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 .
All previous objections and rejections not reiterated herein were overcome by claim amendments and arguments, filed December 31st, 2025, have been fully considered and found persuasive. As such all objections and rejections not reiterated herein have been withdrawn.
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.
Claims 1 – 3, 6, 9 – 10, 12 – 13, 16, 20 – 21, and 23 – 24 are rejected under 35 U.S.C. 103 as being unpatentable over Greer et.al. ((2014), Does Duloxetine Improve Cognitive Function Independently of Its Antidepressant Effect in Patients with Major Depressive Disorder and Subjective Reports of Cognitive Dysfunction?, Depression Research and Treatment, 2014, 1 – 13; cited in the last office action dated January 27th, 2025) in view of Duff et. al. ((2010), Diagnostic Accuracy of the RBANS in Mild Cognitive Impairment: Limitations on Assessing Milder Impairments, Archives of Clinical Neuropsychology, 25, 429-441; cited in the last office action dated October 1st, 2025) and Johnson ((2017), The Use of Duloxetine for Cognition Improvement in Individuals With Mild Cognitive Impairment (DEMO), NCT02590874, Version 6; cited in the last office action dated January 27th, 2025).
Regarding claims 1 – 3, 6, 9 – 10, 12 – 13, 16, 20 – 21, and 23 – 24, Greer et. al. teach that cognitive deficits are commonly reported by patients with major depressive disorder (MDD) (page 1 column 1 paragraph 1). Additionally, Greer et.al. teach that treatment with selective serotonin reuptake inhibitors (SSRIs) has resulted in improved attention memory and learning (page 1 column 2 paragraph 2). Moreover, Greer et.al. teach that duloxetine (claims 2 and 12) is a well-tolerated, efficacious SNRI antidepressant that has been shown to increase extracellular 5-HT, norepinephrine, and dopamine in rat frontal cortex and has been associated with serotonergic and noradrenergic reuptake in humans (page 2 column 1 paragraph 3). Furthermore, Greer et. al. teach that although previous work on cognitive functioning has stressed the importance of intact dopaminergic levels, particularly with respect to functions mediated by prefrontal cortex, such as working memory, it is now being recognized that norepinephrine plays a similarly important role and that both neuromodulators have distinct roles to facilitate information processing in the prefrontal cortex (page 2 column 1 paragraph 3).
Greer et. al. teach that the primary objective of the study was to assess the effect of duloxetine treatment on cognitive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in young adults to middle-aged adults with MDD (page 2 column 2 paragraph 2). Additionally, Greer et.al. teach that duloxetine (claim 2), that is N-methyl-y-(1-naphthalenyloxy)-2-thiopropanamine hydrochloride (claims 6 and 16), was administered at 30 mg per day (claims 3 and 13) for the first four days then increased to 60 mg per day (claims 3 and 13) (page 5 column1 paragraph 2). Moreover, Greer et.al. teach that posthoc analyses of the cognitive domains assessed: revealed significant improvements from baseline on specific tasks within 3 of the cognitive domains— with an increase in verbal recognition memory (claim 1) and delayed matching to sample (page 9 Figure 2). Therefore, Greer et. al. teach a method of treating cognitive decline using the SNRI duloxetine in an effective amount to treat cognitive decline.
With regard to claim 9, the claim recites wherein the SNRI is provided in an amount sufficient to stabilize neurodegeneration or cognitive decline in DepE subjects having at least one of cognitive decline, mild-cognitive impairment, or Alzheimer's disease. The instant specification states that the sufficient amount given to stabilize cognitive decline is 10 – 60 mg daily (page 1). Greer et.al. teach that duloxetine was administered at 30 mg per day for the first four days then increased to 60 mg per day (page 5 column1 paragraph 2). Thus Greer et. al. teach the administration of the SNRI, duloxetine, at an amount sufficient to stabilize cognitive decline.
With regard to claim 10, the claim recites a method of claim 1, wherein the memory loss-related disease is dementia, or Alzheimer's disease; or the reduction in memory loss is in a cognitively normal older adult. The wherein clause of claim 10 narrows the scope of memory loss-related disease, which is one of many options recited in claim 1. As discussed above, Greer et. al. teach a method of treating cognitive decline using the SNRI duloxetine in an effective amount to treat cognitive decline which is one of the many options recited in claim 1.
