DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim 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 112-114, 118-124, and 128-131 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
Independent claim 112 is illustrative:
Step 1: This part of the eligibility analysis evaluates whether the claim falls within any statutory category. MPEP 2106.03. The claim recites a computer-implemented method. Thus, the claim is a process, which is a statutory category of invention. (Step 1: YES).
Step 2A, Prong One: This part of the eligibility analysis evaluates whether the claim recites a judicial exception. As explained in MPEP 2106.04, subsection II, a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim.
Claim 112, lines 2-6 recites “to provide diagnostic information for diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria based at least in part upon at least one calculated measurement derived from information extracted from the ROI corresponding with at least one chemical factor in the ROI comprising propionic acid (PA).” Under its broadest reasonable interpretation consistent with the specification, the plain and ordinary meaning of this limitation requires an evaluation of whether a region of interest in a tissue in a body of a patient is infected with bacteria based on a calculated measurement corresponding to propionic acid. As this step requires evaluating the calculated measurement to diagnose bacterial infection, the limitation falls into the “mental process” grouping of abstract ideas because the evaluation can be practically performed in the human mind. For example, a clinician reviews the spectrogram output by a magnetic resonance spectroscopy machine acquired at the intervertebral disc and identifies whether propionic acid is present in the spectrogram output using the clinician’s knowledge that Propioni-bacterium acnes infection results in accumulation of propionic acid causing intervertebral disc degradation, i.e., Modic change. See MPEP 2106.04 subsections I. and II.A. (Step 2A, Prong One: YES).
Step 2A, Prong Two: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (1) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (2) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. MPEP 2106.04(d).
Claim 112, line 1 recites “a medical diagnostic system.” This merely indicates a field of use or technological environment in which the judicial exception is performed. This type of limitation merely confines the use of the abstract idea to a particular technological environment (medical diagnostic systems) and thus fails to add an inventive concept to the claims. See MPEP 2106.05(h). Furthermore, this recites a machine that is merely an object on which the method operates wherein the generic computer recited at a high level of generality is merely a tool to perform the process that does not amount to significantly more than a judicial exception. To add significantly more the computer must play a significant part in permitting the claimed method to be performed, rather than function solely as a mechanism for permitting the abstract idea to be achieved more quickly, i.e., automating a manual process. See MPEP 2106.05(b). Therefore, it fails to meaningfully limit the claim because it does not require any particular application of the abstract idea and therefore amounts only to a generic instruction to “apply” the exception or to a mere indication of the field of use or technological environment in which the abstract idea is performed. Furthermore, merely adding generic computer components to perform the method is not sufficient. See MPEP 2106.05(f). Thus, the claim must include more than mere instructions to perform the method on a generic component or machinery to qualify as an improvement to an existing technology. See MPEP 2106.05(a). Further, in so far as the medical diagnostic system acquires the information of the chemical factor in the region of interest comprising propionic acid this is insignificant extra-solution activity that amounts to mere data gathering incidental to the limitations of claim 112, lines 2-6. All uses of the judicial exception require receiving of the information of the chemical factor in the region of interest comprising propionic acid (the mental process in claim 112, lines 2-6 uses the information of the chemical factor in the region of interest comprising propionic acid to diagnose the region of interest to be infected with bacteria). See MPEP 2106.05(g).
Claim 112, line 2 recites “a diagnostic processor.” There is no improvement to the functioning of a computer nor to any other technology. At best, the claimed combination amounts to an improvement to the abstract idea (a clinician reviews the spectrogram output by a magnetic resonance spectroscopy machine acquired at the intervertebral disc and identifies whether propionic acid is present in the spectrogram output using the clinician’s knowledge that Propioni-bacterium acnes infection results in accumulation of propionic acid causing intervertebral disc degradation, i.e., Modic change) by automating the diagnostic decision making rather than to any technology. An improvement in the abstract idea itself is not an improvement in technology. Further, although this limitation indicates that a diagnosis is made, it does not provide any information as to how the diagnosis is made, output of the diagnosis, or application of the diagnosis, but instead covers any possible use of the diagnosis. As such, there are no meaningful constraints on the diagnosis step such that the use in conjunction with a particular machine or manufacture consideration would apply because it is not limited to any particular manner or type of adjustment let alone used integrally with any particular machine. The recited “diagnostic processor” and “medical diagnostic system” do not play a significant part in permitting the claimed method to be performed as their involvement is extra-solutionary activity (necessary data-gathering) and field of use (the field of medical diagnostic systems). That the “diagnostic processor” performs the abstract idea recites a machine that is merely an object on which the method operates wherein the generic computer recited at a high level of generality is merely a tool to perform the process that does not amount to significantly more than a judicial exception. To add significantly more the computer must play a significant part in permitting the claimed method to be performed, rather than function solely as a mechanism for permitting the abstract idea to be achieved more quickly, i.e., automating a manual process. See MPEP 2106.05(b). Therefore, it fails to meaningfully limit the claim because it does not require any particular application of the abstract idea and therefore amounts only to a generic instruction to “apply” the exception or to a mere indication of the field of use or technological environment in which the abstract idea is performed. Furthermore, merely adding generic computer components to perform the method is not sufficient. See MPEP 2106.05(f). Thus, the claim must include more than mere instructions to perform the method on a generic component or machinery to qualify as an improvement to an existing technology. See MPEP 2106.05(a).
Claim 112, lines 4-6 recites “at least one calculated measurement derived from information extracted from the ROI corresponding with at least one chemical factor in the ROI comprising propionic acid (PA).” The additional element of acquiring the information of the chemical factor in the region of interest comprising propionic acid is insignificant extra-solution activity that amounts to mere data gathering incidental to the limitations of claim 112, lines 2-6. All uses of the judicial exception require receiving of the information of the chemical factor in the region of interest comprising propionic acid (the mental process in claim 112, lines 2-6 uses the information of the chemical factor in the region of interest comprising propionic acid to diagnose the region of interest to be infected with bacteria). See MPEP 2106.05(g).
Thus, even when considering the elements in combination, the claim as a whole does not integrate the recited exception into a practical application. (Step 2A, Prong Two: NO). Thus, claim 1 is directed to a judicial exception. (Step 2A: YES).
