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
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The instant claims are entitled to an effective filing date of 05/27/2021.
Claims 2-3, 6-7, 9-11, 13-21, 23-38, 40-67, 69, 71-75, 78-79, 87-109, 116-118, 120-122, and 124-159 are canceled.
Claims 1, 4-5, 8, 12, 22, 39, 68, 70, 76-77, 80-86, 110-115, 119, 123, and 160-163 are pending.
Election/Restrictions
Applicant's election without traverse of Group I (claims 1, 4-5, 8, 12, 22, 39, 68, 70, 76-77, 80-81 and 115) in the reply filed on 05/05/2026 is acknowledged.
Claims 82-86, 110-114, 119, 123, and 160-163 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/05/2026.
Accordingly, claims 1, 4-5, 8, 12, 22, 39, 68, 70, 76-77, 80-81 and 115 are under consideration in this action.
Specification
Abstract: The abstract of the disclosure is objected to because it contains minor informalities.
The abstract includes the following repeated statement in lines 4-8: “wherein the tryptamine derivative (I) is not tryptophane, 4-hydroxytryptamine, N-acetyl-4-hydroxytryptamine, norbaeocystin, baeocystin; psilocybin, psilocin, aeruginascin, halogenated tryptophan, halogenated tryptamine, halogenated N-methylated tryptamine, halogenated N,N- dimethyltryptamine or halogenated Ν,Ν,Ν-trimethyltryptamine; said method comprising providing an indole acceptor of the formula (II)”. This recitation in lines 4-8 can be deleted because it is a repeated statement compared to lines 1-4 of the abstract.
The abstract recites “tryptophane” in line 2 (repeated in line 5), which is a misspelling that should be replaced with “tryptophan”.
The abstract recites “Rill” in line 8 should be replaced with “RIII”.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Specification: The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See [0029] for the link http://enzyme.expasy.org/, and [0080] for the link http://111ncbi.nlm.nih.gov.
Claim Objections
Claim 115 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only. See MPEP § 608.01(n). Accordingly, the claim 115 has not been further treated on the merits.
Claims 1, 4, 8, 12, 22, 39, 68, 70, 77, and 81 are objected to because of the following informalities:
Claim 1 recites “tryptophane” in the first line after formula (I), which is misspelled and should be replaced with “tryptophan”.
Claim 4 recites “Psilocybin, Psilocin, Norpsilocin, Baeocystin, Norbaeocystin, Aeruginascin… Bufotenine, Norbufotenine… Ibogaine, Ibogamine, Noribogaine, Mitragynine… Harmalol” in lines 2-6, which should be lowercased because the terms are in the middle of a sentence.
Claim 4 recites “5-hydroxytryptamine” in line 2 and “serotonin” in the last line. The two terms are synonyms, so one recitation can be deleted.
Claim 8 recites “methylation,N-acetylation” in line 3, which should be amended to include a space after the comma.
Claim 12 recites “tehh” in line 2, which is misspelled and should be replaced with “the”.
Claim 12 recites the following terms which should be lowercased: “Uridine, Adenosin, Guanosin, Cytidin” in line 4; and “S-Adenosyl methionine (SAM), S-Adenosyl ethionine (SAE)” in the last two lines.
Claim 22 recites “Strictosidine…4- Hydroxytryptamine kinase… Tryptophan 2-halogenase, a Tryptophan 5-halogenase, a Tryptophan 6-halogenase and a Tryptophan 7-halogenase”, which should be lowercased because the terms are in the middle of a sentence.
Claim 39 recites “such at least” in line 1 of a)-g), i), k)-s) and in line 2 of h). This is grammatically incorrect recitation and should be replaced with “such as at least” or the “such” can be deleted.
Claim 39 recites “g) An”, which should be replaced with “g) an” because the recitation is in the middle of a sentence.
Claim 39 recites “Strictosidine” in lines 1 and 3 of e), which should be lowercased because it is in the middle of a sentence.
Claim 39 recites “h) A”, which should be replaced with “h) a” because the recitation is in the middle of a sentence.
Claim 39 recites the “4-Hydroxytryptamine” lines 1 and 3 of h) and “Tryptophan” in lines 1 and 3 of l)-o), which should lowercase because the terms are in the middle of a sentence.
