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 .
Claim Objections
Claims 6, 16, 29-30 and 32 are objected to because of the following informalities: The acronym PGRN is not defined within the claims. The examiner is interpreting PGRN as progranulin, as known in the art. Appropriate correction is required.
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 1-32 are rejected under 35 U.S.C. 101 because it constitutes abstract ideas.
Regarding independent claim 1, a two-step analysis is performed:Step 1: Does the claim fall within a statutory category?
Yes, it is a method/process.Step 2A, Prong 1: Identify the law of nature/natural phenomenon/abstract ideas.
A method for identifying a subject having, or at risk of having, frontotemporal dementia (FTD), the method comprising: (a) measuring the abundance of glucosylsphingosine (GlcSph) in a test sample from a subject; (b) comparing the difference in abundance between the GlcSph measured in (a) and one or more reference values; and (c) determining from the comparison whether the subject has, or is at risk of having, FTD.
Obtaining an abundance of GlcSph to be used to compare with one or more reference values to determine if a subject has, or is at risk of having FTD is considered to be a mental process, where it is evaluated based on one’s observation, evaluation, judgment and opinion using data as comparison, making this an abstract idea.
Step 2A Prong 2: Has the abstract idea been integrated into a particular practical application?
The claim as a whole does not integrate the abstract idea into a practical application. Other than the abstract idea, claim 1 recites the additional elements: glucosylsphingosine (GlcSph), and measuring an abundance of GlcSph. With respect to GlcSph and measuring an abundance of GlcSph represent insignificant extra solution activity (e.g., mere data gathering). Thus, there is no application of the abstract idea, much less a particular practical application.
Step 2B: Does the claim recite any elements which are significantly more than the abstract idea?
Claim 1 does not provide an inventive concept (significantly more than the abstract idea). GlcSph and measuring an abundance of GlcSph are considered insignificant extra solution activity (e.g., mere data gathering). Furthermore, the additional elements above, alone and in combination within claim 1 as a whole, are well understood, routine, and conventional activities within the prior art (see 35 USC § 103 rejections).
Dependent claims 2 and 6-31 do not resolve any of the issues discussed above because they involve limitations with more insignificant extra-solution activity (i.e., what a reference value comprises) and/or abstract ideas in the form of mental process.
Regarding independent claim 3, a two-step analysis is performed:Step 1: Does the claim fall within a statutory category?
Yes, it is a method/process.
Step 2A, Prong 1: Identify the law of nature/natural phenomenon/abstract ideas.
A method for evaluating a compound or monitoring a subject's response to a compound, pharmaceutical composition, or dosing regimen thereof for treating frontotemporal dementia (FTD), the method comprising: (a) measuring the abundance of GlcSph in a test sample from a subject having FTD, wherein the test sample or subject has been treated with the compound or pharmaceutical composition thereof; (b) comparing the difference in abundance between the GlcSph measured in (a) and one or more reference values; and (c) determining from the comparison whether the compound, pharmaceutical composition, or dosing regimen thereof improves the GlcSph level for treating FTD.
Obtaining an abundance of GlcSph to be used to compare with one or more reference values to determine whether the compound, pharmaceutical composition, or dosing regimen thereof improves the GlcSph levels for treating FTD is considered to be a mental process, where it is evaluated based on one’s observation, evaluation, judgment and opinion using data as comparison, making this an abstract idea.
Step 2A Prong 2: Has the abstract idea been integrated into a particular practical application?
The claim as a whole does not integrate the abstract idea into a practical application. Other than the abstract idea, claim 3 recites the additional elements: glucosylsphingosine (GlcSph), measuring an abundance of GlcSph, and treatment with a compound or pharmaceutical composition. With respect to GlcSph, measuring an abundance of GlcSph and treatment with a compound or pharmaceutical composition represent insignificant extra solution activity (e.g., mere data gathering). Thus, there is no application of the abstract idea, much less a particular practical application.
Step 2B: Does the claim recite any elements which are significantly more than the abstract idea?
Claim 3 does not provide an inventive concept (significantly more than the abstract idea). GlcSph, measuring an abundance of GlcSph and treatment with a compound or pharmaceutical composition are considered insignificant extra solution activity (e.g., mere data gathering). Furthermore, the additional elements above, alone and in combination within claim 3 as a whole, are well understood, routine, and conventional activities within the prior art (see 35 USC § 103 rejections).
Dependent claims 4-5 and 32 do not resolve any of the issues discussed above because they involve limitations with more insignificant extra-solution activity (i.e., adjusting the amount of administration of a compound) and/or abstract ideas in the form of mental process.
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.
Claims 1-2, 6-9, 14-16, 19-24, and 28-31 are rejected under 35 U.S.C. 103 as being unpatentable over Greaves et al. (“An update on genetic frontotemporal dementia”, as cited in the IDS), in view of Liu et al..
Regarding claim 1, Greaves et al. teaches clinical presymptomatic genetic testing for Frontotemporal dementia (FTD), where three biomarkers were identified that can be used in clinical trials for FTD, CSF or blood neurofilament light chain levels (NfL), CSF or blood progranulin levels (in progranulin (GRN) carriers), and CSF poly(GP) dipeptide repeat protein levels (in chromosome 9 open reading frame 72 (C9orf72) carriers). While the markers are not FTD-specific markers, as CSF nor blood assays of tau or TDP-43 have identified any, measures of the three biomarkers appear to have a measure of the FTD disease. For example, increased NfL levels (both in CSF and blood) reflect axonal damage and appear to be a measure of disease intensity, and predict progression and survival in genetic FTD. Whilst an increase in NfL is not specific for FTD, and levels are increased in multiple neurological diseases, evidence from other diseases suggests that a decrease in levels could be a measure of successful disease modification in trials (see Greaves et al., Abstract, Natural history studies and biomarkers, Blood and CSF biomarkers).