Step 2B: This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05.
The additional elements identified in Step 2A, Prong Two should be re-evaluated in Step 2B, in which the extra-solution activity consideration takes into account whether or not an extra-solution activity is well-known.
As discussed above in Step 2A, Prong Two above, claim 1, line 1 merely indicates a field of use or technological environment in which the judicial exception is performed. This type of limitation merely confines the use of the abstract idea to a particular technological environment (medical diagnostic systems) and thus fails to add an inventive concept to the claims. See MPEP 2106.05(h).
As discussed in Step 2A, Prong Two above, the recitation of a diagnostic processor amounts to no more than mere instructions to apply the exception using a generic computer component. Further, an improvement in the abstract idea itself is not an improvement in technology.
As discussed in Step 2A, Prong Two above, the data gathering activities in claim 112, lines 4-6 are recited at a high level of generality and could be described as receiving a chemical factor comprising propionic acid with a magnetic resonance spectroscopy apparatus. The element amounts to mere data gathering. It is necessary to acquire the data in order to use the recited judicial exception to perform the calculation. The information element does not impose any other meaningful limits on the claim. Therefore, the additional limitation is insignificant extra-solution activity. See MPEP 2106.05(g).
Consequently, for the reasons discussed above, the additional elements individually or in combination with the judicial exception do not provide an inventive concept; so, the claim as a whole does not amount to significantly more than a generic instruction to “apply” the judicial exception. (Step 2B: NO). Therefore, claim 112 is not eligible.
Turning to independent claim 122, lines 11-12 recites “wherein the diagnostic processor comprises one or more computer processors running software in computer readable storage.” The computer processors running software in computer readable storage is recited at a high level of generality. The computer processors are used as a tool to perform the generic computer function of receiving chemical factor information. See MPEP 2106.05(f). The non-transitory computer readable storage medium is used to perform the abstract idea, such that it amounts to no more than mere instructions to apply the exception using a generic computer. See MPEP 2106.05(f). Even when viewed in combination, these additional elements do not integrate the recited judicial exception into a practical application (Step 2A, Prong Two: NO), and the claim is directed to the judicial exception. (Step 2A: YES). Even when considered in combination, these additional elements represent mere instructions to implement an abstract idea or other exception on a computer and insignificant extra-solution activity, which do not provide an inventive concept. (Step 2B: NO).
Turning to the dependent claims:
Dependent claims 113 and 123 merely specify that the region of interest is an intervertebral disc in a spine of a patient. This is nothing more than an attempt to generally link the product of nature to a particular technological environment.
Dependent claims 114 and 124 recite preparing an antibiotic treatment for administration to the patient. This does not require any specific treatment or prophylaxis because this claim encompasses administering any antibiotic treatment.
Dependent claims 118 and 128 recite additional necessary data gathering and evaluation (mental process) that can be achieved by the clinician in reviewing the acquired additional chemical factor.
Dependent claims 119 and 129 recite additional necessary data gathering and evaluation (mental process) that can be achieved by the clinician in reviewing the acquired additional chemical factor in combination with the prior chemical factor.
Dependent claims 120 and 130 recite additional necessary data gathering and evaluation (mental process) that can be achieved by the clinician in reviewing the acquired additional chemical factor in a second ROI.
Dependent claims 121 and 131 recite the mathematical concept and/or mental process of scaling/adjusting the chemical factor calculation by a patient-related adjustment factor based on knowledge of the patient-dependent variable and its effect on the chemical factor acquired. For example, patient body weight or BMI may be indicative of fat percentage which will change the magnetic resonance spectroscopy measurement by a factor known to the clinician.
Therefore, claims 112-114, 118-124, and 128-131 are not eligible.
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 112-116 and 118-120 are rejected under 35 U.S.C. 103 as being unpatentable over Majumdar et al. (U.S. Pub. No. 2008/0039710), hereinafter “Majumdar,” in further view of Chen et al. (“Modic changes and disc degeneration caused by inoculation of Propionibacterium acnes inside intervertebral discs of rabbits: a pilot study” 2016), hereinafter “Chen.”
Regarding claim 112, Majumdar discloses a medical diagnostic system (“a medical diagnostic system with a non-invasive imaging modality that is adapted to provide useful information that is indicative of a degree of a property of a region of tissue based upon a chemical signature of a factor associated with that property… the system provides useful information indicative of a degree of degradation of an intervertebral disc.” [0016]-[0023]), comprising:
a diagnostic processor (“Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]) configured to provide diagnostic information for diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is degraded (“a medical diagnostic system with a non-invasive imaging modality that is adapted to provide useful information that is indicative of a degree of a property of a region of tissue based upon a chemical signature of a factor associated with that property… the system provides useful information indicative of a degree of degradation of an intervertebral disc.” [0016]-[0023]; “Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc) based at least in part upon at least one calculated measurement (spectral peak ratio, also referred to as integrated area ratio, area ratio, peak ratio, and ratio throughout the Majumdar’s disclosure and claims, is calculated by binning an identified spectral region and calculating the integrated area under the binned spectral region, [0111]; see also integrated area ratios in [0076], [0099], [0118]-[0119], [0135], [0206], Tables 1A, 1B, 4; see also calculation of the spectral peak ratio for the region including the lactate peak as well as any one of a number of chemical constituents that are lactate related, proteoglycan related, or collagen related with any other one of such chemical constituents in [0017], [0062], [0065], [0069], [0177], [0179], [0191], [0193], and Tables 2-8; See also overlap between “Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]) derived from information extracted from the ROI corresponding with at least one chemical factor in the ROI comprising propionic acid (PA) (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “the system provides the useful information based at least in part upon an NMR spectrum of the region of tissue.” [0025]; “All MRI examinations were performed on a 3 Tesla (3 T) GE Excite Signa whole-body MR scanner... The in-vivo patient evaluation was done using a GE 6-channel spine coil. Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression. Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm; spectral peak ratio, also referred to as integrated area ratio, area ratio, peak ratio, and ratio throughout the Majumdar’s disclosure and claims, is calculated by binning an identified spectral region and calculating the integrated area under the binned spectral region, [0111]; see also integrated area ratios in [0076], [0099], [0118]-[0119], [0135], [0206], Tables 1A, 1B, 4; see also calculation of the spectral peak ratio for the region including the lactate peak as well as any one of a number of chemical constituents that are lactate related, proteoglycan related, or collagen related with any other one of such chemical constituents in [0017], [0062], [0065], [0069], [0177], [0179], [0191], [0193], and Tables 2-8; See also overlap between “Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]).
