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 Group I (claims 1-16, 18-19 and 24) and species of scopolamine, PUP transporter (first transporter), MATE transporter (second transporter), littorine synthase (first heterologous coding sequence), hycoscyamine dehydrogenase (second heterologous coding sequence) and endogenous polyamine regulatory mechanism and ornithine decarboxylase antizyme in the reply filed on 05/05/2026 is acknowledged.
Claim 34 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention/Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/05/2026.
Claims 6, 7, 9, 11-13, 15-16, and 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 05/05/2026.
Applicant states claims 1-5, 8, 10, 14 and 24 read on the elected species. Claim 8 does not require two specific species of transporters; as such, claim 8 does not read on the elected species since two species of heterologous MATE transporter would be an embodiment of claims 1 and 8. However, in the interest of compact prosecution, claim 8 is not withdrawn at this time.
Claim Interpretation
Purine uptake permease-like transporter is a common term in the are as is therefore considered to have a definite meaning. See Jelesko (An expanding role for purine uptake permease-like transporters in plant secondary metabolism, Frontiers Plant Sci. 3, 2012, 78).
Claim Objections
Claims 1 and 4 objected to because of the following informalities:
In claim 1, line 7, and claim 4, line 3, “the group of” should preferable be “the group consisting of” to indicate a closed Markush group. The present claim language of “the group of” is understood as reciting a closed Markush group.
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.
Claims 1-5, 8, 10, 14, 19 and 24 (all non-withdrawn claims) 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 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.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.”). Regents of the University of California v. Eli Lilly & Co., 119, F.3d 1559, 1568, 43 USPQ2d 1398, 1405 (Fed. Cir. 1997).
“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.” MPEP 2163(II)(3)(a).
Furthermore, a “‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure ‘indicates that the patentee has invented species sufficient to constitute the gen[us].’ See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (‘[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.’). ‘A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).” MPEP 2163(II)(3)(a).
Genus of pathway for producing a precursor of a tropane alkaloid or a tropane alkaloid produce or derivative thereof
Claim Scope
Claim 1 recites “a pathway for producing the precursor of a tropane alkaloid product, the tropane alkaloid product, or the derivative of a tropane alkaloid product.” Claim 24 recites “a pathway for producing the tropane alkaloid product or the derivative of a tropane alkaloid product.” Claim 19 recites specific tropane alkaloids including “littorine, hyoscyamine, atropine, anisodamine, scopolamine, calvstegine, cocaine, or a non-natural tropane alkaloid,” including a group of specific tropane alkaloid derivatives for which reference to such list in claim 19 is made in lieu of listing all species here.
As such, the claims expressly recite a genus of any possible tropane alkaloid including “non-natural tropane alkaloids,” which includes tropane alkaloids that are not presently known in the current art or in the prior art, and further specific tropane alkaloids including cocaine and various derivatives of tropane alkaloids as recited in the claims.
Analysis
“It is also known that alkaloids, including morphine, in planta are produced by polypeptide modulated chemical conversion reactions from precursor compounds. In order for relatively complex alkaloid compounds to accumulate in plant tissues, it is required that a plethora of different chemical reactions is performed in concert within these plant tissues. Thus, in principle, it is generally understood that plant polypeptides and the genes encoding these polypeptides, play an instrumental role in the in planta synthesis of plant alkaloids. However for many plant alkaloids, it is unknown which genes and polypeptides are pertinent, and whether and how these genes can be implemented to produce certain plant alkaloids ex planta. There exists, therefore, a paucity of biosynthetic production methodologies for plant alkaloid compounds. On the other hand, the aforementioned synthetic manufacturing methods, as well as techniques for extraction of alkaloids from natural sources known to the art suffer from low alkaloid yields or are expensive.” Facchini et al. (U.S. 2019/0194269 A1) (previously cited), para. [0005].
Facchini does not directly address tropane alkaloids, precursors thereof and derivatives. However, an ordinarily skilled artisan at time of filing would understand that “a paucity of biosynthetic production methodologies for plant alkaloid compounds” applied to alkaloid compounds generally including tropane alkaloids. For example, Wang et al. (Discovery and Engineering of the Cocaine Biosynthetic Pathway, JACS 144, 2022, 22000-007), published after the filing date of the current application, abstract, explains:
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As such, Wang evidences that a pathway for producing a tropane alkaloid being cocaine as directly recited in claim 19 was both 1) unknown at time of filing and 2) unpredictable at the time of filing. The discussion in Wang of a pathway for cocaine being unknown at the time of filing is exemplary that pathways for many tropane alkaloids are unknown at time of filing including for non-natural tropane alkaloids.