Greaves et al. fails to teach measuring glucosylsphingosine (GlcSph) in a test sample from a subject and comparing the difference in abundance between the GlcSph measured in (a) and one or more reference values.
However, in the analogues art of Progranulin (PGRN) and its derivatives for diagnosis and treatment of lysosomal storage diseases, Liu et al. teaches measuring glucosylsphingosine (GlcSph) using high performance liquid chromatography/mass spectrometry (LC-MS/MS on plasma from healthy control patients (i.e. a reference) and patients with Gaucher's Disease. Levels of GlcSph are found to be increased in GD plasma in comparison to healthy control plasma, especially seen in PGRN deficient mice, where an absence of PGRN is known to lead to Gaucher's disease and Frontotemporal dementia (see Liu et al., Fig. 21A-21D, [0014], [0055], [0178], [0182], [0219]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD using measured levels of biomarkers for determining at-risk or severity of the disease of Greaves et al. by incorporating GlcSph as a biomarker and using control groups for comparison (as taught by Liu et al.), for the benefit of diagnosis and developing treatments using progranulin (PGRN) for lysosomal storage diseases, including Gaucher's Disease, where GD Type III patients are known to suffer from dementia. Further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0012], [0178]).
Regarding claim 2, Greaves et al. fails to teach administering to the subject a compound for improving the GlcSph level for treating FTD.
However, Liu et al. teaches potential drugs or compounds effective to modulate lysosomal enzyme trafficking and/or lysosomal substate accumulation by mimicking the activity of PGRN or the PGRN peptides. The test drug or compound is administered to a cellular sample with glucocerebrosidase encoding gene GBA, to determine the effect of the test drug or compound upon β-GlcCer accumulation, by comparison with a control, including wherein the control is PGRN, active PGRN peptide(s), and atsttrin. For beta-glucosylsphingosine (GlcSph), a high elevation correlated to a PGRN deficiency in plasma when tested on mice, and a similar determination of compound or drug effect can be performed while viewing GlcSph (see Liu et al., Fig. 21A-21D, Fig. 22A-22C, [0033], [0182]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. by incorporating the application of drugs or compounds effective in modulating lysosomal enzyme trafficking in mimicking the activity of PGRN, and viewing GlcSph levels (as taught by Liu et al.), for the benefit of facilitating the testing and development of new drugs for treating Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0178], [0197]).
Regarding claim 6, Greaves et al. fails to teach wherein the compound is PGRN, a PGRN derivative, or pharmaceutical compositions thereof.
However, Liu et al. teaches PGRN and PGRN peptides, including atsttrin, as modulators of lysosomal storage disease and of lysosomal trafficking (see Liu et al., [0139]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. by incorporating PGRN and PGRN peptides as compounds for modulating lysosomal trafficking (as taught by Liu et al.), for the benefit of facilitating the testing and development of new drugs for treating Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0178], [0197]).
Regarding claim 7, Greaves et al. fails to teach wherein the compound is a sortilin inhibitor.
However, Liu et al. teaches performing immunoprecipitation with anti-sortilin antibodies in WT and PGRN KO mice, where Sortilin was reported to be a receptor of PGRN and to mediate the delivery of PGRN to the endosome/lysosomal pathway in neurons. It was determined Sortilin forms a ternary complex with LIMP2/GBA/PGRN/HSP70 through PGRN as a linker protein and facilitates the delivery of LIMP2/GBA/PGRN/HSP70 along the endosome/lysosomal pathway. (see Liu et al., Fig 16A-16D, [0050], [0195]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate anti-sortilin antibodies as a compound for PGRN (as taught by Liu et al.), for the benefit of facilitating the testing and development of new drugs for treating Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0178], [0197]).
Regarding claim 8, Greaves et al. fails to teach wherein the sortilin inhibitor is an anti-sortilin antibody.
However, Liu et al. teaches performing immunoprecipitation with anti-sortilin antibodies in WT and PGRN KO mice, where Sortilin was reported to be a receptor of PGRN and to mediate the delivery of PGRN to the endosome/lysosomal pathway in neurons. It was determined Sortilin forms a ternary complex with LIMP2/GBA/PGRN/HSP70 through PGRN as a linker protein and facilitates the delivery of LIMP2/GBA/PGRN/HSP70 along the endosome/lysosomal pathway. (see Liu et al., Fig 16A-16D, [0050], [0195]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate anti-sortilin antibodies as a compound for PGRN (as taught by Liu et al.), for the benefit of facilitating the testing and development of new drugs for treating Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0178], [0197]).
Regarding claim 9, Greaves et al. fails to teach wherein a subject having, or at risk of having, FTD has an increased GlcSph level compared to the reference value.
However, Liu et al. teaches that levels of GlcSph are found to be increased in GD plasma in comparison to healthy control plasma, especially seen in PGRN deficient mice, where an absence of PGRN is known to lead to Gaucher's Disease, or Frontotemporal dementia (see Liu et al., Fig. 21A-21D, Fig. 22A-22C, [0178], [0182]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate a link of deficiently of PGRN, correlating to an increase in GlcSph, can indicate the presence of FTD (as taught by Liu et al.), for the benefit of diagnosis and developing treatments using progranulin (PGRN) for lysosomal storage diseases, including Gaucher's Disease, where GD Type III patients are known to suffer from dementia (see Liu et al., [0009], [0012]).