However, Majumdar does not appear to explictly disclose diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria.
However, in the same field of endeavor of MRI evaluation of Modic change in the intervertebral disc, Chen teaches diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria (the presence of P. acnes and its secreted metabolite propionic acid are a signature of Modic change of the spine and to generate the diagnostic information for diagnosing whether the region of interest (ROI) in the intervertebral disc is infected with bacteria, “P. acnes has a strong connection with Modic change and disc degeneration” P.6, paragraph 1; “propionic acid, the metabolite secreted by P. acnes, resulted in the dissolution of fatty bone marrow and bone, thus represented as Modic changes.” P. 6, paragraph 4; “P. acnes has strong correlation with disc degeneration and Modic changes when inoculated into intervertebral discs” P.6, paragraph 7; note that this limitation encompasses an intended use of the claimed diagnostic system, therefore as the device disclosed in Majumdar is suitable for measuring the ratio of the spectral measurements for the intended use of diagnosing bacterial infection, Majumdar discloses this limitation, see e.g., MPEP 2114).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of using the presence of P. acnes and proprionic acid in the intervertebral disc to identify Modic change as taught by Chen with the known device for MR spectroscopy to diagnose intervertebral disc degeneration using MRI signatures of chemical shifts as disclosed by Majumdar as applying non-invasive assessment to identify signs of intervertebral disc degeneration such as Modic change provides a safer means to provide an assessment of the severity of intervertebral disc generation than invasive methods and avoids potential complications resulting from tissue biopsy.
Regarding claim 113, Majumdar discloses the region of interest ROI comprises at least a portion of an intervertebral disc in a spine of the patient (“a medical diagnostic system with a non-invasive imaging modality that is adapted to provide useful information that is indicative of a degree of a property of a region of tissue based upon a chemical signature of a factor associated with that property… the system provides useful information indicative of a degree of degradation of an intervertebral disc.” [0016]-[0023]; “NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095] and associated figures; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]).
Regarding claim 114, Majumdar does not appear to disclose the diagnostic information is usable to prepare an antibiotic treatment for administration to the patient.
However, in the same field of endeavor of MRI evaluation of Modic change in the intervertebral disc, Chen teaches the diagnostic information is usable to prepare an antibiotic treatment for administration to the patient (“A randomized controlled trial showing that patients acquired excellent pain relief and Modic-I changes attenuation after oral antibiotics treatment further validated this theory.” P. 1, paragraph 2; note that this limitation encompasses an intended use of the claimed diagnostic system, therefore as the device disclosed in Majumdar provides diagnostic information suitable for the intended use of diagnosing bacterial infection and preparing an antibiotic treatment for administration to the patient based on this diagnosis, Majumdar discloses this limitation, see e.g., MPEP 2114).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of responding to the presence of bacterial infection with a course of antibiotics and using the presence of P. acnes and proprionic acid in the intervertebral disc to identify Modic change as taught by Chen with the known device for MR spectroscopy to diagnose intervertebral disc degeneration using MRI signatures of chemical shifts as disclosed by Majumdar as applying non-invasive assessment to identify signs of intervertebral disc degeneration and bacterial infection provides a safer means to provide an assessment of the severity of intervertebral disc generation than invasive methods and avoids potential complications resulting from tissue biopsy.
Regarding claim 115, Majumdar discloses the diagnostic processor comprises a magnetic resonance spectroscopy (MRS) diagnostic processor (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]) configured to provide the diagnostic information (“Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc) based at least in part upon information extracted from a spectral region corresponding with propionic acid (PA) (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “the system provides the useful information based at least in part upon an NMR spectrum of the region of tissue.” [0025]; “All MRI examinations were performed on a 3 Tesla (3 T) GE Excite Signa whole-body MR scanner... The in-vivo patient evaluation was done using a GE 6-channel spine coil. Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression. Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm; spectral peak ratio, also referred to as integrated area ratio, area ratio, peak ratio, and ratio throughout the Majumdar’s disclosure and claims, is calculated by binning an identified spectral region and calculating the integrated area under the binned spectral region, [0111]; see also integrated area ratios in [0076], [0099], [0118]-[0119], [0135], [0206], Tables 1A, 1B, 4; see also calculation of the spectral peak ratio for the region including the lactate peak as well as any one of a number of chemical constituents that are lactate related, proteoglycan related, or collagen related with any other one of such chemical constituents in [0017], [0062], [0065], [0069], [0177], [0179], [0191], [0193], and Tables 2-8; See also overlap between “Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]) of a processed MRS spectrum derived from a multi-frame MRS spectral acquisition series acquired from a voxel prescribed to correspond with the ROI according to an MRS pulse sequence series exam (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]).
Regarding claim 116, Majumdar discloses a magnetic resonance spectroscopy (MRS) signal processor configured to receive the multi-frame MRS spectral acquisition series, the MRS signal processor configured to process the multi-frame MRS spectral acquisition series to produce the processed MRS spectrum (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]).
Regarding claim 118, Majumdar discloses the at least one chemical factor further comprises at least one of lactate (LA) and alanine (AL) chemicals (“Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]; note lactate is the conjugate base of lactic acid as present under physiological conditions, See, e.g, “The Difference Between Lactic Acid and Lactate” 2015).
Regarding claim 119, Majumdar discloses said calculated measurement corresponds with a combined level of PA and at least one other chemical comprising at least one of lactate (LA) and alanine (AL) chemicals in the ROI (“Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]; note lactate is the conjugate base of lactic acid as present under physiological conditions, See, e.g, “The Difference Between Lactic Acid and Lactate” 2015).