With regard to claim 20, the claim recites wherein the duloxetine is provided in an amount sufficient to stabilize neurodegeneration or cognitive decline in DepE subjects having at least one of cognitive decline, mild-cognitive impairment, or Alzheimer's disease. The instant specification states that the sufficient amount given to stabilize cognitive decline is 10 – 60 mg daily (page 1). Greer et.al. teach that duloxetine was administered at 30 mg per day for the first four days then increased to 60 mg per day (page 5 column1 paragraph 2). Thus Greer et. al. teach the administration of the SNRI, duloxetine, at an amount sufficient to stabilize cognitive decline.
With regard to claim 21, the claim recites a method of claim 12, wherein the memory loss-related disease is dementia, or Alzheimer's disease; or the reduction in memory loss is in a cognitively normal older adult. The wherein clause of claim 21 narrows the scope of memory loss-related disease, which is one of many options recited in claim 12. As discussed above, Greer et. al. teach a method of treating cognitive decline using the SNRI duloxetine in an effective amount to treat cognitive decline which is one of the many options recited in claim 12.
With regard to claim 23, that recites the limitation wherein the subject does not have depression, stress- induced incontinence, neuropathic pain or fibromyalgia. Claim 23 states the conditions in the alternative, thus the subject would only need to not exhibit any one of the conditions. As mentioned above, Greer et. al. teach that participants with another secondary comorbid medical condition were excluded from the study (page 3 column 1 paragraph 2). Thus Greer et.al. teach a subject population that does not exhibit fibromyalgia which is one of the options of the claim.
However, Greer et. al. fails to teach a method wherein the delayed memory scores are determined by testing immediate memory, visuospatial/constructional abilities, language, attention, and delayed memory (claims 12). Moreover Greer et. al. is silent about a depressive endophenotype (Dep E) scores (claims 12 and 24).
Nevertheless, Duff et. al. teach that mild cognitive impairment (MCI) is viewed as a transitional stage between healthy aging and dementia, and it is defined as cognitive decline greater than expected for an individual’s age and the education level but that does not notably interfere with activities of daily life (page 429 paragraph 1). Moreover, Duff et. al. teach that early detection of MCI may enable individuals to benefit from interventions that could potentially slow the course of the disease (page 429 paragraph 1). Furthermore, Duff et. al. teach that there is a growing need for measures that are both brief and sensitive in identifying this pattern of cognitive decline, that is MCI (page 429 paragraph 1). Additionally, Duff et. al. teach that the area under the curve (AUC) from the receiver operating characteristic (ROC) analyses suggested adequate separation between the two groups in the current study on measures of learning and memory (page 433 paragraph 3). Moreover, Duff et. al. teach that the specificity values for all memory-related subtests, which include immediate memory, visuospatial constructional, language, attention, and delayed memory (claim 1); and Indexes were 0.82 or better and negative predictive power was similarly high (page 433 paragraph 3). Furthermore, Duff et.al. teach that the delayed memory index and total scale indexes of RBANS had the best combination of sensitivity and specificity at the -1.0 SD cutoff (page 433 paragraph 3).
However, the prior art of Duff et. al. and Greer et. al. are silent about a depressive endophenotype (Dep E) scores (claims 12 and 24).
Nevertheless, Johnson teach a study to determine whether Cymbalta (duloxetine) (claim 12) is effective to improve cognition in individuals with Mild Cognitive Impairment (claims 12 and 21) (page 4 paragraph 1). Furthermore, Johnson teach that to be included in the study the person had to have an elevated DepE score (2 or more) (claim 24) (page 10 paragraph 5). Thus the identification step as recited in claim 24 was inherently completed in order to determine which subjects were suitable for treatment. Moreover, Johnson teach that the active group received duloxetine at 30 mg per day (claim 13) for 2 weeks, duloxetine at 60 mg per day for 4 months, then duloxetine at 30 mg per day for 2 weeks (page 8 – 9).
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Greer et. al. for a method for improving delayed memory scores in a subject in view of Duff et. al. to determine the immediate memory, visuospatial constructional, language, attention, and delayed memory scores and further in view of Johnson et. a., that is wherein the subjects has an elevated DepE score (2 or more). One of ordinary skill would have been motivated to make this modification as a way to briefly measure and identify MCI. Additionally, one of ordinary skill in the art would have a reasonable expectation of success because delayed memory index and total scale indexes of RBANS had the best combination of sensitivity and specificity at the -1.0 SD cutoff.