Regarding claim 14, Greaves et al. fails to teach wherein the reference value is measured in a reference sample obtained from a reference subject or a population of reference subjects.
However, Liu et al. teaches obtaining serum samples from groups of GD patients and healthy patients, and using ELISA on the obtained samples to determine the levels of PGRN, of which GD patients were found to have lower PGRN levels compared to healthy controls, and wherein low PGRN levels are associated with increased GlcSph levels (see Liu et al., Fig. 36A-36C, [0070], [0178]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. by incorporating control groups as a reference (as taught by Liu et al.), for the benefit of diagnosis and developing treatments using progranulin (PGRN) for lysosomal storage diseases, including Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0012], [0178]).
Regarding claim 15, Greaves et al. fails to teach wherein the reference subject or population of reference subjects is a healthy control.
However, Liu et al. teaches obtaining serum samples from groups of GD patients and healthy patients, and using ELISA on the obtained samples to determine the levels of PGRN, of which GD patients were found to have lower PGRN levels compared to healthy controls, and wherein low PGRN levels are associated with increased GlcSph levels (see Liu et al., Fig. 36A-36C, [0070], [0178]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. by incorporating healthy control groups as a reference (as taught by Liu et al.), for the benefit of diagnosis and developing treatments using progranulin (PGRN) for lysosomal storage diseases, including Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0012], [0178]).
Regarding claim 16, Greaves et al. fails to teach wherein the reference subject or population of reference subjects does not have FTD or a decreased level of PGRN.
However, Liu et al. teaches obtaining serum samples from groups of GD patients and healthy patients, and using ELISA on the obtained samples to determine the levels of PGRN, of which GD patients were found to have lower PGRN levels compared to healthy controls, and wherein low PGRN levels are associated with increased GlcSph levels (see Liu et al., Fig. 36A-36C, [0070], [0178]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. by incorporating healthy control groups as a reference, having a higher level of PGRN compared to the GD patients (as taught by Liu et al.), for the benefit of diagnosis and developing treatments using progranulin (PGRN) for lysosomal storage diseases, including Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0012], [0178]).
Regarding claim 19, the combination of Greaves et al. and Liu et al. teaches the limitations of claim 19. Specifically, Greaves et al. teaches the method of claim 1, wherein the test sample or one or more reference values comprise or relate to whole blood, plasma, a cell, a tissue, serum, cerebrospinal fluid, interstitial fluid, sputum, urine, lymph, or a combination thereof (see Greaves et al., Blood and CSF biomarkers, disclosing clinical trials for FTD, where it was found that low serum, plasma, or cerebrospinal fluid (CSF) progranulin levels have almost perfect sensitivity and specificity for detecting pathogenic GRN mutations. Blood also contain neurofilament light chain (NfL) markers which appears to give a measure for disease intensity, and predict progression and survival in genetic FTD.).
Regarding claim 20, the combination of Greaves et al. and Liu et al. teaches the limitations of claim 20. Specifically, Greaves et al. teaches the method of claim 19, wherein the test sample or one or more reference values comprise or relate to plasma (see Greaves et al., Blood and CSF biomarkers, disclosing clinical trials for FTD, where it was found that low serum, plasma, or cerebrospinal fluid (CSF) progranulin levels have almost perfect sensitivity and specificity for detecting pathogenic GRN mutations.).
Regarding claim 21, Greaves et al. fails to teach wherein the cell is a blood cell, a brain cell, a peripheral blood mononuclear cell (PBMC), a bone marrow-derived macrophage (BMDM), a retinal pigmented epithelial (RPE) cell, an erythrocyte, a leukocyte, a neural cell, a microglial cell, a cerebral cortex cell, a spinal cord cell, a bone marrow cell, a liver cell, a kidney cell, a splenic cell, a skin cell, a fibroblast, a heart cell, a lymph node cell, or a combination thereof.
However, Liu et al. teaches finding glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in the fibroblasts and plasma of healthy control and GD patients (see Liu et al., Fig. 21A-21D, [0055]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate cell samples including fibroblast (as taught by Liu et al.), for the benefit of additionally being able to evaluate lysosomes in lysosomal storage disease patients, including Tay-Sachs disease patients, with PGRN modulating the fibroblasts and correcting lysosomes (see Liu et al., [0333]).
Regarding claim 22, Greaves et al. fails to teach the method of claim 19, wherein the tissue comprises a lymph node, bone marrow, skin tissue, blood vessel tissue, lung tissue, spleen tissue, valvular tissue, or a combination thereof.
However, Liu et al. teaches collecting lung, liver, femur, and spine samples from sacrificed 1 year-old wild type (WT) and PGRN KO mice, where the samples were used in histology and micro-CT analysis (see Liu et al., [0184]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate tissue samples of the lung, and spleen (as taught by Liu et al.), for the benefit being able to model Gaucher's disease in KO mice with PGRN deficiency, and to test various treatments on them (see Liu et al., [0015], [0184]).
Regarding claim 23, Greaves et al. fails to teach wherein the test sample comprises an endosome, a lysosome, an extracellular vesicle, an exosome, a microvesicle, or a combination thereof.
