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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/11/2025 has been entered.
Response to Amendment
The amendment filed 11/11/2025 has been entered. Claims 1-12, 14-19 remain pending in the application, have been previously withdrawn, claims 13 and 20-35 have been canceled, and claims 36-37 have been newly added.
Claim Objections
Claim 1 objected to because of the following informalities:
Claim 1 recites “wherein generating the bolus of deoxyhemoglobin comprises targeting a first PETO2 corresponding to hypoxia and targeting a second PETO2”, rather, this should recite wherein generating the bolus of deoxyhemoglobin comprises targeting a first partial pressure of oxygen (PETO2) corresponding to hypoxia and targeting a second partial pressure of oxygen (PETO2)--.
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.
Claim 36 is 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.
The term “rapidly” in claim 36 is a relative term which renders the claim indefinite. The term “rapidly” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how long “rapidly” induced is, compared to a normal time period. Clarification is needed.
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.
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 1, 2, 4, and 36-37 are rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”)
Regarding claim 1, Santosh teaches a method comprising:
generating a bolus of deoxyhemoglobin in a subject's lungs ([0023]-[0025] discloses administration of gas and imaging of the subject to obtain images that contain data which relates to the relative amounts of deoxyhemoglobin [0047] discloses using deoxyhemoglobin as tracer; [0055]-[0057] discloses controlling the gas supply/gas mixture to form a bolus);
conducting magnetic resonance imaging on the subject (magnetic resonance imaging [0023]); and
using the bolus of deoxyhemoglobin as a contrast agent for the magnetic resonance imaging (Signal evaluation assumes that the baseline arises from the signal for deoxyhaemoglobin which is a produced once oxygen is utilised in metabolism. Deoxyhaemoglobin reduces signal as it is paramagnetic but oxyhaemoglobin is not paramagnetic. So, when oxygen binds to deoxyhaemoglobin to form oxyhaemoglobin the said conversion manifests itself as a signal change in the sense that conversion to oxyhaemoglobin is recognisable as an increase in signal [0029]).
Santosh, however does not teach:
wherein generating the bolus of deoxyhemoglobin comprises targeting a first PETO2 corresponding to hypoxia and targeting a second PETO2;
maintaining isocapnia in the subject using the sequential gas delivery apparatus while generating the bolus of deoxyhemoglobin.
Fisher is considered analogous to the instant application as “Method And Apparatus For Inducing And Controlling Hypoxia” is disclosed (title). Santosh teaches:
wherein generating the bolus of deoxyhemoglobin comprises targeting a first PETO2 …. and targeting a second PETO2 ([0027] and [0038] discloses targeting two different pressures of oxygen)
using the sequential gas delivery apparatus (the subject breathes through a sequential gas delivery (SGD) circuit [0005]) while generating the bolus of deoxyhemoglobin (measuring or estimating the subject's oxygen consumption [0032]);
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 Santosh to include wherein generating the bolus of deoxyhemoglobin comprises targeting a first PETO2 and targeting a second PETO2, and using the sequential gas delivery apparatus while generating the bolus of deoxyhemoglobin, as suggested by Fisher. Doing so would allow for reliably inducing hypoxia, and maintaining hypoxia at a fixed level regardless of how hard the subject breathes, as suggested by Fisher ([0004]).
The combined invention still does not teach maintaining isocapnia [in the subject using the sequential gas delivery apparatus while generating the bolus of deoxyhemoglobin].
Niftrik is considered analogous to the instant application as “Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation” is disclosed. Niftrik teaches:
maintaining isocapnia in the subject (Group B (subjects 11–20, Table 1): Here, the CO2 baseline level of each subject was preset to an isocapnic CO2 baseline of ~40 mmHg, Page 124, col 2, paragraph 2 2.3. BOLD-CVR studies and CO2 protocols) using the sequential gas delivery apparatus while generating the bolus of deoxyhemoglobin (The CO2 manipulation was provided by a gas delivery system using a computer controlled gas blender with prospective gas targeting algorithms (RespirAct™, Thornhill Research Institute, Toronto, Canada) which allows for automated precise targeting of arterial partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2), Page 124, column 2; the BOLD responses in both investigations can be influenced by the amount of baseline deoxyhemoglobin within a voxel. (Known as parameter M) [5]. As differences can be seen between subjects as well as between regions in the brain, this could have induced more pronounced differences, page 128 col.1 para. 2).