Claim 68 recites “Psilocin-β-O-glycoside, Norpsilocin-β-O-glycoside…Serotonin-β-O-glycoside, Bufotenine-β-O-glycoside, Norbufotenine-β-O-glycoside…Noribogaine-β-O-glycoside…Harmalol-β-O-glycoside, , Melatonin, Normelatonin” in lines 3-10. These terms should be lowercased and the “, ,” in line 9 should be replaced with “, ” .
Claim 70 recites “such at least” in lines 8 and 15, which is grammatically incorrect and should be replaced with “such as at least” or the “such” can be deleted.
Claim 77 recites “i.” and “ii.”, which should be replaced with “i)” and “ii)”, because MPEP 608.01(m) states that periods may not be used elsewhere in the claims except for abbreviations.
Claim 81 recites “1comprising”, should be replaced with “1, comprising” and the claim recites “E. coli” which should be italicized in accordance with scientific nomenclature.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4-5, 8, 12, 22, 39, 68, 70, 76-77, and 80-81 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “N2” in formula (I), which renders the claim indefinite because it is unclear whether N-2 means the second nitrogen in formula (I) or diatomic nitrogen N-2. The instant specification teaches molecules with one nitrogen at the position labeled N2 in formula (I). See ,e.g., the formula provided in figure 13. Therefore, the N1 and N2 can be replaced with NI and NII respectively or the numbers can be deleted such that N1 and N2 are separately N. Moreover, claim 1 recites “one or more of RII, RIV, RV, RVI or RVII is not H and RIII is H or CH2CH-2NH2 or CH2CHCOOHNH2” in line 7-8, which is indefinite because it is unclear which limitations are alternatives from which “one or more” can be selected from. Therefore, in one interpretation the claim requires one or more of RII, RIV, RV, RVI and RVII to not be H; and under an alternative interpretation the claim requires one or more of: RII to not be H, RIV to not be H, RV to not be H, RVI to not be H, RVII to not be H, and RIII to be H or CH2CH2NH2 or CH2CHCOOHNH2. As such, it is unclear whether the RIII is limited to H, CH2CH2NH2 or CH2CHCOOHNH2. Claim 1 recites “contacting the indole acceptor with a substituent donor in the presence of one or more enzymes substituting one or more H, OH and/or COOH in the indole acceptor with one or more substituents of the substituent donor, wherein optionally one or more of RII, RIV, RV, RVI and/or RVII of the indole acceptor (II) is OH, Cl, Br, F, I, CH3-, NO2, or CH3-O or wherein optionally R4 and/or R5 is OH” in the last 5 lines, which renders the claim indefinite for three additional reasons. The first reason is that it is unclear which H, OH and/or COOH in the indole acceptor is/are required to be substituted because formula (II) does not require the presence of OH and/or COOH. Although RIII of formula (II) may be limited to H or CH2CH2NH2 or CH2CHCOOHNH-2 (see lines 7-8), this limitation encompasses formula (II) embodiments that do not contain OH and/or COOH. The second reason is that it is unclear whether the optional limitation recited in lines 10-11 applies to the indole acceptor formula (II) structure before or after the substitution step. The third reason is that it is unclear whether the “R4 and/or R5” recitation in the last line refers to formula (I), or the RIV and R-v of formula (II) respectively. Only formula (I) recites R4 and R5. Therefore, in one interpretation the last optional wherein clause refers to formula (I). However, based on the context of the limitation, the R4 and R5 could also reasonably be interpreted as the RIV and R-v of formula (II) respectively.
Claims 4-5, 8, 12, 22, 39, 68, 70, 76-77, 80-81 and 115 depend from claim 1 and are rejected for the reason set forth above.
Claim 8 recites “wherein the substitution is an O-alkylation, a N-alkylation, or a C-alkylation, optionally selected from the group consisting of ethylation, methylation, N-acetylation, O-glycosylation and β-O-glycosylation”, which renders the claims indefinite because the optional substitutions are broader in scope and/or do not fall within the scope of O-alkylation, N-alkylation, or C-alkylation. Furthermore, N-acetylation does not fall within N-alkylation because N-acetylation is the addition of an acetyl group (-COCH3), not an alkyl group, to a nitrogen (N). O-glycosylation is the addition of a glycan, not an alkyl group, to an oxygen (O). Consequently, it is unclear whether the required substitution is limited to O-alkylation, a N-alkylation, or a C-alkylation.