However, Liu et al. demonstrates that PGRN binds glycocerebrosidase (GBA1), and the delivery of the GBA1 enzyme to the lysosome is impaired in PGRN KO mice, where enzyme insufficiency causes accumulation of the corresponding substrates in lysosomes (see Liu et al., Fig. 1, [0015], [0035]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate the test sample including lysosomes (as taught by Liu et al.), for the benefit of revealing that PGRN having an important function in lysosomes and trafficking of proteins to the lysosome, and that the mutations of the PGRN gene is associated with lysosomal storage disease (see Liu et al., [0016]).
Regarding claim 24, Greaves et al. fails to teach wherein the abundance of the GlcSph is measured using liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC/MS/MS), gas chromatography-mass spectrometry (GC-MS), gas chromatography-tandem mass spectrometry (GC-MS/MS), enzyme-linked immunosorbent assay (ELISA), or a combination thereof.
However, Liu et al. teaches measuring levels of glucosylsphingosine (GlcSph) by the high-performance liquid chromatography/mass spectrometry from lung and spleen samples of WT and PGRN KO mice (see Liu et al., [0219]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate measuring the level of GlcSph using LC-MS/MS (as taught by Liu et al.), for the benefit of diagnosis and developing treatments using progranulin (PGRN) for lysosomal storage diseases, including Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0012], [0178]).
Regarding claim 28, Greaves et al. fails to teach wherein the subject has one or more mutations in the granulin (GRN) gene.
However, Liu et al. teaches mutation of GRN gene are associated with front-temporal dementia. Insufficiency of PGRN has been associated with neuron degenerative diseases. Liu additionally teaches animal models of lysosomal storage diseases, including Gaucher's Disease and Tay-Sachs disease, based on or including PGRN mutations (see Liu et al., Abstract, [0178], [0201]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate subjects with GRN mutations (i.e., PGRN KO mice) (as taught by Liu et al.), for the benefit being able to model Gaucher's disease in KO mice with PGRN deficiency, and to test various treatments on them (see Liu et al., [0015], [0184]).
Regarding claim 29, Greaves et al. fails to teach wherein the FTD is related to PGRN expression, processing, glycosylation, cellular uptake, trafficking, and/or function.
However, Liu et al. teaches PGRN and PGRN peptides, particularly including the peptide(s) denoted atsttrin, as modulators of lysosomal storage disease and of lysosomal trafficking, and facilitators of lysosomal enzyme trafficking to the lysosomes. Liu et al additionally teaches where PGRN also functions as a neurotrophic factor and mutations in the PGRN gene (GRN) resulting in partial or complete loss of the PGRN protein cause frontotemporal dementia (FTD) neuronal ceroid lipofuscinosis (NCL), respectively (see Liu et al., [0017], [0178]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate measuring PGRN expression in a subject in determining FTD, and the modulation and facilitation lysosomal trafficking by PGRN (as taught by Liu et al.), for the benefit of facilitating the testing and development of new drugs for treating Gaucher's Disease, where GD Type III patients are known to suffer from dementia (see Liu et al., [0009], [0197]).
Regarding claim 30, Greaves et al. fails to teach wherein the FTD is associated with a decreased PGRN level.
However, Liu et al. teaches mutation of GRN gene are associated with front-temporal dementia. Insufficiency of PGRN has been associated with neuron degenerative diseases. Liu et al additionally teaches where partial or complete loss of the PGRN protein cause frontotemporal dementia (FTD) neuronal ceroid lipofuscinosis (NCL), respectively (see Liu et al, [0178], [0201]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate how the insufficiency of PGRN is associated with neuron degenerative diseases and frontotemporal dementia (as taught by Liu et al.), for the benefit of diagnosis and developing treatments using progranulin (PGRN) for lysosomal storage diseases, including Gaucher's Disease, where GD Type III patients are known to suffer from dementia (see Liu et al., [0009], [0012]).
Regarding claim 31, Greaves et al. fails to teach wherein the subject and/or the reference subject is a human or a non-human primate.
However, Liu et al. teaches that subjects include humans and other mammals (e.g. mice) (see Liu et al., [0132]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. to incorporate human subjects (as taught by Liu et al.), for the benefit of being able to elicit a biological, physiological, clinical, or medical response from applying a therapeutically effective amount of a drug or compound in a subject (see Liu et al., [0128]).
Claims 3-5, 10-13, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Greaves et al. and Liu et al. as applied to claim 1 above, and further in view of Sardi et al. (US PG-Pub 20150284472 A1).
Regarding claim 3, Greaves et al. teaches clinical presymptomatic genetic testing for Frontotemporal dementia (FTD), where three biomarkers were identified that can be used in clinical trials for FTD, CSF or blood neurofilament light chain levels (NfL), CSF or blood progranulin levels (in progranulin (GRN) carriers), and CSF poly(GP) dipeptide repeat protein levels (in chromosome 9 open reading frame 72 (C9orf72) carriers). While the markers are not FTD-specific markers, as CSF nor blood assays of tau or TDP-43 have identified any, measures of the three biomarkers appear to have a measure of the FTD disease. For example, oncreased NfL levels (both in CSF and blood) reflect axonal damage and appear to be a measure of disease intensity, and predict progression and survival in genetic FTD. Whilst an increase in NfL is not specific for FTD, and levels are increased in multiple neurological diseases, evidence from other diseases suggests that a decrease in levels could be a measure of successful disease modification in trials. This is further applied to CSF poly(GP) following post-treatment, which also suggests potential disease modification (see Greaves et al., Abstract, Natural history studies and biomarkers, Blood and CSF biomarkers).
