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 .
Amendments Received
Amendments to the claims were received and entered on 02/20/2026.
Election/Restrictions
Applicant’s election without traverse of invention I (i.e., drawn to a method of producing codeinone by also producing a thebaine product), Genus A (i.e., the additional contact of codeinone being with an enzyme having codeinone reductase activity), Genus B (i.e., the additional contact of hydrocodone being with codeinone reductase), and Genus C (i.e., the engineered cell being a fungal cell) in the reply filed on June 10, 2024 is acknowledged.
Claims 6-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 3, 5, 14 and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 10, 2024.
Status of Claims
Claim 21 has been newly added.
Claims 1-10 and 12-21 are currently pending.
Claims 1-2, 4, 12-13, 15-17 and 19-21 are under consideration, as claims 3, 5-10, 14 and 18 are withdrawn.
Priority
The present application is a continuation of PCT/US2020/024735 filed on March25, 2020. Acknowledgment is made of applicant’s claim for benefit under 35 U.S.C. 119(e) of Provisional application No. 62/824,252, filed on March 26, 2019. The present application and all claims are being examined with an effective filing date of March 26, 2019. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Maintained/Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4, 12-13, 15-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Enquist-Newman, et al. (WO2019051046 A1, published Mar 14, 2019, hereinafter “Enquist”, cited in a previous office action) and Dastmalchi et al. (Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy, Nature Chemical Biology, Mar 18 2019, Vol. 15, Iss. 4, pg. 384-390 and Supplementary information pg. 1-41, cited in a previous office action).
Regarding claims 1, 12, and 19, Enquist teaches microorganisms for the production of alkaloids, benzylisoquinoline alkaloids, including benzylisoquinoline alkaloids, intermediates, and morphinan alkaloids, and methods of increasing the efficiency of their synthesis, including the production of reticuline, salutaridine, salutaridinol, salutaridinol-7-O-aceteate, thebaine, morphine, oripavine, oxycodone, hydrocodone, oxymorphone, hydromorphone, or their derivatives (para 0006) from sugar or other carbon substrates. Enquist further teaches that the disclosed cells can be genetically modified with one or more enzymes capable of producing a BIA, such as thebaine, and other pathway intermediates, and identifies pathway reactions from sugar or other carbon source to L-tyrosine, L-tyrosine to L-DOPA, L-DOPA to dopamine, dopamine to norcoclaurine, norcoclaurine to reticuline, reticuline to salutaridine, salutaridine to salutaridinol, salutaridinol to salutaridinol-7-O-acetate, salutaridinol-7-O-acetate to thebaine, and thebaine to other BIAs, including codeine, morphine, hydrocodone, hydromorphone, hydroxycodeinone, and neopinone (para 0042, 0064, 0092, 0099). Enquist specifically teaches wherein the microorganism is Saccharomyces cerevisiae and is genetically modified to encode biosynthetic enzymes that produce thebaine (Example 1, para 000197). Enquist also teaches that thebaine can be converted into numerous derivative alkaloids such as codeine, morphine, neopinone and others; that thebaine can be converted to neopinone by thebaine 6-0-demethylase; and that neopinone can be converted into codeinone - the latter likely occurring in a spontaneous fashion (para 00046). Enquist specifically suggests that genetically modified microorganisms, including those described above, expressing thebaine 6-0-demethylase (para 00066 and 00100), thereby producing a neopinone product. Moreover, Enquist teaches that the genetically modified microorganism may comprise nucleic acids encoding enzymes catalyzing these pathway reactions, including tyrosine hydroxylase (TYR/TyrH), DOPA decarboxylase (DODC), norcoclaurine synthase (NCS), 6-O-methyltransferase (6OMT), coclaurine N-methyltransferase (CNMT), cytochrome P450 N-methylcoclaurine hydroxylase/CYP80B1, 4′-O-methyltransferase (4′OMT), salutaridine synthase (SalSyn), salutaridine reductase (SalR), and salutaridinol-7-O-acetyltransferase (SalAT), or any combination thereof. While Enquist does not expressly teach the enzyme DRS-DRR by name, it is noted that Enquist teaches that the microorganism engineered to the express the enzymes described above, may also be modified to express an enzyme capable of catalyzing the conversion of (S)-reticuline to (R)-reticuline, i.e., DRS-DRR (paras 44, 64, 92). Enquist also teaches that the microorganism can be further modified to express enzymes for downstream morphinan conversions, including thebaine 6-O-demethylase and codeinone reductase ( para 0066). Thus, Enquist teaches or suggests an engineered microbial cell comprising enzymes selected from the enzyme groups recited in claim 1, including three or more such enzymes, the sugar starting material of claim 12, and the enzyme combination recited in claim 19.
With respect to the limitation requiring a sugar or L-tyrosine as a simple starting material, Enquist teaches sugar as the starting material for the production of morphinan and benzylisoquinoline alkaloids, including thebaine (para 0042, 0047, 00064, 00099), which can also be converted into L-tyrosine (para 0043, 00064, 00099). Enquist does not expressly teach the conversion of neopinone into codeinone by neopinone isomerase.
Dastmalchi et al. teaches that the conversion of neopinone into codeinone, previously assumed to be spontaneous, is catalyzed by neopinone isomerase (Abstract). Dastmalchi et al. demonstrates a yeast strain engineered to express thebaine 6-O-demethylase and neopinone isomerase, incubated with thebaine, yielding codeinone and subsequently codeine (pg. 386, left column, pg. 387, right column, 2nd para). It is noted that in the pathway for the conversion of thebaine to codeine, thebaine is first converted to neopinone and neopinone is converted to codeinone (pg. 385, Fig 1). Dastmalchi et al. further confirms that neopinone isomerase activity overcomes energy barriers previously assumed to preclude codeinone formation, establishing codeinone as a discrete enzymatic product rather than a spontaneous or unpredictable intermediate (p. 388, left column).
