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 .
DETAILED ACTION
This Office Action is in response to Applicant’s Arguments and Amendment filed, 10/02/2025, wherein the Amendment amended claims 9, 11, cancelled claims 23 and 27, and added claims 38-40.
Claims 9, 11, 22, 24-26, 28-29, and 38-40 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant elected Group II, and the following species:
EPA and DHA as the omega-3 fatty acid species,
25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 as the vitamin D species, and
betaine as the species capable of reducing plasma homocysteine levels in the reply filed on 06/01/2022.
In the course of the search, the election of species requirement has been withdrawn.
It is noted that claims directed to Group II have been deleted.
Claims 9, 11, 22, 24-26, 28-29, and 38-40 are examined on the merits herein.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s amendments to claims 9 and 11 are sufficient to overcome the objections over these claims.
Double Patenting
Applicant’s argument that Application No. 18/120,189 is a divisional of the present application is sufficient to overcome this rejection.
REJECTIONS—MAINTAINED, MODIFIED, and NEW
In view of the amendments to independent claims 9 and 11, and the addition of claims 38-40, the previous prior art rejections have been modified.
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.
(Modified) Claims 9, 11, 22, 24-26, 28-29, and 38-40 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0268940 to Bredesen (published 2018, PTO-892 of 12/12/2022), in view of Ueland (Total homocysteine in plasma or serum: methods and clinical applications, Clin. Chem., published 1993, IDS of 02/19/2025), Hann (The Am Jn of Clin Nutrition, published 2007, PTO-892 of 4/3/2023), Bowman (Neurology, published 2012, PTO-892), WO 02/03074 to Orning (published 2002, IDS of 10/08/2019), Lee (Arch. Gerontol. Geriatr., published 2009, PTO-892), and US 2007/0078114 to Hobden (published 04/05/2007-PTO-892 of 07/13/2022).
Bredesen teaches a method of treating, reducing or reversing cognitive decline in an individual comprising a) assessing at least 6 factors of Table 1, and b) optimizing these factors if they are abnormal, wherein the optimizing is achieved by performing one or more optimization approaches associated with the factors (pg. 22, claims 1-2, 15; pg. 4-7, Table 1).
Bredesen additionally teaches the assessment of 10 factors, wherein vitamin D levels, such as vitamin D3 levels, homocysteine levels, EPA levels, and DHEA levels, are factors that are measured (pg. 22, claims 6 and 8; pg. 22, claims 10-11).
Bredesen teaches its methods of assessment as computer-implemented methods for implementation of one or more data processors forming part of at least one computing device to facilitate treating, reducing or reversing cognitive decline by receiving, at the one or more data processors, parameters of a patient, comparing, at the one or more data processors, the patient parameters with predefined ranges for the set of physiological characteristics, and determining, at the one or more data processors, a memory loss risk factor for the patient based on the comparison, and determining, by one or more data processors, a memory loss treatment plan based on the patient parameters that exceed the predefined ranges for the associated physiological characteristics, wherein the physiological characteristics include at least 6 factors of Table 1 (pg. 23, claims 29-35).
Bredesen states the following, “The received patient parameters can be compared against predefined ranges for the set of physiological characteristics. The predefined ranges can include the ranges provided in Table 1 and Table 2. A memory loss risk factor is determined for the patient based on the comparison. The memory loss risk factor provides an indication of the current and/or future severity of a patient’s cognitive decline (paragraph 164). The determined memory loss risk factor may be a single score or a combination of scores, presented as an aggregate or individually. The memory loss risk factor can be a binary indicator of cognitive decline. Based on the type and/or number of factors for which the patient exceeds the predefined acceptable range, the patient is identified as being at-risk, or not at-risk for cognitive decline. The determined memory loss risk factor may be a single score. The determined memory loss risk factor may be a combination of scores, presented as an aggregate or individually. The patient parameters that exceed the predefined ranges for the associated physiological characteristics can be aggregated to facilitate provision of the memory loss risk factor. The memory loss risk factor can be a binary indicator of cognitive decline” ([0163]-[0165]).
