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 40-42 are objected to because of the following informalities: MMSE does not show in any of the claims what the abbreviations mean. The full meaning known in the art is Mini-Mental State Examination, and should be referenced in at least claim 40. 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.
Claim 38-55 are rejected under 35 U.S.C. 101 because it constitutes abstract ideas.
Regarding independent claim 38, a two-step analysis is performed:
Step 1: Does the claim fall within a statutory category?
Yes, it is a system/machine.
Step 2A, Prong 1: Identify the law of nature/natural phenomenon/abstract ideas.
A system for detecting salivary biomarkers indicative of Alzheimer's disease (AD) in a saliva sample obtained from a subject to determine whether the subject is afflicted with AD or the severity of AD in the subject, the system comprising: (a) binding agents specific to one or more salivary biomarker selected from the group consisting of Insulin-like growth factor binding protein-2 (IGFBP-2), Insulin-like growth factor binding protein-3 (IGFBP-3), Beta-secretase 1 (BACEl), Reduced glutathione (GSH), TNF- related apoptosis-including ligand (TRAIL), Chitinase-3-like protein 1 (YKL-40), Intercellular Adhesion Molecule 1 (ICAM-1), Neurofilament protein L (NfL), Alpha-1 antitrypsin (A1AT), Transthyretin (TTR), Neurogranin, and Human heart fatty acid binding protein (hFABP), and combinations thereof;(b) a measurable label associated with the binding agents that indicates a proportional reaction based on the amount of biomarker present in the saliva sample; and (c) a measurement device operable to utilize the label to provide a qualitative, semi-quantitative, or quantitative measure of the one or more salivary biomarker indicative of whether the subject is afflicted with AD or the severity of AD in the subject.
Obtaining a qualitative or quantitative measure of a biomarker to be used to determine if the subject is afflicted with AD or the severity is considered 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 38 recites the additional elements: binding agents specific to one or more salivary biomarkers, a measurable label associated with the binding agents, and a measurement device operable to utilize the label. With respect to the binding agents, measurable labels and measurement device represent insignificant extra solution activity. 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 38 does not provide an inventive concept (significantly more than the abstract idea). The binding agents specific to a salivary biomarker, measurable label, and measurement device are considered insignificant extra solution activity (e.g., mere data gathering). Furthermore, the binding agents specific to a salivary biomarker, measurable label, and measurement device, alone and in combination within claim 38 as a whole, are well understood, routine, and conventional activities within the prior art (see 35 USC § 102 & 103 rejections).
Dependent claims 39-47 do not resolve any of the issues discussed above because they involve limitations using comparisons with reference values, and more insignificant extra-solution activity and/or abstract ideas in the form of mental process.
Regarding independent claim 48, a two-step analysis is performed:
Step 1: Does the claim fall within a statutory category?
Yes, it is a kit/machine
Step 2A, Prong 1: Identify the law of nature/natural phenomenon/abstract ideas.
A kit for detecting salivary biomarkers indicative that a subject is afflicted with Alzheimer's disease (AD) or the severity of AD in the subject, the kit comprising:(a) a solid support on which a plurality of binding agents have been affixed, directly or indirectly, capable of binding with one or more biomarker in a saliva sample obtained from the subject selected from the group consisting of; Insulin-like growth factor binding protein-2 (IGFBP-2), Insulin-like growth factor binding protein-3 (IGFBP-3), Beta-secretase 1 (BACE1), Reduced glutathione (GSH), TNF-related apoptosis-including ligand (TRAIL), Interleukin 6 (IL-6), Chitinase-3-like protein 1 (YKL-40), Intercellular Adhesion Molecule 1 (ICAM-1), Vascular cell adhesion protein 1 (VCAM-1), Neurofilament protein L (NfL), Alpha-1 antitrypsin (AlAT), Transthyretin (TTR), Neurogranin, and Human heart fatty acid binding protein (hFABP), and combinations thereof;(b) a measurable label associated with the binding agents which provides a detectable complex indicative of the amount of the one or more detected biomarker in the saliva sample, wherein IGFBP-2 above about 2500 pg/ml, IGFBP-3 above about 1680 ng/ml, BACE1 above about 700 pg/ml, GSH less than about 1.7 μmol/l, TRAIL above about 3 ng/ml, IL-6 above about 20 pg/ml, YKL-40 above about 30 ng/ml, ICAM-1 above about 200 ng/ml, VCAM-1 above about 450 ng/ml, NfL above about 0.3 pg/ml, AlAT less than about 650 ng/ml, TTR less than about 10 μg/ml, Neurogranin above about 5 pg/ml, and/or hFABP above about 0.80 ng/ml, is indicative that the subject is afflicted with AD.
