DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 2, 6, 8-10, 12, 13, 15, 17, 22, and 28-36 are pending in the application.
Restriction/Election
Applicant’s election without traverse of Group I, claims 1, 2, 6, 8-10, 12, 13, 15, 17, and 28-36, and election of the species N-methyltransferase (INMT) as the enzyme or regulatory protein in tryptamine metabolism in claims 1 and 2, SEQ ID NO: 68 as the sequence in claim 12, and recombinant microorganism expresses INMT and produces at least one hydroxy substituted tryptamine compound in claims 30 and 31 in the reply filed on September 26, 2025 is acknowledged.
Claim 22 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 28, 29, and 32-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.
Claims 1, 2, 6, 8-10, 12, 13, 15, 17, 30, and 31 are being examined on the merits with claims 1, 2, and 12 being examined only to the extent the claims read on the elected subject matter as set forth above.
Priority
This application is filed under 35 U.S.C. 371 as a national stage of international application PCT/US2021/036031, filed June 4, 2021, which claims domestic priority under 35 U.S.C. 119(e) to U.S. provisional application no. 63/035,692, filed June 6, 2020.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/035,692, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) for one or more claims of this application.
Regarding claims 1 and 2, the disclosure of Application No. 63/035,692 fails to provide descriptive support for all recited enzymes and regulatory proteins.
Regarding claims 8-10, the disclosure of Application No. 63/035,692 fails to provide descriptive support for a codon optimized nucleic acid encoding a cofolding peptide.
Regarding claim 12, the disclosure of Application No. 63/035,692 fails to provide descriptive support for SEQ ID NO: 68.
Regarding claims 30 and 31, the disclosure of Application No. 63/035,692 fails to provide descriptive support for producing at least one hydroxy substituted tryptamine compound including bufotenine, 5-OH-NMT, or 5-OH-TMT.
The effective filing date of clams 1, 2, 6, 8-10, 12, 13, 15, 17, 30, and 31 is June 4, 2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on January 24, 2023 and September 26, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs have been considered by the examiner.
The listing of references in the specification at pp. 51-52 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 31 is objected to for typographical errors in the terms “5-OH-NMT” and “5-OH-TMT,” which should be replaced with “5-HO-NMT” and “5-HO-TMT,” respectively.
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.
Claims 1, 2, 6, 8-10, 12, 13, 15, 17, 30, and 31 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1 (claims 2, 6, 8-10, 12, 13, 15, 17, 30, and 31 dependent therefrom) and 2 are indefinite in the recitation of “N-methyltransferase (INMT, PsiM, TrpM)” and “tryptamine N-methyltransferase (INMT)…tryptophan N-methyltransferase (TrpM)” because it is unclear as to whether or not the parenthetical phrases are intended to be limiting or to recite examples or preferences. According to MPEP 2173.05(d), “[d]escription of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) should be made.”
Claim 8 (claims 9 and 10 dependent therefrom) is confusing in the recitation of “nucleotides…that encode a codon optimized cofolding peptide” because peptides are not known in the relevant art to be codon optimized. It is suggested that applicant clarify the meaning of the noted phrase.
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, 2, 6, 8, 9, 13, 15, 17, and 30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Applicant’s attention is directed to the "Guidance for Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products”, released on December 16, 2014.
Claim Interpretation: Claim 1 is drawn to (in relevant part) a non-naturally occurring nucleic acid comprising a sequence encoding an N-methyltransferase (INMT, PsiM, TrpM). Given a broadest reasonable interpretation, claim 1 encompasses a genomic sequence encoding an N-methyltransferase.
Claim 2 is drawn to (in relevant part) the nucleic acid of claim 1, encoding a methyltransferase or hydroxylase, wherein the methyltransferase or hydroxylase is a tryptamine N-methyltransferase or a tryptophan N-methyltransferase. Given a broadest reasonable interpretation, claim 2 encompasses a genomic sequence encoding a tryptamine N-methyltransferase or a tryptophan N-methyltransferase.
Claim 6 is drawn to the nucleic acid of claim 1, wherein the sequence is codon-optimized for yeast expression. Given a broadest reasonable interpretation, claim 6 encompasses a genomic sequence encoding a yeast N-methyltransferase.
