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 .
Response to Amendment
This office action is in response to the communications filed on 09/09/2025, concerning Application No. 17/262,459. The claims and remarks filed on 09/09/2025 are acknowledged. Presently, claims 1, 6, and 8-26 remain pending.
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, 6, 8-16, and 19-26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Step 1: The claims are directed to a process/method or a machine/system, and therefore satisfy step 1 of the subject matter eligibility test.
Step 2A, Prong 1: The claims recite the following limitations that are directed to judicial exceptions (abstract ideas): “comparing, by at least one device, quantitative cerebral blood volume (qCBV) information for at least a portion of a brain of the subject to reference qCBV information to identify one or more regions of hypervascularization in the brain of the subject and one or more regions of hypovascularization in the brain of the subject” in claim 1 and similarly in claims 23-24 and 26; “determining that the brain of the subject [includes] a greater number of the one or more regions of hypervascularization than a number of the one or more regions of hypovascularization” in claim 1 and similarly in claims 24 and 26; and “determining that the brain of the subject includes a greater number of the one or more regions of hypovascularization than a number of the one or more regions of hypervascularization” in claim 1 and similarly in claims 24 and 26; etc., which recite mental processes that can be performed in the human mind or with the aid of pen and paper. The comparing/identifying step in claims 1, 24, and 26 can be performed by a user viewing the qCBV map and the pre-determined map of normal brain and mentally/visually comparing the two maps to determine the regions of hyper- and hypo- vascularization; and the determining step in claims 1, 24, and 26 amounts to a user mentally coming up with a decision based on a visual assessment of the regions.
Step 2A, Prong 2: This judicial exception is not integrated into a practical application because the generically recited computer elements do not add a meaningful limitation to the abstract idea (i.e., the mental processes) as the generically recited computer elements only amount to simply implementing the abstract idea on the machine. Additional elements include the “at least one device” in claim 1, the “at least one processor” in claim 24, the “at least one storage medium having encoded thereon executable instructions” in claim 24, the “MRI scanner” in claim 25, the “at least one non-transitory computer-readable storage medium tangibly encoded with computer-executable instructions… executed by a device” in claim 26, and other elements capable of performing the mere data gathering steps and the outputting steps of claims 1, 6, 8-15, 19-24, and 26 (i.e., data gathering of the limitation “wherein the gCBV information for at least the portion of the brain of the subject was produced using one or more magnetic resonance imaging (MRI) images of the brain of the subject” in claims 1, 24, and 26; “outputting… an indication of potential onset of the cerebrovascular disease and/or the neurodegenerative disease in the subject” in claims 1, 24, and 26 and similarly claims 21-22; “outputting… an indication of potential progression of the cerebrovascular disease and/or the neurodegenerative disease in the subject” in claims 1, 24, and 26 and similarly claims 21-22; limitations describing the hyper- and/or hypo-vascularization regions in claims 6 and 8-11; limitations describing obtaining the MRI images in claims 12-15 and 19-20; and data gathering of the limitation “producing a qCBV map of the brain of the subject from the one or more MRI images” in claim 23), etc., which are components at a high level of generality that merely links the judicial exception to a particular technological environment and/or a computer as a tool to perform the abstract idea. Further, claim 16 does set forth the additional step of treating the human subject for ADRD, but this is recited with a high level of generality that merely links the judicial exception to a particular technological environment and/or a computer as a tool to perform the abstract idea.
Step 2B: For similar reasons set forth above, the additional limitations also do not provide an inventive concept that would be substantially more than the judicial exception. Adding insignificant extra-solutionary activity to the judicial exception, e.g., the mere data gathering steps and the outputting steps of claims 1, 6, 8-15, 19-24, and 26 in conjunction with an abstract idea, does not qualify as “significantly more” when recited in a claim with a judicial exception. Further, claim 16 does set forth the additional step of treating the human subject for ADRD, but this is recited at a high level of generality and is considered as conventional extra-solutionary activity, and therefore would not be considered as significantly more than the judicial exception.
Conclusion: Claims 1, 6, 8-16, and 19-26 are not patent-eligible.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 6, 12-15, and 19-26 are rejected under 35 U.S.C. 103 as being unpatentable over Gharagouzloo et al. (WO 2017/019182 A1, of record, cited in the applicant’s IDS filed on 11/03/2022, a copy of which was provided by the applicant on 11/03/2022 and herein used for citation, hereinafter Gharagouzloo) in view of Hua et al. (NPL: "Increased cerebral blood volume in small arterial vessels is a correlate of amyloid-β-related cognitive decline." Neurobiology of Aging, Vol. 76, 2019, Pages 181-193, https://doi.org/10.1016/j.neurobiolaging.2019.01.001; of record, a copy of which was provided by the examiner on 04/09/2025, hereinafter Hua), and further in view of Harris et al. (NPL: "Dynamic susceptibility contrast MRI of regional cerebral blood volume in Alzheimer's disease." The American Journal of Psychiatry, 01 May 1996, 153(5):721-724. DOI: 10.1176/ajp.153.5.721; of record, a copy of the full article of which is herein provided by the examiner, hereinafter Harris).
Examiner notes that current application’s provisional’s specification does not seem to teach specifically [1] outputting from a device an indication of the potential onset of the disease or an indication of the potential progression of the disease (i.e., there is no detail that, in response to one of the above indications being found, that a “device” provides an output as claimed); and [2] the broader evaluation of an onset/progression of any cerebrovascular or neurodegenerative disease (i.e., the provisional provides a specific example of diagnosing the subject for Alzheimer’s Disease, whereas the claims are directed to a method of evaluating potential onset/progression of a “cerebrovascular disease and/or a neurodegenerative disease in a subject”); which are limitations herein claimed by the independent claims; and therefore, the current application’s EFD is 07/29/2019 (filing date of 371 of PCT).