Greaves et al. fails to teach a method for evaluating a compound or monitoring a subject's response to a compound, pharmaceutical composition, or dosing regimen thereof for treating frontotemporal dementia (FTD), the method comprising: (a) measuring the abundance of GlcSph in a test sample from a subject having FTD, wherein the test sample or subject has been treated with the compound or pharmaceutical composition thereof;(b) comparing the difference in abundance between the GlcSph measured in (a) and one or more reference values; and (c) determining from the comparison whether the compound, pharmaceutical composition, or dosing regimen thereof improves the GlcSph level for treating FTD.
However, Liu et al. teaches their invention, which introduces Progranulin (PGRN) as a potential compound which is known for its multiple physiological and pathological functions in development, would healing, anti-inflammation, neuron system disorders, as well as cancer. Mutations in the PGRN genes notably results in partial or complete loss in the PGRN protein, which causes frontotemporal dementia. Liu et al. provides PGRN and PGRN peptides, particularly including the peptide(s) denoted atsttrin, as modulator of lysosomal storage disease and of lysosomal trafficking, and facilitators of lysosomal enzyme trafficking to the lysosome (see Liu et al., [0003] [0017] [0178]). Lung, spleen, plasma and fibroblast samples were collected from wild-type (WT) and PGRN Knockout (KO) mice, where levels of glucosylsphingosine (GlcSph) were measured using LC-MS/MS. Levels of GlcSph in the fibroblast and plasma from Gaucher's Disease (GD) patients and compared with healthy control subjects, where levels of beta-glucosylsphingosine was found to be significantly elevated in the PGRN deficient mice (see Liu et al., Fig. 21A-21D, Fig. 22A-22C, [0055], [0182], [0219]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD using measured levels of biomarkers for determining at-risk or severity of the disease of Greaves et al. to incorporate using PGRN as a potential compound for treating lysosomal storage diseases, and where it is shown that a high level of GlcSph is linked to FTD (as taught by Liu et al.), for the benefit of diagnosis and developing treatments using progranulin (PGRN) for lysosomal storage diseases, including Gaucher's Disease, where GD Type III patients are known to suffer from dementia (see Liu et al., [0009], [0012]).
The combination of Greaves et al. and Liu et al fails to teach determining from the comparison whether the compound, pharmaceutical composition, or dosing regimen thereof improves the GlcSph level for treating FTD.
However, in the analogous art of compositions and methods for treating proteinopathes, Sardi et al. teaches methods for reducing toxic lipids (e.g., glucosylsphingosine (GlcSph)) and reducing/inhibiting the accumulation of protein aggregates in a mammal with a proteinopathy, where the accumulation of toxic lipids like GlcSph can act as a neurotoxin, causing loss of neural function seen in conditions such as Gaucher’s disease and frontotemporal dementia. The method involves administering a therapeutically effective amount of an agent that increases glucocerebrosidase activity, which would improve cognitive function, memory function, and prevent loss of memory or neural function, as well as reduce toxic lipids such as GlcSph. Some embodiments find reductions of toxic GlcSph reduced from at least 10% to 90% or more, reduced to a level not significantly different from a mammal without proteinopathy (see Sardi et al., [0007], [0011], [0014], [0090]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the FTD clinical trials, biomarkers including GlcSph and using PGRN as a compound in treating lysosomal storage diseases from the combination of Greaves et al. and Liu et al. to further incorporate the administration of an agent that would reduce the toxic GlcSph levels (as taught by Sardi et al.), for the benefit of developing effective therapeutics in alleviating or managing the symptoms associated with proteinopathies, including Gaucher’s disease and frontotemporal dementia (see Sardi et al., [0004], [0011]).
Regarding claim 4, Greaves et al. fails to teach further comprising treating another test sample or subject with another compound and selecting a candidate compound that improves the GlcSph level.
However, Liu et al. teaches PGRN and PGRN peptides, particularly including the peptide(s) denoted atsttrin, as modulators of lysosomal storage disease and of lysosomal trafficking, and facilitators of lysosomal enzyme trafficking to the lysosomes. Liu additionally teaches anti-Sortilin antibodies, where sortilin was reported to be a receptor of PGRN and mediates the delivery of PGRN to the endosome/lysosomal pathway in neurons. Sortilin was determined to forms a ternary complex with LIMP2/GBA/PGRN/HSP70 through PGRN as a linker protein and facilitates the delivery of LIMP2/GBA/PGRN/HSP70 along the endosome/lysosomal pathway (see Liu et al., [0017], [0195]). Liu et al further teaches the subjects either consisting of a number of samples and subjects, including humans, other mammals (i.e., PGRN KO Mice), and extracting test samples such as plasma, fibroblast, lung tissues, and spleen tissue, to name a few (see Liu et al., [0132], [0219]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. by incorporating several potential drugs or compounds to be used on several subjects and test samples (as taught by Liu et al.), for the benefit of facilitating the testing and development of new drugs for treating Gaucher's Disease, where GD Type III patients are known to suffer from dementia, further where a partial or complete loss of the PGRN protein would cause frontotemporal dementia (see Liu et al., [0009], [0178], [0197]).
