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 .
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.
Claim Rejections - 35 USC § 112
Claims 1-21 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 1 recites the broad recitation “method for determining absolute concentration values of components, a blood flow, or a blood volume”, and the claim also recites “converting…into absolute concentration values of components” and “calculating at least one of blood flow or blood volume” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Additionally regarding Claim 1, the limitation "calculating at least one of blood flow or blood volume at least one of from the time course… or from parameters…” recited in the last two lines of the claim does not make sense. This limitation is being interpreted to recite “calculating at least one of blood flow or blood volume from at least one of the time course… or from parameters…”
Regarding Claim 2, the limitation "healthy" is a relative term that renders that claim indefinite. The term "healthy" 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 not clear what constitutes a healthy subject. What are the metrics? How are these metrics judged? These issues render Claim 2 indefinite.
Regarding Claim 4, the limitation "accept measurement signals" recited in line 3 of the claim is indefinite. It is unclear if the limitation is referring to the same "measurement signals" recited in line 6 of Claim 1 or if it is referring to different "measurement signals". This limitation is being interpreted to mean "accept the measurement signals".
Additionally, the limitation “emitted radiation” recited in line 5 of the claim is indefinite. It is unclear if the limitation is referring to the same "radiation" that was recited in line 4 of Claim 1 or if it is referring to a different "emitted radiation". This limitation is being interpreted to mean "the emitted radiation".
Furthermore, the limitation "the concentration of the indicator" recited in line 8 of the claim is indefinite. It is unclear if the limitation is referring to the "concentration values of the indicator" recited in lines 12-13 of Claim 1 or if it is referring to something different. These limitations are being interpreted to mean "concentration values of the indicator".
Regarding Claim 4, the limitation "the transport function g(t)" recited in line 11 of the claim lacks proper antecedent basis. This limitation is being interpreted to mean "the at least one of transport function g(t)".
Additionally, the limitation "the determinable mean transit time" recited in line 11 of the claim lacks proper antecedent basis. This limitation is being interpreted to mean "with a determinable mean transit time".
Furthermore, the limitation “determinable mean transit time” recited in line 11 of the claim is indefinite. It is unclear if the “mean transit time” is the same or different from the “mean transit time” recited in line 15 of Claim 1. This limitation is being interpreted to mean a different mean transit time than the one recited in Claim 1.
Finally, the limitation “functions determined in step c)” recited in lines 16-17 of the claim is indefinite. It is unclear what “function” is being referenced from “step c)” as this step of the claim does not recite a function. This limitation is being interpreted to mean “using the time course of the concentration of the indicator in the tissue as determined in step c) or one of the functions determined in step e)”.
Regarding Claim 5, the limitation "the concentration of the indicator" recited in the claim is indefinite. It is unclear if the limitation is referring to the "concentration values of the indicator" recited in lines 12-13 of Claim 1 or if it is referring to something different. These limitations are being interpreted to mean "concentration values of the indicator".
Regarding Claim 8, the limitation “the termination criterion for determining the mean transit time” lacks proper antecedent basis. This limitation is being interpreted to mean “a termination criterion reached when determining the mean transit time (mtt) is defined”.
Regarding Claim 9, the limitation "the determinable mean transit time" recited in the last line of the claim lacks proper antecedent basis. This limitation is being interpreted to mean "with a determinable mean transit time".
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 12 recites the broad recitation “apparatus for determining absolute concentration values of components, a blood flow, or a blood volume”, and the claim also recites “converts…into absolute concentration values of components” and “calculates blood flow or blood volume” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding Claim 13, the limitation "healthy" is a relative term that renders that claim indefinite. The term "healthy" 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 not clear what constitutes a healthy subject. What are the metrics? How are these metrics judged? These issues render Claim 13 indefinite.
Regarding Claim 15, the limitation "accept measurement signals" recited in line 3 of the claim is indefinite. It is unclear if the limitation is referring to the same "measurement signals" recited in lines 6-7 of Claim 12 or if it is referring to different "measurement signals". This limitation is being interpreted to mean "accept the measurement signals".