Regarding claim 2, the neopinone isomerase taught by Dastmalchi et al. is engineered (to be expressed in yeast), as described above.
Regarding claims 4 and 13, Dastmalchi et al. teaches the engineered yeast strain described above, is engineered to also express codeinone reductase for the production of codeine from thebaine (pg. 387, right column, 2nd para). It is noted that in the pathway for the conversion of thebaine to codeine, after thebaine is converted to neopinone and neopinone is converted to codeinone, codeinone is converted to codeine by the action of codeinone reductase (pg. 385, Fig 1). Dastmalchi et al. also teaches the spontaneous formation of 14-hydroxycodeinone from codeinone (Supplementary information, Fig. 20).
Regarding claim 15, Dastmalchi et al. teaches the engineered yeast strain above, engineered to also express codeine O-demethylase in furthering the pathway described above to produce morphine (pg. 387, right column, 3rd para).
Regarding claims 16-17, as described above, the microorganism taught by Dastmalchi et al. is yeast and the microorganisms taught by Enquist are genetically engineered S. cerevisiae.
Regarding claim 20, in addition to the enzymes disclosed above, Enquist teaches that the engineered microorganism can be modified to also express norcoclaurine synthase (para 0064).
Regarding claim 21, Dastmalchi et al. teaches that neopinone isomerase catalyzes conversion of neopinone to codeinone. Therefore, in view of Dastmalchi et al., a person of ordinary skill in the art would have expected that an engineered microbial cell comprising neopinone isomerase would produce an increased amount of codeinone relative to a corresponding control host cell lacking neopinone isomerase. The claimed “at least 10% more codeinone” represents an expected quantitative result of including the enzyme responsible for the neopinone-to-codeinone conversion. Applicant has not provided objective evidence showing that the claimed 10% increase would have been unexpected over the closest prior art or that any alleged improvement is commensurate in scope with the breadth of claim 21.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, Enquist taught genetically modified microorganisms, including yeast, engineered to express enzymes for production of benzylisoquinoline and morphinan alkaloids, including thebaine, from sugar or other carbon substrates. Enquist further identified the pathway enzymes for producing thebaine and related morphinan intermediates, including the enzymes recited in claims 1 and 19. Dastmalchi et al. taught that neopinone isomerase catalyzes the conversion of neopinone to codeinone and demonstrated that yeast expressing thebaine 6-O-demethylase and neopinone isomerase produced codeinone from thebaine. Therefore, it would have been obvious to modify the engineered microorganism/pathway of Enquist to further include neopinone isomerase, as taught by Dastmalchi et al., in order to enzymatically convert neopinone to codeinone and further the known morphinan alkaloid biosynthetic pathway. Because Enquist taught engineered microorganisms comprising the relevant upstream morphinan pathway enzymes and Dastmalchi et al. demonstrated the specific downstream enzymatic conversion of neopinone to codeinone in yeast, a person of ordinary skill in the art would have had a reasonable expectation of success in arriving at the claimed method. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Response to Arguments for Rejections under 35 USC § 103
In the response filed on 02/20/2026, Applicant argues that the cited references fail to establish a reasonable expectation of success because production of codeinone within the same non-plant microbial cell through an entire heterologous pathway would have involved technical challenges, including sufficient pathway flux and sufficient substrate availability. This argument is not persuasive because the rejection does not rely on general speculation that any arbitrary plant pathway could be reconstructed in a microbial host. Rather, Enquist expressly teaches genetically modified microorganisms for producing benzylisoquinoline and morphinan alkaloids, including thebaine, from sugar or other carbon substrates and identifies the relevant pathway reactions and enzymes for proceeding from sugar/L-tyrosine through thebaine and related morphinan intermediates. Thus, Enquist provides a specific teaching of engineered microbial production of the relevant alkaloid pathway products, not merely an abstract proposal to reconstruct an unrelated plant pathway.
Applicant further argues that Enquist only describes partial metabolic pathways and the addition of advanced intermediates such as L-DOPA, norlaudanosoline, reticuline, and salutaridine. This argument is not persuasive because Applicant focuses on selected embodiments and examples while failing to account for the broader disclosure of Enquist. Enquist teaches that a carbon substrate such as sugar can be used to produce morphinan alkaloids and further teaches genetically modified microorganisms and enzymes for producing benzylisoquinoline alkaloids, including thebaine and intermediates, from sugar. Additionally, it is noted that the claims use open-ended language and are not limited to a pathway engineered to express only the specifically recited enzymes, nor do the claims exclude additionally pathway enzymes, intermediates, substrates, or host cell modifications. While certain example involve addition of advanced intermediates, those examples do not limit Enquist’s broader disclosure of engineered microorganisms, including S. cerevisiae, comprising biosynthetic enzymes for producing thebaine and related BIAs and morphinan alkaloids from sugar or other carbon substrates. Enquist explicitly identifies enzymes and pathway conversions from sugar or L-tyrosine through L-DOPA, dopamine, norcoclaurine, reticuline, salutaridine, salutaridinol, salutaridinol-7-O-acetate, and thebaine. Therefore, Enquist is relied upon for its express teaching of engineered microbial cells comprising enzymes of the claimed pathway, including the enzyme groups recited in claims 1 and 19.
