combination thereof at the first time point with that at the second time point; wherein a change in performance on the anxiety test, the sleep test, the smell test, or any combination thereof between the first time point and the second time point indicates a change in Parkinson's disease status or stage in the subject. (see table 3 and see [0061] discloses, “The final functional domain that we evaluated in our subjects was chemosensory in nature ( smell and taste ) , where our PD cohort scored much worse than the healthy control subjects ( Table 3 ) . While not considered pathognomonic , decreased olfaction and taste has been well - documented in PD , including early stages of the disease . Notably , similar decreases in chemosensory function have also been consistently found in subjects with Alzheimer's disease , or a history of mild traumatic brain injury ( MTBI ) . Thus , our findings are consistent with the literature on early stage PD and suggest that these measures may represent useful screening tools , when used in combination with other assessments , for identifying subjects at risk for neurodegenerative disease in general.” And see [0050] discloses, “Chemosensory Scores . PD subjects showed highly significant decreased performance in measures of both taste and smell ( Table 3 ).” / examiner notes it is obvious if the decreased performance is seen at the 7.42 scoring of smell than it is also decreased when below this number)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with MIDDLETON’s teachings, for the same reasons given above for claim 3.
As per claim 13, HATTORI does not teach:
The method of claim 12, wherein impaired performance on the anxiety test is indicated where the anxiety test yields a HADsDTotal score of 8 or above, impaired performance on the sleep test is indicated where the sleep test indicates the presence of REM sleep behavior disorder, or impaired performance on the smell test is indicated where the smell test yields a BsitTotal score of 6 or below.
However, MIDDLETON does teach:
The method of claim 12, wherein impaired performance on the anxiety test is indicated where the anxiety test yields a HADsDTotal score of 8 or above, impaired performance on the sleep test is indicated where the sleep test indicates the presence of REM sleep behavior disorder, or impaired performance on the smell test is indicated where the smell test yields a BsitTotal score of 6 or below. (see table 3 and see [0061] discloses, “The final functional domain that we evaluated in our subjects was chemosensory in nature ( smell and taste ) , where our PD cohort scored much worse than the healthy control subjects ( Table 3 ) . While not considered pathognomonic , decreased olfaction and taste has been well - documented in PD , including early stages of the disease . Notably , similar decreases in chemosensory function have also been consistently found in subjects with Alzheimer's disease , or a history of mild traumatic brain injury ( MTBI ) . Thus , our findings are consistent with the literature on early stage PD and suggest that these measures may represent useful screening tools , when used in combination with other assessments , for identifying subjects at risk for neurodegenerative disease in general.” And see [0050] discloses, “Chemosensory Scores . PD subjects showed highly significant decreased performance in measures of both taste and smell ( Table 3 ).” / examiner notes it is obvious if the decreased performance is seen at the 7.42 scoring of smell than it is also decreased when below this number)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with MIDDLETON’s teachings, for the same reasons given above for claim 3.
As per claim 16, HATTORI does not teach:
The method of claim 10, wherein the subject is actively treated for Parkinson's disease prior to obtaining the second sample, or wherein the subject is not actively treated for Parkinson's disease prior to obtaining the second sample.
However, MIDDLETON does teach:
The method of claim 10, wherein the subject is actively treated for Parkinson's disease prior to obtaining the second sample, or wherein the subject is not actively treated for Parkinson's disease prior to obtaining the second sample. ([0037] discloses, “Thus , once a subject has been determined to be an at risk patient and / or having Parkinson's disease , the subject is treated to reduce and / or attenuate further progression of the disease . Various medications and treatments are known in the art and include Carbidopa levodopa , Dopamine ago nists such pramipexole , ropinirole , rotigotine , and apomor phine , MAO B inhibitors such as selegiline , rasagiline and safinamide , Catechol O - methyltransferase ( COMT ) inhibi tors such as entacapone , anticholinergic medications such as benztropine and trihexyphenidyl , Amantadine , deep brain stimulation , other surgical interventions , prescribed diet and exercise programs.”)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with MIDDLETON’s teachings, for the same reasons given above for claim 3.