Making a comparison between a reference value and a measured value is considered 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 48 recites the additional elements: A solid support, binding agents, biomarkers, and a measurable label. With respect to the above, they represent 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 48 does not provide an inventive concept (significantly more than the abstract idea). A solid support, binding agents, biomarkers, and a measurable label are considered insignificant extra solution activity (e.g., mere data gathering). Furthermore, the additional elements above, alone and in combination within claim 48 as a whole, are well understood, routine, and conventional activities within the prior art (see 35 USC § 102 & 103 rejections).
Dependent claims 49-55 do not resolve any of the issues discussed above because they involve limitations with more insignificant extra-solution activity and/or abstract ideas in the form of mental process (i.e., instructions for interpretation).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 38 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ray et al. (US PG-Pub 20050221348 A1).
Regarding claim 38, Ray et al. teaches a system for detecting salivary biomarkers indicative of Alzheimer's disease (AD) in a saliva sample obtained from a subject to determine whether the subject is afflicted with AD or the severity of AD in the subject (see [0075], which discloses methods of assessing cognitive function, by obtaining measured levels of one or more Alzheimer's disease (AD) diagnosis biomarkers in a biological fluid sample (e.g. saliva), where the markers described are used in diagnosing AD, assessing cognitive function, assessing mild cognitive impairment (MCI), assessing risk of developing AD, stratifying AD, etc.), the system comprising:(a) binding agents specific to one or more salivary biomarker selected from the group consisting of Insulin-like growth factor binding protein-2 (IGFBP-2) (see [0014], AD diagnosis biomarkers selected from a group, including IGFBP-2.), Insulin-like growth factor binding protein-3 (IGFBP-3) (see [0208], disclosing quantitative biomarker levels of IGFBP3 used in correlation with mini-mental state examination (MMSE) scores.) Beta-secretase 1 (BACE1), Reduced glutathione (GSH), TNF- related apoptosis-including ligand (TRAIL), Chitinase-3-like protein 1 (YKL-40), Intercellular Adhesion Molecule 1 (ICAM-1) (see [0014], AD diagnosis biomarkers selected from a group, including ICAM-1.), Neurofilament protein L (NfL), Alpha-1 antitrypsin (A1AT), Transthyretin (TTR), Neurogranin, and Human heart fatty acid binding protein (hFABP), and combinations thereof; (b) a measurable label associated with the binding agents that indicates a proportional reaction based on the amount of biomarker present in the saliva sample (see [0119], disclosing in a standard (direct reaction) format, the level of AD biomarker/affinity reagent complex is directly monitored. This may be accomplished by, for example, determining the amount of a labeled detection reagent that forms are bound to AD biomarker/affinity reagent complexes. In a competitive format, the amount of AD biomarker in the sample is deduced by monitoring the competitive effect on the binding of a known amount of labeled AD biomarker (or other competing ligands) in the complex. Amounts of binding or complex formation can be determined either qualitatively or quantitatively.); and (c) a measurement device operable to utilize the label to provide a qualitative, semi-quantitative, or quantitative measure of the one or more salivary biomarker indicative of whether the subject is afflicted with AD or the severity of AD in the subject (see [0075], disclosing that a quantitative value of measurable concentrations of protein levels can be directly acquired by enzyme-linked immunosorbent assays (ELISA), allowing for quantitative measurement of AD biomarker levels relative to another reference level, which may be relative to the level of another AD biomarker.).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 39, and 43-47 are rejected under 35 U.S.C. 103 as being unpatentable over Ray et al. as applied to claim 38 above, and further in view of O'Bryant (US PG-Pub 20190234967 A1) and Ward et al. (US PG-Pub 20170219611 A1).
Regarding claim 39, Ray et al. teaches several AD diagnosis biomarkers, including to Insulin-like growth factor binding protein-2 (IGFBP-2), and (ICAM-1), with Insulin-like growth factor binding protein-3 (IGFBP-3) used as an additional quantitative biomarker for correlating with mini-mental state examination (MMSE) scores. The biomarkers are quantitatively assayed via ELISA (see Ray et al., [0014], [0075], [0208]).
Ray et al. fails to teach wherein the group of at least one binding agent further includes binding agents specific to Interleukin 6 (IL-6) and Vascular cell adhesion protein 1 (VCAM-1) and wherein the measurement device is operable to detect that the one or more detected biomarker is present in a reference value or amount for the respective biomarker comprising: IGFBP-2 above about 2500 pg/ml, IGFBP-3 above about 1680 ng/ml, BACE1 above about 700 pg/ml, GSH less than about 1.7 μmol/l, TRAIL above about 3 ng/ml, IL-6 above about 20 pg/ml, YKL-40 above about 30 ng/ml, ICAM-1 above 200 ng/ml, VCAM-1 above about 450 ng/ml, NfL above about 0.3 pg/ml, A1AT less than about 650 ng/ml, TTR less than about 10 μg/ml, Neurogranin above about 5 pg/ml, and hFABP above about 0.80 ng/ml, wherein measurement that the biomarker is present in the reference value or amount is indicative that the subject is afflicted with AD.