Applicant also argues that Dastmalchi et al. involves only a partial pathway and requires the addition of thebaine, which is not a simple starting material comprising sugar or L-tyrosine. This argument is not persuasive because Dastmalchi et al. is not relied upon to teach the entire upstream pathway from sugar or L-tyrosine to thebaine. Enquist is relied upon for the engineered microorganism and upstream morphinan pathway teachings, including production of thebaine and related intermediates from sugar or other carbon substrates. Dastmalchi et al. is relied upon for the specific teaching that neopinone isomerase catalyzes conversion of neopinone to codeinone and that yeast expressing thebaine 6-O-demethylase and neopinone isomerase produces codeinone from thebaine. Thus, Dastmalchi et al. provides the missing downstream enzymatic conversion from neopinone to codeinone, and one of ordinary skill in the art would have been motivated to incorporate neopinone isomerase into the engineered pathway of Enquist to enzymatically further the known morphinan alkaloid pathway toward codeinone.
Applicant’s reliance on the Smolke Declaration is also not persuasive. The Declaration generally discusses challenges associated with heterologous pathway reconstruction, including pathway flux and substrate availability. However, the cited prior art is more specific than the generalized uncertainty discussed in the Declaration. Enquist identifies the relevant engineered microbial pathway, enzymes, substrates, and morphinan alkaloid products, while Dastmalchi et al. demonstrates the specific neopinone isomerase activity needed for conversion of neopinone to codeinone in yeast. Accordingly, the evidence of record supports that a person of ordinary skill in the art would have had a reasonable expectation of success in modifying the engineered microorganism/pathway of Enquist to include neopinone isomerase as taught by Dastmalchi et al.
The state of the art before the effective filing date further supports the conclusion that the claimed subject matter would have been within the level of ordinary skill in the art. Applicant/inventor’s own earlier published work, which predates the March 26, 2019 effective filing date and qualifies as prior art under 35 U.S.C. 102(a)(1), further corroborates that engineered host cells, including yeast cells, for production of benzylisoquinoline alkaloids using heterologous biosynthetic pathway enzymes were known before the present filing date. For example, WO2014/143744, published September 18, 2014, describes engineered host cells comprising heterologous coding sequences for enzymes involved in synthetic pathways from starting compounds to benzylisoquinoline alkaloids, and methods of producing BIAs by culturing such host cells under conditions promoting expression of the heterologous enzymes. This prior publication is not relied upon as the primary basis of the rejection, but further confirms that substantial portions of the claimed engineered-cell approach and BIA biosynthetic pathway were already within the level of ordinary skill in the art before the effective filing date.
Applicant further points to paragraphs [0359] and [0360]-[0363] of the instant specification as evidence that the claimed pathway was not readily apparent and that enzymes may not naturally function together in a host cell such as yeast. This argument is not persuasive because the specification’s discussion of general pathway challenges does not overcome the specific teachings of Enquist and Dastmalchi et al. The cited prior art provides a reasoned basis for selecting the relevant enzymes and pathway steps, and Dastmalchi et al. confirms that neopinone isomerase provides the enzymatic conversion of neopinone to codeinone. Therefore, the cited specification paragraphs do not negate the motivation to combine or the reasonable expectation of success established by the prior art.
Applicant additionally argues that new claim 21 recites an engineered microbial cell that produces at least 10% more codeinone than a control host cell and relies on paragraph [0075] and Figure 21 of the specification. This argument is not persuasive. Figure 21A measures codeine, not codeinone, and therefore does not establish increased codeinone production. Figure 21B also does not clearly establish that the engineered microbial cell produces at least 10% more codeinone than the control host cell because codeinone is reported together with neopinone as a combined “codeinone/neopinone” measurement rather than as a separate codeinone value. Moreover, the combined codeinone/neopinone fraction in Figure 21B does not appear to show an increase in the +NPI truncated strain relative to YA1033. Rather, Figure 21 appears primarily to show increased downstream codeine production upon inclusion of the truncated neopinone isomerase variant. Accordingly, Applicant has not established that Figure 21 demonstrates the alleged increased codeinone production recited in claim 21, much less that such increase would have been unexpected over the closest prior art or commensurate in scope with the claim.
Applicant’s arguments have been considered in full and do not overcome the rejections. Therefore, the rejection of claims 1, 2, 4, 12-13, 15-17, and 19-21 under 35 U.S.C. 103 is maintained.
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
In the response filed on February 20, 2026, Applicant states that the obviousness-type double patenting rejections will be addressed, to the extent necessary, upon an indication that the claims are otherwise in condition for allowance. Accordingly, substantive consideration of the obviousness-type double patenting issues is held in abeyance at this time. The obviousness-type double patenting rejections are maintained for the reasons previously set forth in the prior Office action.
It is noted that Applicant has incorporated certain limitations of claim 19 into independent claim 1. However, the amendments do not obviate the obviousness-type double patenting rejections. For Applicant’s convenience, the maintained obviousness-type double patenting rejections are reproduced below.
Claims 1-2, 4, 12-13, 15-17 and 19-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 9,534,241 B2 in view of Dastmalchi et al. (Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy, Nature Chemical Biology, Mar 18 2019, Vol. 15, Iss. 4, pg. 384-390 and Supplementary information pg. 1-41, cited in a previous office action ) and Enquist-Newman, et al. (WO2019051046 A1, published Mar 14, 2019, hereinafter “Enquist”, cited in a previous office action).
