Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Applicant’s preliminary amendment of 20 December 2024, in which claims 2-9, 13, 17, 18 have been amended, and claims 1, 10-12, 14-16 and 19-21 have been cancelled, is acknowledged.
Claims 2-9, 13, 17-18 are pending in the instant application.
Claims 2-9, 13, 17-18 are being examined on their merits herein.
Priority
The instant application is a Continuation of U.S. Patent Application 16/829,657, filed on 25 March 2020, now abandoned, which is a Division of U.S. Patent Application 14/163,827, filed on 24 January 2014, now abandoned, which claims the benefit of U.S. Provisional Patent Application 61/756,208, filed on 24 January 2013, of U.S. Provisional Patent Application 61/799,482, filed on 15 March 2013, and of U.S. Provisional Patent Application 61/852,149, filed on 15 March 2013.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 26 December 2024 is acknowledged and considered.
Objection to the Specification
The Abstract is objected to due to the following informality: The abstract indicates the present invention relates to compositions and methods of treating depression with compounds of formula (I) or formula (II), however formulae (I) and (II) are not shown in the abstract. Appropriate correction is required.
Claims Objection
Claim 2 is objected to due to the following informality: Applicant uses “ -- “ to represent a single bond in moieties such as, for example, --CH2-- or --O-- or --C(=O)-- or --NH--NH--R15(not all such moieties listed). The widely accepted convention in organic chemistry is to represent a single bond with a line, such as –CH2-, -O-, -C(=O)- or –NH-NH-R15. Appropriate correction is required.
Claim 2 contains formula (I), in which the substituents R3, R5, R6, R9, R7 are difficult to read. The same applies to the other moieties drawn in claim 2, and their substituents. Applicant is invited to submit the formula (I) and all other structures as a clear drawing, with all substituents labeled cleanly.
Claim 2 is objected due to the following minor informality: the recitations “Z is void” and “W is void” could read –Z is absent- and –W is absent-.
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 pre-AIA 35 U.S.C. 112, 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, 13 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 pre-AIA the applicant regards as the invention. Claim 4 is drawn to the method of claim 2, wherein the compound of formula I is
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; yet, claim 2 does not recite enantiomers of a compound of formula (I). As such, there is insufficient antecedent basis for the compound of claim 4, in claim 2.
The same analysis applies to claim 13.
Appropriate correction is required.
Claim Rejections- 35 USC 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 2-9, 13, 17-18 are rejected under 35 U.S.C. 103(a) as being unpatentable over) Nishiyama et al. (US 2004/0138227, published 15 July 2004, cited in IDS), in view of Guidance for Industry (Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Pharmacology and Toxicology, July 2005, cited in IDS), and Thayer (Chemical and Engineering News 2008, 86 (24), 1-17, cited in IDS).
Nishiyama (US 2004/0138227) teaches a method of treating depression ([0002], [0009], Example 4, [1886]-[1887]) in a subject by administering to the subject a therapeutically effective amount of a composition [0781] comprising the compound below (compound 88, [1372], page 91):
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Compound 88, Nishiyama Instant formula (I)
which is the very compound of instant claims 4, 13, and is a compound of instant formula (I) for which the following definitions apply: Ra = Rb = Rc = H; X = OH, R1 is
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, wherein Z is absent, R5 is 3,4-dichlorophenyl, R6 = H; V = O; W is absent; the dotted line represents a double bond; R7 is a substituted unsaturated heterocyclic group (methyl substituted 1,3,4-oxadiazole); R3 (?) = H (the examiner notes that the substituent in the 3 position of the benzofuran is unintelligible- the examiner assumes it is R3. Applicant is invited to submit the formula (I) as a clear drawing, with all substituents labeled cleanly).
