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 claims priority to the application: 63/359,712, with the effective
filing date of 8 July 2022.
Claim Status
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6 August 2026 has been entered.
This Office Action is in response to Applicant’s Amendment filed, 6 August 2026, wherein Applicant amended claims 39-40. Claims 2-3, 5-7, 9-10, 12-14, 16, and 28 were previously canceled.
Claims 1, 4, 8, 11, 15, 17-27, and 29-40 are pending.
Information Disclosure Statement
The Information Disclosure Statement filed on 6 August 2026 and the references cited
therein have been considered, unless indicated otherwise.
Rejections Withdrawn
Claim Rejections - 35 USC § 102
1. Claim 39 was rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dunlap (ACS Chem. Neurosci., 2018, 9, 2408-2427, of record, see IDS filed 17 Oct 2025). Applicant’s amendment, see page 6, with respect to claim 39 has been fully considered. The 102(a)(1) rejection of claim 39 has been withdrawn.
Rejections Modified/Maintained/New
Claim Rejections - 35 USC § 103
3. (Maintained) Claims 1, 4, 15, and 17-26 were rejected as being unpatentable over Dunlap (ACS Chem Neurosci., 2018, 9, 2408-2427, of record, see IDS mailed 17 Oct 2025) in view of Harkness (U.S. Patent No. 6,288,057, issued 11 Sept 2001, of record, see PTO-892 mailed 27 Oct 2025) and Shi (J. Chemical Research, October 2004, 681-683, of record, see PTO-892 mailed 27 Oct 2025).
Applicant's arguments filed 6 August 2026 have been fully considered but they are not persuasive.
Applicant argues that the Office used each reference to allegedly teach different discrete and non-overlapping portions of the claimed synthetic scheme and that no teachings or suggestions in the cited references are identified in the Office Action to support why, absent hindsight based on the present specification, a skilled artisan would select the isolated steps. Applicant asserts that that Dunlap teaches multiple processes for the preparation of MDMA with no motivation to select a particular process as the starting point for modification. Applicant asserts that it is only with Applicant’s disclosure that the Examiner would know the specific reactions in the specific schemes within Dunlap to be selected and modified for the obviousness rejection and that the Examiner continues to use the Applicant’s disclosure as a template to construct the obviousness rejection with Harkness and Shi. Applicant asserts that many of the reactions disclosed in Harkness for preparing the final benzodiazepine compound involve the formation of the diazepine ring and that the Examiner has selected only the reaction relating to the functionalization of a side chain for the rejection.
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).
In response to Applicant's argument that a person or ordinary skill in the art facing the synthesis of MDMA in enantiomeric excess would have had no reason to combine the selected reactions from Harkness, Dunlap, and Shi, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would have been motivated to
make such a selection, with a reasonable expectation of success, because:
-Dunlap teaches multiple methods of synthesizing R-MDMA, protecting the amine, and reducing the protected amine in high enantiomeric purity,
-Dunlap teaches motivations to investigate new syntheses due to renewed interest in using psychedelic compounds like psilocybin and MDMA to treat neuropsychiatric disorders and that there are distinct differences pharmacologically between the R- and S-enantiomers of MDMA,
-Dunlap teaches conversion of MDA (Compound 14) into MDMA (Compound 1) via protecting the amine with Boc anhydride, reducing with LAH to generate the free-base, and then isolating the hydrochloride salt as a common, robust process that can generate several different hydrate forms (Figure 2, page 2410; page 2410, column 2, paragraph 2),
-Dunlap teaches previous methods of accessing the MDMA diastereomers in high enantiomeric excess were not effective as 1) traditional resolution did not produce high enantiomeric excess; 2) the use of Raney nickel at 50 psi was crucial for selectivity but did not produce product under atmospheric conditions; and 3) sodium cyanoborohydride yielded an inseparable 1:1 mixture of diastereomers (page 2410, column 2, paragraph 3),
-Dunlap teaches that the chiral pool has been exploited to produce enantiopure MDMA and that the stereocenter is unlikely to epimerize under Grignard addition:
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, methylation, and subsequent deprotection (Figure 3C, page 2410; page 2411, column 1, paragraph 2),
-Harkness teaches setting the stereocenter as soon as possible to form enantiomerically enriched alcohols in high purity,
-Shi teaches functionalizing a side chain of a related psychoactive small molecule (amphetamine-precursor), in particular alcohols to amines through the similar transformations in a chiral method, and treating amphetamine with acid to form a salt,
-Shi teaches that amphetamine and its analogues are of pharmacological interest because of their effects on the central nervous system in humans as well as their anti-inflammatory activity,
-Shi teaches syntheses of racemic or enantiomer-enriched amphetamines have been well documented in the literature, but only few syntheses of homochiral amphetamines have been reported (page 681, column 1, paragraph 1), and
-Shi teaches concise asymmetric syntheses of (R)-amphetamine hydrochloride and (S)-amphetamine hydrochloride starting from optically pure alcohol (page 681, column 1, paragraphs 1 and 3).