Regarding claims 1, 24, and 26, Gharagouzloo discloses a system comprising: at least one processor; and at least one storage medium having encoded thereon executable instructions that, when executed by the at least one processor, cause the at least one processor to carry out a method of evaluating potential onset or progression of a cerebrovascular disease and/or a neurodegenerative disease in a subject (see, e.g., Page 7, lines 6-17, “wherein the subject is a human […] wherein the region of interest is a vascular region […] wherein the region of interest is a brain […] further comprising diagnosing a disease or condition, the disease or condition selected from the group consisting of a neurodegenerative disease, neuropathy, dementia, Alzheimer's disease, cancer, kidney disease, lung disease, heart disease, liver disease, ischemia, abnormal vasculature, hypo-vascularization, hyper- vascularization, and nanoparticle accumulation in tumors, and combinations thereof”, and Page 16, lines 30-33, “The present technique can be used for functional imaging of brain tissue, in which the health of brain tissue can be assessed for indications of disease as well as quantification of disease progression and to provide specific and quantitative spatial information of regional neuropathy, resulting in improved understanding of neurodegenerative pathogenesis”, and Disclosed Claim 46), the method comprising:
comparing, by at least one device, quantitative cerebral blood volume (qCBV) information for at least a portion of a brain of the subject to reference qCBV information to identify one or more regions of hypervascularization in the brain of the subject and one or more regions of hypovascularization in the brain of the subject (see, e.g., Page 13, lines 17-28, “Fig. 23 illustrates resting state capillary blood volume atlas, (a) An anatomical atlas consisting of 174 regions was used to construct a vascular atlas of CBV from (b) fitting the first peak of each region to a Gaussian, which should primarily consist of capillary-filled voxels. The three regions displayed in the histograms demonstrate the variety of blood distributions found throughout the brain— some filled primarily with capillaries (low CBV), some rather heterogeneous (medium CBV) and some rather bio-modal (large and small vessels), (c) The capillary CBV is shown for select slices of the atlas. Fig. 24 illustrates functional changes in CBV compared to baseline measurement. Steady-state functional measurements of a) CBV change comparing 5% C0.sub.2-Challenge to awake baseline and b) CBV change comparing to 3% isoflurane to awake baseline. Positive values denote greater CBV than baseline and negative values denote a lesser CBV than baseline. Values are shown as absolute percent CBV”, where the resting state capillary blood volume atlas corresponds to the claimed pre-determined baseline qCBV map representative of a normal brain, and percent increases and decreases in CBV indicate hypervascularization and hypovascularization when compared to the baseline measurement), wherein the qCBV information for at least the portion of the brain of the subject was produced using one or more magnetic resonance imaging (MRI) images of the brain of the subject (see, e.g., Page 3, line 27 to Page 4, line 9, “In contrast to the prior art techniques, a quantitative ultra-short time to echo technique (termed QUTE-CE) is provided that can be successfully applied to accurately measure CA concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of CBV on a voxel-by-voxel basis. Other aspects of the method and system include the following: 1. A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject; applying a magnetic field to the region of interest; applying a radio frequency pulse sequence at a selected repetition time (TR) and at a magnetic field gradient to provide a selected flip angle to excite protons in the region of interest, wherein the repetition time is less than about 10 ms, and the flip angle ranges from about 10° to about 30°; measuring a response signal during relaxation of the protons at a selected time to echo (TE) to acquire a Ti-weighted signal from the region of interest, wherein the time to echo is an ultra-short time to echo less than about 300 μs; and generating an image of the region of interest”, and Page 7, lines 6-11, “wherein the subject is a human […] wherein the region of interest is a brain”, and Page 18, lines 29-31, “In some embodiments, a quantitative contrast-enhanced MRI technique is provided that utilizes an ultrashort time-to-echo (QUTE-CE) has been shown to generate positive-contrast images of a contrast agent”); and
in response to determining that the brain of the subject includes one or more regions of hypervascularization and hypovascularization, outputting from the at least one device an indication of potential onset or potential progression of the cerebrovascular disease and/or the neurodegenerative disease in the subject (see, e.g., Page 7, lines 6-17, “wherein the subject is a human […] wherein the region of interest is a brain […] further comprising diagnosing a disease or condition, the disease or condition selected from the group consisting of a neurodegenerative disease, neuropathy, dementia, Alzheimer's disease, cancer, kidney disease, lung disease, heart disease, liver disease, ischemia, abnormal vasculature, hypo-vascularization, hyper- vascularization, and nanoparticle accumulation in tumors, and combinations thereof”, and Page 13, lines 24-28, “Fig. 24 illustrates functional changes in CBV compared to baseline measurement. Steady-state functional measurements of a) CBV change comparing 5% C0.sub.2-Challenge to awake baseline and b) CBV change comparing to 3% isoflurane to awake baseline. Positive values denote greater CBV than baseline and negative values denote a lesser CBV than baseline. Values are shown as absolute percent CBV”, where percent increases and decreases in CBV indicate hypervascularization and hypovascularization when compared to the baseline measurement of a normal brain, and Page 16, lines 30-33, “The present technique can be used for functional imaging of brain tissue, in which the health of brain tissue can be assessed for indications of disease as well as quantification of disease progression and to provide specific and quantitative spatial information of regional neuropathy, resulting in improved understanding of neurodegenerative pathogenesis”).
Gharagouzloo does not specifically disclose the method comprising: [1] in response to determining that the brain of the subject includes a greater number of the one or more regions of hypervascularization than a number of the one or more regions of hypovascularization, outputting from the at least one device an indication of potential onset of the cerebrovascular disease and/or the neurodegenerative disease in the subject; and [2] in response to determining that the brain of the subject includes a greater number of the one or more regions of hypovascularization than a number of the one or more regions of hypervascularization, outputting from the at least one device an indication of potential progression of the cerebrovascular disease and/or the neurodegenerative disease in the subject.
However, in the same field of endeavor of vascular analysis of medical images, Hua discloses the method comprising: in response to determining that the brain of the subject includes a greater number of the one or more regions of hypervascularization than a number of the one or more regions of hypovascularization, outputting from the at least one device an indication of potential onset of the cerebrovascular disease and/or the neurodegenerative disease in the subject (see, e.g., Page 184, Section 3: Results, second paragraph, “Table 2, Table 3 summarizes the main findings in the group comparisons. The average GM CBVa values in controls were all in normal range (Hua et al., 2011c, Hua et al., 2018), providing validation for our measurements. Widespread elevation of GM CBVa was detected in many brain regions in patients with MCI compared with controls with relative changes of 17.0%–122.0% and effect sizes of 0.75–1.56. Most of these changes were detected in both hemispheres in corresponding regions, although the cluster sizes varied between the left and right hemispheres in some regions. Significant reduction of GM CBVa was also observed in a few brain regions, but the spatial extent was much smaller than increased CBVa. Some brain regions showed both decreased and increased GM CBVa values in different subregions. No significant difference was found in mean GM CBVa over the whole brain (including all GM voxels, not just significant clusters) between patients and controls. The partial volume correction procedure did not seem to have a major effect on the measured CBVa values (Table 3). Fig. 2A displays the regions with significant increased or decreased GM CBVa in patients with MCI on MNI normalized anatomical images, with an intensity reflecting the relative changes in each significant voxel. Fig. 2B shows the areas with significantly increased PiB-PET retention in patients with MCI on MNI normalized anatomical images” (underlined emphasis added), and Fig. 2A, where there are more regions with increased blood volume than regions of decreased/reduced blood volume; such that hypervascularization is associated/correlated with increased cBV and hypovascularization is associated/correlated with decreased blood volume, and such that MCI (mild cognitive impairment) is discussed as a predementia stage, and therefore this does teach that when there is a greater number of regions of hypervascularization (i.e. increased cBV) than a number of regions of hypovascularization (i.e. reduced cBV), then this serves as a biomarker for an indication of MCI which corresponds to an indicator of a potential onset of Alzheimer’s disease).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method, the system, and the at least one non-transitory computer-readable storage medium of Gharagouzloo by including wherein [1] in response to determining that the brain of the subject includes a greater number of the one or more regions of hypervascularization than a number of the one or more regions of hypovascularization, outputting from the at least one device an indication of potential onset of the cerebrovascular disease and/or the neurodegenerative disease in the subject, as disclosed by Hua. One of ordinary skill in the art would have been motivated to make this modification in order to desirably provide a biomarker for an indication of MCI which corresponds to an indicator of a potential onset of Alzheimer’s disease, as recognized by Hua (see, e.g., Page 184, Section 3: Results, second paragraph).