Nishiyama teaches that the compound above has a serotonin reuptake inhibitory action and a 5-HT1A antagonistic action and is an antidepressant showing quick expression of an anti-depressive effect, namely, a rapid onset antidepressant ([0007], last 5 lines; [0779], lines 1-3; [1905], lines 1-7). Nishiyama teaches (Table 3, [1880]) that compound 88 above has a strong affinity for both 5-HT1A receptor, with a Ki of 0.75 nM, and 5-HT transporter, with a Ki of 0.32 nM. Nishiyama further teaches that the compound of the invention, such as compound 88 above, is superior in bioavailability and transfer into the brain ([1885]).
Importantly, Nishiyama teaches that the compounds of the invention are 5-HT1A antagonists also having 5-HT reuptake inhibitory activity [0008], and are effective to treat a
5-HT mediated CNS disorder [0009] such as recognition disorder/cognitive impairment.
Nishiyama teaches [0780] that, when a compound such as compound 88 above is used as a pharmaceutical agent, a systemic administration of a pharmacologically acceptable amount of the compound or a pharmacologically acceptable salt thereof to a mammal is included. Nishiyama teaches that the dose requires careful consideration for each case, and consideration of the age, body weight and condition of the subject, administration route, as well as nature and severity of the disease. Nishiyama teaches that the general daily dose in the case of parenteral administration is 0.01-100 mg/kg ([0780], line 10); the lowest dose taught by Nishiyama, 0.01 mg/kg, for a subject weighing 50 kg, corresponds to 0.5 mg, as in instant claims 2, 3.
Importantly, Nishiyama teaches (Example 4, page 154, [1886]-[1887]) that the compounds of the invention significantly shortened the immobility time in a mouse model of depression, namely the forced swimming test, by the single oral administration of 0.1-100 mg/kg thereof ([1887]). Nishiyama concludes, based on the results of the forced swimming test, that the compound of the invention is a rapid onset anti-depressant that shows quick expression of the anti-depressive effect.
Nishiyama does not teach specifically a method of treating cognitive impairment/recognition disorder in a human subject comprising orally administering to the subject compound 88, in an amount of 0.5 mg to 10 mg, as in the instant claims.
Nishiyama does not teach the method, wherein the composition is administered to the subject once a day, as in instant claim 5, or twice a day, as in instant claim 6, or less frequently than once a day, as in instant claim 7, or every two days, as in instant claim 8, or every three days, as in instant claim 9.
Guidance for Industry (Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Pharmacology and Toxicology, July 2005) teaches (Table 1, page 7) the conversion of animal doses to human equivalent doses (HED). Guidance for Industry teaches that to convert animal dose in mg/kg to HED in mg/kg (assumes 60 kg human), one has to multiply the dose in mg/kg in mouse by 0.08.
Thus, based on the combined teachings of Nishiyama [1887] and Guidance for Industry, one would convert the dose of 0.1-100 mg/kg administered orally to a mouse, which is effective to treat depression in a mouse model of depression, the forced swimming test, into a human equivalent dose HED calculated to be between:
0.1 mg/kg x 0.08 = 0.008 mg/kg, which corresponds to 0.48 mg for a 60 kg human; and
100 mg/kg x 0.08 = 8 mg/kg, which corresponds to 480 mg for a 60 kg human,
which is overlapping the range in the instant claims.
Thayer (Chemical and Engineering News 2008, 86 (24), 1-17) teaches that more effective drugs are good news for patients because smaller doses of drug mean fewer side effects.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to use the teachings of Nishiyama and Guidance for Industry to arrive at the instantly claimed method. The person of ordinary skill in the art would have been motivated to administer compound 88 taught by Nishiyama to treat depression and/or cognitive impairment in a subject, because Nishiyama teaches that the compounds of the invention are effective as rapid onset antidepressants and are effective to treat cognitive impairment/ recognition disorder. Thus, the person of ordinary skill in the art would have administered compound 88 to a subject suffering from depression and cognitive impairment/recognition disorder, with the expectation that said compound is effective to treat both depression and cognitive impairment in said subject.