“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.” “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.”
The disclosure of a pathways for the production of a limited number of tropane alkaloids does not allow for the prediction of other non-enumerated pathways recited in and encompassed by the genus of such pathways recited in the claims nor constitute a representative number of pathway species or a disclosure of identifying characteristics for undescribed pathways for tropane alkaloid production including pathways representative for precursors and derivatives to such pathways. For example, all of the pathways described in the specification appear to proceed from an ornithine or agmatine precursor that is converted to tropine and additional downstream tropane alkaloids. Fig. 1 of Wang evidences that cocaine is produced through a pathway that does not involve a tropine intermediate through action of EnCYP81AN15and EnMT4 (see Wang, abstract) not described in the art prior to publication of Wang that are not identifiable from the disclosure of the specification. As such, the pathways disclosed by the specification all originating from arginine and/or ornithine as a precursor to tropine and other alkaloids directly made from tropine is not representative of a general genus of pathways for the production of all tropane alkaloids and precursors and derivatives thereof as recited in the claims. The specification fails to provide for an adequate written description of a genus of such pathways for production of tropane alkaloids and precursors and derivatives thereof as generically recited in claims 1 and 24 and specific non-demonstrated alkaloids and derivatives as recited in claim 19, including but not limited to atropine, calystegine, cocaine and non-natural tropane alkaloids, for these reasons.
Genera of transporters
The transporters recited in claim 1 are not required to have any particular function. In contrast, claim 24 recites “a plurality of transporters within a pathway for producing the tropane alkaloid product” or derivative thereof thereby requiring a specific function. Claims 8 and 10 recited recite a genus of MATE and PUP transporters having a function of “alter[ing] the movement of one or more precursors of a tropane alkaloid product, tropane alkaloid products or derivatives of a tropane alkaloid products.”
“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.” “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.”
The specification evidences the unpredictability in identifying a genus of PUP and/or MATE transporters having the functionality referenced. Example 14 describes “Prediction of putative TA transporters using supervised learning models.” In brief, Example 14 analyzes a transcriptome database for A. belladonna with final identification of three genes/transcripts: AbLP1, AbCT1 And AbPUP1. Example 15 evaluates that AbPUP1 and AbLP1 and not AbCt1 (3 species) increase production of some tropane alkaloids, which is a small fraction of transporters screened from A. belladonna. The specification also identifies NtJAT1 and NtMATE1/2 (both from N. tobacum) as useful transporters. However, this disclosure does not allow for the prediction of transporter species from plants other than A. belladonna and N. tobacum and transporters that may have activity to transport alkaloids unrelated to the specific alkaloids being tropine and those derived therefrom (e.g. cocaine) that form the majority of transporter species falling with the genera of transporters recited in claims 8, 10 and 24. Since there is substantial unpredictability for transporter species functional (i.e. functional for movement of tropane alkaloids, precursors and derivatives thereof) within the genera recited in claim 8, 10 and 24 other than the species specifically enumerated in the specification, one having skilled in the art is found not to have been placed in possession of such genera
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.
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.
Claim(s) 1-5, 8, 10, 14, 19 and 24 (all non-withdrawn claims) is/are rejected under 35 U.S.C. 103 as being unpatentable over Srinivasan et al. (Engineering a microbial biosynthesis platform for de novo production of tropane alkaloids, Nature Comm. 10, 2019, 3634) (see IDS 11/29/23, NPL 166) further in view of Szewczak et al. (Hiring cell gatekeepers, J. Biotechnol. Comp. Biol. Bionanotech. 92, 2011, 123-39), Facchini et al. (U.S. 2019/0194269 A1) (previously cited) and Morita et al. (Vacuolar transport of nicotine is mediated by a multidrug and toxic compound extrusion (MATE) transporter in Nicotiana tabacum, PNAS 106, 2009, 2447-52) (see IDS 4/16/24, NPL 2).