Claim 12 recites “the substituent donor is an aldehyde, a ketone, an ether and/or an amine”, which renders the claim indefinite because, in one interpretation, the claim is limiting the functional group from which the substituent is being donated from, and under an alternative interpretation, the claim is limiting the substituent donor as a whole to any molecule with the recited functional group(s). Moreover, claim 12 recites “; and ADP-glucose, S-Adenosyl methionine (SAM), S-Adenosyl ethionine (SAE)”, which renders the claim indefinite because, in one interpretation, the claim is unfinished because there is no conjugation at the end of the list between “(SAM), S-Adenosyl ethionine (SAE)”; and under an alternative interpretation, the ADP-glucose is required to be in combination with S-Adenosyl methionine (SAM) and S-Adenosyl ethionine (SAE) because the “; and” conjunction is before ADP-glucose. To obviate this rejection, the claim can be amended to recite “; ADP-glucose; S-Adenosyl methionine (SAM); and S-Adenosyl ethionine (SAE)”.
Claim 22 recites “optionally” in line 3 and again in line 4, such that it is unclear which alternatives are optional and which are required. Furthermore, claim 22 recites “aglycone/glycoside” in line 9, 10 and 11, which renders the claim indefinite because it is unclear whether the aglycone and glycoside are two separate alternatives, or one . For example, “aglycone/glycoside mono-O-glycosyltransferase” in line 9 can be interpreted as one alternative that includes both aglycone mono-O-glycosyltransferase and glycoside mono-O-glycosyltransferase; or interpreted as two alternatives, such that aglycone mono-O-glycosyltransferase is one alternative, and glycoside mono-O-glycosyltransferase is the other.
Regarding claim 39, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). See the first two lines of a)-s).
Claim 68 recites “the tryptamine derivative (I) is a hydroxytryptamine β-O-glycoside, optionally selected from the group consisting of…Melatonin, Normelatonin, hydroxycinnamoylserotonin, or 4-coumaroylserotonin”, which renders the claim indefinite because melatonin, normelatonin, hydroxycinnamoylserotonin and 4-coumaroylserotonin do not include a β-O-glycoside. Consequently, it is unclear whether the claim limits the tryptamine derivative (I) to hydroxytryptamine β-O-glycoside.
Claim 70 recites “optionally” multiple times (see lines 5, 8, 12 and 14), such that it is unclear which limitations are optional and which are required. Claim 70 further recites the phrases “such at least”, "such as at least" in lines 4-5 of i) and lines 4-5 of ii), which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of claimed optional limitations. See MPEP § 2173.05(d). Moreover, claim 70 recites “indole or indole derivative” in line 3 and the “tryptamine or tryptamine derivative” in line 4, which render the claim indefinite because it is unclear how the indole, indole derivative, tryptamine and tryptamine derivative are interrelated with the indole acceptor and tryptamine derivative of claim 1 from which claim 70 depends.
Claim 77 recites the limitation “the indole or indole derivative or tryptophan or tryptophan derivative” in lines 11-12 and 20-21. There is insufficient antecedent basis for this limitation in the claim. It is unclear which indole or indole derivative and which tryptophan or tryptophan derivative are required because there is no earlier limitation that requires an indole, indole derivative, tryptophan or tryptophan derivative. Furthermore, the phrase "such as" renders claim 77 indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). See i lines 3-4 and 6-8 and see ii lines 3-4. Moreover, claim 77 recites “optionally” multiple times (see lines 10, 12, 15 and 21) such that it is unclear which limitations are optional and which are required.
Claim 80 recites “[t]he method of claim 1 comprising in vitro enzymatic substitution steps and/or optionally in vivo enzymatic substitution steps”, which is indefinite for two reasons. The first reason is that it is unclear whether claim 80 is further limiting the method of claim 1 or limiting the entirety of claim 1 because the claim recites “comprising” rather than ‘further comprising’. The second reason is that it is unclear whether claim 80 requires in vitro enzymatic substitution steps. Since claim 1 recites “and/or optionally” it is unclear whether the in vivo enzymatic substitution step recited after the term “optionally” is an alternative or an optional addition to the in vitro enzymatic substitution. To obviate this rejection, the claim can be amended to recite: The method of claim 1, wherein the enzymatic substitution is in vitro.
