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 .
Priority
The present Application, filed June 22, 2023, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2021/052863, filed September 30, 2021, which claims the benefit of Provisional U.S. Patent Application Nos. 63/239,656, 63/165,395, and 63/085,706, filed September 1, 2021 and March 24, 2021, and September 30, 2020, respectively.
Status of the Claims
In the amendment filed June 22, 2023, claims 1-3, 8, 11, 19, 22-26, 28, and 33-34 are canceled. Claims 9, 17, 27, and 29-32 are amended. Claims 4-7, 9-10, 12-18, 20-21, 27, and 29-32 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on June 27, 2023 is acknowledged.
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 4-7, 9-10, 12-18, 20-21, 27, and 29-32 are rejected for failure to recite eligible subject matter:
Claims 4-7, 9-10, 12-18, 20-21, 27, and 29-32 are rejected under 35 U.S.C. § 101 because the claimed invention is directed to an abstract idea without significantly more. The claim(s) recite(s) methods for stratifying and treating a subject having a neurological disorder, comprising steps of calculating ratios of metabolite levels, determining if the subject has a mitochondrial defect based on metabolic measurements, and stratifying the subject into a subgroup of subjects. Each of these constitutes a mental process: (i) calculating ratios (basic arithmetic), (ii) mentally determining the presence of a metabolic defect based on a known correlation to a metabolite measurement, and (iii) stratifying (mentally categorizing) the subject into a subgroup. This judicial exception is not integrated into a practical application because no practical application is recited in the claim. In particular, with respect to claim 1, while the preamble references a method for treating a subject, no treatment is actually undertaken in the method of claim 4. In fact, the method of claim 1 merely requires obtaining a sample and measuring metabolite levels in the sample, prior to performing the mental steps, and the mental steps do not improve the tangible steps in any way, do not result in treatment, and generally are not integrated into a particular practical application.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps of claim 1 (obtaining a sample from the subject and measuring the concentration levels of one or more mitochondrial biomarker metabolites) are well-understood, routine, conventional activity. In particular, courts have recognized that determining levels of biomarkers by general means is conventional activity for subject matter eligibility purposes (see, for example Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, (Fed. Cir. 2017)).
With respect to claim 5, the method further comprises administering to the subgroup of subjects an effective amount of a therapy to treat the neurological disease, wherein the therapy is determined by the unique and specific mitochondrial metabolic profile of the subgroup of subjects. This also fails to integrate the judicial exception into a practical application because, while the method of claim 2 results in treatment being administered, it is a generalized treatment, rather than a particular treatment, that is recited. Such generalized treatment constitutes mere extra-solution activity that fails to integrate the judicial exception into a practical application. See MPEP 2106.04(d)(2) and cases cited therein.
Claims 6-7 and 10, depending from claim 4, recite constraints on the manner in which the mental “determining” step is performed (specifically, limiting the mitochondrial metabolic defect options). Such constraint on the manner in which the mental step is performed does not transform the recited subject matter into patent eligible subject matter.
Claim 9, depending from claim 5, specifies treatment options, but does not recite a particular treatment. The treatment remains general by virtue of having a substantial number of alternatives, and furthermore because there is no particular connection between the result of the mental steps and a given treatment (e.g. if the subject is stratified into subgroup X, treatment Y is administered). For these reasons, claim 9 fails to integrate the judicial exception into a practical application or to cause the claim as a whole to amount to significantly more than the judicial exception. Claims 27 and 29-32, also depending from claim 5, are likewise subject matter ineligible as these claims, in different respects, narrow the available treatment options, but do not specify a particular treatment and further do not specify any particular connection between a given treatment and an output or result of the mental steps.
Claim 12 narrows the preambular recitation of the neurological disorder, but does not integrate the mental steps into a practical application or cause the claim to amount to significantly more than the judicial exception, as the only effect of this claim is to narrow the population of suitable subjects.