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 Santosh to include maintaining isocapnia in the subject using the sequential gas delivery apparatus while generating the bolus of deoxyhemoglobin, as taught by Niftrik. Doing so would allow for “a preset isocapnic baseline may lead to a higher basal CBF” (a local increase in cerebral blood flow), as suggested by Niftrik (page 122, col 1 para.2).
Regarding claim 2, modified Santosh teaches the method of claim 1, as discussed above. Santosh further comprising synchronizing the magnetic resonance imaging with a flow of deoxyhemoglobin to a target tissue ((b) generating images of the target area of interest of the patient's body before, during and after administration of oxygen [0024]; c) processing said images to obtain data relating to the relative amounts of deoxyhaemoglobin and free oxygen in said target area following administration of oxygen, said data being indicative of the metabolic function of said target area and being useful in the diagnosis of disease [0025]; Therefore by varying the amount of oxygen with T2* imaging tissues can be stratified based on their metabolism [0027]; [0057] discloses the protocol for imaging, which includes timing the scanning based off of the inhaled gas).
Regarding claim 4, modified Santosh teaches the method of claim 1, as discussed above. Santosh further teaches wherein the magnetic resonance imaging comprises a weighting imaging (T2*) of a transverse relaxation time (T2) (T2* weighted magnetic resonance image [0037]; it is known in the art that T2* refers to the indicates the apparent transverse relaxation time i.e. takes into account T2).
Regarding claim 36, modified Santosh teaches the method of claim 1, as discussed above. Niftrik further teaches wherein the bolus of deoxyhemoglobin comprises a discrete amount of deoxyhemoglobin that is rapidly induced in the subject ([0057] discloses inhaling the bio tracer within a set amount of time).
Regarding claim 37, modified Santosh teaches the method of claim 1, as discussed above. Santosh further teaches wherein the bolus of deoxyhemoglobin comprises a pulse of oxygen resaturation induced in the subject ([0074] discloses oxygen administration/steps during imaging)
Claims 3, 5, and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1), and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”), and Prisman, Eitan, et al. "Comparison of the effects of independently‐controlled end‐tidal PCO2 and PO2 on blood oxygen level–dependent (BOLD) MRI." Journal of Magnetic Resonance Imaging: An Official Journal of the International Society for Magnetic Resonance in Medicine 27.1 (2008): 185-191, of record on IDS, hereinafter "Prisman")
Regarding claim 3, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however does not teach further comprising controlling an inhaled gas composition to induce different temporal levels of deoxyhemoglobin in the subject during the magnetic resonance imaging. Prisman is considered analogous to the instant application as “Comparison of the effects of independently-controlled end-tidal PCO2 and PO2 on blood oxygen level–dependent (BOLD) MRI” is disclosed (title).
Prisman teaches: controlling an inhaled gas composition (“During inspiration, two gases (Gas 1 and Gas 2) are delivered to the subject in a predetermined sequence via a SGD breathing circuit (16). If the subject's ventilation exceeds the total flow of Gas 1, then the balance of the breath is made up of Gas 2, which consists of the subject's own exhaled gas collected during the previous exhalation. Gas 2 acts as a neutral filler: it increases lung volume, but has no effect on gas exchange, as its composition approximates the subject's own alveolar gas (16)”, page 187, Column 1, paragraph 1) to induce different temporal levels of deoxyhemoglobin in the subject during the magnetic resonance imaging (“(BOLD) MRI that is dependent on changes in deoxyhemoglobin (dHb) concentrations, which in turn are inversely proportional to changes in cerebral blood flow… hyperoxia may cause vasoconstriction (8), thereby decreasing cerebral blood flow, increasing venous dHb levels (given unchanged metabolic O2 consumption) and ultimately decreasing BOLD signal intensity.”, page 185 column 2 paragraph 1; the “Discussion” section on pages 189-190 further discloses the localized response of deoxyhemoglobin in response to the changing composition of gas/oxygen).
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 combined invention of Santosh to include controlling an inhaled gas composition to induce different temporal levels of deoxyhemoglobin in the subject during the magnetic resonance imaging, as taught by Prisman. Doing so would allow to reduce the signal-to-noise ratio, as suggested by Prisman (“further reduction of the BOLD signal by regression of the highly correlated covariate confounding factor (PETO2) will further reduce the already low BOLD signal-to-noise ratio”, page 190, col. 2 para. 1 Discussion).