Additionally, the limitation “emitted radiation” recited in lines 3-4 of the claim is indefinite. It is unclear if the limitation is referring to the same "radiation" that was recited in line 5 of Claim 12 or if it is referring to a different "emitted radiation". This limitation is being interpreted to mean "the emitted radiation".
Furthermore, the limitation "the concentration of the indicator" recited in line 7 of the claim is indefinite. It is unclear if the limitation is referring to the "concentration values of the indicator" recited in line 12 of Claim 12 or if it is referring to something different. These limitations are being interpreted to mean "concentration values of the indicator".
Furthermore, the limitation “determinable mean transit time” recited in lines 10-11 of the claim is indefinite. It is unclear if the “mean transit time” is the same or different from the “mean transit time” recited in line 13 of Claim 12. This limitation is being interpreted to mean a different mean transit time than the one recited in Claim 1.
Finally, the limitation “functions determined in step c)” recited in lines 14-15 of the claim is indefinite. It is unclear what “function” is being referenced from “step c)” as this step of the claim does not recite a function. This limitation is being interpreted to mean “using the time course of the concentration of the indicator in the tissue as determined in step c) or one of the functions determined in step e)”.
Regarding Claim 16, the limitation "the concentration of the indicator" recited in the last line of the claim is indefinite. It is unclear if the limitation is referring to the "concentration values of the indicator" recited in lines 12 of Claim 12 or if it is referring to something different. These limitations are being interpreted to mean "concentration values of the indicator".
Regarding Claim 19, the limitation “the termination criterion for determining the mean transit time” lacks proper antecedent basis. This limitation is being interpreted to mean “a termination criterion reached when determining the mean transit time (mtt) is defined”.
Regarding Claim 20, the limitation "the determinable mean transit time" recited in the last line of the claim lacks proper antecedent basis. This limitation is being interpreted to mean "with a determinable mean transit time".
Claims not explicitly rejected above are rejected due to their dependence on the above claims.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) as a whole, considering all claim elements both individually and in combination, do not amount to significantly more than an abstract idea. A streamlined analysis of Claim 1 follows.
STEP 1
Regarding Claim 1, the claim recites a series of steps or acts, including determining absolute concentration values; emitting radiation having at least one wavelength; converting, using a system matrix and an evaluation algorithm on an evaluation unit, a temporal change; introducing an indicator comprising a dye; determining a time course of concentration values of the indicator; deriving a mean transit time (mtt) from the time course of concentration values of the indicator and using at least one transport function g(t); and calculating at least one of blood flow or blood volume. Thus, the claim is directed to a process, which is one of the statutory categories of invention.
STEP 2A, PRONG ONE
The claim is then analyzed to determine whether it is directed to any judicial exception. The step of calculating at least one of blood flow or blood volume sets forth a judicial exception. This step describes a concept performed via mathematical operations (i.e., mathematical relationships, mathematical formulas or equations, and mathematical calculations). Thus, the claim is drawn to a Mathematical Concept, which is an Abstract Idea.
STEP 2A, PRONG TWO
Next, the claim as a whole is analyzed to determine whether the claim recites additional elements that integrate the judicial exception into a practical application. The claim fails to recite an additional element or a combination of additional elements to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limitation on the judicial exception. Claim 1 fails to recite any application of calculating at least one of blood flow or blood volume in a manner that imposes a meaningful limitation on the Abstract Idea. The Abstract Idea alone does not provide an improvement to the technological field, the method does not affect a particular treatment or effect a particular change based on a calculated at least one blood flow or volume, nor does the method use a particular machine to perform the Abstract Idea.