Regarding claims 1-2 and 12, patent ‘241 claims a method of preparing a benzylisoquinoline alkaloid product, the method comprising: culturing an engineered microbial cell…wherein the engineered microbial cell comprises a plurality of heterologous coding sequences for encoding a plurality of enzymes within a pathway for producing the benzylisoquinoline alkaloid product, and wherein at least one heterologous coding sequence of the plurality of heterologous coding sequences encodes an enzyme that is within a pathway that converts a thebaine to the benzylisoquinoline alkaloid product…wherein the benzylisoquinoline alkaloid product is selected from the group consisting of a neopine, neomorphine, codeinone, codeine, morphine, morphinone, hydrocodone, dihydrocodeine, oxycodone, 14-hydroxycodeine, hydromorphone, and dihydromorphine (claim 1). Patent ‘241 also claims wherein the engineered microbial cell comprises: one or more heterologous coding sequences for encoding one or more enzymes that are selected from the group consisting of thebaine 6-O-demethylase, codeinone reductase, codeine O-demethylase, morphine dehydrogenase, and morphine reductase. It is noted that thebaine 6-O-demethylase converts thebaine into a neopinone product, and therefore presence of both thebaine and 6-O-demethylase, necessarily results in the production of neopinone (see instant specification, Fig. 5). Patent ‘241 does not teach wherein the engineered microbial cell expresses an engineered neopinone isomerase (which yields codeinone) and wherein thebaine is produced from sugar or L-tyrosine.
Enquist teaches microorganisms for the production of alkaloids, benzylisoquinoline alkaloids, or any benzylisoquinoline alkaloid intermediate, and methods of increasing the efficiency of their synthesis, including but not limited to reticuline, salutaridine, salutaridinol, salutaridinol-7-O-aceteate, thebaine, morphine, oripavine, oxycodone, hydrocodone, oxymorphone, hydromorphone, or their derivatives (para 0006).With respect to the limitation requiring a sugar or L-tyrosine as a simple starting material, Enquist teaches sugar as the starting material for the production of morphinan and benzylisoquinoline alkaloids, including thebaine and (para 0042 and 0047), which also be converted into L-tyrosine (para 0043).
Dastmalchi et al. disclose that the conversion of neopinone into codeinone, previously assumed to be spontaneous, is in fact catalyzed by neopinone isomerase (Abstract). Dastmalchi et al. teach a yeast strain engineered to express thebaine 6-O-demethylase and neopinone isomerase, incubated with (i.e., correlates to “contacting” as recited in the claims) thebaine, yielding codeine (pg. 387, right column, 2nd para). It is noted that in the pathway for the conversion of thebaine to codeine, thebaine is first converted to neopinone and neopinone is converted to codeinone (pg. 385, Fig 1).
Regarding claim 4, patent ‘241 claims wherein the engineered microbial cell described above comprises…codeinone reductase (claim 2). It is noted that codeinone reductase converts codeinone to codeine, therefore when both codeinone reductase and codeinone are present, as indicated above, the reaction yields codeine (see Dastmalchi article, Fig. 1).
Regarding claim 13, Dastmalchi et al. teach the engineered yeast strain described above, engineered to also express codeinone reductase (pg. 387, right column, 2nd para). Dastmalchi et al. also teach the spontaneous formation of 14-hydroxycodeinone from codeinone (Supplementary information, Fig. 20).
Regarding claim 15, patent ‘241 claims the method described above, wherein the engineered microbial cell comprises…codeine O-demethylase (claim 2), and wherein the benzylisoquinoline alkaloid product is morphine (claim 1). It is noted that the codeine product from the methods described above is converted to morphine by the catalytic action of codeine O-demethylase, therefore when both codeine O-demethylase and codeine are both present, as indicated above, the reaction yields morphine (see Dastmalchi article, Fig. 1).
Regarding claims 16-17, in the method claimed by patent ‘241, the engineered microbial cell is a yeast cell (claim 1).
Regarding claim 19, patent ‘241 claims the method described above, wherein the engineered cell comprises cytochrome P450 80B1, Coclaurine-N-methyltransferase, and 4′-O-methyltransferase (claim 7). Patent ‘241 does not claim wherein the cell expresses TyrH, DODC, 6OMT, SalSyn, SalR, SalAT and DRS-DRR. Enquist teaches the production of alkaloids from sugar, which can be converted to L-tyrosine, in genetically engineered microorganisms. Enquist teaches a variety of enzymes for furthering the pathway including, but not limited to tyrosine hydroxylase (i.e., TYR or TyrH) for the conversion of L-tyrosine to 1-DOPA, DOPA decarboxylase (i.e., DODC) for the conversion of 1-DOPA to dopamine, and several other enzymes for the necessary conversions in the morphinan alkaloid pathway, including but not limited to 6-O-Methyltransferase (i.e., 6OMT), coclaurine N-methyltransferase (i.e., CNMT), 4-O-Methyltransferase (i.e., 4OMT), salutaridine synthase (i.e., SalSyn), salutaridine reductase (i.e., SalR), salutaridinol-7-O-acetylytransferase (i.e., SalAT), and cytochrome P450 N-methylcoclaurine hydroxylase (i.e., CYP80B1) (para 0024, 0044, 0064). While Enquist does not expressly teach the enzyme DRS-DRR by name, it is noted that Enquist teaches that the microorganism engineered to the express the enzymes described above, may also be modified to express an enzyme capable of catalyzing the conversion of (S)-reticuline to (R)-reticuline, i.e., DRS-DRR (para 0064, 0092, 0099).