Regarding claim 120, Majumdar discloses the diagnostic processor is configured to provide the diagnostic information based at least in part upon at least a second calculated measurement derived from information extracted from a second region of interest ROI in the body of the patient corresponding with at least one chemical factor in the second ROI comprising propionic acid (PA) (“Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap; Table 7 demonstrates a determination of the extent of degradation across multiple intervertebral discs using the N-Acetyl/Lac + Lip ratio corresponding to propionic acid and proteoglycan).
Claim 121 is rejected under 35 U.S.C. 103 as being unpatentable over Majumdar in further view of Chen as applied to claim 112 above, or, in the alternative, further in view of Peacock et al. (U.S. Pub. No. 2013/0053658), hereinafter “Peacock.”
Regarding claim 121, Majumdar discloses the calculated measurement is adjusted by an adjustment factor that comprises at least one of a volume-related adjustment factor based upon a volume of the ROI, and a patient-related adjustment factor associated with a known value or condition of a patient-dependent variable for the patient (“Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191], CHESS is a selective saturation algorithm for suppressing water and fat (the primary components of percentage body fat) in MR spectroscopy).
Alternatively, in the same field of endeavor of MR spectroscopy, Peacock teaches the calculated measurement is adjusted by an adjustment factor that comprises at least one of a volume-related adjustment factor based upon a volume of the ROI, and a patient-related adjustment factor associated with a known value or condition of a patient-dependent variable for the patient (“To provide an estimate of metabolite concentration, the spectral measures were divided by the region of interest (ROI) volume. Also, given signal strength may vary with ROI depth, subject body mass index (BMI) was also considered as a normalizing factor. This was done by taking the BMI for a subject associated with a given disc sample being evaluated divided by the average BMI across the data set used for the logistic regression modeling.” [0208]).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of normalizing spectral data using BMI data as in Peacock to the known device of a spectral acquisition and analysis device as in Majumdar to achieve the predictable result of presenting normalized data across a subject population to provide for accurate relative results of intervertebral disc degeneration for individual subjects according to the population relationship between spectral values and intervertebral disc degeneration.
Claims 122-126 and 128-130 are rejected under 35 U.S.C. 103 as being unpatentable over Majumdar et al. (U.S. Pub. No. 2008/0039710), hereinafter “Majumdar,” in further view of Chen et al. (“Modic changes and disc degeneration caused by inoculation of Propionibacterium acnes inside intervertebral discs of rabbits: a pilot study” 2016), hereinafter “Chen.”
Regarding claim 122, Majumdar discloses a method (“using 3 T MRI systems with a surface spine coil, thus providing a completely non-invasive diagnostic toolset and method to image and localize degeneration and/or pain.” Abstract) for providing diagnostic information for diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is degraded (“a medical diagnostic system with a non-invasive imaging modality that is adapted to provide useful information that is indicative of a degree of a property of a region of tissue based upon a chemical signature of a factor associated with that property… the system provides useful information indicative of a degree of degradation of an intervertebral disc.” [0016]-[0023]; “Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc), the method comprising:
using a diagnostic processor (“Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]) to:
extract information corresponding with at least one chemical factor in the ROI comprising propionic acid (PA) (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “the system provides the useful information based at least in part upon an NMR spectrum of the region of tissue.” [0025]; “All MRI examinations were performed on a 3 Tesla (3 T) GE Excite Signa whole-body MR scanner... The in-vivo patient evaluation was done using a GE 6-channel spine coil. Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression. Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm; spectral peak ratio, also referred to as integrated area ratio, area ratio, peak ratio, and ratio throughout the Majumdar’s disclosure and claims, is calculated by binning an identified spectral region and calculating the integrated area under the binned spectral region, [0111]; see also integrated area ratios in [0076], [0099], [0118]-[0119], [0135], [0206], Tables 1A, 1B, 4; see also calculation of the spectral peak ratio for the region including the lactate peak as well as any one of a number of chemical constituents that are lactate related, proteoglycan related, or collagen related with any other one of such chemical constituents in [0017], [0062], [0065], [0069], [0177], [0179], [0191], [0193], and Tables 2-8; See also overlap between “Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]);
calculate a measurement from the information corresponding with the propionic acid (PA) chemical factor (spectral peak ratio, also referred to as integrated area ratio, area ratio, peak ratio, and ratio throughout the Majumdar’s disclosure and claims, is calculated by binning an identified spectral region and calculating the integrated area under the binned spectral region, [0111]; see also integrated area ratios in [0076], [0099], [0118]-[0119], [0135], [0206], Tables 1A, 1B, 4; see also calculation of the spectral peak ratio for the region including the lactate peak as well as any one of a number of chemical constituents that are lactate related, proteoglycan related, or collagen related with any other one of such chemical constituents in [0017], [0062], [0065], [0069], [0177], [0179], [0191], [0193], and Tables 2-8; See also overlap between “Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]); and
generate the diagnostic information for diagnosing whether the region of interest (ROI) is infected with bacteria using at least the calculated measurement (“a medical diagnostic system with a non-invasive imaging modality that is adapted to provide useful information that is indicative of a degree of a property of a region of tissue based upon a chemical signature of a factor associated with that property… the system provides useful information indicative of a degree of degradation of an intervertebral disc.” [0016]-[0023]; “Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc);
wherein the diagnostic processor comprises one or more computer processors running software in computer readable storage (“Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]; “a computer readable software program in computer readable media form and that is configured to process data from a nuclear magnetic resonance (NMR) spectrum taken from the first region of tissue. The program is further configured to provide the useful information from the processed data.” [0033]).
However, Majumdar does not appear to disclose diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria.
However, in the same field of endeavor of MRI evaluation of Modic change in the intervertebral disc, Chen teaches diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria (the presence of P. acnes and its secreted metabolite propionic acid are a signature of Modic change of the spine and to generate the diagnostic information for diagnosing whether the region of interest (ROI) in the intervertebral disc is infected with bacteria, “P. acnes has a strong connection with Modic change and disc degeneration” P.6, paragraph 1; “propionic acid, the metabolite secreted by P. acnes, resulted in the dissolution of fatty bone marrow and bone, thus represented as Modic changes.” P. 6, paragraph 4; “P. acnes has strong correlation with disc degeneration and Modic changes when inoculated into intervertebral discs” P.6, paragraph 7).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of using the presence of P. acnes and propionic acid in the intervertebral disc to identify Modic change as taught by Chen with the known process using a device for MR spectroscopy to diagnose intervertebral disc degeneration using MRI signatures of chemical shifts as disclosed by Majumdar as applying non-invasive assessment to identify signs of intervertebral disc degeneration such as Modic change provides a safer means to provide an assessment of the severity of intervertebral disc generation than invasive methods and avoids potential complications resulting from tissue biopsy.