Specifically exemplified is a patient diagnosed with subjective cognitive impairment and slowly progressive memory loss, who was determined to have a 18 mmol/l homocysteine level. As a treatment, the patient was administered 1 mg methylcobalamin (agent capable of reducing plasma homocysteine levels), 50 mg/day pyridoxine-5-phosphate (P5P) (agent capable of reducing plasma homocysteine levels), 5000IU vitamin D3/day, 320mg/day DHA bid, 180mg/day mg EPA bid, and other compounds; after months, his memory was improved and his memory decline was halted ([0193]-[0197], [0203]; pg. 4, Table 1).
Regarding claim 9, while Bredesen teaches determining a memory loss risk factor for a patient by measuring levels of at least homocysteine against controls, and administering at least pyridoxine-5-phosphate (an agent capable of reducing plasma homocysteine levels), vitamin D3, DHA and EPA, it differs from that of the instantly claims invention in that it does not teach assigning a score of n to the homocysteine level.
Ueland teaches total plasma homocysteine values between 5 and 15 mmol/L as normal (abstract).
Hann teaches that high concentrations of homocysteine are linked to a greater risk of Alzheimer’s disease, dementia and cognitive decline and that homocysteine is an independent risk factor for both dementia and cognitive impairment without dementia (CIND) (abstract). Evaluating the association between homocysteine and dementia and CIND is taught (abstract).
Analyses were restricted to participants who were free of dementia or CIND at baseline and who had valuable data on the biomarkers of interest, such as homocysteine (pg. 512).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select homocysteine levels of greater than about 14 µmol or higher as indicative to pre-disposition to cognitive decline, to arrive at instant claim one. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Bredesen teaches a method of detecting levels of various biomarkers to compare against predefined ranges, to diagnose cognitive impairment, and then administering a therapeutic regimen to optimize abnormal factors,
-Bredesen teaches homocysteine levels as such a biomarker,
-Hann teaches high concentrations of homocysteine as linked to a greater risk of Alzheimer’s disease, dementia and cognitive decline and teaches homocysteine as an independent risk factor for both dementia and cognitive impairment without dementia, and
-Ueland teaches total plasma homocysteine values between 5 and 15 mmol/L as normal.
As such, an ordinary artisan would have been motivated to make such a selection to predictably arrive at a more precise method of detecting cognitive impairment and/or determining the effectiveness of treatment.
Further regarding claim 9, while the combination of Bredesen, Ueland, and Hann teaches determining a memory loss risk factor for a patient by measuring levels of at least homocysteine against controls wherein an amount greater than about 14 µmol or higher is indicative of cognitive decline, and administering at least pyridoxine-5-phopshate, vitamin D3, DHA and EPA, it differs from that of the instantly claims invention in that it does not teach calculating an NRI.
Bowman teaches correlations between nutrient biomarker patterns, cognitive function and MRI measures of brain aging (abstract, title), and teaches that reliable blood tests that assess nutritional status in people at risk for dementia are known (pg. 241).
Distinct nutrient biomarker patterns detected in plasma are interpretable and account for a significant degree of variance in both cognitive function and brain volume (pg. 241).
The cross-sectional relationship between nutrient status and psychometry and
imaging indices of brain health is evaluated (pg. 241). Thirty plasma biomarkers of diet were assayed. Principal component analysis of the biomarkers led to the construction of nutrient biomarker patterns (NBPs) and regression models to assess the relationship of nutrients with cognitive and MRI outcomes (pg. 241).
Two NMPs associated with more favorable cognitive and MRI measures are high
plasma vitamins B, C, D and E and high omega 3 fatty acid levels (pg. 241).