Regarding claim 5, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach wherein generating the change in the deoxyhemoglobin in the subject comprises varying a partial pressure of oxygen in the lungs of the subject.
Prisman, however, teaches generating the change in the deoxyhemoglobin in the subject (“(BOLD) MRI that is dependent on changes in deoxyhemoglobin (dHb) concentrations, which in turn are inversely proportional to changes in cerebral blood flow… hyperoxia may cause vasoconstriction (8), thereby decreasing cerebral blood flow, increasing venous dHb levels (given unchanged metabolic O2 consumption) and ultimately decreasing BOLD signal intensity.”, page 185 column 2 paragraph 1; the “Discussion” section on pages 189-190 further discloses the localized response of deoxyhemoglobin in response to the changing composition of gas/oxygen) comprises varying a partial pressure of oxygen in the lungs of the subject (“Precise control and targeting of PETCO2 and PETO2 in-dependent of each other and independent of ventilation”, Page 186, column 2, para 2 Materials and Methods).
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 combined invention of Santosh to include generating the change in the deoxyhemoglobin in the subject comprises varying a partial pressure of oxygen in the lungs of the subject, as taught by Prisman. Doing so would allow to reduce the signal-to-noise ratio, as suggested by Prisman (“further reduction of the BOLD signal by regression of the highly correlated covariate confounding factor (PETO2) will further reduce the already low BOLD signal-to-noise ratio”, page 190, col. 2 para. 1 Discussion).
Regarding claim 6, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach using a single or multiple gradient-echo and a single-shot signal indicative of a dynamic change of deoxyhemoglobin in response to a rapid and controlled change in oxygen concentration provided for inhalation by the subject.
Prisman, however, teaches using a single or multiple gradient-echo and a single-shot signal (BOLD scanning parameters: 15 slice locations from midbrain to centrum semiovale were obtained using a single-shot spiral trajectory through k-space,… A new image was generated at each slice location every two seconds. Functional data was registered to high-resolution T1-weighted images derived from a three-dimensional (3D) volumetric anatomical acquisition (inversion-recovery fast spoiled gradient-recalled echo sequence [IR-FSPGR]) indicative of a dynamic change of deoxyhemoglobin (“(BOLD) MRI that is dependent on changes in deoxyhemoglobin (dHb) concentrations, which in turn are inversely proportional to changes in cerebral blood flow… hyperoxia may cause vasoconstriction (8), thereby decreasing cerebral blood flow, increasing venous dHb levels (given unchanged metabolic O2 consumption) and ultimately decreasing BOLD signal intensity.”, page 185 column 2 paragraph 1; the “Discussion” section on pages 189-190 further discloses the localized response of deoxyhemoglobin in response to the changing composition of gas/oxygen) in response to a rapid and controlled change in oxygen concentration provided for inhalation by the subject (“changes in PETO2 during inhalation of CO2-rich gas mixtures may contribute to a significant portion of the overall changes in the BOLD signal”, Discussion section on pages 189-190; “Precise control and targeting of PETCO2 and PETO2 in-dependent of each other and independent of ventilation”, Page 186, column 2, para 2 Materials and Methods).
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 combined invention of Santosh to include using a single or multiple gradient-echo and a single-shot signal indicative of a dynamic change of deoxyhemoglobin in response to a rapid and controlled change in oxygen concentration provided for inhalation by the subject, as taught by Prisman. Doing so would allow to reduce the signal-to-noise ratio, as suggested by Prisman (“further reduction of the BOLD signal by regression of the highly correlated covariate confounding factor (PETO2) will further reduce the already low BOLD signal-to-noise ratio”, page 190, col. 2 para. 1 Discussion).
Regarding claim 7, Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach comprising using single or multiple spin-echo contrast preparation and a single-shot signal to detect a change in a magnetic resonance imaging signal caused by a change in deoxyhemoglobin to measure blood flow, blood volume, mean transit time, or a combination of such.
