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. Claims 1, 5-9, 11, 13, 14, 16-18, 21-25, 28, 32-33 are still at issue and are present for examination. Election /Restrictions Applicant's election without traverse of the invention of Group 1, claims 1 , 5-7 , to cytochrome P450 monooxygerase , in the paper of 11/14 /2025, is acknowledged. Applicant's election without traverse of the following species: Species Group 1: CPt 10-hydrosylase (CPT10H). Species Group 2: Camptotheca acuminata . Species Group 3 : SEQ ID N O:3 . Species Group 4 : camptothecine. Species Group 5 : 10-hydroxycamptothesin. Species Group 6 : 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (topotecan) . Species Group 7 : 12-[(dimethylamino)methyl]-11-hydroxycamptothecin (topotecan- 11) . in the paper of 11/14/2025, is acknowledged . Claims 8, 9, 11, 13, 14, 16-18, 21-25, 28, 32-33 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Information Disclosure Statement The listing of references in the specification 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 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Th ere are currently no information disclosure statements in the application file. Specification The disclosure is objected to because of the following informalities: The specification comprises multiple amino acid sequences in Figure 5C which require a sequence identifier as per 37 CFR 1.831(b)(see MPEP 2420). Further applicants are required to include the sequence identifier(s) either in the figure itself or the description of the figure. Appropriate correction is required . 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. Claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. Claims 1 and 5-7 are directed to a cytochrome P450 monooxygenase capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety , that is not patent-eligible pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc., 106 USPQ2d 1972 (June 13, 2013). Godbole et al., Genome, Vol 64, pages 1-14, Sept. 2020 , evidence that a cytochrome P450 monooxygenase capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety , naturally occurs in Nothapodytes nimmoniana and is thus not patent eligible. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 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. Claim 5, 6 , 7 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 5 (claim 6 dependent on) recites the limitation “ the camptothecin hydroxylase " in claim 1. There is insufficient antecedent basis for this limitation in the claim. Claim 7 recites “the cytochrome P450 monooxygenase comprising a sequence with 80-100% identity to SEQ ID NO: 3” in claim 1. There is insufficient antecedent basis for this limitation in the claim. Appropriate correction and/or comment 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(s) 1 and 5-7 are 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim(s) 1 and 5-7 are directed to all possible cytochrome P450 monooxygenase capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety . The specification, however, only provides the representative species of that cytochrome P450 monooxygenase capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety comprising the amino acid sequence of SEQ ID NO: 3 , encompassed by these claims. There is no disclosure of any particular structure to function/activity relationship in the disclosed species. The specification also fails to describe additional representative species of these cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate by any identifying structural characteristics or properties, for which no predictability of structure is apparent. Regarding the level of skill and knowledge in the art of amino acid mutation, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with amino acid mutations is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1). Given this lack of additional representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention. Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov . Claim(s) 1 and 5-7 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for that cytochrome P450 monooxygenase capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety having the amino acid sequence of SEQ ID N0: 3, does not reasonably provide enablement for all possible cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s). Claim(s) 1 and 5-7 are so broad as to encompass all cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety . The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety , broadly encompassed by the claims. The claims rejected under this section of U.S.C. 112, first paragraph, place minimal structural limits on the cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. However, in this case the disclosure is limited to that cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety having the amino acid sequence of SEQ ID N0: 3. While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions. The specification does not support the broad scope of the claims which encompass any possible cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety , because the specification does not establish: (A) regions of the cytochrome P450 monooxygenases which may be modified effecting the monoterpenoid indole alkaloid (MIA) substrate oxidation activity; (B) the general tolerance of enzymes of the cytochrome P450 monooxygenases to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of an enzyme of the cytochrome P450 monooxygenases with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required monoterpenoid indole alkaloid (MIA) substrate oxidation activity; and the fact that the relationship between the sequence of a peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g., see Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495; Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of those cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety of the claimed genus. Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including any cytochrome P450 monooxygenases capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety . The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of those cytochrome P450 monooxygenases having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). Claim Rejections - 35 USC § 102 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 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. Claim(s) 1 and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Godbole et al. (Genome, Vol 64, pages 1-14, ISSN: 0831-2796; Sept. 2020) . Godbole et al., Genome, Vol 64, pages 1-14, ISSN: 0831-2796; Sept. 2020 disclose transcriptome-wide identification, characterization and phylogenomic analysis of a cytochrome P450 monooxygenase from Nothapodytes nimmoniana which is capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety . The P450 cytochrome enzymes disclosed by Godbole et al. s how 100% sequence identity with instant SEQ ID NO:18 and 20 and are involved in camptothecin biosynthesis. The P450 cytochrome enzymes disclosed by Godbole et al. shows at least 80% sequence identity with an active fragment or variant thereof of instant SEQ ID NO:3. Godbole et al. further discloses that the P450 enzymes catalyze various reactions like oxidation, hydroxylation, dealk ylation, epoxide formation ring opening and dehalogenation. Thus, claim(s) 1 and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Godbole et al. (Genome, Vol 64, pages 1-14, ISSN: 0831-2796; Sept. 2020) . Claim(s) 1 and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al. (Uniprot Accession No. A0A5J5ABU3 , 12/11/2019). Yang et al. (Uniprot Accession No. A0A5J5ABU3 , 12/11/2019) disclose a cytochrome P450 monooxygenase from Nyssa sinensis which is capable of oxidizing a monoterpenoid indole alkaloid (MIA) substrate, wherein the MIA substrate comprises a quinoline moiety or an indole moiety . The P450 cytochrome enzymes disclosed by Yang et al. shows at least 80% sequence identity with an active fragment or variant thereof of instant SEQ ID NO:3. Yang et al . further discloses that the P450 enzymes catalyze various reactions like oxidation, hydroxylation, dealkylation, epoxide formation ring opening and dehalogenation. Thus, 1 and 7 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yang et al. (Uniprot Accession No. A0A5J5ABU3 , 12/11/2019). Remarks No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT RICHARD G HUTSON whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-0930 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT 6-3 EST Mon-Fri . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, FILLIN "SPE Name?" \* MERGEFORMAT Robert Mondesi can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT (408) 918-7584 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. rgh 12/19/2025 /RICHARD G HUTSON/ Primary Examiner, Art Unit 1652