DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of claims 1-6 and the species SEQ ID NO: 70, residue 155, and benzylisoquinolines in the reply filed on 2/23/2026 is acknowledged.
Claims 7-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/23/2026.
Priority
This application is a 371 of PCT/US21/59980 (11/18/2021) which claims benefit of 63/116,097 (11/19/2020).
Information Disclosure Statement
The information disclosure statements (IDS) filed on 4/7/2025 and 11/21/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84(u)(1) states “View numbers must be preceded by the abbreviation “FIG.”.
In the current case, the view numbers for Figures 1-40 are preceded by the word “Figure” instead of the abbreviation “FIG.”. View numbers should be updated to recite the abbreviation “FIG.”. Any changes to the drawings should also be reflected in the specification.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 1 is objected to because of the following informalities: line 2 of claim 1 recites “host cellthe”. There should be a space between “cell” and “the”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 4 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding written description, 35 U.S.C. 112(a) and the first paragraph of pre-AlA 35 U.S.C. 112 require that the "specification shall contain a written description of the invention ...." This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010). To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention (MPEP § 2163(I)).
MPEP 2163(II)(A)(3)(a)(i and ii) states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., .759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, claim 4 recites norcoclaurine synthase comprises at least 90% sequence identity to the elected SEQ ID NO: 70. There is not sufficient written description support for a sequence 90% identical to SEQ ID NO: 70 with the required increased condensation activity as recited in claim 1. SEQ ID NO: 70 has 173 amino acids. This means that 17 amino acid positions may differ compared to the wildtype enzyme, with 19 possible alternative amino acids at each position. This encompasses a vast number of possible amino acid sequences. There is not a disclosure of a structure-function relationship to indicate which regions or residues are essential for function, and therefore can or cannot be modified, while maintaining the claimed enzyme activity. The specification does not disclose sufficient examples of sequences having 90% identity to SEQ ID NO: 70 to constitute a representative number of species. Given the large number of possible amino acid sequences having 90% identity to SEQ ID NO: 70, the specific examples in the specification, (i.e. norcoclaurine synthase variants identified by specific SEQ ID NOs or amino acid substitutions, see instant specification Examples 14-16; Tables 7-9), are not representative of all possible species.
For these reasons, it is not clear that the applicant was in possession of the full scope of the invention at the time of filing.
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 1-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schwab et al., WO 2018/229305 A1.
Regarding claim 1, a benzylisoquinoline alkaloid (BIA) product includes the benzylisoquinolines norcoclaurine or norlaudanosoline (see instant specification para. 197-199). Schwab teaches a method for the preparation of (S)-norcoclaurine and/or (S)-norlaudanosoline compounds (p. 31 lines 25-26).
Regarding step (a), Schwab teaches a method comprising cultivating a recombinant (engineered) host cell under conditions in which recombinant genes encoding a recombinant mutated norcoclaurine synthases are expressed (p. 32 lines 25-34).
Regarding step (b), a BIA-precursor substrate includes hydroxyphenylacetaldehyde (4-HPAA), 3,4-dihydroxyphenylacetaldehyde (3,4-DHPAA), and dopamine (see instant specification para. 198). Schwab teaches contacting compound 4-HPAA and dopamine and/or 3,4-DhPAA and dopamine with a recombinant norcoclaurine synthase, and cultivating a recombinant host cell a culture medium in presence of 4-HPAA and dopamine and/or 3,4- DhPAA and dopamine (p. 32 lines 19-32).
Regarding step (c), Schwab teaches that the recombinant cells are capable of catalyzation of the condensation of 4-HPAA and dopamine to (S)-norcoclaurine and/or 3,4-DhPAA and dopamine to (S)-norlaudanosoline, that the cells are cultured to promote the catalyzation (i.e. production of BIA product), and (S)-norcoclaurine and (S)-norlaudanosoline are isolated (p. 32 lines 5-15). Condensation of the BIA precursors to produce norcoclaurine or norlaudanosoline indicates that the BIA product is produced within the host cell.
Schwab teaches that the engineered norcoclaurine synthase comprises an N-terminal truncation (p. 12 lines 21-26) and site-specific amino acid mutations for increased activity in heterologous host cells (p. 3 lines 11-15), specifically increased catalyzation of the condensation of 4-HPAA and dopamine to (S)-norcoclaurine and/or 3,4-DHPAA and dopamine to (S)-norlaudanosoline compared to wildtype (p. 2 lines 21-26). Schwab teaches that site-specific mutations result in greater norcoclaurine (BIA product) production compared to wildtype (p. 14 lines 10-12, Fig. 8).
Regarding claim 2, Schwab teaches that the engineered norcoclaurine synthase comprises an N-terminal truncation compared to the wildtype (p. 12 lines 21-26).
Regarding claim 3, Schwab teaches that the engineered norcoclaurine synthase comprises amino acid mutations, or site-specific mutations for increased activity in heterologous host cells compared to wildtype (p. 3 lines 11-15).
Regarding claim 4, Schwab teaches a norcoclaurine synthase (NCS) derived from Coptis japonica, SEQ ID NO: 1, GenBank accession number BAF45338.2, with amino acid substitutions that result in increased activity of the condensation process (p. 5 lines 5-10, Table 1). SEQ ID NO: 1 according to Schwab is 100% identical to residues 2-173 of instant SEQ ID NO: 70, or 99.4% identical to residues 1-173 (see sequence alignment in OA appendix).
Regarding claim 5, position 1 of instant SEQ ID NO: 70 aligns with position 24 of SEQ ID NO: 1 according to Schwab (see sequence alignment in OA appendix). Therefore, position 155 of instant SEQ ID NO: 70 corresponds to position 178 of Schwab SEQ ID NO: 1. Schwab teaches a site-specific mutation corresponding to position 178 of SEQ ID NO: 1 (p. 7 lines 4-11). As such, Schwab teaches an engineered norcoclaurine synthase with an amino acid substitution at position 155 with reference to instant SEQ ID NO: 70.
Regarding claim 6, Schwab teaches that the engineered host cell produces benzylisoquinolines (p. 4 lines 35-36; p. 32 lines 3-15). As set forth in the instant specification, benzylisoquinolines may include norcoclaurine and norlaudanosoline (see instant specification para. 199).
Conclusion
Claims 1-6 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY F EIX whose telephone number is (571)270-0808. The examiner can normally be reached M-F 8am-5pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at (571)272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/EMILY F EIX/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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