As such, a person or ordinary skill would have been motivated to combine the selected reactions from Harkness, Dunlap, and Shi to develop a synthesis of MDMA in enantiomeric excess.
Additionally, Applicant makes the assertion that it is only with Applicant’s disclosure for guidance that Dunlap, Harkness, and Shi are combined to support an obviousness rejection. However, all citations in the previous obviousness rejection are not to Applicant’s specification but are to the prior art, and the Examiner further highlights the motivation for choosing each of the selected reactions in the previous paragraph. Thus, there is no evidence identified by Applicant that the Examiner used Applicant’s specification to support an obviousness rejection.
4. (Maintained) Claims 8, 11, 27, and 29-38 were rejected as being unpatentable over Dunlap (ACS Chem Neurosci., 2018, 9, 2408-2427, of record, see IDS mailed 17 Oct 2025) in view of Harkness (U.S. Patent No. 6,288,057, issued 11 Sept 2001, of record, see PTO-892 mailed 27 Oct 2025), Shi (J. Chemical Research, October 2004, 681-683, of record, see PTO-892 mailed 27 Oct 2025), and Taguri (Euro. J. Org. Chem., 2013, 30, 6924-6933, of record, see PTO-892 mailed 27 Oct 2025).
Applicant's arguments filed 6 August 2026 have been fully considered but they are not persuasive.
Applicant argues that the Office articulates no reason apart from knowledge of Applicant’s disclosure and claims why a skilled artisan would have selected the various element from Dunlap, Harkness, and Shi and combined them and that Taguri does not cure these deficiencies. Applicant further asserts that Taguri is directed to linear alkyl compounds, which are different from MDMA compounds.
Applicant relies upon the argument over claims 1, 4, 15, and 17-26 to overcome the rejection of claims 8, 11, 27, and 29-38. However, Applicant’s arguments over claims 1, 4, 15, and 17-26 were not persuasive.
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).
In response to Applicant’s argument that Taguri is directed to linear alkyl compounds, Taguri teaches (R)-propylene oxide performs similarly to (S)-propylene oxide in Grignard additions, which Harkness teaches. Additionally, Taguri teaches that (R)-propylene oxide is commercially available and inexpensive. Further, as previously stated, the substitution of the (S)- propylene oxide reagent to the (R)-propylene oxide reagent is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters to achieve a beneficial effect is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980), Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007), and MPEP § 2143(B).
5. (Modified) Claim 40 was rejected as being unpatentable over Dunlap (ACS Chem Neurosci., 2018, 9, 2408-2427, of record, see IDS mailed 17 Oct 2025) in view of Harkness (U.S. Patent No. 6,288,057, issued 11 Sept 2001, of record, see PTO-892 mailed 27 Oct 2025), Shi (J. Chemical Research, October 2004, 681-683, of record, see PTO-892 mailed 27 Oct 2025), and Taguri (Euro. J. Org. Chem., 2013, 30, 6924-6933, of record, see PTO-892 mailed 27 Oct 2025).
Applicant's amendments and arguments filed 6 August 2026 have been fully considered but they are not persuasive.