Regarding claim 123, Majumdar discloses the region of interest ROI comprises at least a portion of an intervertebral disc in a spine of the patient (“a medical diagnostic system with a non-invasive imaging modality that is adapted to provide useful information that is indicative of a degree of a property of a region of tissue based upon a chemical signature of a factor associated with that property… the system provides useful information indicative of a degree of degradation of an intervertebral disc.” [0016]-[0023]; “NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095] and associated figures; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]).
Regarding claim 124, Majumdar does not appear to disclose preparing an antibiotic treatment for administration to the patient in response to at least the diagnostic information.
However, in the same field of endeavor of MRI evaluation of Modic change in the intervertebral disc, Chen teaches preparing an antibiotic treatment for administration to the patient in response to at least the diagnostic information (“A randomized controlled trial showing that patients acquired excellent pain relief and Modic-I changes attenuation after oral antibiotics treatment further validated this theory.” P. 1, paragraph 2).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of responding to the presence of bacterial infection with a course of antibiotics and using the presence of P. acnes and propionic acid in the intervertebral disc to identify Modic change as taught by Chen with the known process using MR spectroscopy to diagnose intervertebral disc degeneration using MRI signatures of chemical shifts as disclosed by Majumdar as applying non-invasive assessment to identify signs of intervertebral disc degeneration and bacterial infection provides a safer means to provide an assessment of the severity of intervertebral disc generation than invasive methods and avoids potential complications resulting from tissue biopsy.
Regarding claim 125, Majumdar discloses the diagnostic processor comprises a magnetic resonance spectroscopy (MRS) diagnostic processor (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]) configured to provide the diagnostic information (“Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc) based at least in part upon information extracted from a spectral region corresponding with propionic acid (PA) (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “the system provides the useful information based at least in part upon an NMR spectrum of the region of tissue.” [0025]; “All MRI examinations were performed on a 3 Tesla (3 T) GE Excite Signa whole-body MR scanner... The in-vivo patient evaluation was done using a GE 6-channel spine coil. Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression. Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm; spectral peak ratio, also referred to as integrated area ratio, area ratio, peak ratio, and ratio throughout the Majumdar’s disclosure and claims, is calculated by binning an identified spectral region and calculating the integrated area under the binned spectral region, [0111]; see also integrated area ratios in [0076], [0099], [0118]-[0119], [0135], [0206], Tables 1A, 1B, 4; see also calculation of the spectral peak ratio for the region including the lactate peak as well as any one of a number of chemical constituents that are lactate related, proteoglycan related, or collagen related with any other one of such chemical constituents in [0017], [0062], [0065], [0069], [0177], [0179], [0191], [0193], and Tables 2-8; See also overlap between “Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]) of a processed MRS spectrum derived from a multi-frame MRS spectral acquisition series acquired from a voxel prescribed to correspond with the ROI according to an MRS pulse sequence series exam (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]).
Regarding claim 126, Mujumdar discloses using a magnetic resonance spectroscopy (MRS) signal processor to receive the multi-frame MRS spectral acquisition series, and to process the multi-frame MRS spectral acquisition series to produce the processed MRS spectrum (“NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095]; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]; “Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]).
Regarding claim 128, Majumdar discloses the at least one chemical factor further comprises at least one of lactate (LA) and alanine (AL) chemicals (“Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]; note lactate is the conjugate base of lactic acid as present under physiological conditions, See, e.g, “The Difference Between Lactic Acid and Lactate” 2015).
Regarding claim 129, Majumdar discloses said calculated measurement corresponds with a combined level of PA and at least one other chemical comprising at least one of lactate (LA) and alanine (AL) chemicals in the ROI (“Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]; note lactate is the conjugate base of lactic acid as present under physiological conditions, See, e.g, “The Difference Between Lactic Acid and Lactate” 2015).
Regarding claim 130, Majumdar discloses using the diagnostic processor (“Data analysis included combining the data from multiple channels and calculating the ration of spectroscopy peak height of certain targets to be evaluated, namely N-Acetyl, Choline (Cho), and carbohydrate (carb), and additional data was evaluated for Lactate (Lac).” [0191]; “This aspect includes a processor that is configured to process data related to an NMR spectrum of the tissue in a manner that provides useful information that is indicative of the property in the first region of tissue.” [0029], [0036]) to:
extract information corresponding with at least one chemical factor in a second region of interest (ROI) in the body of the patient, wherein the chemical factor comprises propionic acid (PA) (“Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap; Table 7 demonstrates a determination of the extent of degradation across multiple intervertebral discs using the N-Acetyl/Lac + Lip ratio corresponding to propionic acid and proteoglycan);
calculate a second measurement from the information corresponding with the propionic acid (PA) chemical factor in the second ROI (“Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap; Table 7 demonstrates a determination of the extent of degradation across multiple intervertebral discs using the N-Acetyl/Lac + Lip ratio corresponding to propionic acid and proteoglycan); and
generate the diagnostic information for diagnosing whether the region of interest (ROI) is degraded using at least the second calculated measurement (“Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap; Table 7 demonstrates a determination of the extent of degradation across multiple intervertebral discs using the N-Acetyl/Lac + Lip ratio corresponding to propionic acid and proteoglycan).
However, Majumdar does not appear to disclose diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria.