Claim 81 recites “The method of claim 1comprising”, which renders the claim indefinite because it is unclear whether claim 81 is further limiting the method of claim 1 or limiting the entirety of claim 1 because the claim recites “comprising” rather than ‘further comprising’.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 4 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 4 does not include all of the limitations required in claim 1. Claim 1 requires an indole acceptor of the formula (II) wherein one or more of RII, RIV, RV, RVI or RVII is not H and RIII is H or CH2CH-2NH2 or CH2CHCOOHNH2. Therefore, the indole acceptor formula (II) can reasonably be interpreted as requiring an RIII that is H or CH2CH-2NH2 or CH2CHCOOHNH2. However, claim 4 encompasses indole acceptor embodiments that do not meet the RIII requirements of claim 1. For example, in psilocybin and psilocin RIII is -NCH3CH3, and in norpsilocin RIII is NHCH3 . As such, claim 4 does not include all of the limitations required in claim 1. Claim 4 recites an open list of alternatives because the last alternative is “or serotonin”, rendering the list to select from indefinite.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 4-5, 8, 12, 22, 68, 70, 77, and 80 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon judicial exception without significantly more.
Each step described below is in reference to the subject matter eligibility test for products and processes in MPEP 2106.
Claim 1 is drawn to a method, which is one of the statutory categories (Step 1:Yes).
Claim 1 recites “contacting the indole acceptor with a substituent donor in the presence of one or more enzymes substituting one or more H, OH and/or COOH in the indole acceptor with one or more substituents of the substituent donor” in lines 8-10. Evidentiary reference Xie (Synth Syst Biotechnol. 2022 Jan 12;7(1):544-553) teaches natural melatonin synthesis pathways. See p. 545 section 2. Xie discloses that in fresh plants serotonin is acetylated into N-acetylserotonin (i.e. tryptamine derivative) by serotonin N-acetyltransferase (SNAT) in the chloroplast. See p. 545 section 2 para. 2. As shown in the portion of Xie’s figure 3 below, serotonin (i.e. indole acceptor) is contacted with acetyl-coenzyme A (Ac-CoA) (i.e. acetyl substituent donor), in the presence of the SNAT enzyme substituting the H in the serotonin with the acetyl from Ac-CoA. Serotonin is an indole acceptor formula (II) embodiment where RVI is not H and RIII is CH2CH2NH2, and N-acetylserotonin is a tryptamine derivative of formula (I) that is not N-acetyl-4-hydroxytryptamine. Accordingly, the evidence of record indicates that the claims are directed to a natural phenomenon judicial exception (Step 2A Prong 1: Yes).