Regarding claim 40, Harkness teaches
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(Example 3, column 11, line 60). Shi teaches methods to synthesize S-amphetamine hydrochloride, a related psychedelic to MDMA (page 681, column 1, paragraphs 1 and 3) and specifically teaches
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(Scheme 1, page 681). Accordingly, the combination of Dunlap, Harkness, Shi, and Taguri teaches
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
6. (New) Claim 39 is rejected as being unpatentable over Dunlap (ACS Chem Neurosci., 2018, 9, 2408-2427, of record, see IDS mailed 17 Oct 2025) in view of Harkness (U.S. Patent No. 6,288,057, issued 11 Sept 2001, of record, see PTO-892 mailed 27 Oct 2025) and Shi (J. Chemical Research, October 2004, 681-683, of record, see PTO-892 mailed 27 Oct 2025).
Dunlap teaches multiple methods of synthesizing R-MDMA, protecting the amine, and reducing the protected amine in high enantiomeric purity (abstract; Figure 2, page 2410; page 2410, column 2, paragraph 2). Dunlap teaches motivations to investigate new syntheses due to renewed interest in using psychedelic compounds like psilocybin and MDMA to treat neuropsychiatric disorders and that there are distinct differences pharmacologically between the R- and S-enantiomers of MDMA (page 2410, column 2, paragraph 2). Dunlap teaches conversion of MDA (Compound 14) into MDMA (Compound 1) via protecting the amine with Boc anhydride, reducing with LAH to generate the free-base, and then isolating the hydrochloride salt as a common, robust process that can generate several different hydrate forms (Figure 2, page 2410; page 2410, column 2, paragraph 2). Dunlap teaches previous methods of accessing the MDMA diastereomers in high enantiomeric excess were not effective as 1) traditional resolution did not produce high enantiomeric excess; 2) the use of Raney nickel at 50 psi was crucial for selectivity but did not produce product under atmospheric conditions; and 3) sodium cyanoborohydride yielded an inseparable 1:1 mixture of diastereomers (page 2410, column 2, paragraph 3). Dunlap teaches that the chiral pool has been exploited to produce enantiopure MDMA and that the stereocenter is unlikely to epimerize under Grignard addition:
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, methylation, and subsequent deprotection (Figure 3C, page 2410; page 2411, column 1, paragraph 2).
Regarding claim 39, Dunlap fails to teach Compound 3.
Harkness teaches forming a Grignard reagent from 5- bromobenzodioxole and treating the Grignard reagent with (S)-propylene oxide to form alcohol (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (1) (Scheme II, column 9, lines 30-43; Example 3, column 11, lines 60-67, column 12, lines 1-13).
Shi teaches functionalizing a side chain of a related psychoactive small molecule (amphetamine-precursor), in particular alcohols to amines through the similar transformations in a chiral method, and treating amphetamine with acid to form a salt (page 681, Scheme 1). Shi teaches that amphetamine and its analogues are of pharmacological interest because of their effects on the central nervous system in humans as well as their anti-inflammatory activity (page 681, column 1, paragraph 1). Shi teaches syntheses of racemic or enantiomer-enriched amphetamines have been well documented in the literature, but only few syntheses of homochiral amphetamines have been reported (page 681, column 1, paragraph 1). Shi teaches concise asymmetric syntheses of (R)-amphetamine hydrochloride and (S)-amphetamine hydrochloride starting from optically pure alcohol (page 681, column 1, paragraphs 1 and 3).