Nutrient biomarker patterns using principal component analysis (PCA) is used to capture the effect of nutrients in combination (pg. 241). Table 2 teaches the plasma nutrient biomarkers and the pattern structure and variance of the nutrient biomarker pattern construction (pg. 244). Table 3 teaches nutrient biomarker patterns associated with cognitive function (pg. 245).
Cognitive benefit is gained by a plasma profile high in antioxidants C and E, B vitamins, and vitamin D (pg. 246, Col. 2).
The ability of nutrient biomarker patterns to predict cognitive and brain volume changes offers compelling data (pg. 247). Studies can decipher key nutrient combinations and populations best suited for intervention (pg. 247).
Orning ‘074 teaches a diagnostic or prognostic assay method for Alzheimer’s Disease (abstract title).
The method comprises assaying a body fluid sample or a test sample, such as blood or serum, testing a nutrient level, such as transcobalamin II, and comparing the level with a pre-determined threshold value and assigning the assay result as indicative or non-indicative of Alzheimer’s disease (pgs. 4-5, the spanning paragraph, pg. 9 claims 1-3). Transcobalamin levels are calibrated against transcobalamin levels in a control group of healthy people of the same age range and a group confirmed to suffer from Alzheimer’s disease (AD) in the same age range. This is followed by the step of comparing the transcobalamin value with such predetermined calibration values so as to categorize or stage the human source of the sample as probably having or not having AD or as having AD at a particular stage of development. (pg. 6, last full paragraph).
Vitamin B12, folate and total homocysteine are also taught as levels that are measured in the above method (pg. 9, claims 4-6).
Results were analyzed by mean values and odds-ratios. A value greater than one indicated risk (pg. 7, bottom, pg. 8—Table).
Lee teaches nutritional risk and cognitive impairment in the elderly (abstract, title).
Multiple logistic regression analysis revealed that moderate or high nutritional risk subjects were associated with an increased risk of cognitive impairment (abstract). Blood pressure, fasting serum glucose level, lipid profile, BMI and ApoE genotype were examined (abstract).
Several studies have demonstrated that nutritional factors are linked with Alzheimer’s disease, both as risk or protective factors in the onset of the disease and as elements that are capable of modifying the disease. Therefore, nutritional screening tools should be included in the multidimensional geriatric evaluation of elderly patients (pg. 96, top).
To assess the nutritional state of the elderly, an NSI checklist is utilized (pg. 96, Col. 1). The NSI comprises 10 questions that assess nutritional state (pg. 96, Col. 2, 2.2).
Moderate or high nutritional risk state according to NSI checklist is associated with cognitive impairment (pg. 96, Col. 1; pg. 97, Table 2, 3.2).
The association between altered nutritional status and predictor of severity and progression of cognitive impairment underscores the importance of systematic nutritional assessment at the time of diagnosis and during the follow-up of cognitive impairment cases in order to implement nutritional intervention as soon as it is deemed necessary (pg. 98, Col. 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select and apply the teachings of Bowman, Orning, and Lee to the combined methods of Bredesen, Ueland, and Hann, to arrive at the instantly claimed method of calculating NRI. One of ordinary skill in the art would have been motivated make such a selection and application, with a reasonable expectation of success, because:
-the combination of Bredesen, Ueland, and Hann teach measuring biomarkers of
vitamin D, omega-3 fatty acid and homocysteine levels, and comparing these levels with a baseline measure of a parameter of disease, for the purpose of diagnosing cognitive impairment and for determining the effectiveness of treatment/treatment plans;
-Bowman teaches a) that assessing nutritional status in people at risk for dementia
through reliable blood tests is known; b) analysis and application of nutrient biomarker patterns to predict cognitive changes; c) analysis of principal component constructed nutrient biomarker patterns (NBPs) and regression models to assess the relationship of these with cognitive outcomes; d) measuring vitamins such as vitamin B, D and omega 3 fatty acids; and e) that the ability of nutrient biomarker patterns to predict cognitive changes offers compelling data;
-Orning teaches methods of measuring nutrient levels, such as total homocysteine and other vitamins/nutrients, and comparing these levels with predetermined calibration values so as to categorize or stage the human source of the sample as probably having or not have Alzheimer’s disease; and
-Lee teaches that multiple logistic regression analysis reveals that moderate or high
nutritional risk is associated with increased risk of cognitive impairment, and teaches that the association between altered nutritional status and predictor of severity and progression of cognitive impairment underscores the importance of systematic nutritional assessment at the time of diagnosis and during the follow-up of cognitive impairment cases in order to implement nutritional intervention as soon as it is deemed necessary.