However, in the same field of endeavor of MRI evaluation of Modic change in the intervertebral disc, Chen teaches diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria (the presence of P. acnes and its secreted metabolite propionic acid are a signature of Modic change of the spine and to generate the diagnostic information for diagnosing whether the region of interest (ROI) in the intervertebral disc is infected with bacteria, “P. acnes has a strong connection with Modic change and disc degeneration” P.6, paragraph 1; “propionic acid, the metabolite secreted by P. acnes, resulted in the dissolution of fatty bone marrow and bone, thus represented as Modic changes.” P. 6, paragraph 4; “P. acnes has strong correlation with disc degeneration and Modic changes when inoculated into intervertebral discs” P.6, paragraph 7).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of using the presence of P. acnes and propionic acid in the intervertebral disc to identify Modic change as taught by Chen with the known process using a device for MR spectroscopy to diagnose intervertebral disc degeneration using MRI signatures of chemical shifts as disclosed by Majumdar as applying non-invasive assessment to identify signs of intervertebral disc degeneration such as Modic change provides a safer means to provide an assessment of the severity of intervertebral disc generation than invasive methods and avoids potential complications resulting from tissue biopsy.
Claim 131 is rejected under 35 U.S.C. 103 as being unpatentable over Majumdar in further view of Chen as applied to claim 122 above, or, in the alternative, further in view of Peacock.
Regarding claim 131, Majumdar discloses the calculated measurement is adjusted by an adjustment factor that comprises at least one of a volume-related adjustment factor based upon a volume of the ROI, and a patient-related adjustment factor associated with a known value or condition of a patient-dependent variable for the patient (“Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191], CHESS is a selective saturation algorithm for suppressing water and fat (the primary components of percentage body fat) in MR spectroscopy).
Alternatively, in the same field of endeavor of MR spectroscopy, Peacock teaches the calculated measurement is adjusted by an adjustment factor that comprises at least one of a volume-related adjustment factor based upon a volume of the ROI, and a patient-related adjustment factor associated with a known value or condition of a patient-dependent variable for the patient (“To provide an estimate of metabolite concentration, the spectral measures were divided by the region of interest (ROI) volume. Also, given signal strength may vary with ROI depth, subject body mass index (BMI) was also considered as a normalizing factor. This was done by taking the BMI for a subject associated with a given disc sample being evaluated divided by the average BMI across the data set used for the logistic regression modeling.” [0208]).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of normalizing spectral data using BMI data as in Peacock to the known process using a spectral acquisition and analysis device as in Majumdar to achieve the predictable result of presenting normalized data across a subject population to provide for accurate relative results of intervertebral disc degeneration for individual subjects according to the population relationship between spectral values and intervertebral disc degeneration.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 112 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of U.S. Patent No. 12,239,455 (the ‘455 Patent). Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 9 of the ‘455 Patent teaches a medical diagnostic system (col.135, lines 13-16), comprising:
a diagnostic processor (col.135, lines 17-18) configured to provide diagnostic information for diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria (col.136, lines 34-35; col.136, lines 13-15) based at least in part upon at least one calculated measurement (col.135, lines 32-33) derived from information extracted from the ROI corresponding with at least one chemical factor in the ROI comprising propionic acid (PA) (col.135, lines 19-31).
Claim 113 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent as applied to claim 112 above, in further view of Majumdar.
Majumdar teaches the region of interest ROI comprises at least a portion of an intervertebral disc in a spine of the patient (“a medical diagnostic system with a non-invasive imaging modality that is adapted to provide useful information that is indicative of a degree of a property of a region of tissue based upon a chemical signature of a factor associated with that property… the system provides useful information indicative of a degree of degradation of an intervertebral disc.” [0016]-[0023]; “NMR spectrum of a voxel region in a disc nucleus of the spine” [0086], [0090]-[0095] and associated figures; “Single voxel spectroscopy imaging was conducted using a short-echo point-resolved spectroscopy (PRESS) sequence (TE/TR=35/200 ms, 256 repetitions, 1024 data points), including chemical shift-selected (CHESS) water suppression.” [0191]).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have applied Majumdar’s known technique of performing MR spectroscopy of the intravertebral disc to Claim 9 of the ‘455 Patent’s known apparatus for magnetic resonance spectroscopy of propionic acid in the body to achieve the predictable result that MR spectroscopy of the intravertebral disc provides useful information indicative of a degree of degradation of an intervertebral disc.” Majumdar, [0016]-[0023].
Claim 114 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent as applied to claim 112 above, in further view of Chen.
Chen teaches the diagnostic information is usable to prepare an antibiotic treatment for administration to the patient (“A randomized controlled trial showing that patients acquired excellent pain relief and Modic-I changes attenuation after oral antibiotics treatment further validated this theory.” P. 1, paragraph 2).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of responding to the presence of bacterial infection with a course of antibiotics and using the presence of P. acnes and proprionic acid in the intervertebral disc to identify Modic change as taught by Chen with the known device for MR spectroscopy to diagnose intervertebral disc bacterial infection using MRI signatures of chemical shifts as disclosed by Claim 9 of the ‘455 Patent as applying non-invasive assessment to identify signs of intervertebral disc degeneration and bacterial infection provides a safer means to provide an assessment of the severity of intervertebral disc generation than invasive methods and avoids potential complications resulting from tissue biopsy.
Claim 115 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 9 of the ‘455 Patent teaches the diagnostic processor comprises a magnetic resonance spectroscopy (MRS) diagnostic processor configured to provide the diagnostic information based at least in part upon information extracted from a spectral region corresponding with propionic acid (PA) of a processed MRS spectrum derived from a multi-frame MRS spectral acquisition series acquired from a voxel prescribed to correspond with the ROI according to an MRS pulse sequence series exam (col.135, lines 17-35).
Claim 116 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 9 of the ‘455 Patent teaches a magnetic resonance spectroscopy (MRS) signal processor configured to receive the multi-frame MRS spectral acquisition series, the MRS signal processor configured to process the multi-frame MRS spectral acquisition series to produce the processed MRS spectrum (col.135, lines 17-35).
Claim 117 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 9 of the ‘455 Patent teaches the spectral region corresponding with propionic acid (PA) is below a range associated with lactic acid (LA) (col.135, lines 28-31).
Claim 118 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent as applied to claim 112 above, in further view of Majumdar.