Additionally, Sardi et al. teaches that the agents that is administered to a subject with proteinopathy may encompass a small molecule, an antibody, a nucleic acid molecule, or a polypeptide. For instance, the agent can be a GBA1 polypeptide or equivalent thereof (e.g., fragment, analog, or derivative thereof that catalyzes the cleavage of glucocerebroside) (see Sardi et al., [0016]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the compounds, subjects, and samples from the combination of Greaves et al. and Liu et al. to further incorporate administered agents including small molecules, nucleic acid molecules, or polypeptides (as taught by Sardi et al.), for the benefit of developing effective therapeutics in alleviating or managing the symptoms associated with proteinopathies, including Gaucher’s disease and frontotemporal dementia (see Sardi et al., [0004], [0011]).
Regarding claim 5, the combination of Greaves et al. and Sardi et al. fails to teach maintaining or adjusting the amount or frequency of administration of the compound to the test sample or to the subject; and administering the compound to the test sample or to the subject.
However, Liu et al. teaches methods for facilitating lysosomal delivery of a protein or enzyme in an animal comprising administering to said animal isolated PGRN, or active fragments thereof including atsttrin. The compositions are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount. The quantity to be administered depends on the subject to be treated, capacity of the subject's immune system to utilize the active ingredient, and PGRN activity or PGRN-GBA binding capacity desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual. However, suitable dosages may preferably range from about 0.5 to 10 milligrams of active ingredient per kilogram body weight of individual per day and depend on the route of administration. Suitable regimes for initial administration and subsequent administration are also variable, but are typified by an initial administration followed by repeated doses at one or more-hour intervals by a subsequent injection or other administration. Alternatively, continuous intravenous infusion sufficient to maintain concentrations of ten nanomolar to ten micromolar in the blood are contemplated (see Liu et al. [0021], [0160]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD of Greaves et al. by incorporating different options for dosage for a quantity to be administered at variable intervals to a subject (as taught by Liu et al.), for the benefit of facilitating the testing and development of new drugs for treating Gaucher's Disease (see Liu et al., [0197]).
Regarding claim 10, the combination of Greaves et al. and Liu et al. fail to teach wherein the abundance of the GlcSph in the test sample of a subject having, or at risk of having, FTD is at least about 1.2-fold to about 5-fold higher compared to the reference value.
However, Sardi et al. teaches a graph, Fig. 6D, displaying the progressive accumulation of glucosylsphingosine in GBA1 Gaucher mice models. The GlcSph levels between wild-type (WT) control mice and GBA1 mice shows a sharp increase in GlcSph levels towards the Gaucher mice, from approximately 0.17 ng/mg in 2-month-old WT mice, to an approximately 0.7 ng/mg in 2-month-old GBA 1 mice (see Sardi et al., Fig. 6D, [0032]).
While Sardi et al. doesn't explicitly teach at least about 1.2-fold to about 5-fold for increase GlcSph compared to reference values, it would have been obvious to one of ordinary skill in the art before the effecting filing date of the claimed invention to modify Sardi's ranges of GlcSph accumulation to be about 1.2-fold to about 5-fold, as a result of routine optimization (See MPEP 2144.05 regarding routine optimization; see also In re Aller, 220 F.2d 454, 456 (CCPA 1955) ("[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation"); see In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003) ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").
It also would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify FTD being caused in high amounts of GlcSph from the combination of Greaves et al. and Liu et al. to incorporate at least about an 1.2-fold to about a 5-fold increase in GlcSph compared to reference values (as taught by Sardi et al.), for the benefit of developing effective therapeutics in alleviating or managing the symptoms associated with proteinopathies, including Gaucher’s disease and frontotemporal dementia (see Sardi et al., [0004], [0011]).
Regarding claim 11, the combination of Greaves et al. and Liu et al. fail to teach wherein the improved GlcSph level is an improvement over the GlcSph level prior to treatment, and wherein the improved GlcSph level is closer to the reference value than the GlcSph level prior to treatment.
However, Sardi et al. teaches that the method performed using the agents reduces toxic GlcSph levels in mammals with proteinopathy by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. The reduction in toxic glucosylsphingosine is brought to a level not significantly different than a mammal without a proteinopathy (see Sardi et al., [0014]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the FTD clinical testing from the combination of Greaves et al. and Liu et al. to incorporate the reduction in GlcSph being closer to mammals without proteinopathy (as taught by Sardi et al.), for the benefit of developing effective therapeutics in alleviating or managing the symptoms associated with proteinopathies, including Gaucher’s disease and frontotemporal dementia (see Sardi et al., [0004], [0011]).
Regarding claim 12, the combination of Greaves et al. and Liu et al. fail to teach wherein the improved GlcSph level has a difference compared to the reference value of less than 15%, 10%, or 5%.
However, Sardi et al. teaches that the method performed using the agents reduces toxic GlcSph levels in mammals with proteinopathy by at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more (see Sardi et al., [0014], [0161]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the FTD clinical testing from the combination of Greaves et al. and Liu et al. to incorporate the reduction in GlcSph by at least 5%, 10%, and 15% (as taught by Sardi et al.), for the benefit of developing effective therapeutics in alleviating or managing the symptoms associated with proteinopathies, including Gaucher’s disease and frontotemporal dementia (see Sardi et al., [0004], [0011]).
Regarding claim 13, the combination of Greaves et al. and Liu et al. fail to teach wherein the reference value is the GlcSph level in a test sample of the subject prior to the subject receiving treatment.
