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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 13, 2025 has been entered.
Status of Claims
Claims 1-16, 18-20, and 23 are pending.
Claim Rejections - 35 USC § 102
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.
Claims 1-2, 5-12, 14-15, 18, and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO2019098714 to Cho (the English-language translation is being referred to in this Office action – submitted on March 3, 2025; original document copy provided in IDS).
Regarding Claim 1, Cho discloses a method of detecting iron-related entities in a region of interest (method for detecting iron in the brain with MRI, par. 0001), comprising:
receiving, at least two magnetic resonance imaging (MRI) signals from each of at least two different locations in the region of interest (brain slices are imaged with MRI, the voxels throughout the slice are considered to be each in different locations within the region of interest and at least two MRI signals are obtained by virtue of utilizing different pulse sequences for obtaining the various data of par. 0049, for example by utilizing the different pulse sequences outlined on page 16, lines 671-679, with and without the magnetization transfer effect (MT preparation pulses));
calculating at least four MRI iron-related parameters from the MRI signals from which at least two are of a first type of MRI parameter (T2* map, SWI, QSM, par. 0086) and at least two are of a second type of MRI parameters (T2 map, T1 map, T1-weighted image with MT effect, par. 0086), wherein the iron-related MRI parameters are MRI parameters associated with iron binding compounds, compounds comprising iron ions, or iron ions (the parameters are all of which are related to iron binding compounds, compounds comprising iron ions, or iron ions - neuromelanin (NM) bound to iron and trivalent iron were determined by comparison of the at least four MRI parameters, par. 0086, Figures 5-8);
calculating a slope between the first type of parameters and the second type of parameters (while QSM necessarily relies on interdependencies, i.e. slopes, between variables, Cho specifically teaches T2*/T2 maps, of which represent a map of slopes between T2* and T2 at the different locations within the region of interest; e.g. T2*/T2 at a first voxel, T2*/T2 at a second voxel, represents slopes between two of the first type of MRI parameter T2* and two of the second type of MRI parameter T2), and
determining a presence of at least two different iron-related entities in the region of interest based on the slope, wherein said iron-related entities include iron binding compounds, compounds comprising iron ions, or iron ions (neuromelanin (NM) bound to iron and trivalent iron were determined by comparison of the at least four MRI parameters, in particular the T2*/T2 map, par. 0086, Figures 5-8).
Regarding Claims 2 and 5, Cho further discloses wherein the at least two different iron-related entities are selected from iron-related compounds, loads of iron ions within a compound, spatial distributions of the iron-related compounds, and spatial structures of the iron-related compounds (protein-iron complexes, e.g. neuromelanin (NM), and trivalent iron are mapped which is a spatial distribution, as in Figures 5-8; NM and trivalent iron are different forms of iron and NM is considered to be in the category of iron-binding proteins).
Regarding Claim 6, Cho further discloses wherein the form of iron is selected from free iron, Fe2+, and Fe3+ (trivalent iron is a type of free iron and is Fe3+, as in par. 0029; trivalent iron map is shown in Figures 5-8).
Regarding Claim 7, Cho further discloses wherein the region of interest is selected from a tissue, a laboratory phantom type sample, an in-vivo organ, and an ex-vivo organ (the brain slices being utilized can be considered to be tissue and ex-vivo organ).
Regarding Claim 8, Cho further discloses calculating the relative amount of each iron-related entity in the region of interest (Figures 5-8 the individual voxel signals show the relative amount).
Regarding Claim 9, Cho further discloses estimating the absolute amount of each uron-related entity in the region of interest (quantitative analysis is performed, par. 0020, 0093; quantitative susceptibility maps are determined which estimate iron-related substances in ppm, par. 0048, Figures 5C, 6C).
Regarding Claims 10-11, Cho further discloses determining and presenting locations of each iron-related entity in the region of interest (distribution maps are determined which implicitly determine the locations of the substance in the MRI scan of the region of interest, as in Figures 5-8).
Regarding Claim 12, Cho further discloses identifying different sub-regions in the region of interest based on the determined locations (sub-regions are identified by using tissue masking to highlight the desired structure, as in Figures 5-8, sub-image K for example; creation of the mask sub-region is shown in Figure 4).
Regarding Claim 14, Cho further teaches calculating interdependencies between the at least four MRI parameters and wherein determining the presence of the at least two different iron-related entities is based on the interdependencies (T1 and MT is utilized to identify target anatomy to create a mask for extracting T2*/T2 map data, creating Figure 5K which shows interdependencies of at least T1, MT, T2*, T2 effects; par. 0048).
Regarding Claim 15, Cho further discloses wherein the at least four MRI parameters are selected to be dependent on iron relaxivity (this is an inherent property of iron as it has an effect on T1, T2, T2*, SQM, MT, as in par. 0048, Figures 5-8 or it wouldn’t be able to be detected).
Regarding Claim 18, Cho further discloses determining a medical state of the region of interest based on the presence of the at least two different iron-related entities (Parkinson’s disease, par. 0025).