Gharagouzloo modified by Hua still does not specifically disclose wherein [2] in response to determining that the brain of the subject includes a greater number of the one or more regions of hypovascularization than a number of the one or more regions of hypervascularization, outputting from the at least one device an indication of potential progression of the cerebrovascular disease and/or the neurodegenerative disease in the subject.
However, in the same field of endeavor of vascular analysis of medical images, Harris discloses the method comprising: in response to determining that the brain of the subject includes a greater number of the one or more regions of hypovascularization than a number of the one or more regions of hypervascularization, outputting from the at least one device an indication of potential progression of the cerebrovascular disease and/or the neurodegenerative disease in the subject (see, e.g., Abstract, Results section, lines 1-2, “Temporoparietal cerebral blood volume, expressed as a percentage of the cerebellum value, was reduced 17% bilaterally in the patients with Alzheimer disease”, such that Alzheimer’s disease is associated with reduced cBV, and such that progression to Alzheimer’s disease would correspond to increased regions of hypovascularization/reduced cBV, and Fig. 1 and corresponding title description, “FIGURE 1. Dynamic Susceptibility Contrast MRI of Regional Cerebral Blood Volume (CBV) in an 86-Year-Old Male Patient With Alzheimer’s Disease and an 83-Year-Old Normal Male Comparison Subject”, and Page 723, Col. 1, lines 2-8 and 20-25, “This study, the first of its kind, demonstrates the capability of dynamic susceptibility contrast MRI to detect regional cerebral dysfunction in Alzheimer’s disease, even in patients with mild cognitive decline. Severe deficits in temporoparietal CBV were observed in elderly Alzheimer’s disease patients compared with matched comparison subjects […] In this study, deficits in temporoparietal CBV were observed even in the three Alzheimer’s disease patients with mild cognitive symptoms. This observation suggests that the dynamic susceptibility contrast MRI method may he promising in the evaluation of patients with early Alzheimer’s disease” (underlined emphasis added), and Table 1, where reduced cBV (indicating increased regions of hypovascularization) is shown in patients with Alzheimer’s Disease compared to the comparison subjects, such that an increased reduction of cBV relatively would indicate progression of Alzheimer’s Disease).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method, the system, and the at least one non-transitory computer-readable storage medium of Gharagouzloo modified by Hua by including wherein [2] in response to determining that the brain of the subject includes a greater number of the one or more regions of hypovascularization than a number of the one or more regions of hypervascularization, outputting from the at least one device an indication of potential progression of the cerebrovascular disease and/or the neurodegenerative disease in the subject, as disclosed by Harris. One of ordinary skill in the art would have been motivated to make this modification in order to provide a nonradioactive and potentially lower-cost alternative to other functional neuroimaging methods for evaluating Alzheimer’s disease, as recognized by Harris (see, e.g., Abstract, Results and Conclusions sections).
Regarding claim 6, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo further discloses wherein the one or more regions of hypovascularization and/or the one or more regions of hypervascularization are determined based on a measurement of microvasculature, capillary density, or mean vascularity (see, e.g., Page 39, lines 6-9, “There were approximately 550,000 voxels per QUTE-CE scan for each rat brain distributed throughout different regions. Concerning the distributions of CBV fraction per region, CBV fraction values approaching 1 are unlikely to represent voxels primarily filled with capillaries because this value implies the entire voxel is filled with blood”, where CBV fraction/precent values indicate voxels filled with a proportion of blood (hypovascularization or hypervascularization), and high values nearing 1 (or 100%) likely indicate voxels made up of entirely blood (rather than capillaries), which corresponds to capillary density, and where averages per region (voxels distributed throughout different regions) were determined, which corresponds to mean vascularity).
Regarding claim 12, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo further discloses wherein the one or more MRI images are obtained by introducing a paramagnetic or superparamagnetic contrast agent into the brain of the subject (see, e.g., Page 3, line 27 to Page 4, line 9, “In contrast to the prior art techniques, a quantitative ultra-short time to echo technique (termed QUTE-CE) is provided that can be successfully applied to accurately measure CA concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of CBV on a voxel-by-voxel basis. Other aspects of the method and system include the following: 1. A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject…”, and Page 7, lines 6-11, “wherein the subject is a human […] wherein the region of interest is a brain”, and Page 18, lines 29-31, “In some embodiments, a quantitative contrast-enhanced MRI technique is provided that utilizes an ultrashort time-to-echo (QUTE-CE) has been shown to generate positive-contrast images of a contrast agent”).
Regarding claim 13, Gharagouzloo modified by Hua and Harris discloses the method of claim 12. Gharagouzloo further discloses wherein the paramagnetic or superparamagnetic contrast agent is selected from the group consisting of iron oxide nanoparticles, a gadolinium chelate, and a gadolinium compound (see, e.g., Page 3, lines 32-34, “A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject”, and Page 6, lines 11-12, “wherein the paramagnetic nanoparticles comprise iron oxide nanoparticles, gadolinium chelates, or gadolinium compounds”).
Regarding claim 14, Gharagouzloo modified by Hua and Harris discloses the method of claim 13. Gharagouzloo further discloses wherein the iron oxide nanoparticles comprise a material selected from the group consisting of Fe304 (magnetite), y-Fe203 (maghemite), a-Fe203 (hematite), ferumoxytol, ferumoxides, ferucarbotran, and ferumoxtran (see, e.g., Page 3, lines 32-34, “A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject”, and Page 6, lines 11-16, “wherein the paramagnetic nanoparticles comprise iron oxide nanoparticles, gadolinium chelates, or gadolinium compounds. […] wherein the iron oxide nanoparticles comprise Fe.sub.3C"4 (magnetite), y-Fe.sub.20.sub.3 (maghemite), a-Fe.sub.20.sub.3 (hematite). […] wherein the iron oxide nanoparticles comprise ferumoxytol, ferumoxides, ferucarbotran, or ferumoxtran”).