Regarding claim 20, in addition to the enzymes disclosed above, Enquist teaches that the engineered microorganism can be modified to also express norcoclaurine synthase (para 0064).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of US Patent ‘241, that microorganisms can be genetically engineered to express enzymes (e.g., thebaine 6-O-demethylase) for the production of alkaloids (e.g., codeinone), the teachings of Enquist, that sugar is a starting material in the production of thebaine and various enzymes are required in furthering the pathway in producing alkaloids from sugar, and the teachings of Dastmalchi et al., that expression of thebaine 6-O-demethylase in yeast converts thebaine to neopinone and that neopinone isomerase is the enzyme responsible for converting neopinone to codeinone, would have led said practitioner to modify the method of ‘241 to express neopinone isomerase and other enzymes beneficial and necessary in driving the production of codeinone, starting with sugar. Given that Dastmalchi et al. demonstrate a successful method of producing codeinone in S. cerevisiae expressing said enzymes, said practitioner would have readily predicted that the combination of teachings would successfully result in a method for producing codeinone in an engineered yeast. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1-2, 4, 12-13, 15-17 and 19-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8 and 12 of U.S. Patent No. 10,017,799 B2 in view of Dastmalchi et al. (Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy, Nature Chemical Biology, Mar 18 2019, Vol. 15, Iss. 4, pg. 384-390 and Supplementary information pg. 1-41, cited in a previous office action ) and Enquist-Newman, et al. (WO2019051046 A1, published Mar 14, 2019, hereinafter “Enquist”, cited in a previous office action).
Regarding claims 1-2 and 12, patent ‘799 claims a method of preparing a benzylisoquinoline alkaloid product, the method comprising: culturing an engineered bacterial cell or an engineered yeast cell…wherein the engineered cell comprises at least three heterologous coding sequences for encoding enzymes within a pathway for producing the benzylisoquinoline alkaloid product, and wherein the benzylisoquinoline alkaloid product is selected from the group consisting of…thebaine, neopinone, neopine, neomorphine, codeinone, codeine, morphine, oripavine, morphinone, hydrocodone, 14-hydroxycodeinone, dihydrocodeine, oxycodone, 14-hydroxy codeine, hydromorphone, and dihydromorphine (claim 8). Patent ‘799 also claims wherein the enzymes involved in the pathway that produces said benzylisoquinoline alkaloid product(s) are selected from the group consisting of…thebaine 6-O-demethylase, codeinone reductase, codeine O-demethylase, morphine dehydrogenase, and morphine reductase. It is noted that thebaine 6-O-demethylase converts thebaine into a neopinone product, and therefore presence of both thebaine and 6-O-demethylase, necessarily results in the production of neopinone (see instant specification, Fig. 5). Patent ‘799 does not teach wherein the engineered cell expresses an engineered neopinone isomerase (which yields codeinone) and wherein the starting material is sugar or L-tyrosine.
Enquist teaches microorganisms for the production of alkaloids, benzylisoquinoline alkaloids, or any benzylisoquinoline alkaloid intermediate, and methods of increasing the efficiency of their synthesis, including but not limited to reticuline, salutaridine, salutaridinol, salutaridinol-7-O-aceteate, thebaine, morphine, oripavine, oxycodone, hydrocodone, oxymorphone, hydromorphone, or their derivatives (para 0006).With respect to the limitation requiring a sugar or L-tyrosine as a simple starting material, Enquist teaches sugar as the starting material for the production of morphinan and benzylisoquinoline alkaloids, including thebaine and (para 0042 and 0047), which also be converted into L-tyrosine (para 0043).
Dastmalchi et al. disclose that the conversion of neopinone into codeinone, previously assumed to be spontaneous, is in fact catalyzed by neopinone isomerase (Abstract). Dastmalchi et al. teach a yeast strain engineered to express thebaine 6-O-demethylase and neopinone isomerase, incubated with (i.e., correlates to “contacting” as recited in the claims) thebaine, yielding codeine (pg. 387, right column, 2nd para). It is noted that in the pathway for the conversion of thebaine to codeine, thebaine is first converted to neopinone and neopinone is converted to codeinone (pg. 385, Fig 1).
Regarding claim 4, patent ‘799 claims wherein the engineered microbial cell described above comprises…codeinone reductase (claim 12). It is noted that codeinone reductase converts codeinone to codeine, therefore when both codeinone reductase and codeinone are present, as indicated above, the reaction yields codeine (see Dastmalchi article, Fig. 1).
Regarding claim 13, Dastmalchi et al. teach the engineered yeast strain described above, engineered to also express codeinone reductase (pg. 387, right column, 2nd para). Dastmalchi et al. also teach the spontaneous formation of 14-hydroxycodeinone from codeinone (Supplementary information, Fig. 20).
Regarding claim 15, patent ‘799 claims the method described above, wherein the engineered microbial cell comprises…codeine O-demethylase (claim 12), and wherein the benzylisoquinoline alkaloid product is morphine (claim 8). It is noted that the codeine product from the methods described above is converted to morphine by the catalytic action of codeine O-demethylase, therefore when both codeine O-demethylase and codeine are both present, as indicated above, the reaction yields morphine (see Dastmalchi article, Fig. 1).
Regarding claims 16-17, in the method claimed by patent ‘799, the engineered cell is a bacterial cell or a yeast cell (claim 8).