The method of claim 13 is substantially the same as the method of claim 4, but omits the “stratifying” step (included in claim 14), and recites measuring expression levels of mitochondrial enzymes or transporters rather than levels of metabolites. The generalized step of measuring expression or activity levels of enzymes or transporters fails to integrate the mental steps into a practical application, or to cause the claim as a whole to be significantly more than the mental steps, for the same reasons as does the step of measuring metabolite levels in claim 5. Claims 13 and 14 therefore fail to recite patent-eligible subject matter for the same reason as does claim 4, and claim 15 fails to recite eligible subject matter for the same reason as does claim 5.
Claim 16 recites particular enzymes and transporters, analogous to the metabolites of claim 4, and the measuring step of claim 16 remains fundamentally a mental step, as is the measuring step of claim 4. Claims 17-18 fail to integrate the judicial exception into a practical application or to transform the claim as a whole into significantly more than the judicial exception for the same reasons as do the analogous claims 7 and 9.
Claim 20 is substantially the same as claim 4, but omits the “stratifying” step (like claim 13, and the stratifying step for claim 20 is recited in claim 21), and also in that claim 20 further includes a step of comparing the presence, concentration levels, and ratios of one or more biomarker metabolites related to mitochondrial function in the sample from the subject to the presence, concentration levels, and ratios of the one or more biomarker metabolites in a control sample. This added step also recites a mental step (an abstract idea, i.e. a judicial exception), and thus does not confer subject matter eligibility on the claim. Claim 20 thus recites ineligible subject matter for essentially the same reasons as does claim 4.
Claim 21, in addition to reciting the abstract idea “stratifying” step, also recites a step of administering a therapy that is generally determined by the metabolic profile that is associated with the “stratifying” step. Claim 21 thus recites ineligible subject matter for the same reason as does claim 5.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. § 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 4-7, 9-10, 12, 17, 20-21, 27, and 29-32 are indefinite:
Claims 4-7, 9-10, 12, 17, 20-21, 27, and 29-32 are rejected under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 is indefinite for reciting measuring the concentration levels and calculating the ratios of one or more mitochondrial biomarker metabolites, because one of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. Given that only one mitochondrial biomarker metabolite must be measured, it would be unclear what the “ratio” refers to; i.e. what is the second number that the concentration level of the one mitochondrial biomarker metabolite is compared to.
Claim 20 is similarly indefinite for reciting determining the…ratios of one or more biomarker metabolites for the same reason; it would be unclear what the ratio refers to. Claims 5-7, 9, 12, 21, 27, and 29-32 are indefinite for depending from claim 4 or claim 20 without clearly curing the aspects of indefiniteness.
Claim 7 is further indefinite for reciting that the mitochondrial metabolic defect comprises lower concentration levels of all acylcarnitines, etc., because one of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. In particular, it would be unclear whether the requirement that the metabolic defect “comprises” the various metabolite level anomalies means that the anomaly in question must be actually measured in the subject (and thus limits the “measuring” step), alternatively that the anomaly in question must just generally known in the art to be associated with the particular metabolic defect, alternatively that it must generally be known in the art to be associated with the particular metabolic defect in the context of the particular neurological disorder, or some other meaning. It short, it would be unclear what is required in order for the mitochondrial metabolic defect to comprise the metabolite anomaly within the meaning of claim 7.
Claim 10 is further indefinite for reciting that the mitochondrial metabolic defect comprises a deficiency in amino acids (e.g., branched chain amino acids) and/or short chain fatty acids for the same reason. It would be unclear whether this requires that amino acid or short chain fatty acids deficiency is actually measured in the subject, or something else is required. Similarly, claim 17 is indefinite for reciting that the mitochondrial metabolic defect…comprises CPT defects, etc. Claim 19 is indefinite for reciting that the mitochondrial metabolic defect…comprises disrupted BBOX1, OCTN2, and/or CPT1/2 expression and/or activity, again, for the same reason.