While the above references do not explicitly teach NRI as recited by the instant claims, the prior art teaches that it is well known to measure the nutrient levels of vitamin D, homocysteine, and omega-3 fatty acids, to compare these levels against a baseline, and to use this data to diagnose a cognitive impairment/disease, assess the stage of cognitive impairment/disease, and/or determine and implement nutrition based treatments. As such, an artisan having ordinary skill in the art would have been motivated to select homocysteine levels higher than the average baseline as an indicator of pre-disposition to cognitive decline and as a result, administer a composition known to decrease homocysteine levels, for the purpose of optimizing cognitive health and minimizing cognitive decline.
In summary, the above paragraphs show that it is known in the art to evaluate nutritional markers, such as levels of omega-3 fatty acids, vitamin D and homocysteine, and to mathematically/statistically compare these levels against baseline levels to determine whether or not a patient is suffering from or at risk of suffering from a cognitive impairment. As such, in view of the teachings of the prior art, calculating the NRI, wherein a score of n is 1 is assigned to a homocysteine level of about 14 µmol or higher, as recited in the instant claims, is well within the skill level of an ordinarily skilled artisan.
Further regarding claim 9, while the combination of Bredesen, Ueland, Hann, Bowman, Orning, and Lee teaches the methods of instant claims 9 and 11, it differs from that of instant claim 9 in that it does not teach additionally administering 25-hydroxyvitamin D2.
Bredesen exemplifies Vitamin D as Vitamin D3 (pg. 9, Table 2; [0072]; [0147]-[0149; [0192];[0197]; [0202]).
Hobden teaches methods of treating neurodegenerative disorders, Alzheimer’s disease, dementia, and mild cognitive impairment, with a composition comprising an Aß42 lowering agent and a hormonal modulating agent (pgs. 22-23, claims 25-28). Vitamin D3 derivatives are taught as hormonal modulating agents (pg. 22, claim 6).
Hobden teaches calcidiol, which is 25-hydroxvitamin D3, and ercalcidiol, which is 25-hydroxyvitamin D2, as interchangeable and combinable vitamin D3 related compounds for use as hormonal modulating agents (paragraphs 70 and 71).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the vitamin D3 of the combination of Bredesen, Ueland, Hann, Bowman, Orning, and Lee with a combination of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, to arrive at instant claims 23 and 27. One of ordinary skill in the art would be motivated to make such a substitution, with a reasonable expectation of success, because:
-Hobden and the combination of Bredesen, Ueland, Hann, Bowman, Orning, and Lee, are both directed toward methods of treating cognitive decline,
-Hobden teaches vitamin D3 related compounds, such as 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, as interchangeable and combinable Vitamin D3 for use in treating cognitive decline, and
-substituting equivalents known for the same purpose is prima facie obvious, see MPEP 2144.06.
As such, an ordinary skilled artisan would have been motivated to make such a substitution to predictably arrive at a formulation that provides the therapeutic benefit and optimization of vitamin D3 for treating cognitive decline/impairment.
Regarding claim 11, since the combination of Bredesen, Ueland, Hann, Bowman, Orning, Le, and Hobden teaches the method of claim 9, this method would necessarily reduce plasma homocysteine levels. MPEP 2111.02 states, if the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. Moreover, Bredesen teaches administering methylcobalamin and pyridoxal-5-phosphate (P5P), two compounds which reduce homocysteine levels ([0197]; pg. 4, Table 1).
