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 Arguments
Applicant’s arguments with respect to claim 1 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.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites the limitation “analyzing surface of the target area by calculating surface isothermals and interpolating intensity along each surface isothermal”. The term “isothermal” is neither cited in the specification nor explained as to what exactly this process entails. For the purposes of this examination it is interpreted as analyzing the surface of a target area.
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.
Claim(s) 1-12, & 15-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Khan et al (M. O. Khan et al., “Association between aneurysm hemodynamics and wall enhancement on 3D vessel WALL MRI,” Journal of Neurosurgery, vol. 134, no. 2, pp. 565–575, Feb. 2021.; hereinafter referred to as Khan).
Regarding Claim 1, Khan discloses a method for analyzing an arterial wall (“In recent years, aneurysm wall enhancement (AWE) measured through VWMRI has been shown to be a marker of rupture-prone walls. We hypothesized that abnormal hemodynamic conditions may be associated with the presence of AWE. In this study, we investigated possible correlations between AWE and CFD-derived metrics to understand the role of hemodynamic forces in aneurysm wall degradation.” [Introduction] comprising:
administering gadolinium to a patient (“VWMRI was acquired on a 3T MR scanner (Magnetom Skyra, Siemens) with a 20-channel head coil. The protocol included a vendor-supplied isometric 3D T1 sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) turbo spin echo (TSE) sequences with spectral attenuated inversion recovery (SPAIR) and blood suppression (field of view 179 × 230, repetition time/echo time 939/18 msec, matrix 200 × 256, spatial resolution 0.9 × 0.9 × 0.9 mm) before and after administration of gadoteridol (0.2 ml/kg body weight, maximum 20 ml; ProHance, Bracco Imaging” [Methods]);
scanning a target area of the patient to obtain a scan (“his study was approved by the institutional review board of the University Hospital Düsseldorf (study number 6186R). From September 2016 to September 2017 (1 year), 22 patients with 25 unruptured IAs were included. All patients underwent both DSA and VWMRI within 6 weeks.” [Methods]);
processing the scan (“Multiplanar oblique reconstructions were obtained from precontrast- and postcontrast-enhanced 3D VWMRI and analyzed after coregistration….DSA images were segmented and reconstructed into a 3D model using the open-source Vascular Modeling Toolkit (http://www.vmtk.org). Variable density volumetric meshes were generated with the highest mesh density in the aneurysm sac, where the tetrahedron side length was 0.12 mm on average, previously shown through a 320-fold mesh-refinement study to accurately model IA hemodynamics.22 The number of tetrahedral elements was 4.1 million on average, ranging from 1.3 to 8.7 million, reflecting the variability in IA sizes and extent of CFD model domain” [Methods]);
analyzing surface of the target area by calculating surface isothermals and interpolating intensity along each surface isothermal (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1). More specifically, we quantified MRI-SI along a line that was normal to each mesh node. The MRI-SI was then averaged along the length of the line and normalized to the mean MRI-SI of the entire VWMRI volume (MRI–SI factor [MRI-SIF]).” [Methods]);
generating three-dimensional color maps and histograms representing arterial wall enhancement (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1).” [Methods], see Fig. 1 for 3D color maps and Fig. 3A for histograms regarding AWE)
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calculating one or more metrics for comparison (“We have used VWMRI to investigate the associations between AWE of unruptured IAs and hemodynamic and morphological factors typically associated with ruptured IAs. The presence of AWE was associated with morphological risk factors, particularly size and SR, and hemodynamic factors such as WSS, but only WSS was found to be an independent predictor of AWE.” [Discussion]);
and outputting an instability outcome (“Our results suggest that the presence of AWE in our unruptured IA cohort is associated with conventional hemodynamic and morphological factors. Aneurysms with larger size and SR were more prone to have AWE. However, only low WSS was independently predictive of AWE. Our results support the hypothesis that low WSS in the AWE group may indicate a growth and remodeling process that may predispose such aneurysms to rupture; however, a causality between the two could not be established. VWMRI may be augmented with CFD-based hemodynamic factors to assess patient-specific risk factors.” [Conclusion]).
Regarding Claim 2, Khan discloses that the one or more metrics include one or more of diameter, size ratio, aspect ratio, ellipticity index, non-sphericity index, undulation index, surface area, volume, wall thickness, bleb percentage, and mural thrombosis (See Table 2. For metrics measured and Abbreviation guide below).