However, in the analogous art of blood test for screening out amyloid and Alzheimer’s disease presence, O'Bryant teaches blood test adapted for use in a primary, specialty and clinical trial setting for excluding patients suspected of having Alzheimer's Disease comprising: one or more reagents that comprises a detectable marker adapted for use in a primary care setting, wherein the detectable marker is used to determine the expression levels of the following proteins: VCAM-1, IL-6, and ICAM-1 (see O'Bryant, [0008]).
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 AD diagnosis biomarkers of Ray et al. to further incorporate the markers IL-6 and VCAM-1 (as taught by O'Bryant), for the benefit of eliminating the need for further testing for Alzheimer's disease in patients by comparing the expression level of marker proteins from extracted bodily fluids with a statistically locked-down, multi-ethnic, broad age spectrum statistical sample (see O'Bryant, Abstract).
Furthermore, the combination of Ray et al. and O'Bryant fails to teach wherein the measurement device is operable to detect that the one or more detected biomarker is present in a reference value or amount for the respective biomarker comprising: IGFBP-2 above about 2500 pg/ml, IGFBP-3 above about 1680 ng/ml, BACE1 above about 700 pg/ml, GSH less than about 1.7 μmol/l, TRAIL above about 3 ng/ml, IL-6 above about 20 pg/ml, YKL-40 above about 30 ng/ml, ICAM-1 above 200 ng/ml, VCAM-1 above about 450 ng/ml, NfL above about 0.3 pg/ml, A1AT less than about 650 ng/ml, TTR less than about 10 μg/ml, Neurogranin above about 5 pg/ml, and hFABP above about 0.80 ng/ml, wherein measurement that the biomarker is present in the reference value or amount is indicative that the subject is afflicted with AD.
However, in the analogous art of biomarkers and methods related to Alzheimer’s disease, Ward et al. teaches an vitro method for determining the progression and/or the prognosis of mild cognitive impairment (MCI) to Alzheimer's disease (AD) in a human subject, which comprises determining at testing point in a blood sample obtained from said human subject, the concentration of markers transthyretin (TTR), Intercellular adhesion molecule 1 (ICAM1), and Alpha1 antitrypsin (A1AT), Clusterin, Cystatin C (CST3), Alpha-1-Acid glycoprotein (A1AcidG), etc. When at least three or more of the markers have the concentrations as following: transthyretin less (<) than 222 μg/ml, Alpha1 antitrypsin less (<) than 9.5 μg/ml, Clusterin more (>) than 402 μg/ml, etc., then the human subject will convert from MCI to AD within 12 months from testing point (see Ward et al., [0123]).
While Ward et al. doesn't explicitly teach the ranges of TTR less than about 10 μg/ml, and A1AT less than about 650 ng/ml, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed since it would have been obvious to one of ordinary skill in the art to modify the ranges taught by Ward et al. for TTR to be less than about 10 μg/ml, and A1AT less than about 650 ng/ml, 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 the methods for detecting Alzheimer's Disease diagnosis biomarkers from the combination of Ray et al. and O'Bryant to further incorporate the biomarkers and ranges of TTR and A1AT (as taught by Ward et al.), for the benefit of being able to triage patients using the biomarkers, and allow for identifying potential AD cases before there is observed brain degradation (see Ward et al., Abstract, [0007]).
Regarding claim 43, the combination of Ray et al., O’Bryant and Ward et al. teach the exact limitations of claim 43. Specifically, Ray et al. teaches the system of claim 39 wherein the binding agents are selected from the group consisting of antibodies, antigens, nanoparticles, aptamers, inhibitors, substrates, cofactors, coenzymes, lectins, nucleic acids, protein A, protein G, nonbiological ligands, boronates, triazine dyes, and metal-ion chelates. (see Ray et al., [0109]-[0110], disclosing AD biomarkers levels measured using an affinity-based measurement technology. "Affinity" as relates to an antibody is a term well understood in the art and means the extent, or strength, of binding of antibody to the binding partner, such as an AD diagnosis biomarker as described herein. An affinity reagent may be an antibody, or an aptamer.).
Regarding claim 44, the combination of Ray et al., O'Bryant and Ward et al. teach the exact limitations of claim 44. Specifically, Ray et al. teaches the system of claim 43 further comprising a solid support to which the binding agents are attached, the solid support being selected from an assay selected from the group of assays consisting of a lateral flow immunochromatographic assay (LFA), an enzyme- linked immunosorbent assay (ELISA), an enzyme-linked fluorescence polarization immunoassay (FPIA), a homogeneous immunoassay, a quantitative point-of-care assay using determination of chemiluminescence, fluorescence, magnetic particles, or latex agglutination, a gel electrophoresis assay, a gas chromatograph-mass spectrometry (GC-MS) assay, a separation immunoassay, a heterogeneous immunoassay, a homogenous immunoassay, a latex agglutination assay, a western blot assay, and a biosensor assay (see Ray et al., [0075], disclosing a quantitative method of obtaining protein concentration values in a biological fluid sample, utilizing ELISA to get a direct value.).