Claim 8 is drawn to the nucleic acid of claim 1, having a 5′ end, further comprising additional nucleotides at the 5′ end that encode a codon optimized cofolding peptide. Given a broadest reasonable interpretation, claim 8 encompasses a genomic sequence encoding any enzyme or regulatory protein recited in claim 1 and any upstream genomic sequence encoding a cofolding peptide. The term “codon optimized cofolding peptide” is interpreted as meaning an amino acid sequence that folds concurrently with the enzyme or regulatory protein recited in claim 1.
Claim 9 is drawn to the nucleic acid of claim 8, wherein the codon optimized cofolding peptide comprises an amino acid sequence of any one of SEQ ID NO:554-558. Given a broadest reasonable interpretation, claim 9 encompasses a genomic sequence encoding any enzyme or regulatory protein recited in claim 1 and any upstream genomic sequence encoding any one of SEQ ID NO: 554-558.
Claim 13 is drawn to the nucleic acid of claim 1, further comprising a promoter functional in a yeast. Given a broadest reasonable interpretation, claim 13 encompasses a genomic sequence encoding a yeast N-methyltransferase.
Claim 15 is drawn to a yeast expression cassette comprising the nucleic acid of claim 13. Given a broadest reasonable interpretation, claim 15 encompasses a genomic sequence encoding a yeast N-methyltransferase.
Claim 17 is drawn to a recombinant yeast comprising the expression cassette of claim 15, that expresses the enzyme or regulatory protein encoded therein. Given a broadest reasonable interpretation, claim 17 encompasses a yeast comprising a genomic sequence encoding an N-methyltransferase.
Claim 30 is drawn to the recombinant yeast of claim 17, expressing INMT, wherein the recombinant microorganism produces at least one hydroxy substituted tryptamine compound. Given a broadest reasonable interpretation, claim 30 encompasses a yeast comprising a genomic sequence encoding an N-methyltransferase that produces at least one hydroxy substituted tryptamine compound.
Patent Eligibility Analysis Step 1: The claims are drawn to a nucleic acid, a yeast expression cassette, and a recombinant yeast, which are compositions of matter and are one of the statutory categories of invention.
Patent Eligibility Analysis Step 2A Prong 1: While claim 1 recites “non-naturally occurring” and claim 17 recites “recombinant,” the claimed nucleic acid, yeast expression cassette, and recombinant yeast are not considered to have markedly different characteristics from what occurs in nature, and are considered to be law of nature exceptions. Accordingly, the nucleic acid, yeast expression cassette, and recombinant yeast are directed to judicial exceptions.
Patent Eligibility Analysis Step 2A Prong 2: There are no additional elements recited in the claims beyond the judicial exceptions.
Patent Eligibility Analysis Step 2B: The claims only recite laws of nature and do not include any additional elements that could add significantly more to the judicial exceptions.
As such, the claims do not qualify as eligible subject matter. For these reasons the claims are rejected under section 101 as being directed to non-statutory subject matter.
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(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, 2, 6, 13, 15, 17, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Milne et al. (Metabolic Engineering 60:25-36, 2020; cited on the attached Form PTO-892; hereafter “Milne-1”).
Claim 1 is drawn to (in relevant part) a non-naturally occurring nucleic acid comprising a sequence encoding an N-methyltransferase (INMT, PsiM, TrpM).
Claim 2 is drawn to (in relevant part) the nucleic acid of claim 1, encoding a methyltransferase or hydroxylase, wherein the methyltransferase or hydroxylase is a tryptamine N-methyltransferase (INMT) or a tryptophan N-methyltransferase (TrpM). The instant specification discloses “INMT (PsiM) (p. 31, 5th full paragraph). Given that claim 2 recites “tryptamine N-methyltransferase (INMT)” and the specification discloses “INMT (PsiM),” “tryptamine N-methyltransferase (INMT)” in claim 2 is interpreted as encompassing PsiM.
Claim 6 is drawn to the nucleic acid of claim 1, wherein the sequence is codon-optimized for yeast expression.
Claim 13 is drawn to the nucleic acid of claim 1, further comprising a promoter functional in a yeast.
Claim 15 is drawn to a yeast expression cassette comprising the nucleic acid of claim 13.
Claim 17 is drawn to a recombinant yeast comprising the expression cassette of claim 15, that expresses the enzyme or regulatory protein encoded therein.