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Regarding Claim 3, Khan discloses that the instability outcome is one or more of a likelihood of stroke, indication of aneurysm size, likelihood of rupture, or indication of inflammation of an artery (“Our results suggest that the presence of AWE in our unruptured IA cohort is associated with conventional hemodynamic and morphological factors. Aneurysms with larger size and SR were more prone to have AWE. However, only low WSS was independently predictive of AWE. Our results support the hypothesis that low WSS in the AWE group may indicate a growth and remodeling process that may predispose such aneurysms to rupture; however, a causality between the two could not be established. VWMRI may be augmented with CFD-based hemodynamic factors to assess patient-specific risk factors.” [Conclusion]).
Regarding Claim 4, Khan discloses aligning the scan to a template (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1)” [Methods]).
Regarding Claim 5, Khan discloses extracting spoke variables (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1). More specifically, we quantified MRI-SI along a line that was normal to each mesh node. The MRI-SI was then averaged along the length of the line and normalized to the mean MRI-SI of the entire VWMRI volume (MRI–SI factor [MRI-SIF]). As seen in Fig. 1C, the maximum MRI-SIF corresponded to the region that showed notable AWE on postcontrast VWMRI. Similar to hemodynamics parameters, we computed sac-averaged MRI-SIF as a quantitative measure of AWE. In addition, we computed MRI-SIF in low-, intermediate-, and high-aneurysm WSS regions of the sac, which were defined as regions with < 10%, 10%–30%, and > 30% of parent artery WSS, respectively.” [Methods]).
Regarding Claim 6, Khan discloses extracting surface measures (See Table 2. For metrics measured and Abbreviation guide below).
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.
Regarding Claim 7, Khan discloses measuring gadolinium uptake (“VWMRI was acquired on a 3T MR scanner (Magnetom Skyra, Siemens) with a 20-channel head coil. The protocol included a vendor-supplied isometric 3D T1 sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) turbo spin echo (TSE) sequences with spectral attenuated inversion recovery (SPAIR) and blood suppression (field of view 179 × 230, repetition time/echo time 939/18 msec, matrix 200 × 256, spatial resolution 0.9 × 0.9 × 0.9 mm) before and after administration of gadoteridol (0.2 ml/kg body weight, maximum 20 ml; ProHance, Bracco Imaging” [Methods]).
Regarding Claim 8, Khan discloses determining one or more of aneurysm wall enhancement, generalized aneurysm wall enhancement, specific aneurysm wall enhancement, circumferential aneurysm wall enhancement, and focal aneurysm wall enhancement (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1). More specifically, we quantified MRI-SI along a line that was normal to each mesh node. The MRI-SI was then averaged along the length of the line and normalized to the mean MRI-SI of the entire VWMRI volume (MRI–SI factor [MRI-SIF]). As seen in Fig. 1C, the maximum MRI-SIF corresponded to the region that showed notable AWE on postcontrast VWMRI. Similar to hemodynamics parameters, we computed sac-averaged MRI-SIF as a quantitative measure of AWE. In addition, we computed MRI-SIF in low-, intermediate-, and high-aneurysm WSS regions of the sac, which were defined as regions with < 10%, 10%–30%, and > 30% of parent artery WSS, respectively.” [Methods]).
Regarding Claim 9, Khan discloses projecting spokes into the target area (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1). More specifically, we quantified MRI-SI along a line that was normal to each mesh node. The MRI-SI was then averaged along the length of the line and normalized to the mean MRI-SI of the entire VWMRI volume (MRI–SI factor [MRI-SIF]). As seen in Fig. 1C, the maximum MRI-SIF corresponded to the region that showed notable AWE on postcontrast VWMRI. Similar to hemodynamics parameters, we computed sac-averaged MRI-SIF as a quantitative measure of AWE. In addition, we computed MRI-SIF in low-, intermediate-, and high-aneurysm WSS regions of the sac, which were defined as regions with < 10%, 10%–30%, and > 30% of parent artery WSS, respectively.” [Methods]).