Regarding claim 15, Gharagouzloo modified by Hua and Harris discloses the method of claim 14. Gharagouzloo further discloses wherein the iron oxide nanoparticles comprise ferumoxytol (see, e.g., Page 2, lines 19-25, “Superparamagnetic iron-oxide nanoparticles (SPIONs) have been recognized to be highly biocompatible with minimal toxicity, but their use has been limited by the commonly employed T2-weighted imagining techniques which produce negative contrast or poorer contrast in T1-weighted images. However, imaging using ferumoxytol is known to produce strictly vascular signal changes, which has led to interest in using this product to map blood volume in areas like the brain where quantitative vascular measurements are important for planning tumor biopsy locations”, and Page 3, lines 32-34, “A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject”, and Page 6, lines 11-16, “wherein the paramagnetic nanoparticles comprise iron oxide nanoparticles, gadolinium chelates, or gadolinium compounds. […] wherein the iron oxide nanoparticles comprise Fe.sub.3C"4 (magnetite), y-Fe.sub.20.sub.3 (maghemite), a-Fe.sub.20.sub.3 (hematite). […] wherein the iron oxide nanoparticles comprise ferumoxytol, ferumoxides, ferucarbotran, or ferumoxtran”).
Regarding claim 19, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo further discloses wherein the one or more MRI images are obtained from an MRI process configured with an ultra-short time to echo set to less than about 300 μs and an intravascular contrast agent (see, e.g., Page 3, line 27 to Page 4, line 9, “In contrast to the prior art techniques, a quantitative ultra-short time to echo technique (termed QUTE-CE) is provided that can be successfully applied to accurately measure CA concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of CBV on a voxel-by-voxel basis. Other aspects of the method and system include the following: 1. A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject; applying a magnetic field to the region of interest; applying a radio frequency pulse sequence at a selected repetition time (TR) and at a magnetic field gradient to provide a selected flip angle to excite protons in the region of interest, wherein the repetition time is less than about 10 ms, and the flip angle ranges from about 10° to about 30°; measuring a response signal during relaxation of the protons at a selected time to echo (TE) to acquire a Ti-weighted signal from the region of interest, wherein the time to echo is an ultra-short time to echo less than about 300 μs; and generating an image of the region of interest”, and Page 7, lines 6-11, “wherein the subject is a human […] wherein the region of interest is a brain”, and Page 18, lines 29-31, “In some embodiments, a quantitative contrast-enhanced MRI technique is provided that utilizes an ultrashort time-to-echo (QUTE-CE) has been shown to generate positive-contrast images of a contrast agent”, and Abstract, “A quantitative, ultrashort time to echo, contrast-enhanced magnetic resonance imaging technique is provided”).
Regarding claim 20, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo further discloses wherein the one or more MRI images comprise T1-enhanced positive contrast images (see, e.g., Page 3, line 27 to Page 4, line 9, “In contrast to the prior art techniques, a quantitative ultra-short time to echo technique (termed QUTE-CE) is provided that can be successfully applied to accurately measure CA concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of CBV on a voxel-by-voxel basis. Other aspects of the method and system include the following: 1. A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject; applying a magnetic field to the region of interest; applying a radio frequency pulse sequence at a selected repetition time (TR) and at a magnetic field gradient to provide a selected flip angle to excite protons in the region of interest, wherein the repetition time is less than about 10 ms, and the flip angle ranges from about 10° to about 30°; measuring a response signal during relaxation of the protons at a selected time to echo (TE) to acquire a Ti-weighted signal from the region of interest, wherein the time to echo is an ultra-short time to echo less than about 300 μs; and generating an image of the region of interest”, and Page 7, lines 6-11, “wherein the subject is a human […] wherein the region of interest is a brain”, and Page 18, lines 29-31, “In some embodiments, a quantitative contrast-enhanced MRI technique is provided that utilizes an ultrashort time-to-echo (QUTE-CE) has been shown to generate positive-contrast images of a contrast agent”, and Page 18, lines 29-34 to Page 19, lines 1-4, “a quantitative contrast-enhanced MRI technique is provided that utilizes an ultrashort time-to-echo (QUTE-CE) has been shown to generate positive-contrast images of a contrast agent, particularly using superparamagnetic iron oxide nanoparticles (SPIONs), in vivo. Ultra-fast (e.g. 10-300 μβ) signal acquisition has the benefit of producing positive contrast images, instead of dark contrast images, by acquiring signal before tissue magnetization in the transverse plane dephases, thus allowing complete T.sub.1 contrast enhancement from SPIONs. Thus, UTE is suited for measuring the concentration from clinically relevant concentrations of FDA-approved ferumoxytol. The technique utilizes CA-induced T.sub.1 shortening, combined with rapid signal acquisition at ultra-short TEs, to produce images with little T.sub.2* decay”, and Abstract, “A quantitative, ultrashort time to echo, contrast-enhanced magnetic resonance imaging technique is provided”).
Regarding claim 21, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo further discloses wherein the indication of potential onset or the indication of potential progression is based on a number of structural differences between the qCBV information and the reference qCBV information (see, e.g., Page 7, lines 6-17, “wherein the subject is a human […] wherein the region of interest is a brain […] further comprising diagnosing a disease or condition, the disease or condition selected from the group consisting of a neurodegenerative disease, neuropathy, dementia, Alzheimer's disease, cancer, kidney disease, lung disease, heart disease, liver disease, ischemia, abnormal vasculature, hypo-vascularization, hyper- vascularization, and nanoparticle accumulation in tumors, and combinations thereof”, and Page 13, lines 17-28, “Fig. 23 illustrates resting state capillary blood volume atlas, (a) An anatomical atlas consisting of 174 regions was used to construct a vascular atlas of CBV from (b) fitting the first peak of each region to a Gaussian, which should primarily consist of capillary-filled voxels. The three regions displayed in the histograms demonstrate the variety of blood distributions found throughout the brain— some filled primarily with capillaries (low CBV), some rather heterogeneous (medium CBV) and some rather bio-modal (large and small vessels), (c) The capillary CBV is shown for select slices of the atlas. Fig. 24 illustrates functional changes in CBV compared to baseline measurement. Steady-state functional measurements of a) CBV change comparing 5% C0.sub.2-Challenge to awake baseline and b) CBV change comparing to 3% isoflurane to awake baseline. Positive values denote greater CBV than baseline and negative values denote a lesser CBV than baseline. Values are shown as absolute percent CBV”, where the resting state capillary blood volume atlas corresponds to the claimed pre-determined baseline qCBV map representative of a normal brain, and percent increases and decreases in CBV indicate hypervascularization and hypovascularization when compared to the baseline measurement of a normal brain, and Page 16, lines 30-33, “The present technique can be used for functional imaging of brain tissue, in which the health of brain tissue can be assessed for indications of disease as well as quantification of disease progression and to provide specific and quantitative spatial information of regional neuropathy, resulting in improved understanding of neurodegenerative pathogenesis”).