Regarding claims 22 and 26, Bredesen teaches EPA and DHA ([0193]-[0197], [0203]).
Regarding claim 24, 28, and 40, Bredesen teaches, for example, a 69 year old man ([0194]).
Regarding claims 25, 29, and 38-39, Bredesen teaches trimethylgycine, M-B12, a vitamin B12, M-folate, P5P, and methylcobalamin as optimization approaches for high homocysteine levels (pg. 4, Table 1). As such, an artisan having ordinary skill in the art would have been motivated to substitute the methylcobalamin or P5P ([0193]-[0197], [0203]), with trimethylgycine or M-B12, to arrive at instant claims 25, 29, and 38-40. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because substituting equivalents known for the same purpose is prima facie obvious, see MPEP 2144.06. Alternatively, an artisan having ordinary skill in the art would have been motivated to add trimethylgycine to the combined method of Bredesen, Ueland, Hann, Bowman, Orning, and Lee because "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). MPEP 2144.06
Response to Arguments
On pgs. 7-8, Remarks, Applicant argues that Hobden does not teach the instantly claimed methods wherein a combination of 25-hydroxyvitamin D3 and D2, is administered. Regarding Hobden, Applicant argues that the Office has not provided a sufficient motivation for the skilled artisan to select a combination of 25-hydroxyvitamin D3 and D2.
On pg. 9, Remarks, Applicant argues that [0071] of Hobden merely discloses that vitamin D3 and a laundry list of related derivatives can act as hormonal modulators.
This argument has been fully considered, but is not found persuasive. It is first noted that [0071] is not a laundry list, but recites twenty-two Vitamin D3 related compounds:
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. Since the methods of Bredesen are directed toward a method of optimizing the vitamin D levels in a patient with low vitamin D levels and cognitive decline, by administering vitamin D (Table 1), and exemplifies the administration of vitamin D3, and since Hobden teaches vitamin D derivatives as useful for treating cognitive decline, and teaches 25-hydroxyvitmain D3 and 25-hydroxyvitmain D2 as Vitamin D3 related compounds that can be combined, an ordinary skilled artisan would have been motivated to substitute the vitamin D3 of Bredesen with a combination of vitamin D3 and 25-hydroxyvitamin D2, which Hobden teaches as Vitamin D3 related compounds, to arrive at an optimized formulation for increasing in-vivo vitamin D levels, and thus treating cognitive decline.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the vitamin D3 of the combination of Bredesen, Ueland, Hann, Bowman, Orning, and Lee with a combination of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, to arrive at instant claim 9. One of ordinary skill in the art would be motivated to make such a substitution, with a reasonable expectation of success, because:
-Hobden and the combination of Bredesen, Ueland, Hann, Bowman, Orning, and Lee, are both directed toward methods of treating cognitive decline,
-Hobden teaches vitamin D3, 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, as interchangeable and combinable Vitamin D related compounds, and
-substituting equivalents known for the same purpose is prima facie obvious, see MPEP 2144.06.
As such, an ordinary skilled artisan would have been motivated to make such a substitution to predictably arrive at a formulation that provides the therapeutic benefit of vitamin D for treating cognitive decline/impairment.
On pg. 9, Remarks, Applicant argues that Hobden has not provide any relevant teaching towards the specific selection of 25-hydroxyvitmian D3 and D2 as biomarkers.
This argument has been fully considered, but is not found persuasive. Independent claims 9 and 11 do not require a determination of the level of hydroxyvitamin D3 and D2, since these claims recite “wherein calculating the NRI of the subject comprises at least one of: (a….(b). . .or (c).” Since the primary reference, Bredesen teaches determining (c), a level of homocysteine, this limitation is met.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.Q.W./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622