Srinivasan, abstract, teaches:
Tropane alkaloids (TAs) are a class of phytochemicals produced by plants of the nightshade family used for treating diverse neurological disorders. Here, we demonstrate de novo production of tropine, a key intermediate in the biosynthetic pathway of medicinal TAs such as scopolamine, from simple carbon and nitrogen sources in yeast (Saccharomyces cerevisiae). Our engineered strain incorporates 15 additional genes, including 11 derived from diverse plants and bacteria, and 7 disruptions to yeast regulatory or biosynthetic proteins to produce tropine [a tropane alkaloid product] at titers of 6 mg/L [i.e. heterologous coding sequences for a plurality of enzymes within a pathway for producing a tropane alkaloid]. We also demonstrate the utility of our engineered yeast platform for the discovery of TA derivatives by combining biosynthetic modules from distant plant lineages to achieve de novo production of cinnamoyltropine, a non-canonical TA. Our engineered strain constitutes a starting point for future optimization efforts towards realizing industrial fermentation of medicinal TAs and a platform for the synthesis of TA derivatives with enhanced bioactivities.
“We examined deregulation of polyamine biosynthesis regulatory mechanisms to increase putrescine production by constructing single-gene disruptions for MEU1, OAZ1, SPE4, SKY1, and AGP2 by inserting nonsense mutations within each open reading frame in wild-type yeast.” Srinivasan, page 5, right col. “OAZ1 gene encodes antizyme-1, OAZ1 gene encodes antizyme-1, a competitive inhibitor of ornithine decarboxylase.” Srinivasan, page 5, right col. That is, cell comprises an alteration in an endogenous polyamine regulatory mechanisms and metabolism as recited in claims 4 and 14. OAZ1 is understood to be ornithine decarboxylase antizyme. It is further noted that SPE4 gene in S. cerevisiae is understood to encode spermine synthase as recited in claim 14.
As shown in Fig. 1 of Srinivasan, the engineered yeast described therein have a heterologous coding sequence (nucleic acid) encoding for at least arginine decarboxylase (AsADC) as recited in claim 5. “We combined the top-performing triad of overexpressed native genes (SPE1, ARG2, CAR1) with the top performing heterologous putrescine pathway (AsADC, speB) by co-transforming the wild-type strain with a low-copy plasmid encoding SPE1, AsADC, and speB (pCS4239).” Srinivasan, page 5, left col.
A S. cerevisiae cell is both a microbial and fungal cell.
However, Srinivasan does not teach such an engineered yeast cell having “a plurality of heterologous coding sequences encoding a plurality of transporter proteins” from the group of such transporter proteins recited in claim 1 nor a “plurality of transporters within a pathway for producing the alkaloid product or a derivative of a tropane alkaloid product” as recited in claim 24.
Szewczak, et al, page 136, left col., teaches:
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An ABC transporter is a ATP-binding cassette transporter. Szewczak, page 132, left col. Hycoscyamine is not tropine (or cinnamoyltropine) as taught by Srinivasan. However, “hyoscyamine and scopolamine are derived from littorine, the product of tropine condensation with phenyllactate.” Srinivasan, page 9, right col.
Facchini, abstract, teach:
Polynucleotides and polypeptides useful in the manufacture of a class of chemical compounds known as alkaloids are provided. The polynucleotides and polypeptides may be used to synthesize alkaloids, including reticuline, thebaine and morphine, in vivo and in vitro. The polynucleotides further may be used to examine the presence of the polynucleotides in a cell or a cell extract, and to modulate expression thereof in living cells.
The working embodiments of Facchini are engineered S. cerevisiae yeast cells. See Facchini, Example 4.
.The cells taught by Facchini includes expression of at least one nucleic acid sequences “in a heterologous host cell to facilitate transport of an alkaloid compound across a cellular membrane. In some embodiments, the alkaloid is exported from the cell. In some embodiments, the alkaloid is exported from the cell and secreted in a cell growth medium.” Facchini, para. [0729]. Specific transporters exemplified by Facchini includes: “transformed with a gene expressing a first purine permease (PUP-L) or a second purine permease (PUP-N), each either alone or together with Betv-1.” Facchini, para. [0171]. A purine permease is considered to be a purine uptake permease-like transporter.