Regarding claim 19, patent ‘799 claims the method described above, wherein the engineered cell comprises cytochrome P450 80B1, Coclaurine-N-methyltransferase, Salutaridine Reductase, Salutaridinol 7-O-acetyltransferase, and 4′-O-methyltransferase (claim 7). Patent ‘799 does not claim wherein the cell expresses TyrH, DODC, 6OMT, SalR, and DRS-DRR. Enquist teaches the production of alkaloids from sugar, which can be converted to L-tyrosine, in genetically engineered microorganisms. Enquist teaches a variety of enzymes for furthering the pathway including, but not limited to tyrosine hydroxylase (i.e., TYR or TyrH) for the conversion of L-tyrosine to 1-DOPA, DOPA decarboxylase (i.e., DODC) for the conversion of 1-DOPA to dopamine, and several other enzymes for the necessary conversions in the morphinan alkaloid pathway, including but not limited to 6-O-Methyltransferase (i.e., 6OMT), coclaurine N-methyltransferase (i.e., CNMT), 4-O-Methyltransferase (i.e., 4OMT), salutaridine synthase (i.e., SalSyn), salutaridine reductase (i.e., SalR), salutaridinol-7-O-acetylytransferase (i.e., SalAT), and cytochrome P450 N-methylcoclaurine hydroxylase (i.e., CYP80B1) (para 0024, 0044, 0064). While Enquist does not expressly teach the enzyme DRS-DRR by name, it is noted that Enquist teaches that the microorganism engineered to the express the enzymes described above, may also be modified to express an enzyme capable of catalyzing the conversion of (S)-reticuline to (R)-reticuline, i.e., DRS-DRR (para 0064, 0092, 0099).
Regarding claim 20, in addition to the enzymes disclosed above, Enquist teaches that the engineered microorganism can be modified to also express norcoclaurine synthase (para 0064).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of US Patent ‘799, that bacteria can be genetically engineered to express enzymes (e.g., thebaine 6-O-demethylase) for the production of alkaloids (e.g., codeinone), the teachings of Enquist, that sugar is a starting material in the production of thebaine and several enzymes are required in furthering the pathway to produce alkaloids from sugar, and the teachings of Dastmalchi et al., that expression of thebaine 6-O-demethylase in yeast converts thebaine to neopinone and that neopinone isomerase is the enzyme responsible for converting neopinone to codeinone, would have led said practitioner to modify the method of ‘799 to express both thebaine 6-O-demethylase and neopinone isomerase to drive production of codeinone. Given that Dastmalchi et al. demonstrate a successful method of producing codeinone in S. cerevisiae expressing said enzymes, said practitioner would have readily predicted that the combination of teachings would successfully result in a method for producing codeinone in an engineered yeast. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1-2, 4, 12-13, 15-17 and 19-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 7 of U.S. Patent No. 10,858,681 B2 in view of Dastmalchi et al. (Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy, Nature Chemical Biology, Mar 18 2019, Vol. 15, Iss. 4, pg. 384-390 and Supplementary information pg. 1-41, cited in cited in a previous office action ) and Enquist-Newman, et al. (WO2019051046 A1, published Mar 14, 2019, hereinafter “Enquist”, cited in a previous office action).
Regarding claims 1-2 and 12, patent ‘681 claims an engineered microbial cell that produces a benzylisoquinoline alkaloid product…comprising a plurality of heterologous coding sequences for encoding a plurality of enzymes within a pathway for producing the benzylisoquinoline alkaloid product, and wherein at least one heterologous coding sequence of the plurality of heterologous coding sequences encodes an enzyme that is within a pathway that converts a thebaine to the benzylisoquinoline alkaloid product…wherein the benzylisoquinoline alkaloid product is selected from the group consisting of a neopinone, neopine, neomorphine, codeinone, codeine, morphine, oripavine, morphinone, hydrocodone, 14-hydroxycodeinone, dihydrocodeine, oxycodone, 14-hydroxycodeine, hydromorphone, and dihydromorphine (claim 1). Patent ‘681 also claims wherein the engineered microbial cell comprises one or more heterologous coding sequences for encoding one or more enzymes that are selected from the group consisting of thebaine 6-O-demethylase, codeinone reductase, codeine O-demethylase, morphine dehydrogenase, and morphine reductase. It is noted that thebaine 6-O-demethylase converts thebaine into a neopinone product, and therefore presence of both thebaine and 6-O-demethylase, necessarily results in the production of neopinone (see instant specification, Fig. 5). Patent ‘681 does not teach wherein the engineered microbial cell expresses an engineered neopinone isomerase (which yields codeinone) and wherein the starting material is sugar or L-tyrosine.
Enquist teaches microorganisms for the production of alkaloids, benzylisoquinoline alkaloids, or any benzylisoquinoline alkaloid intermediate, and methods of increasing the efficiency of their synthesis, including but not limited to reticuline, salutaridine, salutaridinol, salutaridinol-7-O-aceteate, thebaine, morphine, oripavine, oxycodone, hydrocodone, oxymorphone, hydromorphone, or their derivatives (para 0006).With respect to the limitation requiring a sugar or L-tyrosine as a simple starting material, Enquist teaches sugar as the starting material for the production of morphinan and benzylisoquinoline alkaloids, including thebaine and (para 0042 and 0047), which also be converted into L-tyrosine (para 0043).
Dastmalchi et al. disclose that the conversion of neopinone into codeinone, previously assumed to be spontaneous, is in fact catalyzed by neopinone isomerase (Abstract). Dastmalchi et al. teach a yeast strain engineered to express thebaine 6-O-demethylase and neopinone isomerase, incubated with (i.e., correlates to “contacting” as recited in the claims) thebaine, yielding codeine (pg. 387, right column, 2nd para). It is noted that in the pathway for the conversion of thebaine to codeine, thebaine is first converted to neopinone and neopinone is converted to codeinone (pg. 385, Fig 1).