Regarding claim 45, the combination of Ray et al., O'Bryant and Ward et al. teach the exact limitations of claim 45. Specifically, Ray et al. teaches the system of claim 44 wherein the measurement device provides a visual indication of the label (see Ray et al., [0117], disclosing array-type heterogeneous assays that are suitable for measuring levels of AD biomarkers when the methods of the invention are practiced utilizing multiple AD biomarkers. The binding of the detection reagent is commonly accomplished using a visual system, such as a fluorescent dye-based system.).
Regarding claim 46, the combination of Ray et al., O'Bryant and Ward et al. teach the exact limitations of claim 46. Specifically, Ray et al. teaches the system of claim 45 wherein the visual indication is a fluorescent indication (see Ray et al., [0117], disclosing array-type heterogeneous assays that are suitable for measuring levels of AD biomarkers when the methods of the invention are practiced utilizing multiple AD biomarkers. The binding of the detection reagent is commonly accomplished using a visual system, such as a fluorescent dye-based system.).
Regarding claim 47, Ray et al. teaches biomarker-specific affinity reagents bound to a solid support to facilitate separation of the AD biomarker from the bulk of the biological sample. Ray et al. additionally teaches that in certain embodiments, the levels of least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20 AD diagnosis biomarkers are obtained and measured with reference levels, where further included are a number of different combinations of AD diagnosis biomarkers that may be used in this embodiment (see Ray et al., [0100]-[0101]).
While Ray et al. does not explicitly teach any of the combinations stated by the instant application's claim 47, Ray does teach both IGFBP-2 as an AD diagnosis biomarker, and IGFBP-3 as an quantitative biomarker used in correlation with mini-mental state examination (MMSE) scores along with IGFBP-2 (see Ray et al., [0208]), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further utilize IGFBP-3 as an AD diagnosis biomarker and create a combination between IGFBP-2 and IGFBP-3 that the biomarker-specific affinity reagents affixed to a solid support may bind with, for the benefit of making the detection and diagnosis of AD more effective by assaying two or more biomarkers.
Claims 40-42 are rejected under 35 U.S.C. 103 as being unpatentable over Ray et al., O’Bryant and Ward et al as applied to claim 39 above, and further in view of Lovell et al. (US PG-Pub 20080026405 A1).
Regarding claim 40, Ray et al. teaches providing a method of aiding diagnosis of Alzheimer's disease ("AD"), comprising comparing a measured level of at least one AD diagnosis biomarker in a biological fluid sample from an individual to a reference level for the biomarker, including to Insulin-like growth factor binding protein-2 (IGFBP-2), and (ICAM-1), with Insulin-like growth factor binding protein-3 (IGFBP-3) used as an additional quantitative biomarker for correlating with mini-mental state examination (MMSE) scores. Individuals tested for mild AD would score 22-27, Moderate AD would score 16-21, and severe AD would score 12-15 (see Ray et al., [0014], [0054]-[0057]).
The combination of Ray et al., O'Bryant, and Ward et al. fails to teach wherein the measurement device is operable to detect that the one or more detected biomarker is present in a reference value or amount for the respective biomarker comprising: IGFBP-2 in the range of about 2567 pg/ml to about 5213 pg/ml, IGFBP-3 in the range of about 2016 ng/ml to about 3268 ng/ml, BACE1 in the range of about 701 pg/ml to about 1784 pg/ml, GSH in the range of about 0.1 μmol/l to about 1.5 μmol/l, TRAIL in the range of about 3.2 ng/ml to about 7.9 ng/ml, IL-6 in the range of about 27.5 pg/ml to about 49.6 pg/ml, YKL-40 in the range of about 34.2 ng/ml to about 58.4 ng/ml, ICAM-1 in the range of about 234 ng/ml to about 482 ng/ml, VCAM-1 in the range of about 678 ng/ml to about 1368 ng/ml, NfL in the range of about 0.5 pg/ml to about 3.5 pg/ml, A1AT in the range of about 103 ng/ml to about 589 ng/ml, TTR in the range of about 2.0 μg/ml to about 9.6 μg/ml, Neurogranin in the range of about 5.1 pg/ml to about 9.6 pg/ml and hFABP in the range of about 0.89 ng/ml to about 2.54 ng/ml, and wherein detection that the biomarker is present in the reference value or amount is indicative that the subject is afflicted with severe AD equivalent to an MMSE score of about 0 to about 10.