Claim 20 is further indefinite for reciting one or more biomarker metabolites related to mitochondrial function, because a person of ordinary skill in the art could not reasonably determine the metes and bounds of this limitation. As a first matter, it would not be clear what constitutes a biomarker metabolite related to mitochondrial function. This could be any metabolite consumed or produced in the mitochondrion, it could be any metabolite whose level is directly or indirectly influenced by the rate of metabolism, or it could be defined in some other way. For the purpose of compact prosecution, a biomarker metabolite related to mitochondrial function will be construed as being any listed “mitochondrial biomarker metabolite” or “biomarker metabolite” of paragraph [0008] of the specification.
Claim 21 is likewise indefinite for repeating this recitation and failing to clarify its meaning.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 20-21 are anticipated by Lim:
Claims 20-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by International Patent Application Publication No. WO2019/195892 to Lim et al. (hereinafter, “Lim”).
Claim 20 recites a method for treating a CNS or neuropsychiatric disease in a subject. The method includes steps of:
obtaining a sample from the subject;
determining the presence, concentration levels, and ratios of one or more biomarker metabolites related to mitochondrial function in the sample from the subject;
comparing the presence, concentration levels, and ratios of one or more biomarker metabolites related to mitochondrial function in the sample from the subject to the presence, concentration levels, and ratios of the one or more biomarker metabolites in a control sample; and
determining if the subject has a CNS or neuropsychiatric disorder, or has an increased risk of developing a CNS or neuropsychiatric disorder when the concentration levels and ratios of the one or more biomarker metabolites in the sample from the subject are different from (greater than or less than) the concentration levels and ratios of the one or more biomarker metabolites in a control sample.
Note that the preamble of claim 20 is regarded as non-limiting, since the claim body recites a relatively complete method of diagnosis, while the preambular recitation of treating a CNS or neuropsychiatric disease is only as a purpose, or hoped-for eventual outcome, of the method, that does not further limit the manner in which the method is performed. Furthermore, the method is plainly not limited to subjects having a CNS or neuropsychiatric disease, since the final step of the method is determining if the subject has a CNS or neuropsychiatric disorder.
Lim teaches a method of determining the presence of, or risk of developing, Alzheimer’s disease (AD) in a subject (e.g. pg. 19, lines 27-28). Lim teaches the method includes a step of detecting in a biological sample from the subject a level of at least two lipid species selected from a group that includes acylcarnitine, ceramide (a sphingolipid), glycerophosphatidylcholine (a glycerophospholipid), and several other lipids that are encompassed by the categories of instant paragraph [0008] (see pg. 19, line 29 through pg. 20, line 4 of Lim). Lim further makes explicit that the sample is obtained from an individual (pg. 15, lines 16-21), and thus teaches (a), obtaining a sample from the subject and (b) determining the presence and concentration levels of one or more biomarker metabolites related to mitochondrial function in the sample. As noted above, determining a ratio of biomarker levels is deemed optional, however, Lim expressly teaches that lipid level data may be processed to produce a report of levels and/or ratios (pg. 17, lines 23-24).
Lim further teaches a step of comparing the levels of the lipid species detected as described above to reference levels of the lipid species (pg. 20, lines 18-19; comparing the levels etc. of biomarkers in the sample to the levels etc. of the biomarkers in a control sample) and a step of determining whether the subject has AD or is likely or not to develop AD on the basis of the comparison (pg. 20, lines 20-21; determining if the subject has a CNS disorder or elevated risk of developing one based on whether the levels etc. in the sample differ from those in the control sample). Lim thus anticipates all steps of the method of claim 20.
Lim further teaches that in some embodiments, the plurality of lipids can be selected from a list that includes acylcarnitine, ceramide (a sphingolipid), glycerophosphatidylcholine (a glycerophospholipid), and several other lipids that are encompassed by the categories of instant paragraph [0008] (see pg. 19, line 29 through pg. 20, line 4 of Lim) and teaches a step of comparing the levels or ratios of levels of the lipid species detected to reference levels or ratios of the lipid species , comparing levels or ratios of levels of the lipid species detected to reference levels or ratios of the lipid species, and determining on the basis of this comparison whether the subject has AD, is likely to develop AD or is unlikely to develop AD (pg. 2, lines 22-33). Lim teaches that the sample is obtained from an individual (pg. 15, lines 16-21), and that in some embodiments, the plurality of lipids can be selected from a list that includes acylcarnitine (pg. 32, lines 34-35 and Table A, pg. 36).