Prisman, however, teaches using a single spin-echo contrast preparation and a single-shot signal to detect a change in a magnetic resonance imaging signal BOLD scanning parameters: 15 slice locations from midbrain to centrum semiovale were obtained using a single-shot spiral trajectory through k-space,… A new image was generated at each slice location every two seconds. Functional data was registered to high-resolution T1-weighted images derived from a three-dimensional (3D) volumetric anatomical acquisition (inversion-recovery fast spoiled gradient-recalled echo sequence [IR-FSPGR]) caused by a change in deoxyhemoglobin (“(BOLD) MRI that is dependent on changes in deoxyhemoglobin (dHb) concentrations, which in turn are inversely proportional to changes in cerebral blood flow… hyperoxia may cause vasoconstriction (8), thereby decreasing cerebral blood flow, increasing venous dHb levels (given unchanged metabolic O2 consumption) and ultimately decreasing BOLD signal intensity.”, page 185 column 2 paragraph 1; the “Discussion” section on pages 189-190 further discloses the localized response of deoxyhemoglobin in response to the changing composition of gas/oxygen) to measure blood flow (BOLD MRI is therefore commonly used as a surrogate indicator of changes in cerebral blood flow to determine CVR in clinical settings …The manipulation of end-tidal partial pressure of CO2 (PETCO2) causes a change in arterial partial pressure of CO2 (PaCO2), thereby providing a suitable stimulus to induce changes in cerebral blood flow, page 185, Column 2, para. 1).
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 combined invention of Santosh to include using a single spin-echo contrast preparation and a single-shot signal to detect a weighted change in a magnetic resonance imaging signal caused by a change in deoxyhemoglobin to measure blood flow, as taught by Prisman. Doing so would allow to reduce the signal-to-noise ratio, as suggested by Prisman (“further reduction of the BOLD signal by regression of the highly correlated covariate confounding factor (PETO2) will further reduce the already low BOLD signal-to-noise ratio”, page 190, col. 2 para. 1 Discussion).
Claims 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”) and Prisman et al. (Prisman, Eitan, et al. "Comparison of the effects of independently‐controlled end‐tidal PCO2 and PO2 on blood oxygen level–dependent (BOLD) MRI." Journal of Magnetic Resonance Imaging: An Official Journal of the International Society for Magnetic Resonance in Medicine 27.1 (2008): 185-191, hereinafter "Prisman"), and Panther et al. (US 20170293005 A1, hereinafter "Panther").
Regarding claim 8, modified Santosh teaches the method of claim 1, as discussed above. Santhosh, however, does not teach, using a combination of gradient echo and spin echo for contrast preparation and a single shot signal indicative of mixed T2-weighted and T2*-weighted changes in a magnetic resonance imaging signal caused by a the bolus of deoxyhemoglobin to measure blood flow, blood volume, mean transit time, or a combination of such.
Panther is considered analogous to the instant application as an MRI system is disclosed (abstract). Panther teaches
using a combination of gradient echo and spin echo (para. [0053] discloses use of gradient and spin echo) and a single shot signal indicative of mixed T2-weighted and T2*-weighted changes in a magnetic resonance imaging signal ([0045-0046] and [0056] disclose T2 and T2* images, and how each exploit different features in the image, further [0046] discloses that T2* is a combination of T2’ and T2; [0092] discloses that multiple MR signal properties can be obtained for each tissue using one or more pulse sequences)caused by a the bolus of deoxyhemoglobin to measure blood flow, blood volume, mean transit time, or a combination of such (Functional MRI (fMRI) studies rely on regional differences in cerebral blood flow to delineate regional activity…BOLD-fMRI is able to detect differences in cerebral blood flow in part due to a difference in the paramagnetic properties of oxygenated hemoglobin and deoxygenated hemoglobin [0058]; [0085] discloses BOLD imaging using the system; detecting differences in blood flow would require to measure blood flow).
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 combined invention of Santosh to include using a combination of gradient echo and spin echo for contrast preparation and a single shot signal indicative of mixed T2-weighted and T2*-weighted changes in a magnetic resonance imaging signal caused by a the bolus of deoxyhemoglobin to measure blood flow, blood volume, mean transit time, or a combination of such, as taught by Panther. Doing so would allow to reduce the MR signal from the tissues in its immediate vicinity, as suggested by Panther ([0058])
Regarding claim 9, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach further comprising deriving from a magnetic resonance imaging signal responsive to a change in deoxyhemoglobin a peak signal change, an onset, a time to peak, a full width half maximum, a recovery half time, an area under the curve, or a combination of such.
Panther is considered analogous to the instant application as an MRI system is disclosed (abstract). Panther teaches deriving from a magnetic resonance imaging signal responsive to a change in deoxyhemoglobin (Functional MRI (fMRI) studies rely on regional differences in cerebral blood flow to delineate regional activity…BOLD-fMRI is able to detect differences in cerebral blood flow in part due to a difference in the paramagnetic properties of oxygenated hemoglobin and deoxygenated hemoglobin [0058]; [0085] discloses BOLD imaging using the system) a peak signal change ([0006], [0051], [0086]-[0091] discloses detection of different peaks within the MR signal).