STEP 2B
Next, the claim as a whole is analyzed to determine whether any element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception. Besides the Abstract Idea, Claim 1 recites additional steps of converting a temporal change of the detected intensities of the radiation emerging from tissue of an organ into absolute concentration values; determining a time course of concentration values of the indicator; and deriving a mean transit time (mtt) from the time course of concentration values of the indicator and using at least one transport function g(t). The converting, determining, and deriving steps are recited at a high level of generality such that they amount to insignificant pre-solution activity, e.g., mere data gathering step necessary to perform the Abstract Idea. When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by medical professionals prior to Applicant's invention. Furthermore, it is well established that the mere physical or tangible nature of additional elements such as the converting, determining, and deriving steps do not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp. v. CLS Bank Int'l, 134 S.Ct. 2347, 2358-59 (2014)).
Consideration of the additional elements as a combination also adds no other meaningful limitations to the exception not already present when the elements are considered separately. Unlike the eligible claim in Diehr in which the elements limiting the exception are individually conventional, but taken together act in concert to improve a technical field, the claim here does not provide an improvement to the technical field. Even when viewed as a combination, the additional elements fail to transform the exception into a patent-eligible application of that exception. Thus, the claim as a whole does not amount to significantly more than the exception itself. The claim is therefore drawn to non-statutory subject matter.
Regarding Claim 12, the claim recites a series of components, including a sensor arrangement for emitting radiation and generating measurement signals; an evaluation unit comprising a processor and memory for storing a system matrix; and a system matrix that converts temporal changes of detected intensities of radiation into absolute concentrations. Thus, the claim is directed to a machine, which is one of the statutory categories of invention. The function of calculating blood flow or blood volume from the time course of concentration values of the indicator set forth a judicial exception. These functions describe a concept performed via mathematical operations (i.e., mathematical relationships, mathematical formulas or equations, and mathematical calculations). Thus, the claim is drawn to a Mathematical Concept, which is an Abstract Idea. Additionally, the device recited in the claim is a generic device comprising generic components configured to perform the abstract idea. The recited “sensor arrangement” is a generic device configured to perform emitting radiation and generating measurement signals as mere pre-solution data gathering; the “evaluation unit”, the “processor”, the “memory”, and the “system matrix” are generic computer programs configured to perform executing an evaluation algorithm, converting a temporal change of detected intensities into absolute concentrations, determining a time course of concentration values of the indicator, deriving a mean transit time (mtt) from the time course of concentration values of the indicator as well as perform the Abstract Idea. According to section 2106.05(f) of the MPEP, merely using a computer as a tool to perform an abstract idea does not integrate the Abstract Idea into a practical application.
Dependent Claims 2-11 and 13-21 fail to add something more to the abstract independent claims as they generally recite steps pertaining to data gathering and processing. Additionally, Claims 7 and 18 recite mathematic formulas which are drawn to an Abstract Idea.
The emitting, generating, converting, determining, deriving, and calculating steps recited in the independent claims, Claims 1 and 12, maintain a high level of generality even when considered in combination with the dependent claims.
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.
Claims 1-5, 7-8, 12-16, and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et. al.'275 (U.S. Patent Publication 20040249275 - cited by applicant) in view of Newberry et. al.'317 (U.S. Patent Publication 20200237317).