However, in the analogous art of biomarker of mild cognitive impairment and Alzheimer’s disease, Lovell et al. teaches a statistically significant negative correlation between the levels of the protein complex measured as ng/ml transthyretin and mini-mental status examination (MMSE) scores, a measure of cognitive function. Figure 5 shows a graph displaying this correlation, where a trendline at 60 ng/ml of transthyretin (TTR) would correspond to a MMSE score of about 10, with points at 110 ng/ml and 30 ng/ml adding variation from the trendline (see Lovell et al., [0093], Fig. 5).
While Lovell et al. doesn't explicitly teaches TTR in the range of about 2.0 μg/ml to about 9.6 μg/ml, 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 ranges taught by Lovell et al. for TTR to be in the range of about 2.0 μg/ml to about 9.6 μg/ml, 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 the methods of diagnosis with biomarkers of the combination of Ray et al., O'Bryant, and Ward et al. to incorporate the correlation between levels of the protein complex and the mini mental status examination scores at 10 (as taught by Lovell et al.), for the benefit of monitoring the efficacy of treatment for subjects with AD and those in early progression of the disease (MCI) (see Lovell et al., [0028]).
Regarding claim 41, Ray et al. teaches providing a method of aiding diagnosis of Alzheimer's disease ("AD"), comprising comparing a measured level of at least one AD diagnosis biomarker in a biological fluid sample from an individual to a reference level for the biomarker, including to Insulin-like growth factor binding protein-2 (IGFBP-2), and (ICAM-1), with Insulin-like growth factor binding protein-3 (IGFBP-3) used as an additional quantitative biomarker for correlating with mini-mental state examination (MMSE) scores. Individuals tested for mild AD would score 22-27, Moderate AD would score 16-21, and severe AD would score 12-15 (see Ray et al., [0014], [0054]-[0057]).
The combination of Ray et al., O'Bryant, and Ward et al. fails to teach wherein the measurement device is operable to detect that the one or more detected biomarker is present in a reference value or amount for the respective biomarker comprising:IGFBP-2 in the range of about 2500 pg/ml to about 4019 pg/ml, IGFBP-3 in the range of about 1680 ng/ml to about 2916 ng/ml, BACE1 in the range of about 700 pg/ml to about 1267 pg/ml, GSH in the range of about 0.7 μmol/l to about 1.7 μmol/l, TRAIL in the range of about 3.0 ng/ml to about 6.3 ng/ml, IL-6 in the range of about 20.0 pg/ml to about 38.4 pg/ml, YKL-40 in the range of about 30.3 ng/ml to about 48.6 ng/ml, ICAM-1 in the range of about 200 mg/ml to about 354 ng/ml, VCAM-1 in the range of about 450 mg/ml to about 1247 ng/ml, NfL in the range of about 0.3 pg/ml to about 2.3 pg/ml, A1AT in the range of about 200 ng/ml to about 648 ng/ml, TTR in the range of about 2.4 μg/ml to about 9.8 μg/ml, Neurogranin in the range of about 5.0 pg/ml to about 7.9 pg/ml, and hFABP in the range of about 0.80 ng/ml to about 2.10 ng/ml, wherein detection that the biomarker is present in the reference value or amount is indicative that the subject is afflicted with mild to moderate AD equivalent to an MMSE score of about 11 to about 26.
However, Lovell et al. teaches a statistically significant negative correlation between the levels of the protein complex measured as ng/ml transthyretin and mini-mental status examination (MMSE) scores, a measure of cognitive function. Figure 5 shows a graph displaying this correlation, where a trendline at approximately 58 ng/ml down to approximately 25 ng/ml of transthyretin (TTR) would correspond to a MMSE score of about 11-26, with numerous scattered points adding variation to the value of TTR (see Lovell et al., [0093], Fig. 5).
While Lovell et al. doesn't explictly teaches TTR in the range of about 2.4 μg/ml to about 9.8 μg/ml, 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 ranges taught by Lovell et al. for TTR to be in the range of about 2.4 μg/ml to about 9.8 μg/ml, 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 the methods of diagnosis with biomarkers of the combination of Ray et al., O'Bryant, and Ward et al. to incorporate the correlation between levels of the protein complex and the mini mental status examination scores at 10 (as taught by Lovell et al.), for the benefit of monitoring the efficacy of treatment for subjects with AD and those in early progression of the disease (MCI) (see Lovell et al., [0028]).
Regarding claim 42, Ray et al. teaches providing a method of aiding diagnosis of Alzheimer's disease ("AD"), comprising comparing a measured level of at least one AD diagnosis biomarker in a biological fluid sample from an individual to a reference level for the biomarker, including to Insulin-like growth factor binding protein-2 (IGFBP-2), and (ICAM-1), with Insulin-like growth factor binding protein-3 (IGFBP-3) used as an additional quantitative biomarker for correlating with mini-mental state examination (MMSE) scores. Individuals tested for mild AD would score 22-27, Moderate AD would score 16-21, and severe AD would score 12-15 (see Ray et al., [0014], [0054]-[0057]).