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 combined invention of Santosh to include comprising deriving from a magnetic resonance imaging signal responsive to a change in deoxyhemoglobin a peak signal change, as taught by Panther. Doing so would allow to average out white noise, as suggested by Panther ([0091]).
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”) and Lu (US 20150231357 A1).
Regarding claim 10, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach applying a Fourier analysis to a characteristic of a magnetic resonance imaging signal to compute a metric for a set of voxels.
Lu is considered analogous to the instant application as “Systems and methods for gas mixture delivery to humans inside an mri scanner” is disclosed (title).
Lu teaches applying a Fourier analysis to a characteristic of a magnetic resonance imaging signal to compute a metric for a set of voxels (a Fast Fourier Transformation (FFT) was applied to the BOLD time-courses on a voxel-by-voxel basis [0044], [0044]-[0046] discloses applying Fourier analysis to define a set of voxels).
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 combined invention of Santosh to include applying a Fourier analysis to a characteristic of a magnetic resonance imaging signal to compute a metric for a set of voxels, as taught by Lu. Doing so would better depict the true vasodilatory property of the brain, as discussed by Lu ([0049]).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over S Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”) Lu (US 20150231357 A1), and Zhao (US 20150287222 A1).
Regarding claim 11, modified Santosh teaches the method of claim 10, as discussed above. Santosh, however, does not teach applying the Fourier analysis to generate a map of an arterial transit time, a capillary transit time, a venous transit time, or a combination of such for use in diagnosis of an arteriovenous fistula, a collateral vessel, or both.
Zhao is considered analogous to the instant application as “Systems and methods for accelerated parameter mapping”.
Zhao teaches applying the Fourier analysis ([0008]-[0009] discloses that MRI measurement is completed in Fourier space) to generate a map of an arterial transit time ([0050] discloses calculating arterial transit time from the arterial transit time, and generating diffusion maps based off this data), for use in diagnosis of an arteriovenous fistula, a collateral vessel, or both ([0061] discloses that the area could correspond to heart/chest region, further, it is well known in the art that collateral vessels/arteriovenous fistulas are located in the heart/chest 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 modified the combined invention of Santosh to include generate map of an arterial transit time for use in diagnosis of an arteriovenous fistula, a collateral vessel, or both, as taught by Zhao. Doing so would detect subtle differences between tissues, improve specificity, and aid diagnosis when the pathology is uniformly distributed across the region of interest, as suggested by Zhao ([0004]).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”), and Lu (US 20150231357 A1), and Riederer (US 20130063146 A1).
Regarding claim 12, modified Santosh teaches method of claim 10, as discussed above. Santosh, however, does not teach further comprising applying time-delay information from a phase map of the Fourier analysis to form a static visualization of vasculature.
Riederer is considered analogous to the instant application as “System and method for controlling calibration and delay phases of parallel, contrast-enhanced magnetic resonance imaging” is disclosed (title). Riederer teaches:
applying time-delay information ([0010] discloses applying a time delay period 14) from a phase map of the Fourier analysis ([0035] and [0043] disclose the MR data processing include applying Fourier transforms/analysis, [0038] further discloses that a phase of the signal is produced) to form a static visualization of vasculature ([0011]-[0012] disclose the time delay 14 is used to produce the images, i.e. “static visualization”).
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 combined invention of Santosh to include applying time-delay information from a phase map of the Fourier analysis to form a static visualization of vasculature, as taught by Riederer. Doing so would improve image quality, as suggested by Riederer ([0014]).
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”), Lu (US 20150231357 A1), and Xu (US 20130116545 A1).
Regarding claim 14, modified Santosh teaches the method of claim 10, as discussed above. Santosh, however, does not teach applying time-delay information from a phase map of the Fourier analysis to output a video of a dynamic contrast change as contrast passes continuously among different vascular levels.
Xu, is considered analogous to the instant application as “System for Cardiac MR & MR Cine Imaging Using Parallel Image Processing”. Xu teaches: applying time-delay information from a phase map of the Fourier analysis ([0014] discloses applying delay time interval in the k-space/in a particular phase) to output a video of a dynamic contrast change as contrast passes continuously among different vascular levels ([0023] discloses acquiring video over time in the heart/chest, which inherently contains different tissues/vascular levels, as shown in figs 3A and 3b).