As per claim 18, HATTORI further teaches:
The method of claim 12, wherein: a change in the level of the first marker, a change in the level of the second marker, a change in performance on the anxiety test, a change in performance on the sleep test, a change in performance on the smell test, or any combination thereof between the first time point and the second time point, indicates progression of Parkinson's disease in the subject. (page 4 para. 2 discloses, “We speculated that modification would play an important role, and examined changes in N-Acetylputrescine (measurable in cohort 1) and N1-AcSPD (measurable in cohort 2) in each disease, as well as their correlation with PD severity. As shown in FIG. 6, both acetylase compound concentrations correlate with PD severity (by analysis of variance) and also positively correlate with N8-AcSPD concentration, indicating that changes in acetylase activity are involved in disease progression. Was suggested.”)
As per claim 22, HATTORI does not teach:
The method of claim 12, further comprising: selecting a treatment for Parkinson's disease for the subject, and/or administering a treatment for Parkinson's disease to the subject, based on the status, the stage or the progression of the Parkinson's disease in the subject; administering a therapeutic for Parkinson's disease to the subject based on the status, the stage, or the progression of the Parkinson's disease in the subject; or withholding an active treatment of the Parkinson's disease in the subject based on nonprogression of the Parkinson's disease in the subject.
However, MIDDLETON does teach:
The method of claim 12, further comprising: selecting a treatment for Parkinson's disease for the subject, and/or administering a treatment for Parkinson's disease to the subject, based on the status, the stage or the progression of the Parkinson's disease in the subject; administering a therapeutic for Parkinson's disease to the subject based on the status, the stage, or the progression of the Parkinson's disease in the subject; or withholding an active treatment of the Parkinson's disease in the subject based on nonprogression of the Parkinson's disease in the subject. ([0037] discloses, “Thus , once a subject has been determined to be an at risk patient and / or having Parkinson's disease , the subject is treated to reduce and / or attenuate further progression of the disease . Various medications and treatments are known in the art and include Carbidopa levodopa , Dopamine ago nists such pramipexole , ropinirole , rotigotine , and apomor phine , MAO B inhibitors such as selegiline , rasagiline and safinamide , Catechol O - methyltransferase ( COMT ) inhibi tors such as entacapone , anticholinergic medications such as benztropine and trihexyphenidyl , Amantadine , deep brain stimulation , other surgical interventions , prescribed diet and exercise programs.”)
It would be obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine HATTORI’s teachings with MIDDLETON’s teachings, for the same reasons given above for claim 3.
Prior Art not cited but made of record
Saiki S, Sasazawa Y, Fujimaki M, Kamagata K, Kaga N, Taka H, Li Y, Souma S, Hatano T, Imamichi Y, Furuya N, Mori A, Oji Y, Ueno SI, Nojiri S, Miura Y, Ueno T, Funayama M, Aoki S, Hattori N. A metabolic profile of polyamines in parkinson disease: A promising biomarker. Ann Neurol. 2019 Aug;86(2):251-263. doi: 10.1002/ana.25516. Epub 2019 Jul 1. PMID: 31155745; PMCID: PMC6772170.
Aging is the highest risk factor for Parkinson disease (PD). Under physiological conditions, spermidine and spermine experimentally enhance longevity via autophagy induction. Accordingly, we evaluated the ability of each polyamine metabolite to act as an age-related, diagnostic, and severity-associated PD biomarker.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ashley Elizabeth Evans whose telephone number is (571) 270-0110. The examiner can normally be reached Monday – Friday 8:00 AM – 5:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mamon Obeid can be reached on (571) 270-1813. The fax phone number for the organization where this application or proceeding is assigned 571-273-8300.
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/ASHLEY ELIZABETH EVANS/Examiner, Art Unit 3687
/MAMON OBEID/Supervisory Patent Examiner, Art Unit 3687