DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2, 5, 12-14, 24, and 64-66 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huddleston et al. (US 2015/0125057; hereinafter Huddleston).
Huddleston shows an in vivo method of determining the progression of Alzheimer's disease over time in a subject ([0109]), said method comprising:(i) obtaining a first Neuromelanin-Magnetic Resonance Imaging (NM-MRI) scan dataset at a first time point ([0060]), performing a voxel-based analysis to determine a concentration and/or volume of NM in a substantia nigra pars compacta (SNc) region (number of voxels correspond to amount of neuromelanin present, [0092]); performing a segmented-based analysis to determine a concentration and/or volume of NM in a locus coeruleus (LC) region (after the region has been segmented, the method may optionally or additionally include a step of determining quantitative information, including the SNc and LC regions; [0106]); (ii) after step (i), obtaining a second NM-MRI scan at a second time point ([0060], [0109]); performing a voxel-based analysis to determine a concentration and/or volume of NM in a substantia nigra pars compacta (SNc) region (number of voxels correspond to amount of neuromelanin present, [0092]); performing a segmented-based analysis to determine a concentration and/or volume of NM in a locus coeruleus (LC) region (after the region has been segmented, the method may optionally or additionally include a step of determining quantitative information, including the SNc and LC regions; [0106]); (iii) comparing the concentration and/or volume of neuromelanin at the first time point in the SNc of the first NM-MRI dataset to said concentration and/or volume of neuromelanin at the second time point in the SNc of the second NM-MRI dataset (classify quantitative information by comparing the information to previous information of the subject to provide information regarding the progression of the disease, [0109]); (iv) comparing the first concentration and/or volume of neuromelanin in the LC of the NM-MRI dataset to said second concentration and/or volume of neuromelanin in the LC of the NM-MRI dataset (classify quantitative information by comparing the information to previous information of the subject to provide information regarding the progression of the disease, [0109]-[0110]) thereby determining whether a change in the concentration and/or volume of neuromelanin occurred between said first time point and said second time point in each imaging region ([0092], [0104], [0107], [0109]).
Huddleston shows a method of diagnosing a patient with Alzheimer's disease ([0109]), said method comprising:(i) measuring a level of neuromelanin ([0092], [0104], [0107], [0109]) by obtaining an NM-MRI dataset; performing a voxel-based analysis to determine the concentration and/or volume of NM in a SNc region (number of voxels correspond to amount of neuromelanin present, [0092]); performing a segmented-based analysis to determine the concentration and/or volume of NM in a LC region (after the region has been segmented, the method may optionally or additionally include a step of determining quantitative information, including the SNc and LC regions; [0106]); (ii) comparing the concentration and/or volume of neuromelanin to a standard control ([0109]), (iii) optionally providing a diagnosis of Alzheimer's disease if the measured level of neuromelanin is lower relative to the standard control (comparing the quantitative information to the predetermined ranges encompasses both states of comparison, the data may be higher or higher or lower, [0109]).
Additionally, Huddleston shows a method of determining if a subject has or is at risk of developing Alzheimer's disease ([0109]), the method comprising analyzing one or more Neuromelanin-Magnetic Resonance Imaging (NM-MRI) scans of the subject's brain region of interest ([0060]), wherein the analyzing comprises: receiving imaging information of the brain region of interest ([0060]); and determining a NM concentration in the brain region of interest using segmented analysis ([0093], [0097]) based on the imaging information ([0092], [0104], [0107], [0109]; wherein the determining if a subject has or is at risk of developing Alzheimer's disease comprises:(1) if the one or more NM-MRI scans has a decreased NM signal compared to a one or more control scans without Alzheimer's disease then the subject has or is at risk of developing Alzheimer's disease (comparing the quantitative information to the predetermined ranges encompasses both states of comparison, the data may be higher or higher or lower, [0109]); or (2) if the one or more NM-MRI scans has a NM signal comparable to the signal of a one or more control scans without Alzheimer's disease then the subject does not have or is not at risk of developing Alzheimer's disease (comparing the quantitative information to the predetermined ranges encompasses both states of comparison, the data may be higher or higher or lower, [0109]).
Huddleston also shows determining a first signal intensity from said first neuromelanin magnetic resonance image and determining a second signal intensity from said second neuromelanin magnetic resonance image, wherein said comparing the first magnetic resonance image to said second magnetic resonance image comprises comparing the first signal intensity to the second signal intensity ([0107], [0109]);; a patient is diagnosed with Alzheimer's disease without displaying symptoms ([0109]); wherein the comparing includes a segmented analysis ([0093], [0097]); wherein the segmented analysis comprises determining at least one topographical pattern within the brain region of interest (determining brain regions such as LC and SN represent topographical patterns of the brain; [0092]-[0097]); wherein the method further comprises a calculation using a first value that represents a volume of a neuromelanin segment associated with the first neuromelanin magnetic resonance image and a second value that represents a volume of a neuromelanin segment associated with the second neuromelanin magnetic resonance image ([0091], [0106], [0109]); wherein the segmented analysis region of interest is the substantia nigra ([0053], [0092]-[0097]); wherein the segmented analysis region of interest the locus coeruleus ([0053], [0092]-[0097]).