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 combined invention of Santosh to include applying time-delay information from a phase map of the Fourier analysis to output a video of a dynamic contrast change as contrast passes continuously among different vascular levels, as taught by Xu. Doing so would temporal and spatial image resolution, as suggested by Xu ([0010]).
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”), and Ostergaard (US 7069068 B1).
Regarding claim 15, modified Santosh teaches the method of claim 2, as discussed above. Santosh, however, does not teach further comprising computing a perfusion quantity based on a signal change during the flow of the bolus of deoxyhemoglobin through the target tissue.
Ostergaard, is considered analogous to the instant application as “Method for determining haemodynamic indices by use of tomographic data” is disclosed (title). Ostergaard teaches
computing a perfusion quantity based on a signal change during the flow of the bolus (data pertaining to the organ or part of tissue during and after a bolus injection of a tracer dose to said mammal, the tracer being substantially intravascular in said tissue…determining a time series of concentration data being indicative of the concentration of the tracer in arteries of the organ or tissue, Col 3 lines 1-8 ) of deoxyhemoglobin through the target tissue (Col. 35 line 64-Col 6 line 2 discloses that “modelling relationship between cellular oxygen consumption and vascular oxygen levels may facilitate a quantitative metabolic interpretation of deoxyhemoglobin concentration changes observed by functional magnetic resonance imaging”, discloses that the data/oxygen delivery data can be used in combination with vascular models).
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 combined invention of Santosh to include computing a perfusion quantity based on a signal change during the flow of the bolus of deoxyhemoglobin through the target tissue, as taught by Ostergaard. This would allow for a non-invasive method that allows assessment of flow and indirect assessment of metabolic parameters, as suggested by Ostergaard (Col. 2 lines 26-31).
Regarding claim 16, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach wherein the perfusion quantity comprises a cerebral blood flow (CBF), a cerebral blood volume (CBV), a mean transit time (MTT), an arterial arrival time (ATT), or a combination of such.
Ostergaard, is considered analogous to the instant application as “Method for determining haemodynamic indices by use of tomographic data” is disclosed (title). Ostergaard teaches wherein the perfusion quantity comprises a cerebral blood flow (CBF) (quantification of cerebral blood flow, Col 12 line 29-35I0
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 combined invention of Santosh to include wherein the perfusion quantity comprises a cerebral blood flow (CBF), as taught by Ostergaard. This would allow for a non-invasive method that allows assessment of flow and indirect assessment of metabolic parameters, as suggested by Ostergaard (Col. 2 lines 26-31).
Regarding claim 17, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach computing an Arterial Input Function (AIF).
Ostergaard, is considered analogous to the instant application as “Method for determining haemodynamic indices by use of tomographic data” is disclosed (title).
Ostergaard teaches comprising computing an Arterial Input Function (AIF) (Col. 22 lines 34-46 disclose computation of the arterial input function; Col 28 line 6-Col 29 line 10 further disclose computation of the AIF).
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 combined invention of Santosh to include computing an Arterial Input Function (AIF), as taught by Ostergaard. This would allow for a non-invasive method that allows assessment of flow and indirect assessment of metabolic parameters, as suggested by Ostergaard (Col. 2 lines 26-31).
Claims 18 is rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”, and Larsson et. al (Larsson, Henrik B W et al. “Brain capillary transit time heterogeneity in healthy volunteers measured by dynamic contrast-enhanced T1 -weighted perfusion MRI.” Journal of magnetic resonance imaging : JMRI vol. 45,6 (2017): 1809-1820. doi:10.1002/jmri.25488, hereinafter "Larsson").
Regarding claim 18, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach further comprising determining a capillary transit time heterogeneity (CTH) with reference to a distribution of transit time within a region or voxel of a signal of the magnetic resonance imaging responsive to a step change in deoxyhemoglobin, wherein the bolus of deoxyhemoglobin induces the step change.
Larsson is considered analogous to the instant application as “Brain capillary transit time heterogeneity in healthy volunteers measured by dynamic contrast‐enhanced T1‐weighted perfusion MRI” is disclosed (title).