Regarding claim 4, patent ‘681 claims wherein the engineered microbial cell described above comprises…codeinone reductase (claim 2). It is noted that codeinone reductase converts codeinone to codeine, therefore when both codeinone reductase and codeinone are present, as indicated above, the reaction yields codeine (see Dastmalchi article, Fig. 1).
Regarding claim 13, patent ‘681 claims the engineered cell described above, which comprises codeinone reductase (claim 2) and produces 14-hydroxycodeinone (claim 1). Additionally, Dastmalchi et al. teach the engineered yeast strain described above, engineered to also express codeinone reductase (pg. 387, right column, 2nd para) and the spontaneous formation of 14-hydroxycodeinone from codeinone (Supplementary information, Fig. 20).
Regarding claim 15, patent ‘681 claims the method described above, wherein the engineered microbial cell comprises…codeine O-demethylase (claim 2), and wherein the benzylisoquinoline alkaloid product is morphine (claim 1). It is noted that the codeine product from the methods described above is converted to morphine by the catalytic action of codeine O-demethylase, therefore when both codeine O-demethylase and codeine are both present, as indicated above, the reaction yields morphine (see Dastmalchi article, Fig. 1).
Regarding claims 16-17, in the method claimed by patent ‘681, the engineered microbial cell is a yeast cell (claim 7).
Regarding claim 19, patent ‘681 claims the method described above, wherein the engineered cell comprises cytochrome P450 80B1, Coclaurine-N-methyltransferase, and 4′-O-methyltransferase (claim 6). Patent ‘681 does not claim wherein the cell expresses TyrH, DODC, 6OMT, SalR, SalAT, SalSyn and DRS-DRR. Enquist teaches the production of alkaloids from sugar, which can be converted to L-tyrosine, in genetically engineered microorganisms. Enquist teaches a variety of enzymes for furthering the pathway including, but not limited to tyrosine hydroxylase (i.e., TYR or TyrH) for the conversion of L-tyrosine to 1-DOPA, DOPA decarboxylase (i.e., DODC) for the conversion of 1-DOPA to dopamine, and several other enzymes for the necessary conversions in the morphinan alkaloid pathway, including but not limited to 6-O-Methyltransferase (i.e., 6OMT), coclaurine N-methyltransferase (i.e., CNMT), 4-O-Methyltransferase (i.e., 4OMT), salutaridine synthase (i.e., SalSyn), salutaridine reductase (i.e., SalR), salutaridinol-7-O-acetylytransferase (i.e., SalAT), and cytochrome P450 N-methylcoclaurine hydroxylase (i.e., CYP80B1) (para 0024, 0044, 0064). While Enquist does not expressly teach the enzyme DRS-DRR by name, it is noted that Enquist teaches that the microorganism engineered to the express the enzymes described above, may also be modified to express an enzyme capable of catalyzing the conversion of (S)-reticuline to (R)-reticuline, i.e., DRS-DRR (para 0064, 0092, 0099).
Regarding claim 20, in addition to the enzymes disclosed above, Enquist teaches that the engineered microorganism can be modified to also express norcoclaurine synthase (para 0064).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of US Patent ‘681, that microorganisms can be genetically engineered to express enzymes (e.g., thebaine 6-O-demethylase) for the production of alkaloids (e.g., codeinone), the teachings of Enquist, that sugar is a starting material in the production of thebaine and several enzymes are required in furthering the pathway for the production of alkaloids from sugar, and the teachings of Dastmalchi et al., that expression of thebaine 6-O-demethylase in yeast converts thebaine to neopinone and that neopinone isomerase is the enzyme responsible for converting neopinone to codeinone, would have led said practitioner to modify the method of ‘681 to express both thebaine 6-O-demethylase and neopinone isomerase to drive production of codeinone. Given that Dastmalchi et al. demonstrate a successful method of producing codeinone in S. cerevisiae expressing said enzymes, said practitioner would have readily predicted that the combination of teachings would successfully result in a method for producing codeinone in an engineered yeast. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Claims 1-2, 4, 12-13, 15-17 and 19-20 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 14 of U.S. Patent No. 11,214,819 B2 in view of Dastmalchi et al. (Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy, Nature Chemical Biology, Mar 18 2019, Vol. 15, Iss. 4, pg. 384-390 and Supplementary information pg. 1-41, cited in a previous office action) and Enquist-Newman, et al. (WO2019051046 A1, published Mar 14, 2019, hereinafter “Enquist”, cited in a previous office action).
Regarding claims 1-2, 12 and 16-17, patent ‘819 claims a yeast cell that produces thebaine, wherein the cell comprises heterologous coding sequences (correlating to being an “engineered” cell as required by instant claim 1) to express the enzymes salutaridine synthase (SalSyn), salutaridine reductase (SalR) and salutaridinol 7-O-acetyltransferase (SalAT) that are integrated stably into the genome of the cell and enable the cell to produce thebaine. (claim 1). Patent ‘819 also claims wherein the yeast cell expresses one or more enzymes selected from the group consisting of codeine O-demethylase (CODM), thebaine 6-O-demethylase (T6ODM), codeinone reductase (COR), morphine dehydrogenase (morA) and morphinone reductase (morB). It is noted that thebaine 6-O-demethylase converts thebaine into a neopinone product, and therefore presence of both thebaine and 6-O-demethylase, necessarily results in the production of neopinone (see instant specification, Fig. 5). Patent ‘819 does not teach wherein the engineered microbial cell expresses an engineered neopinone isomerase (which yields codeinone) and wherein the starting material is sugar or L-tyrosine.