Claims 26 – 28, 30 – 31, and 33 – 34, are rejected under 35 U.S.C. 103 as being unpatentable over Greer et.al. ((2014), Does Duloxetine Improve Cognitive Function Independently of Its Antidepressant Effect in Patients with Major Depressive Disorder and Subjective Reports of Cognitive Dysfunction?, Depression Research and Treatment, 2014, 1 – 13; cited in the last office action dated January 27th, 2025) in view of Duff et. al. ((2010), Diagnostic Accuracy of the RBANS in Mild Cognitive Impairment: Limitations on Assessing Milder Impairments, Archives of Clinical Neuropsychology, 25, 429-441; cited in the last office action dated October 1st, 2025) and Johnson ((2017), The Use of Duloxetine for Cognition Improvement in Individuals With Mild Cognitive Impairment (DEMO), NCT02590874, Version 6; cited in the last office action dated January 27th, 2025).
Regarding claims 26 – 28, 30 – 31, and 33 – 34, Greer et. al. teach that cognitive deficits are commonly reported by patients with major depressive disorder (MDD) (page 1 column 1 paragraph 1). Additionally, Greer et.al. teach that treatment with selective serotonin reuptake inhibitors (SSRIs) has resulted in improved attention memory and learning (page 1 column 2 paragraph 2). Moreover, Greer et.al. teach that duloxetine (claim 33) is a well-tolerated, efficacious SNRI antidepressant that has been shown to increase extracellular 5-HT, norepinephrine, and dopamine in rat frontal cortex and has been associated with serotonergic and noradrenergic reuptake in humans (page 2 column 1 paragraph 3). Furthermore, Greer et. al. teach that although previous work on cognitive functioning has stressed the importance of intact dopaminergic levels, particularly with respect to functions mediated by prefrontal cortex, such as working memory, it is now being recognized that norepinephrine plays a similarly important role and that both neuromodulators have distinct roles to facilitate information processing in the prefrontal cortex (page 2 column 1 paragraph 3).
Greer et. al. teach that the primary objective of the study was to assess the effect of duloxetine treatment on cognitive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in young adults to middle-aged adults with MDD (page 2 column 2 paragraph 2). Additionally, Greer et.al. teach that duloxetine (claim 33) was administered at 30 mg per day for the first four days then increased to 60 mg per day (page 5 column1 paragraph 2). Moreover, Greer et.al. teach that posthoc analyses of the cognitive domains assessed: revealed significant improvements from baseline on specific tasks within 3 of the cognitive domains— with an increase in verbal recognition memory (claim 26) and delayed matching to sample (page 9 Figure 2). Therefore, Greer et. al. teach a method of improving cognitive decline using the SNRI duloxetine in an effective amount to treat cognitive decline.
With regard to claim 28, that recites the limitation wherein the subject does not have depression, stress- induced incontinence, neuropathic pain or fibromyalgia. Claim 28 states the conditions in the alternative, thus the subject would only need to not exhibit any one of the conditions. As mentioned above, Greer et. al. teach that participants with another secondary comorbid medical condition were excluded from the study (page 3 column 1 paragraph 2). Thus Greer et.al. teach a subject population that does not exhibit fibromyalgia which is one of the options of claim 28.
With regard to claim 30, that recites the limitation wherein the delayed memory score is without a diagnosis of MCI, dementia or Alzheimer’s disease. Claim 30 states the conditions in the alternative, thus the subject would only need to not exhibit any one of the conditions. As mentioned above, Greer et. al. teach that participants with another secondary comorbid medical condition were excluded from the study (page 3 column 1 paragraph 2). Moreover, as taught above, Greer et. al. teach that the subjects of the present study were diagnosed with major depressive disorder (MDD) not MCI, dementia or Alzheimer’s disease. Thus Greer et.al. teach a subject population that was not diagnosed with MCI, dementia or Alzheimer’s disease which are the options of claim 30.
However, Greer et. al. fails to teach a method wherein the delayed memory scores are determined by testing immediate memory, visuospatial/constructional abilities, language, attention, and delayed memory (claims 26). Moreover Greer et. al. is silent about a depressive endophenotype (Dep E) scores (claims 26).