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 modify the alcohol of Harkness to the azide of Shi to access a method of preparing (R)-MDMA and intermediates thereof, which are of pharmacological interest. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Dunlap teaches multiple methods of synthesizing R-MDMA, protecting the amine, and reducing the protected amine in high enantiomeric purity,
-Dunlap teaches motivations to investigate new syntheses due to renewed interest in using psychedelic compounds like psilocybin and MDMA to treat neuropsychiatric disorders and that there are distinct differences pharmacologically between the R- and S-enantiomers of MDMA,
-Dunlap teaches conversion of MDA (Compound 14) into MDMA (Compound 1) via protecting the amine with Boc anhydride, reducing with LAH to generate the free-base, and then isolating the hydrochloride salt as a common, robust process that can generate several different hydrate forms (Figure 2, page 2410; page 2410, column 2, paragraph 2),
-Dunlap teaches previous methods of accessing the MDMA diastereomers in high enantiomeric excess were not effective as 1) traditional resolution did not produce high enantiomeric excess; 2) the use of Raney nickel at 50 psi was crucial for selectivity but did not produce product under atmospheric conditions; and 3) sodium cyanoborohydride yielded an inseparable 1:1 mixture of diastereomers (page 2410, column 2, paragraph 3),
-Dunlap teaches that the chiral pool has been exploited to produce enantiopure MDMA and that the stereocenter is unlikely to epimerize under Grignard addition:
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, methylation, and subsequent deprotection (Figure 3C, page 2410; page 2411, column 1, paragraph 2),
-Harkness teaches setting the stereocenter as soon as possible to form enantiomerically enriched alcohols in high purity,
-Shi teaches functionalizing a side chain of a related psychoactive small molecule (amphetamine-precursor), in particular alcohols to amines through the similar transformations in a chiral method, and treating amphetamine with acid to form a salt,
-Shi teaches that amphetamine and its analogues are of pharmacological interest because of their effects on the central nervous system in humans as well as their anti-inflammatory activity,
-Shi teaches syntheses of racemic or enantiomer-enriched amphetamines have been well documented in the literature, but only few syntheses of homochiral amphetamines have been reported (page 981, column 1, paragraph 1), and
-Shi teaches concise asymmetric syntheses of (R)-amphetamine hydrochloride and (S)-amphetamine hydrochloride starting from optically pure alcohol (page 681, column 1, paragraphs 1 and 3).
As such, a person or ordinary skill would have been motivated to combine the selected reactions from Harkness, Dunlap, and Shi to access
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.
7. (New) Claim 39 is rejected as being unpatentable over Harkness (U.S. Patent No. 6,288,057, issued 11 Sept 2001, of record, see PTO-892 mailed 27 Oct 2025) in view of Ashenhurst (“Tosylates and Mesylates,” Mastering Organic Chemistry¸ 2020, <web.archive.org/web/20200613145240/https://www.masterorganicchemistry.com/2015/03/10/tosylates-and-mesylates/>, accessed 17 Aug 2026) and Shi (J. Chemical Research, October 2004, 681-683, of record, see PTO-892 mailed 27 Oct 2025).
Harkness teaches forming a Grignard reagent from 5-bromobenzodioxole and treating the Grignard reagent with (S)-propylene oxide to form alcohol (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (1):
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(Scheme II, column 9, lines 30-43; Example 3, column 11, lines 60-67, column 12, lines 1-13).
Regarding claim 39, Harkness fails to teach Compound 2:
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Ashenhurst teaches that alcohols are poor substrates for substitution reactions and that the hydroxyl group is a strong base (and thus a poor leaving group; page 2, paragraph 2). Ashenhurst teaches that converting alcohols into good leaving groups via tosylation or mesylation (page 3, paragraph 4; page 4, paragraphs 2 and 4; page 5, paragraphs 1-4). Ashenhurst teaches that the mesylate (abbreviated OMs) has all the advantages of a great leaving group without the drawback of an acidic proton to react with nucleophiles (alkyl hydrogen sulfate; page 4, paragraph 2; page 5, paragraph 2). Ashenhurst teaches that mesylate and tosylate have essentially identical leaving group ability, are interchangeable in these purposes (substitution reactions), and both work (page 5, paragraph 4). Further, Ashenhurst teaches that the stereochemistry is unchanged at the chiral center post activation of the alcohol via mesylation or tosylation (page 6, paragraph 3).
Shi teaches functionalizing a side chain of a related psychoactive small molecule (amphetamine-precursor), in particular alcohols to amines through the similar transformations in a chiral method, and treating amphetamine with acid to form a salt (page 681, Scheme 1). Shi teaches that amphetamine and its analogues are of pharmacological interest because of their effects on the central nervous system in humans as well as their anti-inflammatory activity (page 681, column 1, paragraph 1). Shi teaches syntheses of racemic or enantiomer-enriched amphetamines have been well documented in the literature, but only few syntheses of homochiral amphetamines have been reported (page 681, column 1, paragraph 1). Shi teaches concise asymmetric syntheses of (R)-amphetamine hydrochloride and (S)-amphetamine hydrochloride starting from optically pure alcohol (page 681, column 1, paragraphs 1 and 3).