Claim 23 is rejected for the same reasoning as for claim 1 above. In addition, Cho teaches processor and memory to execute the method (the image processing unit implicitly requires a computer processor and memory to carry out MR image processing, par. 0034).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019098714 to Cho in view of NPL “Imaging iron stores in the brain using magnetic resonance imaging” to Haacke (copy provided with March 3, 2025 Office action).
Regarding Claims 3-4, Cho teaches quantifying trivalent iron (Fe3+) (par. 0029; trivalent iron map is shown in Figures 5-8) and protein-iron complexes (neuromelanin (NM), and trivalent iron are mapped which is a spatial distribution, as in Figures 5-8; NM and trivalent iron are different forms of iron and NM is considered to be in the category of iron-binding proteins). However, Cho does not teach measuring two different iron-binding proteins, as required by claim 3.
Haacke teaches a review of MRI used to detect iron-related entities in brain tissues, including ferritin-bound iron (Section 2.2.2) and transferrin-bound iron (Section 2.2.3).
As such, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to use the method of Cho to measure additional iron-related entities including ferritin-bound iron and transferrin-bound iron, since Haacke teaches these are of interest to measuring disease in the brain with MRI and are measurable with MRI parameters.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over WO2019098714 to Cho in view of NPL “Brain Tumor Detection through MR Images: A Review of Literature” to Rana (copy provided with March 3, 2025 Office action).
Regarding Claim 13, Cho does not teach wherein identifying different-sub-regions comprises differentiating between the sub-regions based on amounts of each iron-related entity in each sub-region. Instead, Cho teaches identifying sub-regions based on masking determined by identification of a target tissue (substantia nigra (SN) mask, par. 0047).
Rana teaches image segmentation techniques utilized in brain anatomy for MR images to identify target anatomy. In most approaches, a similarity of neighboring tissues is utilized to determine if it is part of the target tissue or not (e.g. thresholding technique, region growing technique, clustering, edge detection, fuzzy methods, section 3.1-3.5) and also atlas-based approaches where a specific anatomy is identified for use as a mask (section 3.6). These are considered functionally equivalent to one of ordinary skill in the art for determination of target anatomy in brain MR images.
As such, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to substitute the atlas-based approach of Cho with any of the similarity techniques of Rana so as to identify different sub-regions of the brain tissue based on amount of iron-related entities, since iron-related entitities are known to be associated with disease conditions and be of interest. For example, one of ordinary skill would be motivated to select the edge detection method when the image contrast is high.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over WO2019098714 to Cho in view of WO2019135248 to Mezer (copy provided with March 3, 2025 Office action).
Regarding Claim 16, while Cho teaches quantitative MRI (qMRI) parameters, Cho does not teach wherein the at least four MRI parameters are selected from the group consisting of R1, R2, R2’, R2*, and QSM. Instead, Cho teaches T1 with MT, T2, T2*, QSM, and SWI as the parameters (e.g. par. 0035).
Mezer teaches utilization of qMRI techniques to quantify molecular compositions in MR tissue images (Abstract), especially brain tissue (par. 0016). qMRI parameters include T1, T2, R1, R2, MT, MTV, susceptibility, and CEST (par. 0015). Mezer further teaches displaying the interdependencies of the parameters in a graph representation (Figure 9-10C).
As such, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to provide additional qMRI parameters as taught by Mezer to be useful for identifying and quantifying molecular composition in MR brain tissue images, so as to better understand the interdependencies between the parameters and the disease states.
Claims 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO2019098714 to Cho in view of NPL “Magnetic iron compounds in the human brain: a comparison of tumour and hippocampal tissue” to Brem (copy provided with IDS).
Regarding Claims 19-20, Cho does not teach wherein the detected medical state is a brain tumor. Rather, Cho is looking at the substantia nigra within the brain for Parkinson’s disease (par. 0025).
Brem teaches that iron accumulation is associated with brain tumors (Abstract) and can be identified using magnetic measurement techniques.
Since Cho has demonstrated qMRI techniques can identify iron accumulations in brain tissue, one of ordinary skill in the art before the effective filing date of the claimed invention would have found it obvious to try the qMRI to identify brain tumors since Brem teaches there would be a reasonable expectation of success in identification of brain tumor tissues since brain tumor tissues are known to have abnormal iron characteristics compared to healthy tissue. The motivation to try such an approach to identify brain tumors would be to improve identification of brain tumors, since their early detection is especially difficult.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1-16, 18-20, and 23 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Applicant previously argued that Cho does not teach a “slope” as required by claim 1. Examiner addressed arguments directed to Cho in the Office action August 14, 2025. Specifically, Cho teaches a ratio which meets the definite of a slope, as it complies with the geometry definition of slope equaling rise over run (i.e. y-axis value divided by x-axis value). Examiner also points out that the claim does not specifically define the MRI parameters, what the slope represents, or what iron-related entity is being measured.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANGELA MARIE HOFFA whose telephone number is (571)270-7408. The examiner can normally be reached Monday - Friday 9:30 am - 6:00 pm.
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ANGELA M. HOFFA
Primary Examiner
Art Unit 3799
/Angela M Hoffa/Primary Examiner, Art Unit 3799