Regarding claim 22, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo further discloses wherein the neurodegenerative disease comprises Alzheimer's Disease or Related Dementias (ADRD) (see, e.g., Page 7, lines 6-17, “wherein the subject is a human […] wherein the region of interest is a vascular region […] wherein the region of interest is a brain […] further comprising diagnosing a disease or condition, the disease or condition selected from the group consisting of a neurodegenerative disease, neuropathy, dementia, Alzheimer's disease, cancer, kidney disease, lung disease, heart disease, liver disease, ischemia, abnormal vasculature, hypo-vascularization, hyper-vascularization, and nanoparticle accumulation in tumors, and combinations thereof”, and Page 16, lines 30-33, “The present technique can be used for functional imaging of brain tissue, in which the health of brain tissue can be assessed for indications of disease as well as quantification of disease progression and to provide specific and quantitative spatial information of regional neuropathy, resulting in improved understanding of neurodegenerative pathogenesis”).
Regarding claim 23, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo further discloses wherein the comparing comprises producing a qCBV map of the brain of the subject from the one or more MRI images and comparing the qCBV map to a pre-determined qCBV map representative of a normal brain (see, e.g., Abstract, “A quantitative, ultrashort time to echo, contrast-enhanced magnetic resonance imaging technique is provided. The technique can be used to accurately measure contrast agent concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of cerebral blood volume on a voxel-by-voxel basis”, and Page 2, lines 22-25, “imaging using ferumoxytol is known to produce strictly vascular signal changes, which has led to interest in using this product to map blood volume in areas like the brain where quantitative vascular measurements are important for planning tumor biopsy locations”, and Page 3, line 27 to Page 4, line 15, “In contrast to the prior art techniques, a quantitative ultra-short time to echo technique (termed QUTE-CE) is provided that can be successfully applied to accurately measure CA concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of CBV on a voxel-by-voxel basis. Other aspects of the method and system include the following: 1. A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject; […] measuring a response signal during relaxation of the protons at a selected time to echo (TE) to acquire a Ti-weighted signal from the region of interest, wherein the time to echo is an ultra-short time to echo less than about 300 μβ; and generating an image of the region of interest. 2. The method of item 1, wherein the acquired signal is representative of a concentration of the contrast agent in the region of interest. 3. The method of any of items 1-2, wherein the acquired signal is representative of a blood volume in the region of interest. 4. The method of item 3, wherein the blood volume fraction comprises a cerebral blood volume fraction or a total blood volume fraction”, and Page 7, lines 6-11, “wherein the subject is a human […] wherein the region of interest is a brain”, and Page 13, lines 17-28, “Fig. 23 illustrates resting state capillary blood volume atlas, (a) An anatomical atlas consisting of 174 regions was used to construct a vascular atlas of CBV from (b) fitting the first peak of each region to a Gaussian, which should primarily consist of capillary-filled voxels. The three regions displayed in the histograms demonstrate the variety of blood distributions found throughout the brain— some filled primarily with capillaries (low CBV), some rather heterogeneous (medium CBV) and some rather bio-modal (large and small vessels), (c) The capillary CBV is shown for select slices of the atlas. Fig. 24 illustrates functional changes in CBV compared to baseline measurement. Steady-state functional measurements of a) CBV change comparing 5% C0.sub.2-Challenge to awake baseline and b) CBV change comparing to 3% isoflurane to awake baseline. Positive values denote greater CBV than baseline and negative values denote a lesser CBV than baseline. Values are shown as absolute percent CBV”, where the resting state capillary blood volume atlas corresponds to the claimed pre-determined baseline qCBV map representative of a normal brain, and percent increases and decreases in CBV indicate hypervascularization and hypovascularization when compared to the baseline measurement).
Regarding claim 25, Gharagouzloo modified by Hua and Harris discloses the system of claim 24. Gharagouzloo further discloses the system further comprising: an MRI scanner (see, e.g., Page 3, line 27 to Page 4, line 9, “In contrast to the prior art techniques, a quantitative ultra-short time to echo technique (termed QUTE-CE) is provided that can be successfully applied to accurately measure CA concentration in the blood, to provide clear, high-definition angiograms, and to measure absolute quantities of CBV on a voxel-by-voxel basis. Other aspects of the method and system include the following: 1. A method of positive-contrast magnetic resonance imaging of a subject, comprising: introducing a paramagnetic or superparamagnetic contrast agent into a region of interest in the subject; applying a magnetic field to the region of interest; applying a radio frequency pulse sequence at a selected repetition time (TR) and at a magnetic field gradient to provide a selected flip angle to excite protons in the region of interest, wherein the repetition time is less than about 10 ms, and the flip angle ranges from about 10° to about 30°; measuring a response signal during relaxation of the protons at a selected time to echo (TE) to acquire a Ti-weighted signal from the region of interest, wherein the time to echo is an ultra-short time to echo less than about 300 μβ; and generating an image of the region of interest”, and Page 14, lines 10-12, “a paramagnetic or super paramagnetic contrast agent in introduced into a region of interest (ROI) in a subject, and a static magnetic field, using any suitable magnetic resonance imaging (MRI) machine, is applied to the region of interest”, and Page 18, lines 7-31, “Any suitable magnetic resonance imaging (MRI) machine or equipment can be used. […] In some embodiments, a quantitative contrast-enhanced MRI technique is provided that utilizes an ultrashort time-to-echo (QUTE-CE) has been shown to generate positive-contrast images of a contrast agent”).
Claims 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Gharagouzloo (WO 2017/019182 A1) in view of Hua (NPL) and Harris (NPL), as applied to claim 1 above, and further in view of Poltroak (US 2019/0247662 A1, of record, hereinafter Poltroak).
Regarding claims 8 and 9, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo discloses wherein the one or more regions of hypervascularization and the one or more regions of hypovascularization (respectively) comprise one or more regions of the subject's brain (see, e.g., Page 7, lines 6-17, “wherein the subject is a human […] wherein the region of interest is a brain […] further comprising diagnosing a disease or condition, the disease or condition selected from the group consisting of a neurodegenerative disease, neuropathy, dementia, Alzheimer's disease, […] hypo-vascularization, hyper-vascularization, and nanoparticle accumulation in tumors, and combinations thereof”, and Page 13, lines 24-28, “Fig. 24 illustrates functional changes in CBV compared to baseline measurement. […] Positive values denote greater CBV than baseline and negative values denote a lesser CBV than baseline. Values are shown as absolute percent CBV”, and Page 16, lines 30-33, “The present technique can be used for functional imaging of brain tissue, in which the health of brain tissue can be assessed for indications of disease as well as quantification of disease progression…”, and Page 38, lines 13-14, “After applying the inhomogeneity correction, it is feasible to measure CBV in an absolute quantitative way throughout the brain”, where percent increases and decreases in and/or measurements of CBV indicate hypervascularization and hypovascularization in various regions throughout the brain).