Larrson teaches determining a capillary transit time heterogeneity (CTH) with reference to a distribution of transit time within a region or voxel of a signal of the magnetic resonance imaging (Materials and Methods, page 1810-page 1811 disclose calculating CTH using distribution of transit times across in an area of tissue or voxel; “The fundamental equation relating the tissue concentration as a function of time, Ct(t), the arterial concentration as a function of time (AIF), Ca(t), the perfusion f, and the residue impulse response function, RIF(t)… The RIF(t) is defined as the CA fraction remaining in the tissue, after a brief injected bolus, directly into the tissue (or voxel), as a function of time. The distribution of transit times, i.e., the fraction of the CA, which leaves the tissue at time t, per time unit, after a bolus injection is the frequency function h(t). The RIF(t) is related to the distribution of transit times, i.e., the frequency function by…”) responsive to a step change in deoxyhemoglobin, wherein the bolus of deoxyhemoglobin induces the step change (This idea could also have an important impact for oxygen delivery in brain tumors, where the normal capillary architecture is severely disturbed, and high perfusion and hypoxia may co-exist in some parts of the tumors. For this reason, methods allowing us to estimate the distribution of capillary transit times in healthy and diseased tissue may be of importance, and CTH estimation may provide new important physiological information like conventional measurements of other tissue parameters, such as CBF or CBV, page 1810, col. 2 para. 1).
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 combined invention of Santosh to include determining a capillary transit time heterogeneity (CTH) with reference to a distribution of transit time within a region or voxel of a signal of the magnetic resonance imaging responsive to a step change in deoxyhemoglobin, wherein the bolus of deoxyhemoglobin induces the step change, as taught by Larsson. Doing so would provide new important physiological information like conventional measurements of other tissue parameters, such as CBF or CBV, as suggested by Larsson (Page 2, col 2, para.1 “methods allowing us to estimate the distribution of capillary transit times in healthy and diseased tissue may be of importance, and CTH estimation may provide new important physiological information like conventional measurements of other tissue parameters, such as CBF or CBV”).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Santosh et al. (US 20090246138 A1), hereinafter Santosh), in view of Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”) and Meyer (US 20160324427 A1, hereinafter "Meyer")
Regarding claim 19, modified Santosh teaches the method of claim 1, as discussed above. Santosh, however, does not teach computing a performance status of the left ventricle of the subject, wherein the performance status comprises a cardiac output (0), a stroke volume (SV), or a left ventricular ejection fraction (LVEF).
Meyer is considered analogous to the instant application as “Method for determining a personalized cardiac model using a magnetic resonance imaging sequence” is disclosed (title). Meyer teaches:
computing a performance status of the left ventricle of the subject, wherein the performance status comprises a cardiac output (0), a stroke volume (SV), ([0067] discloses that Cardiac Magnetic Resonance (CMR) is used, which can be used to calculate cardiac output and quantify left ventricle volume, ventricle mass and stroke volume as disclosed on paragraphs [0007], and [0016] which discloses characterizing cardiac model based on MRI data).
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 combined invention of Santosh to include computing a performance status of the left ventricle of the subject, wherein the performance status comprises a cardiac output (0), a stroke volume (SV), as taught by Meyer. Doing so would improve the time resolution precision in MRI cine retrospective reconstructions, as suggested by Meyer ([0015]).
.
Response to Arguments
Applicant's arguments filed 01/24/2025 have been fully considered but they are moot.
On page 7-10 of remarks, regarding the 35 USC §103 rejection of claim 1, applicant’s arguments are premised upon the assertion that the prior art does not teach the newly added limitation regarding “wherein generating the bolus of deoxyhemoglobin comprises targeting a first PETO2 corresponding to hypoxia and targeting a second PETO2;maintaining isocapnia in the subject using the sequential gas delivery apparatus while generating the bolus of deoxyhemoglobin”. This argument is moot in view of new grounds of rejection which relies upon Fisher (US 20090173348 A1) and van Niftrik et al. (van Niftrik, Christiaan Hendrik Bas, et al. "Impact of baseline CO2 on Blood-Oxygenation-Level-Dependent MRI measurements of cerebrovascular reactivity and task-evoked signal activation." Magnetic resonance imaging 49 (2018): 123-130, hereinafter “Niftrik”) to teach these limitations. Accordingly, the argument is moot.
Applicant argument’s on page 10 are premised upon the assertion that the remaining claims rejected under 35 USC §103 are allowable due to dependency on an allowable claim. The examiner respectfully disagrees for the reasons discussed above.
Conclusion
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/N.B./Examiner, Art Unit 3798
/PASCAL M BUI PHO/Supervisory Patent Examiner, Art Unit 3798