DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claim 1-8 are objected to because of the following informalities:
With regards to claims 1-8, the claims should avoid the use of “characterized” and instead consider language such as --- comprising ---, ---further comprising ---, etc..
With regards to claim 1, 3 and 7, Applicant should remove the use of capitalization when reciting the steps.
With regards to claims 1-8, Applicant should maintain consistency when referring to the “resting-state functional magnetic resonance imaging (R-fMRI)” term. Note that the claim uses the acronym “R-fMRI” in claim 4 but then refers to the term as “resting-state fMRI” or “R-fMRI” in other places.
With regards to claim 4, in line 2, “ROI” should be replaced with --- region of interest (ROI) ---.
In claim 7, in line 6, “R-fMRI” should be replaced with –resting-state functional magnetic resonance imaging (R-fMRI) ---.
In claim 7, in line 6, “MDD” should be replaced with --- major depressive disorder (MDD) ---.
In claim 7, in line 10, “sgACC” should be replaced with ---spherical subgenual anterior cingulate cortex (sgACC) --.
In claim 7, in line 11, “DLPFC” should be replaced with ---dorsolateral prefrontal cortex (DLPFC) ---.
With regards to claim 7, it is suggested that “is used” be avoided and instead --- is configured – be used instead.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
With regards to claims 1-8, the claims are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors. The claims contain numerous indefinite issues which are listed below and Applicant is respectfully requested to carefully review claims to avoid indefiniteness.
Claim 1 recites the limitation "the targets" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the preprocessed individual resting-state fMRI data" in line 8. There is insufficient antecedent basis for this limitation in the claim. Claim 7 is similarly rejected.
Claim 1 recites the limitation "the spherical subgenual anterior cingulate cortex (sgACC)" in lines 8-9. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the seed point" in line 9. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the seed-based functional connectivity" in lines 9-10. There is insufficient antecedent basis for this limitation in the claim.
Claim 1 recites the limitation "the sgACC functional connectivity maps" in line 10. There is insufficient antecedent basis for this limitation in the claim. Claim 7 is similarly rejected.
Claim 1 recites the limitation "the dorsolateral prefrontal cortex (DLPFC) region mask" in line 11. There is insufficient antecedent basis for this limitation in the claim. Claim 7 is similarly rejected.
Claim 1 recites the limitation "the MDD group" in lines 12-13. There is insufficient antecedent basis for this limitation in the claim.
With regards to claim 1, in lines 13-16, limitations appear after a period in line 13, thus rendering the claim indefinite as it is unclear where the claim ends. For examination purposes, the limitations following the period in line 13 are considered to not be part of the claimed invention. Applicant should rewrite the claim to only include a single period. Since the limitations following the period are not considered to be part of the claimed invention, these limitations have not been reviewed for indefiniteness. If Applicant does include these limitations, Applicant should carefully review the claim to avoid indefiniteness issues. Claims 5 and 7 are similarly rejected as the claims include multiple periods.
Claim 2 recites the limitation "the empirical Bayesian Combat algorithm" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 3 recites the limitation "the initial time points" in line 3. There is insufficient antecedent basis for this limitation in the claim.
With regards to claim 3, the claim refers to the acronym “BIDS” without defining what “BIDS” stands for, thereby rendering the claim indefinite.
Claim 3 recites the limitation "the converted MR structural and functional imaging data" in lines 6-7. There is insufficient antecedent basis for this limitation in the claim.
With regards to claim 3, in lines 1-2, the claim refers to “the data preprocessing in Step 2 includes the following specific methods”, but then in lines 3-8, the claim refers to Steps 3.1-3.4, thereby creating confusion as to whether the steps in lines 3-8 are further limiting step 2 or step 3.
Claim 3 recites the limitation "the filtering and smoothing" in lines 10-11. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites the limitation "the whole-brain functional connectivity" in lines 3-4. There is insufficient antecedent basis for this limitation in the claim.
With regards to claim 4, in the last 2 lines, it is unclear as to whether the “functional connectivity” is referring the same “functional connectivity” set forth in line 10 of claim 1 or referring to a different functional connectivity. For examination purposes, Examiner assumes the latter.