The person of ordinary skill in the art would have been motivated to convert the animal dose to human equivalent doses (HED) and administer compound 88 taught by Nishiyama to treat depression and cognitive impairment in a subject. The person of ordinary skill in the art, based on the teachings of Nishiyama and Guidance for industry, would have calculated the HED to be between 0.008 mg/kg, to 8 mg/kg, which corresponds to 0.48 mg - 480 mg for a 60 kg human for single dose oral administration, which is overlapping with the instantly claimed range.
Further, the person of ordinary skill in the art would have been motivated to administer the minimum effective dose of antidepressant compound 88, because Thayer teaches that smaller doses of drugs mean fewer side effects. Thus, the person of ordinary skill in the art would have been motivated to explore different doses of compound 88 for administration to a human patient suffering from depression, in order to achieve therapeutic effect in treating depression, while minimizing side effects. Further, determining the minimum dose (associated with fewer side effects) of active ingredient in order to achieve therapeutic effect with a drug formulation is considered routine for the skilled artisan.
Furthermore, regarding claims 5-9, the person of ordinary skill in the art would have explored different frequencies of administration of the therapeutically active compound 88, in a method of treating depression taught by Nishiyama, because optimizing the frequency of drug administration so that it is daily, twice a day, every two days, etc., in order to optimize the therapeutic effect achieved, is a routine step well within the competency of the skilled artisan.
Regarding claim 17, the person of ordinary skill in the art would have been motivated to administer compound 88 to a subject suffering from cognitive impairment/recognition disorder, wherein the subject does not suffer from depression, because Nishiyama teaches that the compounds of the invention are 5-HT1A antagonists also having 5-HT reuptake inhibitory activity, and are effective to treat a 5-HT mediated CNS disorder such as recognition disorder/cognitive impairment. Thus, the person of ordinary skill in the art would have been motivated to administer compound 88 of Nishiyama to patients suffering from recognition disorder/cognitive impairment, with the expectation that said compound is effective to treat cognitive impairment in said patients.
As such, claims 2-9, 13, 17-18 are rejected as prima facie obvious.
Claims 2-9, 13, 17-18 are rejected under 35 U.S.C. 103(a) as being unpatentable over) Nishiyama et al. (US 2004/0138227, published 15 July 2004, cited in IDS), in view of Guidance for Industry (Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Pharmacology and Toxicology, July 2005, cited in IDS), and Thayer (Chemical and Engineering News 2008, 86 (24), 1-17, cited in IDS), in further view of Papazacharias et al. (Psychiatria Danubina 2012, 24, Suppl. 1, 179-182, cited in IDS), Schmitt et al. (Current Pharmaceutical Design 2006, 12, 2473-2486, cited in IDS) and Suzuki et al. (US 2005/0256103, cited in PTO-892).
Nishiyama, Guidance for Industry, and Thayer are as above.
Nishiyama teaches that compound 88 has a serotonin reuptake inhibitory action and a 5-HT1A antagonistic action and is an antidepressant showing quick expression of an anti-depressive effect, namely, a rapid onset antidepressant ([0007], last 5 lines; [0779], lines 1-3; [1905], lines 1-7). Nishiyama teaches (Table 3, [1880]) that compound 88 has a strong affinity for both 5-HT1A receptor, with a Ki of 0.75 nM, and 5-HT transporter, with a Ki of 0.32 nM. Nishiyama further teaches that the compound of the invention, such as compound 88 above, is superior in bioavailability and transfer into the brain ([1885]).
Importantly, Nishiyama teaches that the compounds of the invention are 5-HT1A antagonists also having 5-HT reuptake inhibitory activity [0008], and are effective to treat a
5-HT mediated CNS disorder [0009] such as recognition disorder/cognitive impairment.
Papazacharias (Psychiatria Danubina 2012, 24, Suppl. 1, 179-182, cited in IDS) teaches that cognitive impairment is comorbid with depression. Papazacharias teaches that depression and cognitive impairment share a common neuropathological platfeorm in cortical and sub-cortical brain areas implicated in emotional and cognitive processing (Abstract).