Regarding Claim 10, Khan discloses probing a signal intensity along each spoke (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1). More specifically, we quantified MRI-SI along a line that was normal to each mesh node. The MRI-SI was then averaged along the length of the line and normalized to the mean MRI-SI of the entire VWMRI volume (MRI–SI factor [MRI-SIF]). As seen in Fig. 1C, the maximum MRI-SIF corresponded to the region that showed notable AWE on postcontrast VWMRI. Similar to hemodynamics parameters, we computed sac-averaged MRI-SIF as a quantitative measure of AWE. In addition, we computed MRI-SIF in low-, intermediate-, and high-aneurysm WSS regions of the sac, which were defined as regions with < 10%, 10%–30%, and > 30% of parent artery WSS, respectively.” [Methods]).
Regarding Claim 11, Khan discloses store a maximum signal intensity for each spoke (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1). More specifically, we quantified MRI-SI along a line that was normal to each mesh node. The MRI-SI was then averaged along the length of the line and normalized to the mean MRI-SI of the entire VWMRI volume (MRI–SI factor [MRI-SIF]). As seen in Fig. 1C, the maximum MRI-SIF corresponded to the region that showed notable AWE on postcontrast VWMRI. Similar to hemodynamics parameters, we computed sac-averaged MRI-SIF as a quantitative measure of AWE. In addition, we computed MRI-SIF in low-, intermediate-, and high-aneurysm WSS regions of the sac, which were defined as regions with < 10%, 10%–30%, and > 30% of parent artery WSS, respectively.” [Methods]).
Regarding Claim 12, Khan discloses normalizing spoke values to a reference structure (“CFD models were registered to postcontrast VWMRI using an in-house landmark-based image registration tool. To quantify the AWE on postcontrast VWMRI, we projected the MRI signal intensity (MRI-SI) onto the CFD model and normalized it according to the nominal intensity of the image volume (Fig. 1). More specifically, we quantified MRI-SI along a line that was normal to each mesh node. The MRI-SI was then averaged along the length of the line and normalized to the mean MRI-SI of the entire VWMRI volume (MRI–SI factor [MRI-SIF]). As seen in Fig. 1C, the maximum MRI-SIF corresponded to the region that showed notable AWE on postcontrast VWMRI. Similar to hemodynamics parameters, we computed sac-averaged MRI-SIF as a quantitative measure of AWE. In addition, we computed MRI-SIF in low-, intermediate-, and high-aneurysm WSS regions of the sac, which were defined as regions with < 10%, 10%–30%, and > 30% of parent artery WSS, respectively.” [Methods]).
Regarding Claim 15, Khan discloses calculating morphological indices (See Table 2. For metrics measured and Abbreviation guide below).
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Regarding Claim 16, Khan discloses gadolinium is administered prior to the scan (“VWMRI was acquired on a 3T MR scanner (Magnetom Skyra, Siemens) with a 20-channel head coil. The protocol included a vendor-supplied isometric 3D T1 sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) turbo spin echo (TSE) sequences with spectral attenuated inversion recovery (SPAIR) and blood suppression (field of view 179 × 230, repetition time/echo time 939/18 msec, matrix 200 × 256, spatial resolution 0.9 × 0.9 × 0.9 mm) before and after administration of gadoteridol (0.2 ml/kg body weight, maximum 20 ml; ProHance, Bracco Imaging” [Methods]).
Regarding Claim 17, Khan discloses determining a contrast ratio (“Recently VWMRI has been used in patients with IAs, and AWE on VWMRI is considered to be a marker of wall inflammation, and thus aneurysm wall weakening. Matouk et al. showed the presence of AWE in 5 of 5 ruptured aneurysms.30 Similarly, Nagahata et al. investigated 61 ruptured and 83 unruptured IAs and found strong to faint signs of AWE in 98.4% of ruptured and only 18.1% of unruptured IAs.33 Distinguishing strong from faint enhancement is a subjective process, and thus Wang et al. quantitatively measured enhancement ratios of IA walls, bodies, and necks on pre- versus postcontrast images, with a threshold value of 61.5% to distinguish ruptured from unruptured IAs.36” [Discussion]).
Regarding Claim 18, Khan discloses the contrast ratio is normalized to a reference structure (“Recently VWMRI has been used in patients with IAs, and AWE on VWMRI is considered to be a marker of wall inflammation, and thus aneurysm wall weakening. Matouk et al. showed the presence of AWE in 5 of 5 ruptured aneurysms.30 Similarly, Nagahata et al. investigated 61 ruptured and 83 unruptured IAs and found strong to faint signs of AWE in 98.4% of ruptured and only 18.1% of unruptured IAs.33 Distinguishing strong from faint enhancement is a subjective process, and thus Wang et al. quantitatively measured enhancement ratios of IA walls, bodies, and necks on pre- versus postcontrast images, with a threshold value of 61.5% to distinguish ruptured from unruptured IAs.36” [Discussion]).