With regards to claim 6, the claim appears to refer to “step 5” in line 4, wherein “step 5” is not considered to be part of the claimed invention (see the above 35 USC 112(b) rejection of claim 1 with regards to the limitations following the period in line 13). The claim is indefinite as it is unclear how claim 6 is further limiting claim 1 when it refers to a step that is not considered to be part of the claimed invention. For examination purposes, claim 6 is therefore considered to include limitations which are not part of the claimed invention. Since the limitations of claim 6 are not considered to be part of the claimed invention, these limitations have not been reviewed for indefiniteness. If Applicant does include these limitations, Applicant should carefully review the claim to avoid indefiniteness issues.
Claim 7 recites the limitation "the MDD group" in lines 6-7. There is insufficient antecedent basis for this limitation in the claim.
Claim 7 recites the limitation "the matched normal control group" in line 7. There is insufficient antecedent basis for this limitation in the claim.
Claim 7 recites the limitation "the collected rs-fMRI data" in line 8. There is insufficient antecedent basis for this limitation in the claim.
With regards to claim 8, in the last line, it is unclear as to whether the “sites” is referring to the same “sites” set forth in line 7 of claim 7, or referring to different sites. For examination purposes, Examiner assumes the former.
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(s) 1, 4 and 6-7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pascual-Leone et al. (US Pub No. 2015/0119689).
With regards to claims 1 and 7, Pascual-Leone et al. disclose an individualized TMS targeting system and method for individualized localizing the targets of transcranial magnetic stimulation (TMS) for depression based on group-level difference statistical maps, characterized by the following steps:
Step 1: Collect resting-state functional magnetic resonance imaging (R-fMRI) data from subjects (i.e. “13 subjects with major depressive disorder”) diagnosed with major depressive disorder (MDD) and a matching normal control group (i.e. “healthy”/”normal” control subjects) (paragraphs [0057], [0059], referring to the resting state fMRI data being obtained; paragraphs [0158]-[0159], [0470], [0487], [0577], referring to the healthy [control’ subjects and subjects with major depressive disorder, wherein the subjects complete resting state fMRI scans; paragraphs [0176], [0247], referring to “Intrinsic (resting state) functional connectivity MRI; Figure 2, step 202);
Step 2: Preprocess the collected resting-state fMRI data (paragraphs [0061]-[0062], referring to the fMRI data being preprocessed; paragraphs [0583]-[0584], referring to the functional data being preprocessed to decrease image artifacts and between-slide timing differences; Figure 2, step 204);
Step 3: On the preprocessed individual resting-state fMRI data, using the spherical subgenual anterior cingulate cortex (sgACC) as the seed point, calculate the seed-based functional connectivity for each subject, and extract the sgACC functional connectivity maps within the dorsolateral prefrontal cortex (DLPFC) region mask (paragraphs [0578]-[0579], [0589]; referring to defining a ROI in the “subgenual cingulate cortex” and the ROI is defined as a 10mm sphere and masked, thus the subgenual cingulate cortex ROI comprises a “spherical subgenual anterior cingulate cortex (sgACC)”, wherein “coordinates were identified in the left DLPFC that could potentially serve as optimized TMS targets by computing seed-based functional connectivity with two regions: our a priori ROI in the subgenual and our effective-ineffective map”; paragraph [0593], referring to the ROI in the subgenual cingulate cortex being displayed in volume space; paragraph [0183], referring to surface-based maps being masked to show only voxels in the left DLPFC; Figure 20);
Step 4: Perform a two-sample t-test (i.e. “two-tailed t-test”) on the sgACC functional connectivity maps of the MDD group and the normal control group (paragraph [0592], referring to the analyses being also performed in 11 normal subjects and compared to the 13 patients with depression “using two-tailed t-tests”).
Note that the limitations “Within the DLPFC mask, extract significant clusters of differences between the subjects of the MDD group and the normal control group from the two-sample t-test statistical map and designate them as group-level targeting points for TMS in the MDD group; Step 5: Combine the identified group-level TMS targeting points for MDD with the preprocessed individual MDD resting-state fMRI data and use a dual regression algorithm to obtain individualized TMS targets” are not considered to be part of the claimed invention (see the above 35 USC 112(b) rejection).
Additionally, with regards to claim 7, Pascual-Leone et al. disclose a computer (306) and data collection module, data preprocessing module, functional connectivity calculation module, statistical difference target acquision module and indiviualzied target acquisiton module running on the computer to perform the above steps (paragraph [083]; Figure 3).