However, Sardi et al. teaches that the method performed using the agents reduces toxic GlcSph levels in mammals with proteinopathy by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. The reduction in toxic glucosylsphingosine is brought to a level not significantly different than a mammal without a proteinopathy (see Sardi et al., [0014]).
While Sardi et al. doesn't explicity teach wherein the reference value is the GlcSph level in a test sample of the subject prior to the subject receiving treatment, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to recognize the percentile reductions of GlcSph is based on the previous value of GlcSph found in the sample prior to administration of a therapeutically effective amount of agent (see Sardi et al., [0014], [0161]). It also would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the FTD clinical testing from the combination of Greaves et al. and Liu et al. to incorporate having the reference value be the GlcSph level in a test sample prior to administering an agent (as taught by Sardi et al.), for the benefit of developing effective therapeutics in alleviating or managing the symptoms associated with proteinopathies, including Gaucher’s disease and frontotemporal dementia (see Sardi et al., [0004], [0011]).
Regarding claim 32, the combination of Greaves et al. and Sardi et al. fails to teach wherein the subject is a PGRN knockout mouse or PGRN knockout rat.
However, Liu et al. teaches animal models for lysosomal storage diseases, including Gaucher's disease. Animals with altered PGRN or PGRN knock out/null (KO) develop lysosomal storage disease, resembling clinical Gaucher's disease. Particularly, PGRN KO mice are used (see Liu et al., [0172]-[0173]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD and administration of agents from the combination of Greaves et al. and Sardi et al. to incorporate PGRN KO mice as subjects (as taught by Liu et al.), for the benefit being able to model Gaucher's disease in KO mice with PGRN deficiency, and to test various treatments on them (see Liu et al., [0015], [0184]).
Claims 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Greaves et al. and Liu et al. as applied to claim 1, and further in view of Astarita et al. (WO 2020081575 A1).
Regarding claim 17, the combination of Greaves et al. and Liu et al fails to teach wherein step (a) further comprises measuring the abundance of one or more bis(monoacylglycero)phosphate (BMP) species.
However, in the analogous art of method for treating and monitoring progranuilin-associated disorders, Astarita et al. teaches a method for evaluating a compound or monitoring a subject’s response to a compound, pharmaceutical composition, or dosing regimen thereof for treating a progranulin (PGRN)-associated disorder, the method comprising: measuring an abundance of one or more bis(monoacylglycero)phosphate (BMP) species in a test sample from a subject having a PGRN-associated disorder (see Astarita et al, [0003]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD using GlcSph from the combination of Greaves et al. and Liu et al. to incorporate measuring the abundance of one or more bis(monoacylglycero)phosphate species (as taught by Astarita et al.), for the benefit of having an additional marker for being able to get a measure for PGRN-associated disorders such as frontotemporal dementia (see Astarita et al, [0003]).
Regarding claim 18, the combination of Greaves et al. and Liu et al fails to teach wherein the one or more BMP species comprise BMP(16:0_18:1), BMP(16:0_18:2), BMP(18:0_18:0), BMP(18:0_18:1), BMP(18:1_18:1), BMP(16:0_20:3), BMP(18:1_20:2), BMP(18:0_20:4), BMP(16:0_22:5), BMP(20:4_20:4), BMP(22:6_22:6), BMP(20:4_20:5), BMP(18:2_18:2), BMP(16:0_20:4), BMP(18:0_18:2), BMP(18:0e_22:6), BMP(18:1e_20:4), BMP(20:4_22:6), BMP(18:0e_20:4), BMP(18:2_20:4), BMP(18:1_22:6), BMP(18:1_20:4), BMP(18:0_22:6), and/or BMP(18:3_22:5).
However, Astarita et al. teaches a subject (e.g, a target subject) determined to have a PGRN- associated disease or a decreased level of PGRN when the abundance of at least one of the BMP species selected from the group consisting of BMP(16:0_18: 1), BMP(16:0_18:2), BMP(18:0_18:0), BMP(18:0_18: 1), BMP(18:1_18: 1), BMP(16:0_20:3), BMP(18: 1_20:2), BMP(18:0_20:4), BMP(16:0_22:5), BMP(20:4_20:4), BMP(22:6_22:6), BMP(20:4_20:5), BMP(18:2_18:2), BMP(16:0_20:4), BMP(18:0_18:2), BMP(l8:0e_22:6), BMP(18: le_20:4), BMP(20:4_22:6), BMP(18:0e_20:4), BMP(18:2_20:4), BMP(18: 1_22:6), BMP(18: 1_20:4), BMP(18:0_22:6), and BMP(18:3_22:5) (see Astarita et al, [0063]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the testing for FTD using GlcSph from the combination of Greaves et al. and Liu et al. to incorporate a number of possible BMP species from a subject to measure the abundance of (as taught by Astarita et al.), for the benefit of having an additional marker for being able to get a measure for PGRN-associated disorders such as frontotemporal dementia (see Astarita et al, [0003]).
Claims 25-26 are rejected under 35 U.S.C. 103 as being unpatentable over Greaves et al. and Liu et al. as applied to claim 1 above, and further in view of Mirzaian et al. (“Mass spectrometric quantification of glucosylsphingosine in plasma and urine of type 1 Gaucher patients using an isotope standard").
Regarding claim 25, the combination of Greaves et al. and Liu et al. fails to teach wherein an internal GlcSph standard is used when measuring the abundance of the GlcSph.