Gharagouzloo modified by Hua and Harris does not disclose wherein the one or more regions of the subject’s brain is specifically selected from the group consisting of ventral tegmental area, raphe linear, reticulotegmental nucleus, raphe obscurus nucleus, habenula nucleus, median raphe nucleus, dorsomedial tegmental area, dorsal raphe, pontine nuclei, raphe magnus, ventral subiculum, motor trigeminal nucleus, copula of the pyramis, pontine reticular nucleus caudal, pontine reticular nucleus oral, trapezoid body, subiculum dorsal, parabrachial nucleus, reticular nucleus midbrain, retrosplenial caudal ctx, pedunculopontine tegmental area, red nucleus, sub coeruleus nucleus, PCRt, inferior colliculus, facial nucleus, 9th cerebellar lobule, gigantocellular reticular nucleus, principal sensory nucleus trigeminal, entorhinal ctx, root of trigeminal nerve, visual 1 ctx, 10th cerebellar lobule, prelimbic ctx, precuniform nucleus, infralimbic etx, superior colliculus, solitary tract nucleus, and periaqueductal gray thalamus.
However, in the same field of endeavor of measuring brain/cerebral activity utilizing functional MRI, Poltroak discloses (see, e.g., Para. [0160], “It is known that “neuronal activity causes local changes in cerebral blood flow, blood volume, and blood oxygenation””, and Para. [0185], “Functional magnetic resonance imaging or functional MRI (fMRI) is a functional neuroimaging procedure using MRI technology that measures brain activity by detecting changes associated with blood flow”) wherein the one or more regions of the subject’s brain is selected from the group consisting of ventral tegmental area, raphe linear, reticulotegmental nucleus, raphe obscurus nucleus, habenula nucleus, median raphe nucleus, dorsomedial tegmental area, dorsal raphe, pontine nuclei, raphe magnus, ventral subiculum, motor trigeminal nucleus, copula of the pyramis, pontine reticular nucleus caudal, pontine reticular nucleus oral, trapezoid body, subiculum dorsal, parabrachial nucleus, reticular nucleus midbrain, retrosplenial caudal ctx, pedunculopontine tegmental area, red nucleus, sub coeruleus nucleus, PCRt, inferior colliculus, facial nucleus, 9th cerebellar lobule, gigantocellular reticular nucleus, principal sensory nucleus trigeminal, entorhinal ctx, root of trigeminal nerve, visual 1 ctx, 10th cerebellar lobule, prelimbic ctx, precuniform nucleus, infralimbic etx, superior colliculus, solitary tract nucleus, and periaqueductal gray thalamus (see, e.g., Para. [0039], where different regions of brain structures are listed, the list including but not limited to ‘red nucleus’, which is claimed as being one region in the selection group of the one or more regions of the subject’s brain region).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Gharagouzloo modified by Hua and Harris by including wherein the one or more regions of the subject’s brain is specifically selected from the group consisting of ventral tegmental area, raphe linear, reticulotegmental nucleus, raphe obscurus nucleus, habenula nucleus, median raphe nucleus, dorsomedial tegmental area, dorsal raphe, pontine nuclei, raphe magnus, ventral subiculum, motor trigeminal nucleus, copula of the pyramis, pontine reticular nucleus caudal, pontine reticular nucleus oral, trapezoid body, subiculum dorsal, parabrachial nucleus, reticular nucleus midbrain, retrosplenial caudal ctx, pedunculopontine tegmental area, red nucleus, sub coeruleus nucleus, PCRt, inferior colliculus, facial nucleus, 9th cerebellar lobule, gigantocellular reticular nucleus, principal sensory nucleus trigeminal, entorhinal ctx, root of trigeminal nerve, visual 1 ctx, 10th cerebellar lobule, prelimbic ctx, precuniform nucleus, infralimbic etx, superior colliculus, solitary tract nucleus, and periaqueductal gray thalamus, as disclosed by Poltroak. One of ordinary skill in the art would have been motivated to make this modification in order to provide and allow for non-invasive recording of large quantities of information from the brain at multiple spatial and temporal scales by utilizing MRI to the desired brain region(s), where integration of noninvasive measurement and neuromodulation techniques for identifying brain states from neural activity would be very valuable for clinical therapies, such as brain stimulation and related technologies often attempting to treat disorders of cognition, as recognized by Poltroak (see, e.g., Para. [0022-0039]).
Regarding claims 10 and 11, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo discloses wherein the one or more regions of hypervascularization and the one or more regions of hypovascularization (respectively) comprise one or more regions of the subject's brain (see, e.g., Page 7, lines 6-17, “wherein the subject is a human […] wherein the region of interest is a brain […] further comprising diagnosing a disease or condition, the disease or condition selected from the group consisting of a neurodegenerative disease, neuropathy, dementia, Alzheimer's disease, […] hypo-vascularization, hyper-vascularization, and nanoparticle accumulation in tumors, and combinations thereof”, and Page 13, lines 24-28, “Fig. 24 illustrates functional changes in CBV compared to baseline measurement. […] Positive values denote greater CBV than baseline and negative values denote a lesser CBV than baseline. Values are shown as absolute percent CBV”, and Page 16, lines 30-33, “The present technique can be used for functional imaging of brain tissue, in which the health of brain tissue can be assessed for indications of disease as well as quantification of disease progression…”, and Page 38, lines 13-14, “After applying the inhomogeneity correction, it is feasible to measure CBV in an absolute quantitative way throughout the brain”, where percent increases and decreases in and/or measurements of CBV indicate hypervascularization and hypovascularization in various regions throughout the brain).
Gharagouzloo modified by Hua and Harris does not disclose wherein the one or more regions of the subject's brain is specifically selected from the group consisting of paraventricular nucleus, ventral subiculum, dorsal raphe, visual 2 ctx, dorsomedial tegmental area, inferior colliculus, motor trigeminal nucleus, primary somatosensory ctx trunk, triangular septal nucleus, ventral medial striatum, lateral preoptic area.