With regards to claim 4, Pascual-Leone et al. disclose that in Step 3, on the preprocessed individual resting-state fMRI data, use a spherical ROI of sgACC based on volume space or an sgACC template ROI based on cortical space to calculate the whole-brain functional connectivity based on the sgACC seed point; use Pearson correlation to calculate functional connectivity (paragraphs [0578]-[0579], [0589]; referring to defining a ROI in the “subgenual cingulate cortex” and the ROI is defined as a 10mm sphere and masked, thus the subgenual cingulate cortex ROI comprises a “spherical subgenual anterior cingulate cortex (sgACC)”; paragraph [0593], referring to the ROI in the subgenual cingulate cortex being displayed in volume space; paragraphs [0163], [0584], referring to the Pearson’s correlation coefficient being computed between the extracted time course and that of all other voxels when performing functional connectivity analysis).
With regards to claim 6, claim 6 is further limiting Step 5 (see line 4 of claim 6), and thus since Step 5 is part of the limitations which are not considered to be part of the claimed invention (see the above 35 USC 112(b) rejection), claim 6 is considered to be met by Pascual-Leone et al. as it includes no further limitations of the claimed invention since Step 5 is not considered to be part of the claimed invention (see the above 35 USC 112(b) rejection).
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.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pascual-Leone et al. as applied to claim 1 above, and further in view of Reynolds et al . (“ComBat Harmonization: Empirical Bayes versus fully Bayes approaches”, 2023).
With regards to claim 2, as discussed above, Pascual-Leone et al. meet the limitations of claim 1. Further, Pascual-Leone et al. disclose that the R-fMRI data collected in Step 1 come from multiple sites (paragraph [0577], referring to the fMRI datasets comprising of multiple subjects and thus there are multiple sites of R-fMRI data; paragraph [0578], referring to the “several regions of interest (ROI) and multiple ROIs).
However, Pascual-Leone et al. do not specifically disclose that R-fMRI data from the multiple sites are standardized using the empirical Bayesian Combat algorithm.
Reynolds et al. disclose removing bias-inducing factors from data of multiple datasets (Abstract; pgs. 1-2, “Introduction”). ComBat is one of the most common methods applied to features from structural images, wherein ComBAt uses a hierarchical Bayesian model and uses the empirical Bayes approach to infer the distribution of the unknown factors and wherein Empirical Bayesian Combat more effectively removes scanner strength information and is more computationally efficient (Abstract; pg. 16, left column, first paragraph).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the R-fMRI data of Pascual-Leone et al. from the multiple sites be standardized using the empirical Bayesian Combat algorithm, as taught by Reynolds et al., in order to more effectively remove bias-inducing factors, such as scanner strength information, from the data in a computationally efficient manner (Abstract; pg. 16, left column, first paragraph).
Claim(s) 3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pascual-Leone et al. as applied to claim 1 above, and further in view of Savidge et al. (US Pub No. 2024/0325353).
With regards to claim 3, as discussed above, Pascual-Leone et al. meet the limitations of claim 1. Further, Pascual-Leone et al. disclose that the data preprocessing in Step 2 includes the following specific methods: Step 3.3: Employ a linear regression method to denoise the preprocessed resting-state fMRI data and Step 3.4: Use spatial smoothing methods to complete the filtering and smoothing of the resting-state fMRI data (paragraphs [0061]-[0062], referring to the fMRI data be preprocessed, wherein the preprocessing includes spatially smoothing the fMRI data using a Gaussian kernel and removing spurious or nonspecific sources of variance by regression of the variables including six movement parameters computed by rigid body translation and rotation during preprocessing and the inclusion of the first temporal derivatives of these regressors “within the linear model” may be accounted for the time-shifted versions of spurious variance).
However, Pascual-Leone et al. do not specifically disclose that the data preprocessing in Step 2 further includes Step 3.1: Remove the initial time points of the collected resting-state fMRI data to ensure magnetic field homogeneity and subject adaptation to scanning conditions; Step 3.2: Convert the resting-state fMRI data to BIDS format and use preprocessing tools based on anatomical or cortical space to preprocess the converted MR structural and functional imaging data, and Step 3.4 further comprises using a band-pass temporal filter to complete the filtering of the resting-state fMRI data.