Schmitt teaches (Abstract) serotonin is a target for pharmacological cognition enhancement particularly for restoration of impaired cognitive performance due to 5-HT dysfunction (Abstract).
Schmitt teaches (Abstract) that stimulating 5-HT activity in depression has beneficial effects on cognition, independent of a general relief of depressive symptoms.
Suzuki (US 2005/0256103) teaches [0011] that 5-HT1A receptor is associated with cognition, memory and learning. Suzuki teaches [0011] that 5-HT1A antagonists ameliorate cognitive impairment and are effective to treat cognitive disorder, or memory or learning disorder.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to use the teachings of Nishiyama, Papazacharias, Schmitt and Suzuki to arrive at the instantly claimed method. The person of ordinary skill in the art would have been motivated to administer compound 88 taught by Nishiyama to treat cognitive impairment in a subject, because
Nishiyama teaches that compound 88 is a strong 5-HT1A antagonist (Ki = 0.75 nM), also having strong 5-HT reuptake inhibitory activity (Ki = 0.32 nM),
Schmitt teaches that serotonin is a target for pharmacological cognition enhancement particularly for restoration of impaired cognitive performance due to 5-HT dysfunction, and
Suzuki teaches that 5-HT1A antagonists ameliorate cognitive impairment and are effective to treat cognitive disorder, or memory or learning disorder.
Thus, a person of ordinary skill in the art would have been motivated to administer compound 88 taught by Nishiyama to a subject suffering from impaired cognition, whether or not said subject suffers from comorbid depression (as in instant claims 17, 18), with the expectation that compound 88 will be effective to treat cognitive impairment due to its dual action as 5-HT1A antagonist and 5-HT reuptake inhibitor (both mechanisms being associated with treatment of cognitive impairment).
Further, regarding claim 18, since Nishiyama teaches that compound 88 is a rapid onset antidepressant, and Papazacharias teaches that cognitive impairment is comorbid with depression, and that depression and cognitive impairment share a common neuropathological platform in cortical and sub-cortical brain areas implicated in emotional and cognitive processing, the person of ordinary skill in the art would have administered compound 88 to subjects suffering from depression and comorbid cognitive impairment, with the expectation that said antidepressant is effective to treat cognitive impairment in said subjects.
Further, the person of ordinary skill in the art would have been motivated to convert the animal dose to human equivalent doses (HED) and administer compound 88 taught by Nishiyama to treat depression and cognitive impairment in a subject. The person of ordinary skill in the art, based on the teachings of Nishiyama and Guidance for industry, would have calculated the HED to be between 0.008 mg/kg, to 8 mg/kg, which corresponds to 0.48 mg - 480 mg for a 60 kg human for single dose oral administration, which is overlapping with the instantly claimed range.
Further, the person of ordinary skill in the art would have been motivated to administer the minimum effective dose of antidepressant compound 88, because Thayer teaches that smaller doses of drugs mean fewer side effects. Thus, the person of ordinary skill in the art would have been motivated to explore different doses of compound 88 for administration to a human patient suffering from depression, in order to achieve therapeutic effect in treating depression, while minimizing side effects. Further, determining the minimum dose (associated with fewer side effects) of active ingredient in order to achieve therapeutic effect with a drug formulation is considered routine for the skilled artisan.
Furthermore, regarding claims 5-9, the person of ordinary skill in the art would have explored different frequencies of administration of the therapeutically active compound 88, in a method of treating depression taught by Nishiyama, because optimizing the frequency of drug administration so that it is daily, twice a day, every two days, etc., in order to optimize the therapeutic effect achieved, is a routine step well within the competency of the skilled artisan.
As such, claims 2-9, 13, 17-18 are rejected as prima facie obvious.
Conclusion
Claims 2-9, 13, 17-18 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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