However, in the same field of endeavor of measuring brain/cerebral activity utilizing functional MRI, Poltroak discloses (see, e.g., Para. [0160], “It is known that “neuronal activity causes local changes in cerebral blood flow, blood volume, and blood oxygenation””, and Para. [0185], “Functional magnetic resonance imaging or functional MRI (fMRI) is a functional neuroimaging procedure using MRI technology that measures brain activity by detecting changes associated with blood flow”) wherein the one or more regions of the subject's brain is selected from the group consisting of paraventricular nucleus, ventral subiculum, dorsal raphe, visual 2 ctx, dorsomedial tegmental area, inferior colliculus, motor trigeminal nucleus, primary somatosensory ctx trunk, triangular septal nucleus, ventral medial striatum, lateral preoptic area (see, e.g., Para. [0039], where different regions of brain structures are listed, the list including but not limited to ‘paraventricular nucleus’, ‘dorsal raphe nucleus’, ‘inferior colliculi’, and ‘motor nucleus for the trigeminal nerve’, which are each claimed as being regions in the selection group of the one or more regions of the subject’s brain region).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Gharagouzloo modified by Hua and Harris by including wherein the one or more regions of the subject's brain is specifically selected from the group consisting of paraventricular nucleus, ventral subiculum, dorsal raphe, visual 2 ctx, dorsomedial tegmental area, inferior colliculus, motor trigeminal nucleus, primary somatosensory ctx trunk, triangular septal nucleus, ventral medial striatum, lateral preoptic area, as disclosed by Poltroak. One of ordinary skill in the art would have been motivated to make this modification in order to provide and allow for non-invasive recording of large quantities of information from the brain at multiple spatial and temporal scales by utilizing MRI to the desired brain region(s), where integration of noninvasive measurement and neuromodulation techniques for identifying brain states from neural activity would be very valuable for clinical therapies, such as brain stimulation and related technologies often attempting to treat disorders of cognition, as recognized by Poltroak (see, e.g., Para. [0022-0039]).
Claims 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Gharagouzloo (WO 2017/019182 A1) in view of Hua (NPL) and Harris (NPL), as applied to claim 1 above, and further in view of Alam (US 2012/0289511 A1, of record, hereinafter Alam).
Regarding claim 16, Gharagouzloo modified by Hua and Harris discloses the method of claim 1. Gharagouzloo further discloses performing the method of claim 1 to diagnose the onset or progression of Alzheimer's Disease or Related Dementias (ADRD) in the human subject (see, e.g., Page 7, lines 6-17, “wherein the subject is a human […] wherein the region of interest is a vascular region […] wherein the region of interest is a brain […] further comprising diagnosing a disease or condition, the disease or condition selected from the group consisting of a neurodegenerative disease, neuropathy, dementia, Alzheimer's disease, cancer, kidney disease, lung disease, heart disease, liver disease, ischemia, abnormal vasculature, hypo-vascularization, hyper-vascularization, and nanoparticle accumulation in tumors, and combinations thereof”, and Page 16, lines 30-33, “The present technique can be used for functional imaging of brain tissue, in which the health of brain tissue can be assessed for indications of disease as well as quantification of disease progression and to provide specific and quantitative spatial information of regional neuropathy, resulting in improved understanding of neurodegenerative pathogenesis”, and further see the rejection of claim 1 set forth above).
Gharagouzloo modified by Hua and Harris does not disclose a method of treating Alzheimer's Disease or Related Dementias (ADRD) in a human subject, the method comprising: treating the human subject for the onset or the progression of ADRD.
However, in the same field of endeavor of analyzing MRI images of the brain to diagnose Alzheimer's disease, Alam discloses (see, e.g., Para. [0060-0075]) a method of treating Alzheimer's Disease or Related Dementias (ADRD) in a human subject, the method comprising: treating the human subject for the onset or the progression of ADRD (see, e.g., Para. [0014], “The term "patient", as used herein, means a mammal to which a formulation or composition comprising a formulation is administered, and in some embodiments includes humans”, and Para. [0088], “the present invention provides a method of treating Alzheimer's disease comprising administering to a subject a therapeutically effective amount of a p38 inhibitor together with one or more additional therapeutic agents”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Gharagouzloo modified by Hua and Harris by including a method of treating Alzheimer's Disease or Related Dementias (ADRD) in a human subject, the method comprising: treating the human subject for the onset or the progression of ADRD, as disclosed by Alam. One of ordinary skill in the art would have been motivated to make this modification in order to desirably treat Alzheimer's disease by administering to a subject a therapeutically effective amount of an inhibitor and therapeutic agents, as recognized by Alam (see, e.g., Para. [0088]).
Regarding claim 17, Gharagouzloo modified by Hua, Harris, and Alam discloses the method of claim 16. Gharagouzloo modified by Hua and Harris does not disclose wherein the step of treating comprises administering a cholinesterase inhibitor, such as donepezil, rivastigmine, galantamine, memantine; an antidepressant such as citalopram, fluoxetine, paroxeine, sertraline, or trazodone; an anxiolytic, such as lorazepam or oxazepam; or an antipsychotic, such as aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone or any combination thereof.
However, in the same field of endeavor of analyzing MRI images of the brain to diagnose Alzheimer's disease, Alam discloses (see, e.g., Para. [0060-0075]) wherein the step of treating comprises administering a cholinesterase inhibitor, such as donepezil, rivastigmine, galantamine, memantine; an antidepressant such as citalopram, fluoxetine, paroxeine, sertraline, or trazodone; an anxiolytic, such as lorazepam or oxazepam; or an antipsychotic, such as aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone or any combination thereof (see, e.g., Para. [0088], “the present invention provides a method of treating Alzheimer's disease comprising administering to a subject a therapeutically effective amount of a p38 inhibitor together with one or more additional therapeutic agents. In some embodiments, the present invention provides a method of treating Alzheimer's disease comprising administering to a subject a therapeutically effective amount of a p38 inhibitor together with one or more additional therapeutic agents selected from cholinesterase inhibitors, N-methyl-D-aspartate antagonists, vitamin E, antidepressants, anxiolytics, antipsychotics, mood stabilizers and sleep aids”, and Para. [0089-0092], where specific cholinesterase inhibitors, antidepressants, anxiolytics, and antipsychotics are listed).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Gharagouzloo modified by Hua, Harris, and Alam by including wherein the step of treating comprises administering a cholinesterase inhibitor, such as donepezil, rivastigmine, galantamine, memantine; an antidepressant such as citalopram, fluoxetine, paroxeine, sertraline, or trazodone; an anxiolytic, such as lorazepam or oxazepam; or an antipsychotic, such as aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone or any combination thereof, as disclosed by Alam. One of ordinary skill in the art would have been motivated to make this modification in order to desirably treat Alzheimer's disease by administering to a subject a therapeutically effective amount of an inhibitor and therapeutic agents, as recognized by Alam (see, e.g., Para. [0088]).