Savidge et al. disclose that preprocessing steps may be performed on resting state BOLD-fMRI data by first converting all data to the BIDS format for processing with the CONN toolbox, performing slice timing correction by correcting temporal misalignment between different slides of the rs-fMRI scans by applying an approprirate timeshift to match the actual acquisition time [note the timeshift would encompass removing initial time points and using temporal band-pass filtering to remove temporal frequencies below a desired frequency from the signal in order to focus on slow-frequency fluctuations while minimizing the influence of physiological, headmotion and other noise sources (paragraphs [0147]-[0154]).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the data preprocessing in Step 2 of Pascual-Leone et al. further include Step 3.1: Remove the initial time points of the collected resting-state fMRI data to ensure magnetic field homogeneity and subject adaptation to scanning conditions; Step 3.2: Convert the resting-state fMRI data to BIDS format and use preprocessing tools based on anatomical or cortical space to preprocess the converted MR structural and functional imaging data, and Step 3.4 further comprises using a band-pass temporal filter to complete the filtering of the resting-state fMRI data, as taught by Savidge et al., in order to correct temporal misalignment, provide processing with the CONN toolbox, and provide the ability to focus on slow-frequency fluctuations while minimizing the influence of physiological, headmotion and other noise sources (paragraphs [0147]-[0154]).
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pascual-Leone et al. as applied to claim 1 above, and further in view of Geha (US Patent No. 11,707,221).
With regards to claim 5, as discussed above, Pascual-Leone et al. meet the limitations of claim 1. However, Pascual-Leone et al. do not specifically disclose that when performing the two-sample t-test on the sgACC functional connectivity maps of the MDD group and normal control group, use cluster enhancement and permutation testing method (paragraph [0075], referring to a comparison being performed using a paired t-test and then determining a local maxima using FSL clustering algorithm, wherein any suitable parameters of the clustering algorithm may be used and a threshold may be selected in any suitable manner).
However, Pascual-Leone et al. do not specifically disclose that the cluster enhancement and permutation is based on unthresholded cluster enhancement for multiple comparisons correction or gaussian random field correction of the sgACC functional connectivity maps from the two-sample t-test.
Geha discloses identifying group differences in seed based connectivity in fMRI datasets using permutation based inference to allow rigorous comparisons of significance within the framework of the general linear model with p < 0.05, wherein group contrast clusters were identified using threshold-free cluster enhancement (TFCE) method, which bypasses the arbitrary threshold necessary in methods that use voxel-based thresholds (Abstract; column 16, line 66-column 17, line 23).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the cluster enhancement and permutation of Pascual-Leone et al. be based on unthresholded cluster enhancement for multiple comparisons correction or gaussian random field correction of the sgACC functional connectivity maps from the two-sample t-test, as taught by Geha, in order to allow rigorous comparisons of significance and bypass the arbitrary threshold necessary in methods that use voxel-based thresholds (column 16, line 66-column 17, line 23).
Note that the limitations “Within the DLPFC mask, extract the corrected significant clusters of differences between the MDD group and the normal control group as group-level DLPFC TMS targets for treating MDD.” are not considered to be part of the claimed invention (see the above 35 USC 112(b) rejection).
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pascual-Leone et al. as applied to claim 7 above, and further in view of Fan et al. (US Pub No. 2015/0243023).
With regards to claim 8, as discussed above, Pascual-Leone et al. meet the limitations of claim 7. Further, Pascual-Leone et al. further disclose that the system further includes a data normalization module running on the computer, used for standardizing the data collected from different sites (paragraphs [0164], [0279], referring to normalizing the distributions for statistical comparison).
However, Pascual-Leone et al. do not specifically disclose that the system is based on dual regression of two-sample groups.
Fan et al. disclose, based on the fMRI data collected at resting-state, the brain functional connectivity is typically investigated using regional correlation analysis based approaches or independent component analysis (ICA) methods (paragraph [0002]). For ICA studies of multiple subjects, the spatial ICA is typically applied to concatenated group imaging data formed by concatenating imaging data from all subjects in the temporal dimension, and subject specific ICs are then obtained by back reconstruction or dual regression (paragraph [0003]).
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to have the system of Pascual-Leone et al. be based on dual regression of two-sample groups, as taught by Fan et al., in order to analyze the fMRI data based on ICA methods and obtain subject specific ICs from the concatenated group imaging data (paragraph [0003]).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE L FERNANDEZ whose telephone number is (571)272-1957. The examiner can normally be reached Monday-Friday 9:00 AM - 5:30 PM (ET).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Pascal Bui-Pho can be reached at (571) 272-2714. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KATHERINE L FERNANDEZ/Primary Examiner, Art Unit 3798
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