Claim 30 is drawn to the recombinant yeast of claim 17, expressing INMT, wherein the recombinant microorganism produces at least one hydroxy substituted tryptamine compound.
Regarding claims 1 and 2, Milne-1 teaches a Saccharomyces cerevisiae expressing a heterologous biosynthetic pathway sourced from Psilocybe cuensis, including PsiM gene (p. 25, abstract; p. 27, Fig. 2 under “Heterologous genes introduced”).
Regarding claim 6, Milne-1 teaches the heterologous genes were codon-optimized for expression in S. cerevisiae (p. 28, column 1, top).
Regarding claim 13, Milne-1 teaches genes are expressed from strong constitutive promoters (p. 28, top, heading for Table 1).
Regarding claims 15 and 17, Milne-1 teaches S. cerevisiae was transformed with the heterologous genes and acknowledges successful genomic integration of overexpression cassettes by confirming increased production of a metabolite of interest (p. 28, column 1, top).
Regarding claim 30, Milne-1 teaches production of 4-hydroxytryptamine derivatives in the engineered S. cerevisiae (paragraph bridging pp. 31 and 33; p. 32, Fig. 6).
Therefore, Milne-1 anticipates claims 1, 2, 6, 13, 15, 17, and 30 as written.
Claims 1, 2, 6, 13, 15, 17, 30, and 31 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Milne et al. (WO 2022/248635 A2 with priority to EP 21176391.7 filed May 27, 2021; cited on the attached Form PTO-892; hereafter “Milne-2”).
Regarding claim 1, Milne-2 teaches a DNA encoding N-methyltransferase enzymes (p. 58, bottom) including Citrus sinensis N-methyltransferase (CsSNMT).
Regarding claim 2, Milne-2 teaches CsSNMT converts serotonin to N-methyl serotonin (paragraph bridging pp. 87-88). Since CsSNMT is an N-methyltransferase that uses serotonin as a substrate and serotonin is an indolethylamine, CsSNMT is considered to be an indolethylamine N-methyltransferase (INMT). Given the indefiniteness of ““tryptamine N-methyltransferase (INMT),” CsSNMT is considered to be encompassed by “tryptamine N-methyltransferase (INMT)” in claim 2.
Regarding claim 6, Milne-2 teaches the genes encoding enzymes were codon optimized (paragraph bridging pp. 68-69).
Regarding claims 13, 15, and 17, Milne-2 teaches genes encoding enzymes were codon optimized and S. cerevisiae was transformed with expression plasmids or plasmids were integrated into the genome of S. cerevisiae (paragraph bridging pp. 68-69). Milne-2 teaches p415(TEF (CsSNMT1) expression plasmid (p. 70, middle). Milne-2 teaches the polynucleotides for expression comprise a control sequence including a promoter sequence (paragraphs [0083], [0085], and [0143]).
Regarding claims 30 and 31, Milne-2 teaches constructing an engineered Saccharomyces cerevisiae that produces tryptamine by expressing Ruminococcus gnavus tryptophan decarboxylase (RgTdc), converting the tryptamine to serotonin by expressing Oryza sativa tryptamine 5-hydroxylase (OsT5H) and Fusarium oxysporum cytochrome P450 reductase (FoCPR), and converting serotonin to N-methyl serotonin by expressing Citrus sinensis N-methyltransferase (CsSNMT1) (paragraph bridging pp. 87-88; pp. 56 for RgTdc; p. 57 for OsT5H and FoCPR; p. 58 for CsSNMT). Serotonin is also known as 5-hydroxytryptamine and N-methyl serotonin is also known as 5-hydroxy-N-methyltryptamine and abbreviated as “5-HO-NMT.”
Therefore, Milne anticipates claims 1, 2, 6, 13, 15, 17, 30, and 31 as written.
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 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Milne-1 in view of Riggs et al. (WO 2007/120809 A1; cited on the attached Form PTO-892; hereafter “Riggs”) and Dälken et al. (PLoS ONE 5:e14404, 2010, 10 pages; cited on the attached Form PTO-892; hereafter “Dälken”).
Claim 8 is drawn to the nucleic acid of claim 1, having a 5′ end, further comprising additional nucleotides at the 5′ end that encode a codon optimized cofolding peptide.
Claim 9 is drawn to the nucleic acid of claim 8, wherein the codon optimized cofolding peptide comprises an amino acid sequence of any one of SEQ ID NO:554-558.