Regarding claim 18, Gharagouzloo modified by Hua, Harris, and Alam discloses the method of claim 16. Gharagouzloo modified by Hua and Harris does not disclose wherein the step of treating the human subject comprises applying a behavioral therapy; such as changing an environment, redirecting attention, avoiding a confrontation, providing rest, or monitoring one or more of pain, hunger, thirst, constipation, full bladder, fatigue, infection, skin irritation, and room temperature; and any combination thereof.
However, in the same field of endeavor of analyzing MRI images of the brain to diagnose Alzheimer's disease, Alam discloses (see, e.g., Para. [0060-0075]) wherein the step of treating the human subject comprises applying a behavioral therapy; such as changing an environment, redirecting attention, avoiding a confrontation, providing rest, or monitoring one or more of pain, hunger, thirst, constipation, full bladder, fatigue, infection, skin irritation, and room temperature; and any combination thereof (see, e.g., Para. [0088], “the present invention provides a method of treating Alzheimer's disease comprising administering to a subject a therapeutically effective amount of a p38 inhibitor together with one or more additional therapeutic agents. In some embodiments, the present invention provides a method of treating Alzheimer's disease comprising administering to a subject a therapeutically effective amount of a p38 inhibitor together with one or more additional therapeutic agents selected from cholinesterase inhibitors, N-methyl-D-aspartate antagonists, vitamin E, antidepressants, anxiolytics, antipsychotics, mood stabilizers and sleep aids”, where rest/sleep is provided by administering sleep aids).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the method of Gharagouzloo modified by Hua, Harris, and Alam by including wherein the step of treating the human subject comprises applying a behavioral therapy; such as changing an environment, redirecting attention, avoiding a confrontation, providing rest, or monitoring one or more of pain, hunger, thirst, constipation, full bladder, fatigue, infection, skin irritation, and room temperature; and any combination thereof, as disclosed by Alam. One of ordinary skill in the art would have been motivated to make this modification in order to desirably treat Alzheimer's disease by administering to a subject a therapeutically effective amount of an inhibitor and therapeutic agents, as recognized by Alam (see, e.g., Para. [0088]).
Response to Arguments
Applicant's arguments, see Remarks filed 09/09/2025, with respect to the claim rejections under 35 U.S.C. 103, have been fully considered but they are not persuasive.
Regarding Gharagouzloo (WO 2017/019182 A1) in view of Hua (NPL) and Harris (NPL), Applicant argues that independent claim 1 patentably distinguishes any combination of Gharagouzloo, Hua, and Harris. Specifically, Applicant argues that Hua does not qualify as prior art to the present application, and that Harris does not disclose the quoted claim language.
Examiner respectfully disagrees and emphasizes that Gharagouzloo modified by Hua and Harris does disclose each and every feature of independent claims 1, 24, and 26, as set forth above. Examiner emphasize that the current application’s provisional’s specification does not seem to teach specifically [1] outputting from a device an indication of the potential onset of the disease or an indication of the potential progression of the disease (i.e., there is no detail that, in response to one of the above indications being found, that a “device” provides an output as claimed); and [2] the broader evaluation of an onset/progression of any cerebrovascular or neurodegenerative disease (i.e., the provisional provides a specific example of diagnosing the subject for Alzheimer’s Disease, whereas the claims are directed to a method of evaluating potential onset/progression of a “cerebrovascular disease and/or a neurodegenerative disease in a subject”); which are limitations herein claimed by the independent claims; and therefore, the current application’s EFD is 07/29/2019 (filing date of 371 of PCT). Therefore, Hua does qualify as prior art.
Examiner further emphasizes that Gharagouzloo is modified by Hua and Harris, where Harris discloses the method comprising: in response to determining that the brain of the subject includes a greater number of the one or more regions of hypovascularization than a number of the one or more regions of hypervascularization, outputting from the at least one device an indication of potential progression of the cerebrovascular disease and/or the neurodegenerative disease in the subject (see, e.g., Abstract, Results section, lines 1-2, “Temporoparietal cerebral blood volume, expressed as a percentage of the cerebellum value, was reduced 17% bilaterally in the patients with Alzheimer disease”, such that Alzheimer’s disease is associated with reduced cBV, and such that progression to Alzheimer’s disease would correspond to increased regions of hypovascularization/reduced cBV, and Fig. 1 and corresponding title description, “FIGURE 1. Dynamic Susceptibility Contrast MRI of Regional Cerebral Blood Volume (CBV) in an 86-Year-Old Male Patient With Alzheimer’s Disease and an 83-Year-Old Normal Male Comparison Subject”, and Page 723, Col. 1, lines 2-8 and 20-25, “This study, the first of its kind, demonstrates the capability of dynamic susceptibility contrast MRI to detect regional cerebral dysfunction in Alzheimer’s disease, even in patients with mild cognitive decline. Severe deficits in temporoparietal CBV were observed in elderly Alzheimer’s disease patients compared with matched comparison subjects […] In this study, deficits in temporoparietal CBV were observed even in the three Alzheimer’s disease patients with mild cognitive symptoms. This observation suggests that the dynamic susceptibility contrast MRI method may he promising in the evaluation of patients with early Alzheimer’s disease” (underlined emphasis added), and Table 1, where reduced cBV (indicating increased regions of hypovascularization) is shown in patients with Alzheimer’s Disease compared to the comparison subjects, such that an increased reduction of cBV relatively would indicate progression of Alzheimer’s Disease).
Therefore, Gharagouzloo modified by Hua and Harris does disclose each and every feature of independent claims 1, 24, and 26, as set forth above.
Regarding the claim rejections under 35 U.S.C. 101, Applicant's arguments (see Remarks filed 09/09/2025) have been fully considered but they are not persuasive. Examiner respectfully disagrees with the Applicant’s argument that the rejection is premised on incorrect assertions regarding insignificant extra-solution activity. Examiner emphasizes that rather than being directed to an improvement, the “determining…” steps of claim 1 are directed to the abstract idea/mental process, and, as stated in MPEP 2106.05(a), “the judicial exception alone cannot provide the improvement. The improvement can be provided by one or more additional elements”. Examiner further emphasizes that the judicial exception is not integrated into a practical application because the generically recited computer elements do not add a meaningful limitation to the abstract idea (i.e., the mental processes) as the generically recited computer elements only amount to simply implementing the abstract idea on the machine (i.e., the additional elements include a “device”, “processor”, etc. capable of performing the mere data gathering steps and the outputting steps as set forth above, where these additional elements are components claimed at a high level of generality that merely links the judicial exception to a particular technological environment and/or a computer as a tool to perform the abstract idea, and where adding insignificant extra-solutionary activity to the judicial exception does not qualify as “significantly more” when recited in a claim with a judicial exception). Therefore, the claim rejections under 35 U.S.C. 101 as previously set forth are maintained.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/T.D./Examiner, Art Unit 3798
/PASCAL M BUI PHO/Supervisory Patent Examiner, Art Unit 3798