Majumdar teaches the at least one chemical factor further comprises at least one of lactate (LA) and alanine (AL) chemicals (“Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]; note lactate is the conjugate base of lactic acid as present under physiological conditions, See, e.g, “The Difference Between Lactic Acid and Lactate” 2015).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have applied Majumdar’s known technique of performing MR spectroscopy of the intravertebral disc to extract a chemical factor including lactate and/or alanine chemicals to Claim 9 of the ‘455 Patent’s known apparatus for magnetic resonance spectroscopy of propionic acid in the body to achieve the predictable result that MR spectroscopy of the intravertebral disc provides useful information indicative of a degree of degradation of an intervertebral disc.” Majumdar, [0016]-[0023].
Claim 119 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent as applied to claim 112 above, in further view of Majumdar.
Majumdar teaches said calculated measurement corresponds with a combined level of PA and at least one other chemical comprising at least one of lactate (LA) and alanine (AL) chemicals in the ROI (“Resolvable peaks include… B. lactate… C. alanine” [0074]-[0075], [0114]-[0115]; 1.32 ppm: Lactate, 1.49 ppm Alanine, [0079]; alanine 1.49 ppm, lactate 1.35 ppm, [0122]; Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, lactate, lipids and alanine, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap) and Kapsalaki et al. (“The role of proton magnetic resonance spectroscopy in the diagnosis and categorization of cerebral abscesses” 2008) single voxel spectrum in Fig. 3 and discussed in Spectral Characteristics on P.3 demonstrate the one or more spectral features of the combined Lac+Lip, or the combination of the lactate and lipid regions, the lipid region including propionic acid, encompasses the range of 0.8 to 1.2-1.3 ppm); Tables 5-8 demonstrate that the ratio is taken between N-Acetyl/Lac+Lip to evaluate the degree of degradation of the intervertebral disc, alanine is shown in Figs. 1Y-3Z to have an overlapping range with lactate and lipid spectral regions, also see [0079], [0115], [0122]; note lactate is the conjugate base of lactic acid as present under physiological conditions, See, e.g, “The Difference Between Lactic Acid and Lactate” 2015).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have applied Majumdar’s known technique of performing MR spectroscopy of the intravertebral disc to extract a combined level of PA and at least one other chemical comprising at least one of lactate (LA) and alanine (AL) to Claim 9 of the ‘455 Patent’s known apparatus for magnetic resonance spectroscopy of propionic acid in the body to achieve the predictable result that MR spectroscopy of the intravertebral disc provides useful information indicative of a degree of degradation of an intervertebral disc.” Majumdar, [0016]-[0023].
Claim 120 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent as applied to claim 112 above, in further view of Majumdar.
Majumdar teaches the diagnostic processor is configured to provide the diagnostic information based at least in part upon at least a second calculated measurement derived from information extracted from a second region of interest ROI in the body of the patient corresponding with at least one chemical factor in the second ROI comprising propionic acid (PA) (“Resolvable peaks include… B. lactate” [0074]-[0075], [0114], Figs. 1Y-3Z; “lactate resonance (1.31 ppm, doublet)” [0177], Figs. 7A-7B; “additional data was evaluated for Lactate (Lac).” [0191], “NMR spectra corresponding with each of these images, annotating the target peak spectral sections used for spectral evaluation, are shown in following corresponding FIGS.: 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, and 20B, respectively.” [0193], Figs. 8B-11B and Tables 5-8 all demonstrate identifying spectral features in a spectral peak region corresponding with propionic acid; the imaged and analyzed spectra inherently corresponds with propionic acid as evidenced by applicant’s specification paragraph [0459] the peak region for propionic acid ”in a range of about 0.2 ppm from between about 0.9 ppm to about 1.1 ppm” overlaps with the peak region of lactate “between about 1.0, 1.5, or 1.1 ppm on one end to about 1.45 or even about 1.5 ppm on the other end of the region”, i.e, the region indicated as Lac+Lip in Figs. 8B-11B of Majumdar corresponds at least in part with propionic acid, and additionally by Munshi et al. (“Nuclear Magnetic Resonance Based Profiling of Biofluids Reveals Metabolic Dysregulation in HIV-Infected Persons and Those on Anti-Retroviral Therapy” 2013) in the bottom spectrum of Fig. 1, entries for lactic acid and propionic acid in Table 2, the MR spectral peak ranges of propionic acid and lactate overlap; Table 7 demonstrates a determination of the extent of degradation across multiple intervertebral discs using the N-Acetyl/Lac + Lip ratio corresponding to propionic acid and proteoglycan).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have applied Majumdar’s known technique of performing MR spectroscopy of the intravertebral disc to extract a chemical factor corresponding to propionic acid in a first and second ROI to Claim 9 of the ‘455 Patent’s known apparatus for magnetic resonance spectroscopy of propionic acid in the body to achieve the predictable result that MR spectroscopy of the intravertebral disc provides useful information indicative of a degree of degradation of an intervertebral disc.” Majumdar, [0016]-[0023].
Claim 121 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 9 of the ‘455 Patent as applied to claim 112 above, in further view of Peacock.
Peacock teaches the calculated measurement is adjusted by an adjustment factor that comprises at least one of a volume-related adjustment factor based upon a volume of the ROI, and a patient-related adjustment factor associated with a known value or condition of a patient-dependent variable for the patient (“To provide an estimate of metabolite concentration, the spectral measures were divided by the region of interest (ROI) volume. Also, given signal strength may vary with ROI depth, subject body mass index (BMI) was also considered as a normalizing factor. This was done by taking the BMI for a subject associated with a given disc sample being evaluated divided by the average BMI across the data set used for the logistic regression modeling.” [0208]).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to apply the known technique of normalizing spectral data using BMI data as in Peacock to the known device of a spectral acquisition and analysis device as in Claim 9 of the ‘455 Patent to achieve the predictable result of presenting normalized data across a subject population to provide for accurate relative results of intervertebral disc degeneration for individual subjects according to the population relationship between spectral values and intervertebral disc degeneration.
Claims 122-131 recite substantially similar features as claims 112-121 addressed above, and a rejected on substantially the same grounds over Claim 9 of the ‘455 Patent, Claim 9 of the ‘455 Patent in further view of Majumdar, Claim 9 of the ‘455 Patent in further view of Chen, or Claim 9 of the ‘455 Patent in further view of Peacock as detailed above.