The relevant teachings of Milne-1 as applied to claims 1, 2, 6, 13, 15, 17, and 30 are set forth above.
While Milne-1 teaches the heterologous genes were codon-optimized for expression in S. cerevisiae (p. 28, column 1, top), Milne-1 does not teach a codon optimized cofolding peptide as recited in claims 8 and 9.
Riggs teaches many proteins that are soluble in their native host are insoluble when expressed as a recombinant protein, while fusion to maltose binding protein (MBP) renders them soluble (paragraph bridging pp. 1-2). Dälken teaches that increased solubility, enhanced stability and markedly improved yields have been reported after fusion to MBP, which has been explained by the ability of MBP to act as a chaperone in the context of a fusion protein, and promote the proper folding of the fusion partner (p. 1, paragraph bridging columns 1-2) Dälken teaches MBP acts like a chaperone and promotes proper folding of a fusion partner in yeast (p. 6, column 1). Riggs teaches the amino acid sequence of wild-type MBP (p. 4, lines 17-18; Figure 2A), which is identical to instant SEQ ID NO: 554 (see Appendix for sequence alignment).
In view of the combination of Milne-1, Riggs, and Dälken, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to express the heterologous genes of Milne-1 as fusions with MBP. One would have been motivated to do this because Riggs and Dälken teach fusion with MBP imparts advantageous properties including increased solubility, enhanced stability and markedly improved yields. One would have expected success because Dälken teaches MBP acts like a chaperone and promotes proper folding of a fusion partner in yeast.
Therefore, the nucleic acid of claims 8 and 9 would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 8 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Milne-2 in view of Riggs and Dälken.
The relevant teachings of Milne-2 as applied to claims 1, 2, 6, 13, 15, 17, 30, and 31 are set forth above.
While Milne-2 teaches the genes encoding enzymes were codon optimized (paragraph bridging pp. 68-69), Milne-2 does not teach a codon optimized cofolding peptide as recited in claims 8 and 9.
Riggs teaches many proteins that are soluble in their native host are insoluble when expressed as a recombinant protein, while fusion to maltose binding protein (MBP) renders them soluble (paragraph bridging pp. 1-2). Dälken teaches that increased solubility, enhanced stability and markedly improved yields have been reported after fusion to MBP, which has been explained by the ability of MBP to act as a chaperone in the context of a fusion protein, and promote the proper folding of the fusion partner (p. 1, paragraph bridging columns 1-2) Dälken teaches MBP acts like a chaperone and promotes proper folding of a fusion partner in yeast (p. 6, column 1). Riggs teaches the amino acid sequence of wild-type MBP (p. 4, lines 17-18; Figure 2A), which is identical to instant SEQ ID NO: 554 (see Appendix for sequence alignment).
In view of the combination of Milne-2, Riggs, and Dälken, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to express the enzymes of Milne-2 as fusions with MBP. One would have been motivated to do this because Riggs and Dälken teach fusion with MBP imparts advantageous properties including increased solubility, enhanced stability and markedly improved yields. One would have expected success because Dälken teaches MBP acts like a chaperone and promotes proper folding of a fusion partner in yeast.
Therefore, the nucleic acid of claims 8 and 9 would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Claim Rejections – Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 2, 6, and 30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 7 of U.S. Patent No. 11,441,164 B2 (cited on the attached Form PTO-892).
Regarding instant claims 1 and 2, claim 1 of the patent recites a recombinant host organism comprising:
a plurality of cells transfected by a gene expressed in the recombinant host organism;
wherein the recombinant host organism is a fungal species selected from the group consisting of Schizosaccharomyces cerevisiae, Schizosaccharomyces japonicus, Schizosaccharomyces pombe, Schizosaccharomyces cryophilus, Saccharomyces cerevisiae, Kluyveromyces lactis, Kluyveromyces dobzhanskii, and Yarrowia lipolytica;
wherein the gene is codon optimized for expression in the recombinant host organism and is selected from a group consisting of PsiD, PsiH, PsiK, and PsiM; wherein:
PsiD encodes an L-tryptophan decarboxylase and comprises nucleic acid sequence SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3;
PsiH encodes a tryptamine 4-monooxygenase and comprises nucleic acid sequence SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6;
PsiK encodes a 4-hydroxytryptamine kinase and comprises nucleic acid sequence SEQ ID NO:7 or SEQ ID NO:8; and
PsiM encodes a methyl transferase and comprises codon optimized nucleic acid sequences SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, or SEQ ID NO:13.