Regarding Claim 1, Keller et. al.'275 discloses a method for determining absolute concentration values of components, a blood flow, or a blood volume in tissue of an organ (Paragraph [0024] - The indicator concentration with reference to the cerebral tissue depends on the indicator concentration in the blood that flows through the tissue, as well as on the amount of the blood that flows through the tissue), the method comprising:
emitting radiation having at least one wavelength in a near-infrared spectrum into the tissue of the organ and generating, by near-infrared spectroscopy, measurement signals responsive to detected intensities of radiation emerging from the tissue of the organ (Paragraph [0023] - A radiation source (not shown) for emitting near infrared radiation into the cerebral tissue of the patient…The wavelength of the emitted radiation and the indicator used must be coordinated with one another…The intensity of the proportion of the infrared radiation that exits from the cerebral tissue at the location of second optode 3 is detected by second optode 3 and passed to the evaluation unit 4);
converting, using an evaluation algorithm executed on an evaluation unit, a temporal change of the detected intensities of the radiation emerging from the tissue of the organ into absolute concentration values of components (Paragraph [0023] - The intensity of the proportion of the infrared radiation that exits from the cerebral tissue at the location of second optode 3 is detected by second optode 3 and passed to the evaluation unit 4; Paragraph [0026] - Evaluation unit 4 is set up, in terms of program technology; Paragraph [0028] - The (time-dependent) optical density, which is essentially proportional to the indicator concentration in the tissue);
introducing an indicator comprising a dye having an absorption maximum in the near-infrared spectrum and determining a time course of concentration values of the indicator in the tissue of the organ (Paragraph [0023] - the near infrared radiation is passed by means of a light guide to first optode 2, where the radiation is emitted. The wavelength of the emitted radiation and the indicator used must be coordinated with one another; Paragraph [0028] - The (time-dependent) optical density, which is essentially proportional to the indicator concentration in the tissue, is divided up into its pulsatile component and its non-pulsatile component; Paragraph [0031] - the outflow function o(t) describes the proportion of the change in the concentration of the indicator in the cerebral tissue that comes from the amount of outflowing blood. The time immediately after the injection of indicator is t=0);
deriving a mean transit time (mtt) from the time course of concentration values of the indicator and using at least one transport function g(t) that characterizes blood flow in the tissue of the organ (Paragraph [0029] - The mean transit time mtt is sometimes also referred to as the "pass-through" time, and is a characteristic dwell time that corresponds to the time that a volume element needs, on the average, in order to pass through the system being considered; Paragraph [0032] - the transport function g(t) is calculated with the mtt iteration step (let m be the counting variable)); and
calculating at least one of blood flow or blood volume at least one of from the time course of concentration values of the indicator or from parameters derived therefrom (Paragraph [0023] - The device according to the invention shown schematically in FIG. 1 serves to determine the cerebral blood flow of a patient, for example an intensive-care patient in neurosurgery; Paragraph [0049] - The cerebral blood volume CBV is calculated as the quotient of an indicator concentration in the blood, C.sub.blood).
Keller et. al.'275 discloses a program technology but fails to disclose a system matrix. Newberry et. al.'317 teaches a neural network used to store and adjust equations/functions (Paragraph [0186] - Sometimes the various machine learning techniques are intimately associated with a particular learning rule. The function ƒ may be a definition of a class of functions (where members of the class are obtained by varying parameters, connection weights, thresholds, etc.). The neural network learns by adjusting its parameters, weights and thresholds iteratively to yield desired output). It would have been obvious to one of ordinary skill in the art at the time the invention was effectively filed to have modified the method of Keller et. al.’275 to include program technology containing a neural network capable storing and adjusting functions in order to adjust parameters and yield desired outputs as seen in Newberry et. al.’317.
Regarding Claim 12, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 1 disclose an apparatus comprising the elements set forth in the claim.
Regarding Claim 2, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 1 above but fails to disclose the system matrix is calibratable using known concentration values of components in the tissue of the organ, measurable concentration values of components in healthy tissue or definable boundary conditions for limiting concentration values of components in the tissue of the organ. Newberry et. al.'317 teaches a calibratable neural network (Paragraph [0159] - To determine a concentration level of the substance, a calibration table or database is used that associates the obtained R value to a concentration level of the substance at 720. The calibration database correlates the R value with a concentration level. The calibration database may be generated for a specific user or may be generated from clinical data of a large sample population. For example, it is determined that the R values should correlate to similar NO concentration levels across a large sample population. Thus, the calibration database may be generated from testing of a large sample of a general population to associate R values and NO concentration levels). It would have been obvious to one of ordinary skill in the art at the time the invention was effectively filed to have modified the method of Keller et. al.’275 to include program technology containing a calibratable neural network capable storing and adjusting functions in order to provide correlated and desirable values to specific users as seen in Newberry et. al.’317. It is to be noted that the method does not positively recite calibrating a system matrix based on the limitations recited in the claims. A neural network contains a system matrix and system matrices are capable of being calibrated using the recited limitations.