Enquist teaches microorganisms for the production of alkaloids, benzylisoquinoline alkaloids, or any benzylisoquinoline alkaloid intermediate, and methods of increasing the efficiency of their synthesis, including but not limited to reticuline, salutaridine, salutaridinol, salutaridinol-7-O-aceteate, thebaine, morphine, oripavine, oxycodone, hydrocodone, oxymorphone, hydromorphone, or their derivatives (para 0006).With respect to the limitation requiring a sugar or L-tyrosine as a simple starting material, Enquist teaches sugar as the starting material for the production of morphinan and benzylisoquinoline alkaloids, including thebaine and (para 0042 and 0047), which also be converted into L-tyrosine (para 0043).
Dastmalchi et al. disclose that the conversion of neopinone into codeinone, previously assumed to be spontaneous, is in fact catalyzed by neopinone isomerase (Abstract). Dastmalchi et al. teach a yeast strain engineered to express thebaine 6-O-demethylase and neopinone isomerase, incubated with (i.e., correlates to “contacting” as recited in the claims) thebaine, yielding codeine (pg. 387, right column, 2nd para). It is noted that in the pathway for the conversion of thebaine to codeine, thebaine is first converted to neopinone and neopinone is converted to codeinone (pg. 385, Fig 1).
Regarding claim 4, patent ‘819 claims wherein the yeast cell described above comprises…codeinone reductase (claim 14). It is noted that codeinone reductase converts codeinone to codeine, therefore when both codeinone reductase and codeinone are present, as indicated above, the reaction yields codeine (see Dastmalchi article, Fig. 1).
Regarding claim 13, patent ‘819 claims the yeast cell described above, which comprises codeinone reductase (claim 14) and other enzymes capable of producing compounds selected from morphine, codeine, oxycodone, hydrocodone, oxymorphone, hydromorphone and oripavine (claim 2). Additionally, Dastmalchi et al. teach the engineered yeast strain described above, engineered to also express codeinone reductase (pg. 387, right column, 2nd para) and the spontaneous formation of 14-hydroxycodeinone from codeinone (Supplementary information, Fig. 20).
Regarding claim 15, patent ‘819 claims the yeast cell described above, wherein the engineered microbial cell comprises…codeine O-demethylase (claim 14), and wherein the benzylisoquinoline alkaloid product is morphine (claim 2). It is noted that the codeine product from the methods described above is converted to morphine by the catalytic action of codeine O-demethylase, therefore when both codeine O-demethylase and codeine are both present, as indicated above, the reaction yields morphine (see Dastmalchi article, Fig. 1).
Regarding claim 19, patent ‘819 claims the engineered yeast cell described above, comprising SalSyn, SalR and SalAT (claim 1) . Patent ‘819 does not claim wherein the cell expresses TyrH, DODC, 6OMT, CYP80B1, CNMT, 4OMT and DRS-DRR. Enquist teaches the production of alkaloids from sugar, which can be converted to L-tyrosine, in genetically engineered microorganisms. Enquist teaches a variety of enzymes for furthering the pathway when starting with sugar including, but not limited to tyrosine hydroxylase (i.e., TYR or TyrH) for the conversion of L-tyrosine to 1-DOPA, DOPA decarboxylase (i.e., DODC) for the conversion of 1-DOPA to dopamine, and several other enzymes for the necessary conversions in the morphinan alkaloid pathway, including but not limited to 6-O-Methyltransferase (i.e., 6OMT), coclaurine N-methyltransferase (i.e., CNMT), 4-O-Methyltransferase (i.e., 4OMT), salutaridine synthase (i.e., SalSyn), salutaridine reductase (i.e., SalR), salutaridinol-7-O-acetylytransferase (i.e., SalAT), and cytochrome P450 N-methylcoclaurine hydroxylase (i.e., CYP80B1) (para 0024, 0044, 0064). While Enquist does not expressly teach the enzyme DRS-DRR by name, it is noted that Enquist teaches that the microorganism engineered to the express the enzymes described above, may also be modified to express an enzyme capable of catalyzing the conversion of (S)-reticuline to (R)-reticuline, i.e., DRS-DRR (para 0064, 0092, 0099).
Regarding claim 20, in addition to the enzymes disclosed above, Enquist teaches that the engineered microorganism can be modified to also express norcoclaurine synthase (para 0064).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of US Patent ‘819, that a yeast cell can be genetically engineered to express enzymes (e.g., thebaine 6-O-demethylase) for the production of alkaloids, the teachings of Enquist, that sugar is a starting material in the production of thebaine, and the teachings of Dastmalchi et al., that expression of thebaine 6-O-demethylase in yeast converts thebaine to neopinone and that neopinone isomerase is the enzyme responsible for converting neopinone to codeinone, would have led said practitioner to modify the method of ‘819 to express both thebaine 6-O-demethylase and neopinone isomerase to drive production of codeinone. Given that Dastmalchi et al. demonstrate a successful method of producing codeinone in S. cerevisiae expressing said enzymes, said practitioner would have readily predicted that the combination of teachings would successfully result in a method for producing codeinone in an engineered yeast. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Pertinent Art
Nakagawa et al. (Total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli. Nat Commun. 2016 Feb 5;7:10390, cited in PTO-892) teaches total biosynthesis of opiates by stepwise fermentation using engineered Escherichia coli. Nakagawa et al. further teaches that fermentative opiate production in microbes had been investigated, that complete biosynthesis of opiates from a simple carbon source had recently been accomplished in yeast, and that engineered E. coli strains can be used to produce thebaine from glycerol and further produce downstream opioids such as hydrocodone.
Conclusion
No claim is in condition for allowance.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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