The combination of Ray et al., O'Bryant, and Ward et al. fails to teach wherein the measurement device is operable to detect that the one or more detected biomarker is present in a reference value or amount for the respective biomarker comprising:IGFBP-2 in the range of about 2600 pg /ml to about 3800 pg/ml, IGFBP-3 in the range of about 2100 ng/ml to about 3000 ng/ml, BACE1 in the range of about 800 pg/ml to about 1100 pg/ml, GSH in the range of about 1 μmol/l to about 1.6 μmol/l, TRAIL in the range of about 3 ng/ml to about 5.5 ng/ml, IL-6 in the range of about 25 pg/ml to about 35 pg/ml, YKL-40 in the range of about 32 ng/ml to about 50 ng/ml, ICAM-1 in the range of about 200 ng/ml to about 320 ng/ml, VCAM-1 in the range of about 720 ng/ml to about 1065 ng/ml, NfL in the range of about 0.5 pg/ml to about 2.5 pg/ml, A1AT in the range of about 250 ng/ml to about 500 ng/ml, TTR in the range of about 3 μg/ml to about 10 μg/ml, Neurogranin in the range of about 4.5 pg/ml to about 7 pg/ml, and hFABP in the range of about 0.96 ng/ml to about 1.78 ng/ml, and wherein detection that the biomarker is present in the reference value or amount range is indicative that the subject is afflicted with mild cognitive impairment with probable early AD (MCIAD) equivalent to an MMSE score of about 26.5 to about 26.8.
However, Lovell et al. teaches a statistically significant negative correlation between the levels of the protein complex measured as ng/ml transthyretin and mini-mental status examination (MMSE) scores, a measure of cognitive function. Figure 5 shows a graph displaying this correlation, where a trendline at approximately 17 ng/ml of transthyretin (TTR) would correspond to a MMSE score of about 26.5-26.8, with scattered points adding variation to the value of TTR (see Lovell et al., [0093], Fig. 5).
While Lovell et al. doesn't explictly teaches TTR in the range of about 3 μg/ml to about 10 μg/ml, 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 ranges taught by Lovell et al. for TTR to be in the range of about 3 μg/ml to about 10 μg/ml, 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 the methods of diagnosis with biomarkers of the combination of Ray et al., O'Bryant, and Ward et al. to incorporate the correlation between levels of the protein complex and the mini mental status examination scores at 10 (as taught by Lovell et al.), for the benefit of monitoring the efficacy of treatment for subjects with AD and those in early progression of the disease (MCI) (see Lovell et al., [0028]).
Claims 48-51 and 54-55 are rejected under 35 U.S.C. 103 as being unpatentable over Ray et al., in further in view of Ward et al.
Regarding claim 48, Ray et al. teaches providing kits for carrying out the methods of diagnosis of Alzheimer's Disease (AD) in an individual by measuring the amount of one or more AD diagnosis biomarkers in a biological fluid sample, and comparing the measured amount with a reference value for each AD diagnosis biomarker measured. The kit can also comprise AD biomarker reference samples for use as reference values. The kit can be used for AD diagnosis markers including, but not limited to GCSF; IGFBP-1; IGFBP-2; etc. (see Ray et al., [0014], [0153]) More commonly, kits of the invention comprise at least two different AD biomarker-specific affinity reagents, where these reagent(s) will be labeled with a detectable marker (such as fluorescent dye or a detectable enzyme), or be modified to facilitate detection (e.g., biotinylated to allow for detection with a avidin- or streptavidin-based detection system). (see Ray et al., [0154], [0156]).
Ray et al. fails to teach wherein IGFBP-2 above about 2500 pg/ml, IGFBP-3 above about 1680 ng/ml, BACE1 above about 700 pg/ml, GSH less than about 1.7 μmol/l, TRAIL above about 3 ng/ml, IL-6 above about 20 pg/ml, YKL-40 above about 30 ng/ml, ICAM-1 above about 200 ng/ml, VCAM-1 above about 450 ng/ml, NfL above about 0.3 pg/ml, AlAT less than about 650 ng/ml, TTR less than about 10 μg/ml, Neurogranin above about 5 pg/ml, and/or hFABP above about 0.80 ng/ml, is indicative that the subject is afflicted with AD.