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This judicial exception is not integrated into a practical application because the claim elements do not impose any meaningful limitations on the judicial exception. Claim 4 limits the indole acceptor (II) to a group that includes 5-hydroxytryptamine or serotonin. Claim 5 requires the substituent to be selected from a group that includes an acetyl group. Claim 8 recites “wherein the substitution is…optionally selected from the group consisting of…N-acetylation”. Therefore, claims 4, 5 and 8 merely describe the judicial exception without adding any elements to the judicial exception that could integrate it into a practical application. At most the limitations of claims 4, 5 and 8 are attempts to generally link the natural phenomenon to it’s field of use. Claim 12 requires the substituent donor to be an aldehyde, a ketone, an ether and/or an amine. This limitation fails to add an element to the judicial exception because the claim encompasses any molecule with one of the recited functional groups (e.g. Ac-CoA includes an amine group). Claim 22 limits the one or more enzymes to a group that includes acetyltransferases. As such, claim 22 is an attempt to generally link the enzymes involved in the natural phenomenon to their field of use. Claim 68 limits the tryptamine derivative (I) to a group that includes melatonin. As such, the limitation of claim 68 merely serves to generally link the judicial exception to its field of use. Claim 70 requires the method of claim 1 to further comprise one or more steps selected from a) converting an indole or indole derivative into tryptophan or a tryptophan derivative; and b) converting tryptophan or tryptophan derivative into tryptamine or tryptamine derivative. This fails to add an element to the judicial exception because serotonin and N-acetyl-serotonin are derived from tryptophan. Claim 77 requires the method to further comprise one or more further steps of a) glycosylation; b) methylation; c) hydroxylation; d) condensation; e) nitration; f) oxidation; g) lyase deamidation; or h) dephosphorylation. The limitation of claim 77 is recited with a high level of generality, because it encompasses any of the recited additional reactions including reactions that do not entail the indol acceptor, tryptamine derivative or substituent donor required in claim 1. This provides insufficient specificity to add anything of significance to the judicial exception because at best the claim merely implies that additional reactions may occur. Claim 80 requires in vitro enzymatic substitution steps and/or optionally in vivo enzymatic substitution steps. This limitation is recited with a high level of generality, because together in vitro (outside of a living organism) and in vivo (inside of a living organism) encompass all locations. Therefore, claim 80 is merely an attempt to generally link the natural phenomenon to its field of use. Accordingly, the claim as a whole does not integrate the judicial exception into a practical application (Step 2A Prong 2: No)
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the insignificant limitations were well known and conventional in the art at the time of filing. Peiffer (US 2023/0242919, effectively filed Jun. 6, 2020) teaches growing E. coli cells, harboring an indolethylamine N-methyltransferase (INMT)-expression vector, in a culture medium. Peiffer teaches adding serotonin and S-adenosyl-L-methionine (SAMe) (substituent donor) into the cell culture media (i.e. contacting). See [0182]. Peiffer discloses that INMT catalyzes the alkylation (i.e., adding a methyl (CH3) group) of the primary amine on a tryptamine substrate. The methylation reaction uses up the methyl donor cofactor, SAMe (substituent donor). See [0057]. Thus, the additional limitations in claims 1, 4-5, 8, 12, 22, 68, 70, 77, and 80 fail to amount to an inventive concept (Step 2B: No).
For all of these reasons, claims 1, 4-5, 8, 12, 22, 68, 70, 77, and 80 are not patent eligible.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4-5, 8, 12, 22, 39, 76-77 and 80 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Peiffer (US 2023/0242919, effectively filed Jun. 6, 2020).
Regarding claim 1, Peiffer, in example 21, teaches converting serotonin (indole acceptor) to 5-OH-DMT (tryptamine derivative), which also referred to as bufotemine. Peiffer teaches growing E. coli cells, harboring an indolethylamine N-methyltransferase (INMT)-expression vector, in a culture medium. Peiffer teaches adding (i.e. contacting) serotonin and S-adenosyl-L-methionine (SAMe) (substituent donor) into the cell culture media. See [0182]. Peiffer discloses that INMT catalyzes the alkylation (i.e., adding a methyl (CH3) group) of the primary amine on a tryptamine substrate. The methylation reaction uses up the methyl donor cofactor, SAMe (substituent donor). See [0057]. As shown in figure 4 C) provided herein, the INMT enzyme substitutes the H in the serotonin (indole acceptor) with methyl groups from the SAMe (substituent donor).
With respect to the instant claims, serotonin is an indole acceptor of instant formula (II) that includes an R-VII that is not H and an RIII that is CH2CH-2NH2. Moreover, 5-OH-DMT is a tryptamine derivative of formula (I), because 5-OH-DMT (i.e. DMT is N,N-dimethyltryptamine) is not halogenated N,N-dimethyltryptamine.
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Regarding claim 4, Pieffer teaches indole compounds in figure 2. See [0012]. Serotonin is shown in figure 2 B). Peiffer, in example 21, teaches INMT-expression vector, in a culture medium. Serotonin and SAMe (substituent donor) are added into the cell culture media. See [0182]. As shown in figure 4 C) provided herein, the INMT enzyme substitutes the H in the serotonin (indole acceptor) with methyl groups from the SAMe (substituent donor).