With respect to claim 21, Lim further teaches a step of comparing the levels of the lipid species detected as described above to reference levels of the lipid species (pg. 20, lines 18-19; comparing the levels etc. of biomarkers in the sample to the levels etc. of the biomarkers in a control sample) and a step of determining whether the subject has AD or is likely or not to develop AD on the basis of the comparison (pg. 20, lines 20-21; stratifying the subject into a subgroup of subject (e.g. having AD or at elevated risk to develop AD) based on the measured concentration levels in the sample as compared to a control sample). Lim also teaches assessing AD according to the disclosed method and administering AD treatment based upon the results of the method (pg. 55, lines 4-6). As such, Lim teaches stratifying the subject into a subgroup based on a unique and specific mitochondrial metabolic profile (the profile of the AD subjects is distinct from the profile of the non-AD but high risk subjects, for example) and also teaches administering therapy based on this determination (treatment is administered to a patient diagnosed as having AD, but not to one diagnosed as not having AD).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. § 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. § 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 4-6, 12-15 are obvious over Lim and Ciavardelli:
Claims 4-6, 12-15 are rejected under 35 U.S.C. § 103 as being unpatentable over Lim, in view of the non-patent publication, Medium-chain plasma acylcarnitines, ketone levels, cognition, and gray matter volumes in healthy elderly, mildly cognitively impaired, or Alzheimer's disease subjects, 43, pgs. 1-12 (2016) by Ciavardelli et al. (hereinafter, “Ciavardelli”).
Claim 4 recites a method for stratifying and treating a subject having a neurological disorder, or at risk of developing a neurological disorder, based on the subject's mitochondrial metabolic profile. The method includes steps of:
(a) obtaining a sample from the subject;
(b) measuring the concentration levels and calculating the ratios of one or more mitochondrial biomarker metabolites in the sample, wherein the one or more mitochondrial biomarker metabolites are selected from carnitine, short-chain acylcarnitines, medium-chain acylcarnitines, or long-chain acylcarnitines; ketone bodies; amino acids, branched chain amino acids; biogenic amines; glycerophospholipids; sphingolipids; short-chain fatty acids; endocannabinoids; eicosanoids; other metabolites of glycolysis, TCA cycle, fatty acid beta-oxidation, urea cycle, or ketogenesis; or combinations thereof;
(c) determining if the subject has a mitochondrial metabolic defect related to disrupted acylcarnitine homeostasis, TCA cycle, glycolysis, fatty acid beta-oxidation, ketogenesis, urea cycle, or combinations thereof based on the measured concentration levels and calculated ratios of the one or more mitochondrial biomarker metabolites in the sample as compared to a control sample; and
(d) stratifying the subject into a subgroup of subjects, wherein an individual subgroup of subjects is defined by a unique and specific mitochondrial metabolic profile based on the measured concentration levels and calculated ratios of the one or more mitochondrial biomarker metabolites in the sample as compared to a control sample and the mitochondrial metabolic defect determined for the subject.
Note that the preamble of claim 4 is regarded as limiting only to the extent that it limits the choice of subjects to those having, or at risk of developing, a neurological disorder. The preambular recitation of “stratifying and treating” is understood only as a purpose, or hoped-for outcome, of the method, that does not further limit or add any detail to the manner in which the method is performed.