Further, Claim 112 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 1 of U.S. Patent No. 11,564,619 (the ‘619 Patent). Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 1 of the ‘619 Patent teaches a medical diagnostic system (col.134, lines 2-5), comprising:
a diagnostic processor (col.134, line 17) configured to provide diagnostic information for diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria (col.134, lines 2-5 and 26-29) based at least in part upon at least one calculated measurement (col.134, line 23) derived from information extracted from the ROI corresponding with at least one chemical factor in the ROI comprising propionic acid (PA) (col.134, lines 18-25).
Claim 113 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 1 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 1 of the ‘619 Patent teaches the region of interest ROI comprises at least a portion of an intervertebral disc in a spine of the patient (col.134, lines 2-5, 11-12, and 26-29).
Claim 114 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 11 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 11 of the ‘619 Patent teaches a medical diagnostic system (col.135, lines 5-12), comprising:
a diagnostic processor (col.135, line 13-14) configured to provide diagnostic information for diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria (col.135, lines 1-8 and 21-24) based at least in part upon at least one calculated measurement (col.135, line 20) derived from information extracted from the ROI corresponding with at least one chemical factor in the ROI comprising propionic acid (PA) (col.135, lines 5-19),
wherein the diagnostic information is usable to prepare an antibiotic treatment for administration to the patient (Col.135, lines 62-64).
Claim 115 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 14 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 14 of the ‘619 Patent teaches a medical diagnostic system (col.136, lines 10-13), comprising:
a diagnostic processor (col.136, line 22) configured to provide diagnostic information for diagnosing whether a region of interest (ROI) in a tissue in a body of a patient is infected with bacteria (col.136, lines 10-13 and 30-33) based at least in part upon at least one calculated measurement (col.135, line 20) derived from information extracted from the ROI corresponding with at least one chemical factor in the ROI comprising propionic acid (PA) (col.136, lines 14-28),
wherein the diagnostic processor comprises a magnetic resonance spectroscopy (MRS) diagnostic processor configured to provide the diagnostic information based at least in part upon information extracted from a spectral region corresponding with propionic acid (PA) of a processed MRS spectrum derived from a multi-frame MRS spectral acquisition series acquired from a voxel prescribed to correspond with the ROI according to an MRS pulse sequence series exam (col.136, lines 14-39).
Claim 116 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 14 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 14 of the ‘619 Patent teaches a magnetic resonance spectroscopy (MRS) signal processor configured to receive the multi-frame MRS spectral acquisition series, the MRS signal processor configured to process the multi-frame MRS spectral acquisition series to produce the processed MRS spectrum (col.136, lines 14-39).
Claim 117 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 14 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 14 of the ‘619 Patent teaches the spectral region corresponding with propionic acid (PA) is below a range associated with lactic acid (LA) (col.136, lines 23-28).
Claim 118 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 20 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 20 of the ‘619 Patent teaches the at least one chemical factor further comprises at least one of lactate (LA) and alanine (AL) chemicals (col.136, line 61 – col.137, line 3).
Claim 119 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 20 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 20 of the ‘619 Patent teaches said calculated measurement corresponds with a combined level of PA and at least one other chemical comprising at least one of lactate (LA) and alanine (AL) chemicals in the ROI (col.136, line 61 – col.137, line 3).
Claim 120 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 25 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 25 of the ‘619 Patent teaches the diagnostic processor is configured to provide the diagnostic information based at least in part upon at least a second calculated measurement derived from information extracted from a second region of interest ROI in the body of the patient corresponding with at least one chemical factor in the second ROI comprising propionic acid (PA) (col.138, lines 4-17).
Claim 121 is rejected on the ground of nonstatutory double patenting as being unpatentable over Claim 23 of the ‘619 Patent. Although the claims at issue are not identical, they are not patentably distinct from each other because Claim 23 of the ‘619 Patent teaches the calculated measurement is adjusted by an adjustment factor that comprises at least one of a volume-related adjustment factor based upon a volume of the ROI, and a patient-related adjustment factor associated with a known value or condition of a patient-dependent variable for the patient (col.137, line 16 – col.138, line 3).
Claims 122-131 recite substantially similar features as claims 112-121 addressed above, and are rejected on substantially the same grounds over Claims 1, 11, 14, 20, 23, or 25 of the ‘619 Patent as detailed above.
Allowable Subject Matter
Claims 117 and 127 are rejected under 35 U.S.C. 101 and non-statutory obviousness type double patenting as detailed above, but would be allowable if amended to overcome the rejections under 35 U.S.C. 101 and amended to overcome the non-statutory obviousness type double patenting rejections or subject to terminal disclaimer and rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Hesselink (“Fundamental of MR Spectroscopy” 2006) discloses the identification of lactate and alanine spectral peaks in magnetic resonance spectroscopic acquisition of a voxel of a region of interest and the correspondence of such peaks to biochemical changes due to tumors, stroke, epilepsy, metabolic disorders, infections (including bacterial), and neurodegenerative disease to diagnose these conditions.
Keshari et al. (“Lactic acid and proteoglycans as metabolic markers for discogenic back pain” 2008, “Characterization of intervertebral disc degeneration by high-resolution magic angle spinning (HR-MAS) spectroscopy” 2005, “Correlation of HR-MAS spectroscopy derived metabolite concentrations with collagen and proteoglycan levels and Thompson grade in the degenerative disc” 2005) and Majumdar & Kurhanewicz et al. (U.S. Pub. No. 2013/0144155) disclose subject matter similar to that of Majumdar including identifying spectral peaks using chemical shift imaging for various endogenous chemical species and taking the ratio between these spectral peaks to assess intervertebral disc degeneration.
Dudli et al. (“Pathobiology of Modic change” 2016), Dudli et al. (“Propionibacterium acnes infected intervertebral discs cause vertebral bone marrow lesions consistent with Modic change” 2016), and Rollason et al. (“Genotypic and antimicrobial characterization of Propionibacterium acnes isolates from surgically excised lumbar disc herniations” 2013) disclose the diagnosis of bacterial infection of the intervertebral disc based on the presence of propionic acid generated as a byproduct of probionibacterium acnes infection.
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/J.M./Examiner, Art Unit 3798
/KEITH M RAYMOND/Supervisory Patent Examiner, Art Unit 3798