Nevertheless, Duff et. al. teach that mild cognitive impairment (MCI) (claim 31) is viewed as a transitional stage between healthy aging and dementia, and it is defined as cognitive decline greater than expected for an individual’s age and the education level but that does not notably interfere with activities of daily life (page 429 paragraph 1). Moreover, Duff et. al. teach that early detection of MCI may enable individuals to benefit from interventions that could potentially slow the course of the disease (page 429 paragraph 1). Furthermore, Duff et. al. teach that there is a growing need for measures that are both brief and sensitive in identifying this pattern of cognitive decline, that is MCI (page 429 paragraph 1). Additionally, Duff et. al. teach that the area under the curve (AUC) from the receiver operating characteristic (ROC) analyses suggested adequate separation between the two groups in the current study on measures of learning and memory (page 433 paragraph 3). Moreover, Duff et. al. teach that the specificity values for all memory-related subtests, which include immediate memory (claim 27), visuospatial constructional, language, attention, and delayed memory (claim 26); and Indexes were 0.82 or better and negative predictive power was similarly high (page 433 paragraph 3). Furthermore, Duff et.al. teach that the delayed memory index and total scale indexes of RBANS had the best combination of sensitivity and specificity at the -1.0 SD cutoff (page 433 paragraph 3).
However, the prior art of Duff et. al. and Greer et. al. are silent about a depressive endophenotype (Dep E) scores (claims 28).
Nevertheless, Johnson teach a study to determine whether Cymbalta (duloxetine) (claim 33) is effective to improve cognition in individuals with Mild Cognitive Impairment (claims 26) (page 4 paragraph 1). Furthermore, Johnson teach that to be included in the study the person had to have an elevated DepE score (2 or more) (claims 27 – 28, and 34) (page 10 paragraph 5). Thus the identification step as recited in claims 26 – 27 and 34 was inherently completed in order to determine which subjects were suitable for treatment.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Greer et. al. for a method for improving delayed memory scores in a subject in view of Duff et. al. to determine the immediate memory, visuospatial constructional, language, attention, and delayed memory scores and further in view of Johnson et. a., that is wherein the subjects has an elevated DepE score (2 or more). One of ordinary skill would have been motivated to make this modification as a way to briefly measure and identify MCI. Additionally, one of ordinary skill in the art would have a reasonable expectation of success because delayed memory index and total scale indexes of RBANS had the best combination of sensitivity and specificity at the -1.0 SD cutoff.
Response to Arguments
Applicant's arguments with regard to the prior art rejection, filed December 31st, 2025, have been fully considered but they are not persuasive.
Applicant argues that the prior art reference of Johnson ((2017), The Use of Duloxetine for Cognition Improvement in Individuals With Mild Cognitive Impairment (DEMO), NCT02590874, Version 6; cited in the last office action dated January 27th, 2025)) does not qualify as prior art because the study’s focus is as a proof of concept (see applicant’s remarks page 7 paragraph 4). Moreover applicant argues that the prior art of Johnson does not suggest what would be a therapeutically effective or useful amount of the SNRI (see applicant’s remarks page 7 paragraph 5). Additionally, the applicant argues that the prior art reference of Johnson is not enabled since a clinical trial is per se a trial that requires undue experimentation and for which no “reduction to practice” has been shown (see applicant’s remarks page 9 paragraph 3).
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Moreover, Office personnel should not impose on applicants the unnecessary burden of providing evidence from human clinical trials. There is no decisional law that requires an applicant to provide data from human clinical trials to establish utility for an invention related to treatment of human disorders (see In re Isaacs, 347 F.2d 889, 146 USPQ 193 (CCPA 1963); In re Langer, 503 F.2d 1380, 183 USPQ 288 (CCPA 1974)), even with respect to situations where no art-recognized animal models existed for the human disease encompassed by the claims. Ex parte Balzarini, 21 USPQ2d 1892 (Bd. Pat. App. & Inter. 1991)(MPEP 2107.03(IV)). The teaching of Johnson specifically taught the concept of using am elevated depressive endophenotype (DepE score) for population selection. Specifically, Johnson teach that to be included in the study the person had to have an elevated DepE score (2 or more) (claims 27 – 28, and 34) (page 10 paragraph 5).
Conclusion
Claims 1 – 3, 6, 9 – 10, 12 – 13, 16, 20 – 21, 23 – 24, 26 – 28, 30 – 31, and 33 – 34 are rejected.
THIS ACTION IS MADE FINAL. 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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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
/JULIET C SWITZER/Primary Examiner, Art Unit 1682