However, Ward et al. teaches a vitro method for determining the progression and/or the prognosis of mild cognitive impairment (MCI) to Alzheimer's disease (AD) in a human subject, which comprises determining at testing point in a blood sample obtained from said human subject, the concentration of markers transthyretin (TTR), Intercellular adhesion molecule 1 (ICAM1), and Alpha1 antitrypsin (A1AT), Clusterin, Cystatin C (CST3), Alpha-1-Acid glycoprotein (A1AcidG), etc. When at least three or more of the markers have the concentrations as following: transthyretin less (<) than 222 μg/ml, Alpha1 antitrypsin less (<) than 9.5 μg/ml, Clusterin more (>) than 402 μg/ml, etc., then the human subject will convert from MCI to AD within 12 months from testing point (see Ward et al., [0123]).
While Ward et al. doesn't explicitly teach the ranges of TTR less than about 10 μg/ml, and A1AT less than about 650 ng/ml, 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 ranges taught by Ward et al. for TTR to be less than about 10 μg/ml, and A1AT less than about 650 ng/ml, 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 the kit for detecting Alzheimer's Disease diagnosis biomarkers of Ray et al. to incorporate the biomarkers and ranges of TTR and A1AT (as taught by Ward et al.), for the benefit of being able to triage patients using the biomarkers, and allow for identifying potential AD cases before there is observed brain degradation (see Ward et al., Abstract, [0007]).
Regarding claim 49, the combination of Ray et al. and Ward et al. teach the exact limitations of claim 49. Specifically, Ray et al. teaches the kit of claim 48 wherein the binding agents are selected from the group consisting of antibodies, antigens, nanoparticles, aptamers, inhibitors, substrates, cofactors, coenzymes, lectins, nucleic acids, protein A, protein G, nonbiological ligands, boronates, triazine dyes, and metal-ion chelates (see Ray et al., [0109]-[0110], disclosing AD biomarkers levels measured using an affinity-based measurement technology. "Affinity" as relates to an antibody is a term well understood in the art and means the extent, or strength, of binding of antibody to the binding partner, such as an AD diagnosis biomarker as described herein. An affinity reagent may be an antibody, or an aptamer.).
Regarding claim 50, the combination of Ray et al. and Ward et al. teach the exact limitations of claim 50. Specifically, Ray et al. teaches the kit of claim 49 wherein the binding agents are secured to the solid support to thereby immobilize the bound biomarkers on the solid support (see [0115]-[0116], disclosing affinity-based assays may be in competition or direct reaction formats, utilize sandwich-type formats, and may further be heterogeneous (e.g., utilize solid supports) or homogenous (e.g., take place in a single phase). In a heterogeneous format, the assay utilizes two phases (typically aqueous liquid and solid). Typically, an AD biomarker-specific affinity reagent is bound to a solid support to facilitate separation of the AD biomarker from the bulk of the biological sample.).
Regarding claim 51, Ray et al. teaches biomarker-specific affinity reagents bound to a solid support to facilitate separation of the AD biomarker from the bulk of the biological sample. Ray et al. additionally teaches that in certain embodiments, the levels of least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20 AD diagnosis biomarkers are obtained and measured with reference levels, where further included are a number of different combinations of AD diagnosis biomarkers that may be used in this embodiment (see Ray et al., [0100]-[0101]).
While Ray et al. does not explicitly teach any of the combinations stated by the instant application's claim 51, Ray does teach both IGFBP-2 as a AD diagnosis biomarker, and IGFBP-3 as an quantitative biomarker used in correlation with mini-mental state examination (MMSE) scores along with IGFBP-2 (see Ray et al., [0208]), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further utilize IGFBP-3 as an AD diagnosis biomarker and create a combination between IGFBP-2 and IGFBP-3 that the biomarker-specific affinity reagents affixed to a solid support may bind with, for the benefit of making the detection and diagnosis of AD more effective by assaying two or more biomarkers.
Regarding claim 54, the combination of Ray et al. and Ward et al. teach the exact limitations of claim 54. Specifically, Ray et al. teaches the kit of claim 50 wherein the kit is selected from the group consisting of an enzyme-linked immunosorbent assay (ELISA) type, and a lateral flow immunochromatographic assay (LFA) type (see Ray et al., [0158], disclosing the kit including a modified substate or other system for capture of AD biomarkers, when the kit is designed for use in a sandwich-format assay (i.e. Sandwich ELISA).).
Regarding claim 55, the combination of Ray et al. and Ward et al. teach the exact limitations of claim 55. Specifically, Ray et al. teaches the kit of claim 54 further comprising instructions describing how to use the kit and interpret each visible indication (see Ray et al., [0153], [0157], [0160]-[0161], disclosing the kit including instructions for carrying out the methods, describing how the contents of the kit are used to carry out the method, and includes information as sample requirements (e.g., form, pre-assay processing, and size), steps necessary to measure the AD biomarker(s), and interpretation of results. The instructions can be included in several formats, such as written on a label, package insert, or machine-readable instructions.).
Claim 52 is rejected under 35 U.S.C. 103 as being unpatentable over Ray et al. as applied to claim 51 above, and further in view of Ward et al. and Ko et al. (US PG-Pub 20200095280 A1).