Huddleston fails to show wherein if the change in the level, signal and/or concentration of neuromelanin at the second time point is more than about 1%, more than about 2%, more than about 3%, more than about 4%, more than about 5%, more than about 6%, more than about 7%, more than about 8%, more than about 9%, more than about 10%, more than about 11%, more than about 12%, more than about 13%, more than about 14%, more than about 15%, more than about 20%, or more than about 25% less than the level, signal and/or concentration of neuromelanin at the first time point, Alzheimer's disease is progressing; wherein if the change in the level, signal and/or concentration of neuromelanin at the second time point is more than about 5% less or more than about 10% less than the level, signal and/or concentration of neuromelanin at the first time point, wherein the first time point and the second time point are about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years apart, a diagnosis of Alzheimer's disease is provided; wherein if the change in the level, signal and/or concentration of neuromelanin at the second time point is more than about 35% less, more than about 40% less, more than about 45% less, or more than about 50% less signal and/or concentration of neuromelanin at the first time point, wherein the first time point and the second time point are about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years apart, a diagnosis of Alzheimer's disease is provided; wherein the second time point is about 3 months, about 6 months, about 9 months, about 12 months, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years, about 20 years, about 25 years, or about 30 years after the first time point.
However, Huddleston shows comparing the data to detect Alzheimer’s disease ([0109]), it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to modify to comparison as it would be an obvious design choice to one of ordinary skill in the art, without undue experimentation, to have modified the comparison of Huddleston to be based on specific ranges such as “wherein if the change in the level, signal and/or concentration of neuromelanin at the second time point is more than about 1%, more than about 2%, more than about 3%, more than about 4%, more than about 5%, more than about 6%, more than about 7%, more than about 8%, more than about 9%, more than about 10%, more than about 11%, more than about 12%, more than about 13%, more than about 14%, more than about 15%, more than about 20%, or more than about 25% less than the level, signal and/or concentration of neuromelanin at the first time point, Alzheimer's disease is progressing”, as the selection of a specific range is within the level of one of ordinary skill in the art and may vary based upon the user’s preference.
Similarly, Huddleston shows comparing the data to detect Alzheimer’s disease ([0109]), it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to modify to comparison as it would be an obvious design choice to one of ordinary skill in the art, without undue experimentation, to have modified the comparison of Huddleston to be based on specific ranges such as “wherein if the change in the level, signal and/or concentration of neuromelanin at the second time point is more than about 5% less or more than about 10% less than the level, signal and/or concentration of neuromelanin at the first time point, wherein the first time point and the second time point are about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years apart, a diagnosis of Alzheimer's disease is provided”, as the selection of a specific range and specific timepoints is within the level of one of ordinary skill in the art and may vary based upon the user’s preference.
Similarly, Huddleston shows comparing the data to detect Alzheimer’s disease ([0109]), it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to modify to comparison as it would be an obvious design choice to one of ordinary skill in the art, without undue experimentation, to have modified the comparison of Huddleston to be based on specific ranges such as “wherein if the change in the level, signal and/or concentration of neuromelanin at the second time point is more than about 35% less, more than about 40% less, more than about 45% less, or more than about 50% less signal and/or concentration of neuromelanin at the first time point, wherein the first time point and the second time point are about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years apart, a diagnosis of Alzheimer's disease is provided”, as the selection of a specific range and specific timepoints is within the level of one of ordinary skill in the art and may vary based upon the user’s preference.
Similarly, Huddleston shows comparing the data to detect Alzheimer’s disease ([0109]), it would have been obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention to modify to comparison as it would be an obvious design choice to one of ordinary skill in the art, without undue experimentation, to have modified the comparison of Huddleston to be based on specific time points such as “wherein the second time point is about 3 months, about 6 months, about 9 months, about 12 months, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years, about 20 years, about 25 years, or about 30 years after the first time point”, as the selection of specific time points is within the level of one of ordinary skill in the art and may vary based upon the user’s preference.
Additionally, regarding comparing steps (iii) and (iv), the examiner notes that it would be within the level of one of ordinary skill in the art, without undue experimentation, to both compare the volume of NM in a SNc region over time and to compare the volume of NM in a LC region over time to monitor the progression of the disease as desired by Huddleston ([0109]) by utilizing all of the obtained data to obtain a more accurate diagnosis.