Regarding Claim 13, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 2 disclose an apparatus comprising the elements set forth in the claim.
Regarding Claim 3, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 1 above. Keller et. al.'275 further discloses the measurement signals correspond to absolute concentration values of one or more of hemoglobin, deoxyhemoglobin, water, background, or the indicator, and enable determination of the blood volume or the blood flow in the tissue of the organ (Paragraph [0031] - The inflow function i(t) describes the proportion of the change in the concentration of the indicator in the cerebral tissue that comes from the amount of inflowing blood; the outflow function o(t) describes the proportion of the change in the concentration of the indicator in the cerebral tissue that comes from the amount of outflowing blood). It is to be noted that the method does not positively recite determining a blood volume or blood flow in the tissue of the organ based on the limitations recited in the claims. Measurement signals of the recited limitations are capable of determining blood volume or blood flow using the recited limitations.
Regarding Claim 14, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 3 disclose an apparatus comprising the elements set forth in the claim.
Regarding Claim 4, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 1 above. Keller et. al.'275 further discloses wherein the evaluation algorithm (Paragraph [0032] - In a computing step, the value of the inflow function for the time t is calculated according to the balance equation) is programmed to:
accept the measurement signals that transmitted to the evaluation unit, the measurement signals based on an emitted and detected portion of the emitted radiation with at least one wavelength in the near-infrared spectrum (Paragraph [0011] - using an injected indicator which includes a radiation source for emitting near infrared radiation into tissue of the organ at a first location, a sensor for detecting a proportion of the emitted near infrared radiation that exits from the organ at a second location, and an evaluation unit that detects the proportion of emitted near infrared radiation that exits from the tissue of the organ as an input signal);
determine absolute concentration values of components in the tissue of the organ of at least hemoglobin, deoxyhemoglobin, background, or water (Paragraph [0048] - In this equation, .alpha.ICG is the absorption coefficient of the indicator, .alpha..sub.Hb is the absorption coefficient of the hemoglobin, and C.sub.Hb is the hemoglobin concentration in the blood);
determine the time course of concentration values of the indicator in the tissue of the organ from the measurement signals (Paragraph [0025] - The indicator concentration in the blood that flows through the tissue changes over time, because the blood that flows out of the cerebral tissue has a different concentration from the blood that is flowing in; Paragraph [0028] - The (time-dependent) optical density, which is essentially proportional to the indicator concentration in the tissue);
iteratively determine an inflow function i(t) and an outflow function o(t) indicative of blood flow in the tissue of the organ using the at least one of transport function g(t) with a determinable mean transit time (mtt) until a termination criterion is reached (Paragraph [0032] Each iteration step includes a step-by-step calculation of an approximation of the inflow function i(t) and an approximation of the outflow function o(t), as well as the calculation of an approximation of the transport function g(t), so that the mtt approximation of the inflow function i(t), the outflow function o(t), and the transport function g(t) is calculated with the mtt iteration step (let m be the counting variable));
fit the iteratively determined inflow function i(t) and the iteratively determined outflow function o(t) using a lognormal function or another function representing tissue transit system (Paragraph [0027] - The optical density OD is formed from the intensity signal as a negative decadic logarithm of the transmission; Paragraph [0035] - In the next step, the convolution integral o(t)=i(t)*g(t) with the transport function g(t) is used for calculating the value of the outflow function at the time t; see g(t) Equation below);
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g(t) Equation
calculate the blood volume in the tissue of the organ using the time course of the concentration of the indicator in the tissue as determined in step c) or one of the functions determined in step e) (Paragraph [0047] - The indicator concentration in the blood, C.sub.blood, required for calculating the cerebral blood volume CBV is calculated according to the following formula, wherein A.sub.OD(t>0) corresponds to the value of the amplitude of the optical density for t approaching 0 that was obtained from the function extrapolated back (which is less dependent on the sharpness of the first signal peak after administration of the indicator, as compared with a value determined by direct measurement)); and
calculate the blood flow in the tissue of the organ as a quotient of the blood volume calculated in step f) and the mean transit time (mtt) determined in step d) (Paragraph [0050] - The cerebral blood flow CBF is determined as a quotient of the cerebral blood volume CBV and the mean transit time mtt).