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 activate the alcohol of Harkness via conversion to a mesylate as taught by Ashenhurst akin to Shi for further functionalization to make compounds of pharmacological interest. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Harkness teaches setting the stereocenter as soon as possible to form enantiomerically enriched alcohols in high purity,
-Harkness teaches forming a Grignard reagent from 5-bromobenzodioxole and treating the Grignard reagent with (S)-propylene oxide to form alcohol (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (1):
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,
-Ashenhurst teaches that alcohols are poor substrates for substitution reactions and that the hydroxyl group is a strong base (and thus a poor leaving group),
-Ashenhurst teaches that converting alcohols into good leaving groups via tosylation or mesylation,
-Ashenhurst teaches that the mesylate (abbreviated OMs) has all the advantages of a great leaving group without the drawback of an acidic proton to react with nucleophiles (alkyl hydrogen sulfate),
-Ashenhurst teaches that mesylate and tosylate have essentially identical leaving group ability, are interchangeable in these purposes (substitution reactions), and both work, and
-Ashenhurst teaches that the stereochemistry is unchanged at the chiral center post activation of the alcohol via mesylation or tosylation.
-Shi teaches functionalizing a side chain of a related psychoactive small molecule (amphetamine-precursor), in particular alcohols to amines through the similar transformations in a chiral method, and treating amphetamine with acid to form a salt,
-Shi teaches that amphetamine and its analogues are of pharmacological interest because of their effects on the central nervous system in humans as well as their anti-inflammatory activity,
-Shi teaches syntheses of racemic or enantiomer-enriched amphetamines have been well documented in the literature, but only few syntheses of homochiral amphetamines have been reported (page 981, column 1, paragraph 1), and
-Shi teaches concise asymmetric syntheses of (R)-amphetamine hydrochloride and (S)-amphetamine hydrochloride starting from optically pure alcohol (page 681, column 1, paragraphs 1 and 3).
As such, a person or ordinary skill would have been motivated to combine the selected reactions from Harkness, Ashenhurst, and Shi to access
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8. (New) Claim 40 is rejected as being unpatentable over Harkness (U.S. Patent No. 6,288,057, issued 11 Sept 2001, of record, see PTO-892 mailed 27 Oct 2025) in view of Ashenhurst (“Tosylates and Mesylates,” Mastering Organic Chemistry¸ 2020, <web.archive.org/web/20200613145240/https://www.masterorganicchemistry.com/2015/03/10/tosylates-and-mesylates/>, accessed 17 Aug 2026), Shi (J. Chemical Research, October 2004, 681-683, of record, see PTO-892 mailed 27 Oct 2025), and Taguri (Euro. J. Org. Chem., 2013, 30, 6924-6933, of record, see PTO-892 mailed 27 Oct 2025).
Harkness teaches forming a Grignard reagent from 5-bromobenzodioxole and treating the Grignard reagent with (S)-propylene oxide to form alcohol (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (1):
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(Scheme II, column 9, lines 30-43; Example 3, column 11, lines 60-67, column 12, lines 1-13).
Regarding claim 40, Harkness fails to teach Compound 9:
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Ashenhurst teaches that alcohols are poor substrates for substitution reactions and that the hydroxyl group is a strong base (and thus a poor leaving group; page 2, paragraph 2). Ashenhurst teaches that converting alcohols into good leaving groups via tosylation or mesylation (page 3, paragraph 4; page 4, paragraphs 2 and 4; page 5, paragraphs 1-4). Ashenhurst teaches that the mesylate (abbreviated OMs) has all the advantages of a great leaving group without the drawback of an acidic proton to react with nucleophiles (alkyl hydrogen sulfate; page 4, paragraph 2; page 5, paragraph 2). Ashenhurst teaches that mesylate and tosylate have essentially identical leaving group ability, are interchangeable in these purposes (substitution reactions), and both work (page 5, paragraph 4). Further, Ashenhurst teaches that the stereochemistry is unchanged at the chiral center post activation of the alcohol via mesylation or tosylation (page 6, paragraph 3).