Lim, as discussed above in reference to rejection of claim 20 for anticipation, teaches a method of determining the presence of, or risk of developing, Alzheimer’s disease (AD) in a subject (e.g. pg. 19, lines 27-28; thus the method is directed to people having a neurological disorder or potentially at risk of developing a neurological disorder). Lim teaches the method includes a step of detecting in a biological sample from the subject a level of at least two lipid species selected from a group that includes acylcarnitine, ceramide (a sphingolipid), glycerophosphatidylcholine (a glycerophospholipid), and several other lipids that are encompassed by the categories of instant paragraph [0008] (see pg. 19, line 29 through pg. 20, line 4 of Lim). Lim further makes explicit that the sample is obtained from an individual (pg. 15, lines 16-21), and thus teaches (a), obtaining a sample from the subject and (b) concentration levels of one or more biomarker metabolites related to mitochondrial function in the sample. As noted above, determining a ratio of biomarker levels is deemed optional, however, Lim expressly teaches that lipid level data may be processed to produce a report of levels and/or ratios (pg. 17, lines 23-24).
Lim further teaches a step of comparing the levels of the lipid species detected as described above to reference levels of the lipid species (pg. 20, lines 18-19; comparing the levels etc. of biomarkers in the sample to the levels etc. of the biomarkers in a control sample) and a step of determining whether the subject has AD or is likely or not to develop AD on the basis of the comparison (pg. 20, lines 20-21; stratifying the subject into a subgroup of subject (e.g. having AD or at elevated risk to develop AD) based on the measured concentration levels in the sample as compared to a control sample). Lim thus teaches the first three steps of the method of claim 4 and the fifth step of method with the exception that the stratification is not expressly based, in part, on a mental determination of a recited mitochondrial defect. Lim does not express teach the fourth step of (mentally) determining if the subject has a recited mitochondrial metabolic defect based on the measured concentration levels, and considering this determination of a metabolic defect in the fifth (stratification) step.
It would have been obvious, however, to determine the subject has a mitochondrial metabolic disorder such as impaired ketogenesis, based on the lipid levels and ratios of Lim, because the coincidence of defective mitochondrial metabolic processes, like ketogenesis, with alterations in was well-known in the art. See, for example, Ciavardelli.
Ciavardelli teaches measurements of lipid levels in three groups of subjects: healthy elderly control subjects (HC), mildly cognitively impaired subjects (MCI), and Alzheimer’s disease (AD) patients (Abstract). Ciavardelli demonstrates correlations between lipid levels/ratios and the grouping (HC, MCI, or AD) of the subjects; for example Ciavardelli teaches that the C12:1/C14 acylcarnitine ratio can distinguish HC from AD subjects and the C14:1/C14 acylcarnitine ratio can distinguish MCI from AD subjects (paragraph spanning the right column of pg. 6 to the top of the left column of pg. 7).
Ciavardelli further teaches significantly lower acylcarnitine levels overall in the AD patients (Abstract), including that lower levels of medium-chain acylcarnitines and free carnitine (pg. 5, section 3.1 Plasma ACC profiles of the study cohort) as well as b-HBA (pg. 7, Analysis of plasma b-HBA in the study cohort, second paragraph) are not only correlated to incidence of AD, but are also interpreted as correlating to defective functioning of hepatic FAO (pg. 12, Conclusions, first paragraph) and impaired ketogenesis (pg. 10, left column, first paragraph). Ciavardelli further teaches that
It would have been obvious, when performing the method of Lim, to specifically focus on acylcarnitine levels/ratios and b-HBA levels, as taught by Ciavardelli, to particularly distinguish subgroups such as AD subjects and MCI subjects. It would further have been obvious, when observing diminished acylcarnitine levels and/or b-HBA levels in subjects, to mentally note the impaired ketogenesis and reduced fatty acid beta-oxidation that correlate with these metabolic alterations. In short, Ciavardelli teaches the step of determining if the subject has a mitochondrial metabolic defect that is not expressly taught by Lim, and it would have been obvious to note this known correlation when performing the method of Lim. Claim 4 is therefore obvious over Lim as modified by Ciavardelli.
With respect to claim 5, Lim teaches assessing AD according to the disclosed methods (i.e. according to the method of Lim, as modified by Ciavardelli) and administering AD treatment based upon the results of the method (pg. 55, lines 4-6). With respect to claim 6, the acylcarnitines of Ciavardelli expressly include medium-chain and long-chain acylcarnitines such as C12, C14, and C14:1 acylcarnitines (paragraph spanning the right column of pg. 6 to the top of the left column of pg. 7).