The instant specification discloses “INMT (PsiM) (p. 31, 5th full paragraph). Given that claim 2 recites “tryptamine N-methyltransferase (INMT)” and the specification discloses “INMT (PsiM),” “tryptamine N-methyltransferase (INMT)” in claim 2 is interpreted as encompassing PsiM.
Regarding instant claim 6, claim 2 of the patent recites the recombinant host organism of claim 1, comprising PsiD, PsiH, PsiK and PsiM, all codon optimized for expression in the recombinant host organism, wherein the organism synthesizes psilocybin.
Regarding instant claim 30, claim 7 of the patent recites the recombinant host organism of claim 3, synthesizing at least one psilocybin intermediates selected from the group consisting of tryptamine, 4-hydroxytryptamine, norbaeocystin, baeocystin, and psilocin.
Therefore, claims 1, 2, 6, and 30 of this application are unpatentable over claims 1, 2, and 7 of the patent.
Claims 8 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 7 of U.S. Patent No. 11, 441,164 B2 (cited on the attached Form PTO-892) in view of Riggs and Dälken.
While the claims of the patent recite the PsiM is codon optimized, the claims of the patent do not recite a codon optimized cofolding peptide as recited in instant claims 8 and 9.
Riggs teaches many proteins that are soluble in their native host are insoluble when expressed as a recombinant protein, while fusion to maltose binding protein (MBP) renders them soluble (paragraph bridging pp. 1-2). Dälken teaches that increased solubility, enhanced stability and markedly improved yields have been reported after fusion to MBP, which has been explained by the ability of MBP to act as a chaperone in the context of a fusion protein, and promote the proper folding of the fusion partner (p. 1, paragraph bridging columns 1-2) Dälken teaches MBP acts like a chaperone and promotes proper folding of a fusion partner in yeast (p. 6, column 1). Riggs teaches the amino acid sequence of wild-type MBP (p. 4, lines 17-18; Figure 2A), which is identical to instant SEQ ID NO: 554 (see Appendix for sequence alignment).
In view of the combination of Riggs and Dälken, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to express the PsiM of the claims of the patent as a fusion with MBP. One would have been motivated to do this because Riggs and Dälken teach fusion with MBP imparts advantageous properties including increased solubility, enhanced stability and markedly improved yields. One would have expected success because Dälken teaches MBP acts like a chaperone and promotes proper folding of a fusion partner in yeast.
Therefore, claims 8 and 9 of this application are unpatentable over claims 1, 2, and 7 of the patent in view of Riggs and Dälken.
Claims 13, 15, and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, and 7 of U.S. Patent No. 11, 441,164 B2 (cited on the attached Form PTO-892) in view of Milne-1.
The claims of the patent do not recite a promoter and an expression cassette as recited in instant claims 13, 15, and 17.
Milne-1 teaches a Saccharomyces cerevisiae expressing a heterologous biosynthetic pathway sourced from Psilocybe cuensis, including PsiM gene (p. 25, abstract; p. 27, Fig. 2 under “Heterologous genes introduced”) for production of 4-hydroxytryptamine derivatives including psilocybin in the engineered S. cerevisiae (paragraph bridging pp. 31 and 33; p. 32, Fig. 6).
Regarding instant claim 13, Milne-1 teaches the genes are expressed from strong constitutive promoters (p. 28, top, heading for Table 1).
Regarding instant claims 15 and 17, Milne-1 teaches the S. cerevisiae was transformed with the heterologous genes and acknowledges successful genomic integration of overexpression cassettes by confirming increased production of a metabolite of interest (p. 28, column 1, top).
In view of the Milne-1, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the claims of the patent to express PsiM using an expression cassette with a strong constitutive promoter. One would have been motivated to and would have expected success to do this because the claims of the patent recite and Milne-1 teaches a Saccharomyces cerevisiae expressing a PsiM gene for production of 4-hydroxytryptamine and psilocybin in the S. cerevisiae, and Milne-1 teaches expression of PsiM is achieved by using an expression cassette with a strong constitutive promoter.