Shi teaches functionalizing a side chain of a related psychoactive small molecule (amphetamine-precursor), in particular alcohols to amines through the similar transformations in a chiral method, and treating amphetamine with acid to form a salt (page 681, Scheme 1). Shi teaches that amphetamine and its analogues are of pharmacological interest because of their effects on the central nervous system in humans as well as their anti-inflammatory activity (page 681, column 1, paragraph 1). Shi teaches syntheses of racemic or enantiomer-enriched amphetamines have been well documented in the literature, but only few syntheses of homochiral amphetamines have been reported (page 681, column 1, paragraph 1). Shi teaches concise asymmetric syntheses of (R)-amphetamine hydrochloride and (S)-amphetamine hydrochloride starting from optically pure alcohol (page 681, column 1, paragraphs 1 and 3).
Taguri teaches (R)-propylene oxide performs similarly to (S)-propylene oxide in Grignard additions, which Harkness teaches (page 7, paragraph 1). Additionally, Taguri (S)- and (R)-propylene oxide were chosen as the reagents to set the stereocenter, because they are commercially available and inexpensive (page 2, paragraph 2). Further, as previously stated, the substitution of the (S)- propylene oxide reagent to the (R)-propylene oxide reagent is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters to achieve a beneficial effect is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980), Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007), and MPEP § 2143(B).
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 activate the alcohol of Harkness and Taguri via conversion to a mesylate as taught by Ashenhurst akin to Shi for further functionalization to make compounds of pharmacological interest. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Harkness teaches setting the stereocenter as soon as possible to form enantiomerically enriched alcohols in high purity,
-Harkness teaches forming a Grignard reagent from 5-bromobenzodioxole and treating the Grignard reagent with (S)-propylene oxide to form alcohol (S)-1-(benzo[d][1,3]dioxol-5-yl)propan-2-ol (1):
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,
-Ashenhurst teaches that alcohols are poor substrates for substitution reactions and that the hydroxyl group is a strong base (and thus a poor leaving group),
-Ashenhurst teaches that converting alcohols into good leaving groups via tosylation or mesylation,
-Ashenhurst teaches that the mesylate (abbreviated OMs) has all the advantages of a great leaving group without the drawback of an acidic proton to react with nucleophiles (alkyl hydrogen sulfate),
-Ashenhurst teaches that mesylate and tosylate have essentially identical leaving group ability, are interchangeable in these purposes (substitution reactions), and both work, and
-Ashenhurst teaches that the stereochemistry is unchanged at the chiral center post activation of the alcohol via mesylation or tosylation.
-Shi teaches functionalizing a side chain of a related psychoactive small molecule (amphetamine-precursor), in particular alcohols to amines through the similar transformations in a chiral method, and treating amphetamine with acid to form a salt,
-Shi teaches that amphetamine and its analogues are of pharmacological interest because of their effects on the central nervous system in humans as well as their anti-inflammatory activity,
-Shi teaches syntheses of racemic or enantiomer-enriched amphetamines have been well documented in the literature, but only few syntheses of homochiral amphetamines have been reported (page 981, column 1, paragraph 1),
-Shi teaches concise asymmetric syntheses of (R)-amphetamine hydrochloride and (S)-amphetamine hydrochloride starting from optically pure alcohol (page 681, column 1, paragraphs 1 and 3).
-Taguri teaches (R)-propylene oxide performs similarly to (S)-propylene oxide in Grignard additions, which Harkness teaches, and
-Taguri (S)- and (R)-propylene oxide were chosen as the reagents to set the stereocenter, because they are commercially available and inexpensive (page 2, paragraph 2). Further, as previously stated, the substitution of the (S)- propylene oxide reagent to the (R)-propylene oxide reagent is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters to achieve a beneficial effect is within the skill in the art of an ordinary artisan.
As such, a person or ordinary skill would have been motivated to combine the selected reactions from Harkness, Ashenhurst, and Shi to access
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Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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