With respect to claim 12, the AD of Lim and Ciavardelli is a CNS disorder.
With respect to claims 13-14, claim 14 depends from claim 13, and recites essentially the same method as does claim 4, except that the claim recites measuring the expression level and/or activity of one or more mitochondrial enzymes and or transporters involved in mitochondrial metabolism, rather than measuring the concentration levels and calculating the ratios of one or more mitochondrial biomarker metabolites selected from the recited group. However, as noted, Ciavardelli teaches the measurement of plasma b-HBA (2-hydroxybutyric acid) (pg. 2, left column, final paragraph), the levels of which are indicative of the activity of enzymes such as HMG-CoA Synthase 2 and b-hydroxybutyrate Dehydrogenase 1, both of which are involved in ketogenesis (see, for example, the non-patent publication, Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis, Mol. Metab., 61, art. 101494 pgs. 1-18 (2022) by Asif et al). Ciavardelli and Lim also teach the measurement of plasma carnitine and acylcarnitines, both of which are indicators of the activity of enzymes such as carnitine palmitoyltransferases which are involved in acylcarnitine biosynthesis (see, for example, the non-patent publication, L-Carnitine and Acylcarnitines: Mitochondrial Biomarkers for Precision Medicine, Metabolites, 11, art. 11010051 pgs. 1-21 (2021) by McCann et al. (hereinafter, “McCann”)). As such, claims 13-15 are obvious over Lim and Ciavardelli for the same reason that claims 4 is, and because the measuring carnitine and acylcarnitines of Lim and Ciavardelli and measuring b-HBA of Ciavardelli is both a step of measuring mitochondrial metabolites of claim 4 and a step of measuring the activity level of one or more mitochondrial enzymes of claim 13.
Claim 15, depending from claim 14, is analogous to claim 5 and is obvious over Lim and Ciavardelli for the same reason as is claim 5, in view of the reasoning applied to claims 13 and 14. With respect to claim 16, as noted, the measured levels of plasma acylcarnitines in the method of Lim/Ciavardelli is a marker of the activity of, among other enzymes, carnitine palmitoyltransferases 1 and 2 (see McCann).
Claims 9, 18, and 29 are obvious over Lim, Ciavardelli, and Henderson:
Claims 9, 18, and 29 are rejected under 35 U.S.C. § 103 as being unpatentable over Lim, in view of Ciavardelli, further in view of U.S. Patent No. 9,603,823 to Henderson (hereinafter, “Henderson”).
Claims 9 and 29 recite the method of claim 5 wherein the therapy comprises one or more selected from a list that includes various categories of compounds and specific compounds. Claim 18 recites the method of claim 15 wherein the therapy is selected from the same list as that of claim 9. All three lists have several compounds or types of compounds in common, such as medium chain fatty acids.
Lim and Ciavardelli are applied to claims 9, 18, and 29 as to claims 5 and 15, above, but, while Lim teaches administering a therapy to a subject identified as having AD, neither Lim nor Ciavardelli discloses the use of specific therapies that are recited in claims 9, 18, and 29. It would have been obvious, however, to use such a therapy, because the use of many of the recited compounds for AD therapy was well-known in the art. See, for example, Henderson.
Henderson teaches a method of treating or preventing dementia of Alzheimer's type, or other loss of cognitive function caused by reduced neuronal metabolism, comprising administering an effective amount of free fatty acids derived from medium chain triglycerides to a patient in need thereof (col. 9, lines 19-24). Henderson further teaches that medium chain fatty acids promote increased blood levels of ketone bodies, while Ciavardelli teaches, as noted, a likely reduced ketogenesis in AD subjects, and further teaches that ketone bodies counteract counteract neuronal hyperexcitability that is a contributing factor in AD-related neuronal loss (pg. 10, left column, first two full sentences). It thus would have been obvious to administer medium chain fatty acids, as taught by Henderson, as the treatment administered to subjects determined to have AD in the method of Lim and Ciavardelli, in order to ameliorate symptoms and counteract AD-related neuronal loss.