However, in the analogous art of mass spectrometric quantification of glucosylsphingosine in plasma and urine of type 1 Gaucher patients using an isotope standard, Mirzaian et al. teaches quantitatively detecting and measuring GlcSph by LC-ESI-MS/MS, by using the internal isotope-labelled standard 13C5-GlcSph, which was synthesized for used as the internal standard (see Mirzaian et al., Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the measurements of GlcSph from the combination of Greaves et al. and Liu et al. to incorporate an internal isotope standard for measuring GlcSph (as taught by Mirzaian et al.), for the benefit of improving quantification of GlcSph manifestation in mass spectrometric detection (see Mirzaian et al., Introduction).
Regarding claim 26, the combination of Greaves et al. and Liu et al. fails to teach wherein the internal GlcSph standard comprises a GlcSph species that is not naturally present in the subject.
However, Mirzaian et al. teaches that the internal standard for quantitative LC-ESI-MS/MS measurement was synthesized, of which the isotope labelled 13C5-GlcSph is explicitly created, not obtained elsewhere. (see Mirzaian et al., Introduction, Synthesis of [5-9] 13C5-labelled glucosylsphingosine).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the measurements of GlcSph from the combination of Greaves et al. and Liu et al. to incorporate the synthesis of the GlcSph standard (as taught by Mirzaian et al.), for the benefit of improving quantification of GlcSph manifestation in mass spectrometric detection (see Mirzaian et al., Introduction).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Greaves et al., Liu et al., and Mirzaian et al. as applied to claim 25 above, and further in view of Han (US PG-Pub 20090029473 A1).
Regarding claim 27, the combination of Greaves et al. and Liu et al. fails to teach wherein the internal GlcSph standard comprises a deuterium-labeled GlcSph.
However, Mirzaian et al. teaches quantitatively detecting and measuring GlcSph by LC-ESI-MS/MS, by using the internal isotope-labelled standard 13C5-GlcSph, which was synthesized for used as the internal standard (see Mirzaian et al., Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the measurements of GlcSph from the combination of Greaves et al. and Liu et al. to incorporate an internal isotope-labelled standard for measuring GlcSph (as taught by Mirzaian et al.), for the benefit of improving quantification of GlcSph manifestation in mass spectrometric detection (see Mirzaian et al., Introduction).
Furthermore, the combination of Greaves et al, Liu et al, and Mirzaian et al. fails to teach that the internal GlcSph standard comprises a deuterium-labeled GlcSph.
However, in the analogous art of Lipid profile as a biomarker for early detection of neurological disorders, Han teaches elevated cholesterol mass levels being a risk factor for Alzheimer's Disease (AD), and the elevated cholesterol may lead to an accumulation of cytotoxic derivatives of oxidized cholesterol, which will ultimately lead to developing AD. The method is capable of derivatization of primary, secondary, and tertiary alcohols using N,N-dimethylglycine (DMG), 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide, and 4-(N,N-dimethyl-amino) pyridine. By controlling the ratio of the derivatization reagents to the amount of alcohol, the reaction temperature, and/or the reaction time, one or both hydroxyl groups in oxysterols could be selectively derivatized. The fragment(s) from each oxysterol can be selected from its mono-DMG or di-DMG derivative (or both) for quantitation by comparison to a deuterated internal standard. To confirm that there are no interfering contributions from other oxysterol isomers, the effects of other potential oxysterols on the quantitation must be examined with deuterium labeled 24S-OH-Chol as one of the derivatized oxysterols, to obtain a quantification of 24S-OH-Chol (see Han, [0060]-[0061]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the internal isotope-labelled standard from the combination of Greaves et al., Liu et al., and Mirzaian et al. to further incorporate deuterium as a label (as taught by Han), for the benefit of being able to confirm that the quantification of a target substance or compound is not being influenced by interfering other substances or compounds (e.g., contributions from other oxysterol isomers) (see Han, [0061]).
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Sardi et al., in view of Mirzaian et al.
Regarding claim 33, Sardi et al. teaches a kit comprising any one of the agents (e.g., small molecule, antibody, polypeptide), useful for increasing glucocerebrosidase activity in a mammal diagnosed with proteinopathy, which may include frontotemporal dementia. Increasing glucocerebrosidase in a mammal has therapeutically beneficial outcomes such as improving neural function, improving memory function, preventing loss of memory or neural function, reducing toxic lipids (e.g., glucosylsphingosine). These kits can be used therapeutically and can be used in combination with other known therapies for proteinopathies. For example, common treatments for proteinopathies include Levodopa, dopamine agonists, MAO-B inhibitors, amantadine, anticholinergics, surgery, rehabilitation, and diet management (see Sardi et al., [0090], [0100], [0163]).
Sardi et al. fails to teach that the kit further comprises a GlcSph standard for measuring the abundance of GlcSph in a test sample from the subject.
However, Mirzaian et al. teaches quantitatively detecting and measuring GlcSph by LC-ESI-MS/MS, by using the internal isotope-labelled standard 13C5-GlcSph, which was synthesized for used as the internal standard (see Mirzaian et al., Abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the kit for administering an agent for treating frontotemporal dementia from Sardi et al. to incorporate an internal isotope-labelled standard for measuring GlcSph (as taught by Mirzaian et al.), for the benefit of improving quantification of GlcSph manifestation in mass spectrometric detection (see Mirzaian et al., Introduction).
Conclusion
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/TRACY CHING-TIAN COLENA/ Examiner, Art Unit 1797
/JENNIFER WECKER/Primary Examiner, Art Unit 1797