Regarding claim 52, Ray et al. teaches biomarker-specific affinity reagents bound to a solid support to facilitate separation of the AD biomarker from the bulk of the biological sample. Ray et al. additionally teaches that in certain embodiments, the levels of least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20 AD diagnosis biomarkers are obtained and measured with reference levels, where further included are a number of different combinations of AD diagnosis biomarkers that may be used in this embodiment (see Ray et al., [0100]-[0101]).
While Ray et al. does not explicitly teach IGFBP-2, IGFBP-3, and BACE1 as stated by the instant application's claim 52, Ray does teach both IGFBP-2 as an AD diagnosis biomarker, and IGFBP-3 as an quantitative biomarker used in correlation with mini-mental state examination (MMSE) scores along with IGFBP-2 (see Ray et al., [0208]), it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further utilize IGFBP-3 as an AD diagnosis biomarker and create a combination between IGFBP-2 and IGFBP-3 that the biomarker-specific affinity reagents affixed to a solid support may bind with, for the benefit of making the detection and diagnosis of AD more effective by assaying two or more biomarkers.
The combination of Ray et al. and Ward et al. fails to teach wherein the binding agents affixed to the solid support bind with a specific one of the biomarkers BACE1.
However, in the analogous art of methods of using GM6 in diagnosing and testing Alzheimer’s disease, Ko et al. teaches a method of preventing, delaying the onset, or treating Alzheimer's disease that comprising selecting a patient, and quantifying a biomarker for Alzheimer's disease in said patient, wherein one of the biomarkers is selected from a group, which includes BACE1 (see Ko et al., [0021]).
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 AD diagnosis biomarker combination of Ray et al. and Ward et al. for further incorporating BACE1 as a biomarker to be bound (as taught by Ko et al.), for the benefit of rapid and accurate Alzheimer's disease diagnosis, and potential reduction in size and duration of clinical drug trials, which would speed up drug development (see Ko et al., [0054]).
Claim 53 is rejected under 35 U.S.C. 103 as being unpatentable over Ray et al. as applied to claim 51 above, and further in view of Ward et al., Vanmechelen et al. (US PG-Pub 20190113527 A1) and Fryar-Williams (US PG-Pub 20120094315 A1).
Regarding claim 53, Ray et al. teaches biomarker-specific affinity reagents bound to a solid support to facilitate separation of the AD biomarker from the bulk of the biological sample. Ray et al. additionally teaches that in certain embodiments, the levels of least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, or 20 AD diagnosis biomarkers are obtained and measured with reference levels, where further included are a number of different combinations of AD diagnosis biomarkers that may be used in this embodiment, where IGFBP-2 may be included in one of the combinations (see Ray et al., [0100]-[0101]).
The combination of Ray et al., and Ward et al. fails to teach wherein the binding agents affixed to the solid support bind with a specific one of the biomarkers Neurogranin, and GSH.
However, in the analogous art of assay for the diagnosis of a neurological disease, Vanmechelen et al. teaches immobilizing and capturing Neurogranin, BACE1, or any additional biomarker using a reagent binding specifically to said biomarkers, such as antibodies, in the diagnosis of Alzheimer's disease (see Vanmechelen et al., [0043], [0049]).
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 AD diagnosis biomarker combination of Ray et al. and Ward et al. to incorporate Neurogranin as an additional biomarker to be bound (as taught by Vanmechelen et al.), for the benefit of being able to use the diagnosis to distinguish mild Alzheimer's disease from depression, with or without cognitive impairment (see Vanmechelen et al., Abstract).
Furthermore, the combination of Ray et al., Ward et al., and Wanmechelen et al. fails to teach wherein the binding agents affixed to the solid support bind with a specific one of the biomarker GSH.
However, in the analogous art of biomarkers for the diagnosis and/or prediction of susceptibility to mental and neurodegenerative disorders, Fryar-Williams teaches the identification of biomarkers and biomarker combinations for the diagnosis of, and prediction of susceptibility to, mental and neurodegenerative disorders, where one of the biomarkers that may be selected includes reduced glutathione (GSH) (see Fryar-Williams, [0001], [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 AD diagnosis biomarker combination including IGFBP-2 and Neurogranin of Ray et al., Ward et al., and Vanmechelen et al. to further incorporate GSH as an additional biomarker to be bound (as taught by Fryar-Williams), for the benefit of determining appropriate treatment regimens for sufferers of mental and neurodegenerative disorders (i.e. Alzheimer's disease) as well as methods for evaluating and monitoring the efficacy and progress of treatment regimens (see Fryar-Williams, [0001], [0074]-[0075]).
Conclusion
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/TRACY CHING-TIAN COLENA/ Examiner, Art Unit 1797
/JENNIFER WECKER/ Primary Examiner, Art Unit 1797