Regarding Claim 19, Khan discloses comparing the one or more metrics for two scan, one taken before administration of contrast, and one taken after administration of contrast (“VWMRI was acquired on a 3T MR scanner (Magnetom Skyra, Siemens) with a 20-channel head coil. The protocol included a vendor-supplied isometric 3D T1 sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) turbo spin echo (TSE) sequences with spectral attenuated inversion recovery (SPAIR) and blood suppression (field of view 179 × 230, repetition time/echo time 939/18 msec, matrix 200 × 256, spatial resolution 0.9 × 0.9 × 0.9 mm) before and after administration of gadoteridol (0.2 ml/kg body weight, maximum 20 ml; ProHance, Bracco Imaging” [Methods])..
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Khan in view of Roa et al (J. A. Roa et al., “Objective quantification of contrast enhancement of unruptured intracranial aneurysms: A high-resolution vessel wall imaging validation study,” Journal of Neurosurgery, vol. 134, no. 3, pp. 862–869, Feb. 2020; hereinafter referred to as Roa.
Regarding Claim 13, Khan discloses all limitations noted above except that the reference structure is a pituitary stalk.
However, in a similar field of endeavor, Roa teaches different methods of aneurysm wall enhancement measurement to determine the most sensitive and specific [Introduction.
Roa also teaches the reference structure is a pituitary stalk (“The University of Iowa HR-VWI Project database was analyzed. This database compiles patients with UIAs who prospectively underwent HR-VWI on a 3T Siemens MRI scanner. The mean and maximal SI values of the aneurysm wall, pituitary stalk and genu of the corpus callosum, were used to compare three different measurement methods: (1) aneurysm enhancement ratio (AER = SIpost − SIpre/SIpre); (2) aneurysm-to-pituitary stalk ratio (CRstalk = SIpost/Pituitary stalkpost); and (3) aneurysm enhancement index (AEI = SIpost/SIbrain post − SIpre/SIbrain pre/SIpre/SIbrain pre). Size ≥7 mm was used as a surrogate of aneurysm instability for receiver-operating characteristic (ROC) curve analysis.” [Abstract]
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Khan as outlined above with the reference structure is a pituitary stalk as taught by Roa, because Unruptured intracranial aneurysms (UIAs) pose a therapeutic dilemma as the risk-benefit of therapeutic interventions has to be balanced against the natural history of the disease [Introduction].
Regarding Claim 14, Khan discloses all limitations noted above except that the reference structure is the corpus callosum.
However, in a similar field of endeavor, Roa teaches the reference structure is the corpus callosum (“The University of Iowa HR-VWI Project database was analyzed. This database compiles patients with UIAs who prospectively underwent HR-VWI on a 3T Siemens MRI scanner. The mean and maximal SI values of the aneurysm wall, pituitary stalk and genu of the corpus callosum, were used to compare three different measurement methods: (1) aneurysm enhancement ratio (AER = SIpost − SIpre/SIpre); (2) aneurysm-to-pituitary stalk ratio (CRstalk = SIpost/Pituitary stalkpost); and (3) aneurysm enhancement index (AEI = SIpost/SIbrain post − SIpre/SIbrain pre/SIpre/SIbrain pre). Size ≥7 mm was used as a surrogate of aneurysm instability for receiver-operating characteristic (ROC) curve analysis.” [Abstract]
It would have been obvious to an ordinary skilled person in the art before the effective filing
date of the claimed invention to modify the system of Khan as outlined above with the reference structure is the corpus callosum as taught by Roa, because Unruptured intracranial aneurysms (UIAs) pose a therapeutic dilemma as the risk-benefit of therapeutic interventions has to be balanced against the natural history of the disease [Introduction].
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN MALDONADO whose telephone number is 703-756-1421. The examiner can normally be reached 8:00 am-4:00 pm PST M-Th Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at
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/Steven Maldonado/
Patent Examiner, Art Unit 3797
/CHRISTOPHER KOHARSKI/Supervisory Patent Examiner, Art Unit 3797