Regarding Claim 15, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 4 disclose an apparatus comprising the elements set forth in the claim.
Regarding Claim 5, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 4 above. Keller et. al.'275 further discloses wherein in step f) the blood volume in the tissue of the organ is determinable using an exponential regression analysis of the time course of concentration of the indicator (Paragraph [0041] - For this purpose, the non-pulsatile component of the time progression of the optical density OD is simulated in an interval t.sub.1>0 to t.sub.2, by regression by means of an exponential function). It is to be noted that the method does not positively recite determining a blood volume based on the limitations recited in the claims. A blood volume in the tissue of an organ is capable of being determined using the recited limitations.
Regarding Claim 16, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 5 disclose an apparatus comprising the elements set forth in the claim.
Regarding Claim 7, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 4 above. Keller et. al.'275 further discloses wherein the iterative determination of the inflow function i(t) comprises several steps, wherein in each step an approximation to the inflow function i(t) is calculated according to the formula (Paragraph [0031] - The inflow function i(t) describes the proportion of the change in the concentration of the indicator in the cerebral tissue that comes from the amount of inflowing blood; Paragraph [0032] - In a computing step, the value of the inflow function for the time t is calculated according to the balance equation: i(t)=d/dt (C.sub.tissue(t))+o(t-t.sub.k); see i(t) Equation below);
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i(t) Equation
where d/dt(cICG(t)) is a determinable temporal change in concentration of the indicator in the tissue of the organ, and o(t) is an outflow function determinable from deconvolution of a convolution integral of the inflow function i(t) and the at least one of transport function g(t) (Paragraph [0033] - In this equation, t.sub.k is a constant small time interval, so that the value of the outflow function at the time t-t.sub.k is to be inserted for o(t-t.sub.k). The term d/dt (C.sub.tissue(t)) expresses the change in the indicator concentration with reference to the cerebral tissue; Paragraph [0035] - In the next step, the convolution integral o(t)=i(t)*g(t) with the transport function g(t) is used for calculating the value of the outflow function at the time t).
It is to be noted that the method does not positively recite determining d/dt(cICG(t)) as a temporal change in concentration of the indicator in the tissue of the organ or determining o(t) from deconvolution of a convolution integral of the inflow function i(t) and the at least one transport function. The recited functions d/dt(cICG(t)) and o(t) are capable of being determined using the recited limitations.
Regarding Claim 18, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 7 disclose an apparatus comprising the elements set forth in the claim.
Regarding Claim 8, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 4 above. Keller et. al.'275 further discloses wherein a termination criterion reached when determining the mean transit time (mtt) is defined by a plausibility criterion for the inflow function i(t) and the outflow function o(t) (Paragraph [0029] - The mean transit time mtt is sometimes also referred to as the "pass-through" time, and is a characteristic dwell time that corresponds to the time that a volume element needs, on the average, in order to pass through the system being considered; Paragraph [0032] - Each iteration step includes a step-by-step calculation of an approximation of the inflow function i(t) and an approximation of the outflow function o(t), as well as the calculation of an approximation of the transport function g(t), so that the mtt approximation of the inflow function i(t), the outflow function o(t), and the transport function g(t) is calculated with the mtt iteration step (let m be the counting variable); Paragraph [0038] - If, on the other hand, the end value has exceeded t.sub.2, a check is performed in the next step to see whether the function progressions of the inflow function i(t) and the outflow function o(t) are plausible. A plausibility criterion (i.e. a stop criterion of the iteration) may be that neither the inflow function i(t) nor the outflow function o(t) have values below a threshold value).