Claims 29-31 are obvious over Lim, Ciavardelli, and Herrmann:
Claims 29-31 are rejected under 35 U.S.C. § 103 as being unpatentable over Lim, in view of Ciavardelli, further in view of the non-patent publication, Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease, 27, pgs. 1161-1173 (2019) by Herrmann et al. (hereinafter, “Herrmann”).
Claims 29-31 recite the method of claim 5 wherein the therapy comprises one or more selected from a list that includes various categories of compounds and specific compounds, such as nabilone (claims 29-30) and anxiolytics (claim 31).
Lim and Ciavardelli are applied to claims 29-31 as to claim 5, above, but, while Lim teaches administering a therapy to a subject identified as having AD, neither Lim nor Ciavardelli discloses the use of specific therapies that are recited in claims 29-31. It would have been obvious, however, to use such a therapy, because the use of many of the recited compounds for AD therapy was well-known in the art. See, for example, Herrmann.
Herrmann discloses a 14-week randomized double-blind crossover trial comparing nabilone to placebo for the treatment of agitation in patients with moderate-to-severe AD (Abstract). Based on the results, Herrmann teaches that nabilone may be an effective treatment for agitation in AD subjects (Abstract; Conclusions), based on moderately lower agitation scores in the nabilone cohort as compared to the placebo cohort (Figure 2). Herrmann notes that agitation is seen in 20%-50% of those with moderate-to-severe Alzheimer’s. It would have been obvious to administer nabilone as a treatment to subjects identified in the method of Lim and Ciavardelli as having AD, at least to the portion exhibiting agitation, in order to ameliorate the symptom as taught by Herrmann.
With respect to claim 31, nabilone can be regarded as an anxiolytic (i.e. a compound having anxiolytic or anxiety-reducing properties). See, for example, the non-patent publication, The efficacy and safety of nabilone (a synthetic cannabinoid) in the treatment of anxiety, 21, pgs. 377S-1173 (1981) by Fabre et al. (Abstract only supplied), which refers to “the anxiolytic properties of nabilone” (Abstract).
Claims 31-32 are obvious over Lim, Ciavardelli, and Cirrito:
Claims 31-32 are rejected under 35 U.S.C. § 103 as being unpatentable over Lim, in view of Ciavardelli, further in view of the non-patent publication, Effect of escitalopram on Aβ levels and plaque load in an Alzheimer mouse model, 95, pgs. e2666-e2674 (2020) by Cirrito et al. (hereinafter, “Cirrito”).
Claims 31-32 recite the method of claim 5 wherein the therapy comprises one or more selected from a list that includes various categories of compounds and specific compounds, such as nabilone (claims 29-30) and anxiolytics (claim 31).
Lim and Ciavardelli are applied to claims 31-32 as to claim 5, above, but, while Lim teaches administering a therapy to a subject identified as having AD, neither Lim nor Ciavardelli discloses the use of specific therapies that are recited in claims 31-32. It would have been obvious, however, to use such a therapy, because the use of many of the recited compounds for AD therapy was well-known in the art. See, for example, Cirrito.
Cirrito teaches a study of the effect of acute and chronic treatment with escitalopram on Ab plaque size in the brain interstitial fluid and in the histologically examined brain sections of AD model mice (Abstract). Cirrito teaches that chronic escitalopram treatment significantly reduced the appearance of new [Symbol font/0x41]β plaques compared to vehicle-treated animals (pg. e2671, Discussion, first paragraph), indicating a potential therapeutic role for preventing or slowing the progression of AD. It would have been obvious to administer escitalopram to subject determined to have AD or be at high risk of developing AD (such as MCI subjects) in the method of Lim and Ciavardelli, to slow or prevent [Symbol font/0x41]β plaque formation and potentially delay disease progression, as taught by Cirrito.
Conclusion
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629