Therefore, claims 13, 15, and 17 of this application are unpatentable over claims 1, 2, and 7 of the patent in view of Milne-1.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: The prior art of record does not teach or suggest the nucleotide sequences of SEQ ID NO: 68 and 265-269.
Conclusion
Status of the claims:
Claims 1, 2, 6, 8-10, 12, 13, 15, 17, 22, and 28-36 are pending.
Claims 22, 28, 29, and 32-36 are withdrawn.
Claims 1, 2, 6, 8-10, 12, 13, 15, 17, 30, and 31 are rejected.
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID J STEADMAN whose telephone number is (571)272-0942. The examiner can normally be reached Monday to Friday, 7:30 AM to 4:00 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MANJUNATH N RAO can be reached on 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/David Steadman/Primary Examiner, Art Unit 1656 APPENDIX
ID ANK79256 standard; protein; 387 AA.
XX
AC ANK79256;
XX
DT 28-DEC-2007 (first entry)
XX
DE Maltose binding protein (MBP) wild-type SEQ ID NO:2.
XX
KW protein engineering; protein purification; protein solubilization; MBP;
KW maltose binding protein.
XX
OS Escherichia coli.
XX
CC PN WO2007120809-A1.
XX
CC PD 25-OCT-2007.
XX
CC PF 14-APR-2007; 2007WO-US009100.
XX
PR 14-APR-2006; 2006US-0792133P.
XX
CC PA (NEWE ) NEW ENGLAND BIOLABS INC.
XX
CC PI Riggs PD, Hsieh P, Walker I, Colussi PA, Ganatra M, Taron CH;
XX
DR WPI; 2007-816453/76.
DR N-PSDB; ANK79255.
XX
CC PT New modified maltose-binding protein, useful as an affinity tag for
CC PT expression and purification of target proteins.
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CC PS Example 1; SEQ ID NO 2; 53pp; English.
XX
CC The present invention relates to a modified maltose-binding protein (MBP)
CC comprising an MBP amino acid sequence having a mutation which brings
CC about changes in the properties of the protein which can be useful in
CC protein purification and in solubilization. The mutations introduced in
CC this invention are aimed at altering the binding affinity of the protein
CC for a maltodextrin substrate. The mutants of the invention show much
CC higher affinity for the substrate than the wild type. The modified MBP is
CC fused to a target protein to form a fusion protein which has higher
CC solubility than the fusion protein constructed with the wild type MBP.
CC The mutation in the MBP can be located in the hinge regions between
CC helices XI and XIi or in the C domain of the protein. The inventors have
CC also claimed a vector sequence that carries the DNA encoding for the
CC mutant protein and a host system for the same. The invention can be very
CC useful in purification and solubilization of target proteins. The present
CC sequence is that of the E. coli maltose binding protein.
XX
SQ Sequence 387 AA;
Query Match 100.0%; Score 2033; Length 387;
Best Local Similarity 100.0%;
Matches 387; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAATGDGPDI 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAATGDGPDI 60
Qy 61 IFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIAYPIAVEALSLIYNK 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 IFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIAYPIAVEALSLIYNK 120
Qy 121 DLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTWPLIAADGGYAFKYENGKYDIK 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 DLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTWPLIAADGGYAFKYENGKYDIK 180
Qy 181 DVGVDNAGAKAGLTFLVDLIKNKHMNADTDYSIAEAAFNKGETAMTINGPWAWSNIDTSK 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DVGVDNAGAKAGLTFLVDLIKNKHMNADTDYSIAEAAFNKGETAMTINGPWAWSNIDTSK 240
Qy 241 VNYGVTVLPTFKGQPSKPFVGVLSAGINAASPNKELAKEFLENYLLTDEGLEAVNKDKPL 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 VNYGVTVLPTFKGQPSKPFVGVLSAGINAASPNKELAKEFLENYLLTDEGLEAVNKDKPL 300
Qy 301 GAVALKSYEEELAKDPRIAATMENAQKGEIMPNIPQMSAFWYAVRTAVINAASGRQTVDE 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 GAVALKSYEEELAKDPRIAATMENAQKGEIMPNIPQMSAFWYAVRTAVINAASGRQTVDE 360
Qy 361 ALKDAQTNSSSNNNNNNNNNNLGIEGR 387
|||||||||||||||||||||||||||
Db 361 ALKDAQTNSSSNNNNNNNNNNLGIEGR 387