Claim(s) 7, 34, and 67-68 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huddleston et al. (US 2015/0125057; hereinafter Huddleston) as applied to claims 5 and 64-65 above, and further in view of Huddleston et al. (US 2021/0007603; hereinafter Huddleston ‘603).
Huddleston fails to show wherein a standard control is a level of neuromelanin present at approximately the same levels in a population of subjects, or said standard control is approximately the average level of neuromelanin present in a population of subjects; the method is used with a second imaging method, wherein the second imaging method is selected from the group consisting of positron emission tomography (PET), structural MRI, comprises functional MRI (fMRI), blood oxygen level dependent (BOLD) fMRI, iron sensitive MRI, quantitative susceptibility mapping (QSM), diffusion tensor imaging DTI, and single photon emission computed tomography (SPECT), DaTscan and DaTquant.
Huddleston ‘603 discloses systems and methods of generating biomarkers of disease. Huddleston ‘603 teaches wherein a standard control is a level of neuromelanin present at approximately the same levels in a population of subjects, or said standard control is approximately the average level of neuromelanin present in a population of subjects ([0097]); the method is used with a second imaging method, wherein the second imaging method is selected from the group consisting of positron emission tomography (PET), structural MRI, comprises functional MRI (fMRI), blood oxygen level dependent (BOLD) fMRI, iron sensitive MRI, quantitative susceptibility mapping (QSM), diffusion tensor imaging DTI, and single photon emission computed tomography (SPECT), DaTscan and DaTquant ([0039]-[0041], [0101]-[0103]).
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 invention of Huddleston to utilize a comparison based upon a control representative of a population as taught by Huddleston ‘603, as the use of a control population is a scientific standard which allows for data obtained from previous patients to be effectively utilized to provide a baseline or standard by which to compare future patients, so that abnormalities may be distinguished. Furthermore, it would have been obvious to utilize a second imaging method as taught by Huddleston ‘603, as the use of an additional imaging method provides additional complementary data to more accurately diagnose the patient.
Claim(s) 8-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huddleston et al. (US 2015/0125057; hereinafter Huddleston) in view of King et al. (US 6288545; hereinafter King).
Huddleston shows the invention substantially as described in the 102 rejection above.
Huddleston fails to show wherein a neuromelanin gradient phantom is used to measure the level, signal and/or concentration of neuromelanin; wherein a neuromelanin phantom concentration gradient is scanned about once per patient, about once an hour, about once a day, about once a week, or about once a month; wherein a neuromelanin phantom gradient is scanned daily; wherein a neuromelanin phantom gradient is scanned with each patient.
King discloses methods and apparatus for calibration of magnetic resonance imaging systems. King teaches wherein a phantom is used to measure the level, signal and/or concentration (column 4, lines 23-40).
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 invention of Huddleston which employs neuromelanin MRI measurements to utilize a phantom as taught by King, as the use of a phantom will allow for calibration as described by King, and ultimately will improve the final accuracy of the results. Furthermore, while King is silent as to the timing of when the phantom is scanned, it would be an obvious design choice and within the level of one of ordinary skill in the art, without undue experimentation, to utilize a phantom for calibration purposes at various timepoints including “wherein a neuromelanin phantom concentration gradient is scanned about once per patient, about once an hour, about once a day, about once a week, or about once a month; wherein a neuromelanin phantom gradient is scanned daily; wherein a neuromelanin phantom gradient is scanned with each patient”, as the selection of specific time points at which to scan the phantom may be determined as desired by the user in order to calibrate the system when desired by the user.
Response to Arguments
Applicant's arguments filed 7/21/25 have been fully considered but they are not persuasive.
In response to applicant’s arguments regarding Huddleston, examiner respectfully disagrees. Huddleston teaches performing voxel based and segmentation based analyses to obtain information regarding both the SNc and LN ([0092], [0106]). Furthermore, regarding comparing steps (iii) and (iv), the examiner notes that it would be within the level of one of ordinary skill in the art without undue experimentation, after obtaining the data on both the volume of NM in an SNc region and LN region, to both compare the volume of NM in a SNc region over time and to compare the volume of NM in a LC region over time to monitor the progression of the disease as desired by Huddleston ([0109]) by utilizing all of the obtained data to obtain a more accurate diagnosis.
The examiner would suggest further amending the claims to recite specific processing steps of the voxel-based analysis and the segmented-based analysis. The claim language as currently written is given the broadest reasonable interpretation, and encompasses a wide range of possible techniques.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JONATHAN CWERN/ Primary Examiner, Art Unit 3797