Regarding claim 5, Peiffer discloses that INMT catalyzes the alkylation, i.e., adding a methyl (CH3) group (i.e. methyl is an alkyl group) of the primary amine on a tryptamine substrate. See [0057]. As shown in figure 4 C) provided herein, the INMT enzyme substitutes the H in the serotonin indole acceptor with methyl groups (i.e. alkyl groups) from the SAMe substituent donor.
Regarding claim 8, Peiffer teaches figure 4 C), which shows the INMT enzyme substituting each H in the -NH2 of serotonin with methyl groups (i.e. N-alkylation).
Regarding claim 12, Peiffer teaches adding S-adenosyl-L-methionine (SAMe) (substituent donor) into the cell culture media. See [0182]. As shown in figure 4 C) provided herein, the SAMe has an amine functional group.
Regarding claim 22, Peiffer teaches E. coli cells, harboring indolethylamine N-methyltransferase (INMT) (i.e. alkyltransferase). See [0182]. INMT catalyzes alkylation. See [0057].
Regarding claim 39c), Peiffer teaches E. coli cells, harboring indolethylamine N-methyltransferase (INMT) (i.e. alkyltransferase). See [0182]. Peiffer teaches INMT (SEQ ID NO: 363). See [0604]. Peiffer’s SEQ ID NO: 363 is an 88.6% identity match to instant SEQ ID NO: 122. See the office action appendix for the alignment.
Regarding claim 76, Peiffer teaches constructing S. cerevisiae with two or more enzymes, N-acetyltransferase (NAT) acetylation of serotonin (i.e. indole acceptor) produces the intermediate N-acetyl-serotonin or NAS. NAS is converted to melatonin (i.e. tryptamine derivative) with the IOMT enzyme. See [0169]. As shown in figure 7 C) the NAT enzyme substitutes the H in the serotonin indole acceptor with an acetyl group. Peiffer teaches an N-acetyl transferase (NAT) SEQ ID NO: 422. See [0663]. Peiffer’s NAT SEQ ID NO: 422 is a 93.5% identity match to instant SEQ ID NO: 142. See the alignment provided in the office action appendix. As shown in figure 4 F), Acetyl-CoA acts as the substituent donor in serotonin to N-acetyl serotonin conversion in the presence of NAT.
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Regarding claim 77, Peiffer teaches constructing S. cerevisiae with two or more enzymes. N-acetyltransferase (NAT) acetylation of serotonin (i.e. indole acceptor) produces the intermediate N-acetyl-serotonin or NAS. NAS is converted to melatonin (i.e. tryptamine derivative) with the IOMT enzyme. See [0169]. As shown in figure 7 C) the NAT enzyme substitutes the H in the serotonin indole acceptor with an acetyl group, and the hydroxytryptamine O-methyltransferase (IOMT) further methylates the N-acetyl serotonin to form melatonin (i.e. methylation). Furthermore, Peifer teaches tryptamines and tryptophans modified by hydroxylation, halogenation, methylation, and halogenation in recombinant organisms. See [0050].
Regarding claim 80, Peiffer discloses that the enzyme can be isolated in vitro and used in vitro to provide enzyme activity. Alternatively, the enzyme can be expressed in a recombinant organism. See [0142].
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 68 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Peiffer (US 2023/0242919, effectively filed Jun. 6, 2020).
Regarding claim 68, the tryptamine derivative (I) of the instant claim is interpreted as encompassing melatonin. Peiffer teaches constructing S. cerevisiae with two or more enzymes. N-acetyltransferase (NAT) acetylation of serotonin (i.e. indole acceptor) produces the intermediate N-acetyl-serotonin or NAS. NAS is converted to melatonin (i.e. tryptamine derivative) with the IOMT enzyme. See [0169].
Although Peiffer does not teach a tryptamine derivative (I) that is a hydroxy tryptamine β-O-glycoside, Peiffer teaches melatonin which meets the instant claim limitation.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention that Peiffer’s serotonin indole acceptor when contacted with NAT and NAS enzymes is converted to (I) melatonin.
Regarding claim 70, Peiffer teaches constructing a strain that expresses an AADC gene which encodes the enzyme that converts L-tryptophan to tryptamine. See [0163]. AADC is aromatic amino acid decarboxylase; tryptophan decarboxylase. See table 2, which is in [0049]. Peiffer suggests a recombinant microorganism embodiment that expresses INMT and AADC. See [00133].