Regarding Claim 19, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 8 disclose an apparatus comprising the elements set forth in the claim.
Claims 6 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et. al.'275 (U.S. Patent Publication 20040249275 - cited by applicant) in view of Newberry et. al.'317 (U.S. Patent Publication 20200237317), as applied to Claim 4 above, and further in view of Sutin et. al.'831 (U.S. Patent Publication 20180070831 - cited by applicant).
Regarding Claim 6, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 4 above but fails to disclose wherein in step f) the blood volume in the tissue of the organ is determined from an area under the inflow function i(t) and the outflow function o(t). Sutin et. al.’831 teaches determining phase differences between integral values of blood inflow and blood outflow corresponding to blood volume (Paragraph [0053] - In some aspects, the controller 110 may be programmed to determine a phase difference between various computed quantities, including an index of blood flow, a blood volume, a blood inflow, a blood outflow, a derivative of blood volume, an integral of blood volume, a derivative of the index of blood flow, an integral of the index of blood flow, or combinations thereof; Paragraph [0054] - The controller 110 may be further configured to determine a condition of the subject based on determined quantities, such as absolute blood flow, and others; Paragraph [0059] - Absolute cerebral blood flow, referred to hereafter as CBF, and CBV are related to blood inflow and blood outflow of a vascular network or vascular cerebral region through complementary ways). It would have been obvious to one of ordinary skill in the art at the time the invention was effectively filed to have modified the method of Keller et. al.’275 in view of Newberry et. al.’317 to include determining blood volume based on calculated areas of inflow and outflow within a tissue of an organ in order to account for and analyze how cerebral blood volume is related to inflow and outflow as seen in Sutin et. al.’831.
Regarding Claim 17, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 6 disclose an apparatus comprising the elements set forth in the claim.
Claims 9 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et. al.'275 (U.S. Patent Publication 20040249275 - cited by applicant) in view of Newberry et. al.'317 (U.S. Patent Publication 20200237317), as applied to Claim 8 above, and further in view of Goyal et. al.'652 (U.S. Patent Publication 20190274652).
Regarding Claim 9, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 8 above. Keller et. al.’275 further discloses a plausibility criterion containing a mean transit time (mtt) corresponding to the time that a volume of indicator takes to pass through the system (Paragraph [0029] - The mean transit time mtt is sometimes also referred to as the "pass-through" time, and is a characteristic dwell time that corresponds to the time that a volume element needs, on the average, in order to pass through the system being considered) but fails to disclose plausibility criterion is definable as a distance between a centroid of the inflow function i(t) and a centroid of the outflow function o(t) and corresponds to a determinable mean transit time (mtt). Goyal et. al.'652 teaches configuring a dwell time based on arterial peak - inflow centroid - and venous peak – outflow centroid (Paragraph [0059] - When a second (P2) and third (P3) set of CT images are obtained, ideally they are timed to generally correspond to particular phases of contrast moving through the brain. Generally, the first set (P1) of images is timed to coincide with peak dye flow through the arterial side of the brain (i.e. the normal side), the second set timed to coincide with peak dye flow to the venous side of the brain (i.e. the normal side) and peak flow through affected tissue and the third set to coincide with clearance of dye through the normal side but towards the tail end of dye moving through affected tissue). It would have been obvious to one of ordinary skill in the art at the time the invention was effectively filed to have modified the method of Keller et. al.’275 in view of Newberry et. al.’317 to include a plausibility criterion accounting for time between an inflow and outflow peak in order to understand how an indicator moves in the brain as seen in Goyal et. al.’652.
It is to be noted that the method does not positively recite defining a plausibility criterion based on the recited limitations. The plausibility criterion is capable of being defined using the recited limitations.
Regarding Claim 20, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 9 disclose an apparatus comprising the elements set forth in the claim.