Although Peiffer teaches converting L-tryptophan into tryptamine which meets the limitation of instant claim 70 b), Peiffer does not teach the conversion in combination with a step that entails contacting the indole acceptor with a substituent donor in the presence of one or more enzymes substituting one or more H, OH and/or COOH in the indole acceptor with one or more substituents of the substituent donor (relevant to instant claim 1 from which claim 70 depends).
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to combine Peiffer’s L-tryptophan to tryptamine conversion with Peiffer’s E. coli cell harboring INMT for converting the serotonin indole acceptor to the tryptamine derivative 5-OH-DMT. One of ordinary skill in the art would have been motivated to do so because Peiffer suggests combining INMT with AADC in one microorganism, and the AADC gene encodes an enzyme that converts L-tryptophan to tryptamine. There would have been a reasonable expectation of success because Peiffer demonstrates converting serotonin (i.e. indole acceptor) to 5-OH-DMT (i.e. tryptamine derivative) (example 21 [0182]), tryptophan to tryptamine (example 10 [0163]).
Peiffer further discloses that by engineering various enzymes into a microorganism, tryptamine and other substituted indoles can be modified into a large array of useful compounds, which can be harvested from cultures of the microorganisms. See [0053]. In example 21, Peiffer, teaches producing 5-OH-DMT (i.e. tryptamine derivative). Peiffer teaches growing E. coli cells, harboring an INMT-expression vector, in a culture medium. Peiffer teaches adding serotonin and SAMe (substituent donor). See [0182]. As shown in figure 4 C) provided herein, the INMT enzyme substitutes the H in the serotonin (indole acceptor) with methyl groups from the SAMe (substituent donor) to produce 5-OH-DMT. Media is collected. See [0182].
Claim 81 is rejected under 35 U.S.C. 103 as being unpatentable over Peiffer (US 2023/0242919, effectively filed Jun. 6, 2020) in view of Okura (JP2009034028).
The teachings of Peiffer with respect to instant claim 1, from which claim 81 depends, are discussed above.
Regarding claim 81, Peiffer, in example 21, teaches growing E. coli cells, harboring an indolethylamine N-methyltransferase (INMT)-expression vector, in a culture medium. Peiffer teaches adding serotonin (indole acceptor) and S-adenosyl-L-methionine (SAMe) (substituent donor) into the cell culture media. See [0182]. Peiffer suggests that INMT is secreted. See [0182].
Peiffer does not teach expressing a glycosyl transferase in E. coli and performing in vitro glycosylation of the indole acceptor.
Okura teaches a glycosyltransferase that exhibits broad receptor specificity and preferentially catalyzes the transfer reaction to phenolic hydroxyl groups, and has high glycosylation activity. See [0012]. Okura teaches introducing recombinant DNA [encoding β-glucosidase enzyme] into E. coli. See [0057]. Okura teaches synthesizing serotonin glycosides by reacting β-glucosidase with a mixture containing serotonin. See [0093]. As a result, the glucose portion of the substrate phenyl β-D-glucoside is transferred to serotonin (i.e. glycosylation) forming serotonin glycoside. See [0094]. Okura teaches that it is usually advantageous to extract the recombinant enzyme from the bacterial cells (i.e. in vitro) before use. See [0033].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to express Okura’s glycosyl transferase in Peiffer’s E. coli and glycosylate the serotonin indole acceptor of Peiffer in vitro. One of ordinary skill in the art would have been motivated to do so because Okura suggests that the glycosyltransferase catalyzes a transfer reaction to phenolic hydroxyl groups, and has high glycosylation activity. There would have been a reasonable expectation of success, because Okura and Peiffer demonstrate expressing enzymes in E. coli and performing in vitro enzymatic reactions with serotonin. To clarify, Okura demonstrates expressing glycosyltransferase in E. coli (see [0057]), and Okura demonstrates an in vitro glycosylation of serotonin (see [0094]). Furthermore, Peiffer demonstrates transforming E. coli with INMT, which Peiffer suggests secretes from the cell (see [0182]), and consequently Peiffer indicates that the INMT and the serotonin react in the culture medium, i.e. in vitro.
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657
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