Claims 10-11 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et. al.'275 (U.S. Patent Publication 20040249275 - cited by applicant) in view of Newberry et. al.'317 (U.S. Patent Publication 20200237317), as applied to Claim 8 above, further in view of Keller et. al.'276 (EP Patent Application 1464276), and further in view of Fantini et. al.'2016 (Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods).
Regarding Claim 10, Keller et. al.'275 in view of Newberry et. al.’317 discloses the method outlined in Claim 8 above but fails to disclose wherein the plausibility criterion is definable as a ratio of an area under the inflow function i(t) and an area under the outflow function o(t). Keller et. al.’276 – same device as Keller et. al.’275 – teaches a plausibility criterion corresponding to values obtained from inflow and outflow functions (Page 4 Paragraph 6 - t has exceeded the end value t .sub.2 , the next step is to check whether the function curves obtained for the inflow function i(t) and the outflow function o(t) are plausible. The plausibility criterion (i.e. termination criterion of the iteration) can be that neither the inflow function i(t) nor the outflow function o(t) have values less than a threshold value. This threshold value should suitably be chosen to be greater than or equal to 0). Fantini et. al.'2016 teaches using arterial - inflow - and venous – outflow - functions to obtain a concentrative equilibrium corresponding to area under a curve (Page 9 Figure 3 description - Three basic approaches to the measurement of cerebral blood flow. (a) The Fick principle, (b) the central volume principle, and (c) the Doppler effect or autocorrelation methods. (a) A global CBF measurement is based on recording time traces of the arterial and venous blood concentrations ([𝑥]𝑎 and [𝑥]𝑣, respectively) of a diffusible and physiologically inert intravascular tracer 𝑥 over a time Δ𝑡 that is sufficiently long to achieve equilibrium - ratio- in the blood–brain tracer diffusion; see Figure 3(a) below). It would have been obvious to one of ordinary skill in the art at the time the invention was effectively filed to have modified the method of Keller et. al.'275 in view of Newberry et. al.’317 to include obtaining a plausibility criterion based on the inflow and outflow functions as seen in Keller et. al.’276 in order to obtain a concentrative equilibrium state – ratio - indicative of an inverse flow time related to cerebral blood flow in order to better understand cerebral blood flow as seen in Fantini et. al.’2016 (Page 10 Section 3.2.1 - at which time a steady state was reached, such that [N2O]𝑎=[N2O]𝑣. This steady state carries no information about CBF, but the time required to reach it is inversely related to CBF).
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Figure 3(a)
It is to be noted that the method does not positively recite defining a plausibility criterion based on the recited limitations. The plausibility criterion is capable of being defined using the recited limitations.
Regarding Claim 21, the sections of Keller et. al.'275 in view of Newberry et. al.’317 cited above for Claim 10 disclose an apparatus comprising the elements set forth in the claim.
Regarding Claim 11, Keller et. al.'275 in view of Newberry et. al.’317 and further in view of Keller et. al.’276 discloses the method outlined in Claim 10 above. Keller et. al.’275 fails to disclose wherein the ratio is 1:1. Fantini et. al.'2016 teaches an equal concentrated area under a function – 1:1 ratio (Page 10 Section 3.2.1 - The dynamic measurements were performed over a time interval Δ𝑡=10 min following the beginning of N2O inhalation, at which time a steady state was reached, such that [N2O]𝑎=[N2O]𝑣. This steady state carries no information about CBF, but the time required to reach it is inversely related to CBF). It would have been obvious to one of ordinary skill in the art at the time the invention was effectively filed to have modified the method of Keller et. al.'275 in view of Newberry et. al.’317 and further in view of Keller et. al.’276 to include a plausibility criterion that represents a 1:1 ratio of inflow and outflow concentrations in order to understand cerebral blood flow corresponding to the steady state of indicator concentrations in a subjects tissue of an organ as seen in Fantini et. al.’2106.
Conclusion
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/SARAH ANN WESTFALL/Examiner, Art Unit 3791
/ETSUB D BERHANU/Primary Examiner, Art Unit 3791
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