Facchini, in the claims, teaches:
41. A use of a polynucleotide comprising a nucleic acid sequence set forth in claim 1, expressed in an heterologous host to facilitate transport of an alkaloid compound across a cellular membrane, wherein the nucleic acid sequence is selected from SEQ.ID NO: 384; SEQ.ID NO: 902 and SEQ.ID NO: 903.
“In another aspect, the present disclosure provides, in at least one embodiment, a polynucleotide comprising at least one nucleic acid sequence selected from the group consisting of:
(a) SEQ.ID NO: 384; SEQ.ID NO: 902 or SEQ.ID NO: 903.” Facchini, para. [0101].
The teaching of Facchini that at least one of the indicated nucleic acid sequences encoding a transporter for an alkaloid is a direct suggestion that two of the same may be expressed. That is, “at least one” directly indicates the acceptable possibility of more than one or plural (i.e. two).
The purine permeases identified as PUP-L and PUP-N are understood to be purine uptake permease-like (PUP) transporters. That is, any purine permease associated with the notation PUP in the art would appear to be within the broadest reasonable interpretation of a purine uptake permease-like (PUP) transporter as recited in claims 1 and 10.
The specific alkaloids including reticuline, thebaine and morphine are not of the same specific class of alkaloids as tropane alkaloids and the same is fully understood and acknowledged. However, Facchini directly teaches that expression of a purine uptake permease-like transporter (e.g. PUP-L or PUP-N) is known to assist in the export of heterologously produced alkaloids in S. cerevisiae cells and that expressing a transporter to allow for transport of such alkaloids to exit the yeast cell is beneficial. “To facilitate transport of an alkaloid compound across a cellular membrane” is a direct indication that such transport benefits alkaloid production including the amount of alkaloid that may be produced. “However, and surprisingly, reticuline production increased 25-fold to more than 1,000 μg/L/OD in the medium containing strains transformed with both PUP-L and PUP-L and Betv1.” Facchini, para. [0853].
The ability of the specific PUP-L or PUP-N purine permeases of Facchini to specifically transport tropane alkaloids including tropine, is not directly described. However, additional transporters known to transport tropane alkaloids are known in the prior art. Morita, abstract, teaches:
Alkaloids play a key role in plant defense mechanisms against
Pathogens and herbivores, but the plants themselves need to cope
with their toxicity as well. The major alkaloid of the Nicotiana
species, nicotine, is translocated via xylem transport from the root
tissues where it is biosynthesized to the accumulation sites, the
vacuoles of leaves. To unravel the molecular mechanisms behind
this membrane transport, we characterized one transporter, the
tobacco (Nicotiana tabacum) jasmonate-inducible alkaloid trans
porter 1 (Nt-JAT1), whose expression was coregulated with that of
nicotine biosynthetic genes in methyl jasmonate-treated tobacco
cells. Nt-JAT1, belonging to the family of multidrug and toxic
compound extrusion transporters, was expressed in roots, stems,
and leaves, and localized in the tonoplast of leaf cells. When
produced in yeast cells, Nt-JAT1 occurred mainly in the plasma
membrane and showed nicotine efflux activity.
“Our results indicated that Nt-JAT1 is not exclusively specific for nicotine, the major endogenous metabolite in tobacco, but might also recognize anabasine, another endogenous tobacco alkaloid, and hyoscyamine (a tropane alkaloid) and berberine (an isoquinoline alkaloid) derived from other plant species.” Morita, page 2451, left col. “[H]yoscyamine and scopolamine are derived from littorine, the product of tropine condensation with phenyllactate.” Srinivasan, page 9, right col.
“Here, we characterized this MATE transporter, designated as Nicotiana tabacum jasmonate-inducible alkaloid transporter 1 (Nt-JAT1).” Morita, page 2447, right col.
To summarize the above, Facchini teaches that it is desirable to express transporter proteins for alkaloids to increase yield of alkaloids produced by heterologous pathways engineered into such yeast plants. While Facchini does not discuss tropane alkaloids specifically, an ordinarily skilled artisan at the time of filing would have recognized from the teachings of Facchini that expression of an appropriate transporter will assist in the heterologous production for any alkaloid that may be produced in an engineered yeast cell. The prior art teaches at least two transporters expressible in S. cerevisiae that are known to assist in the efflux of tropane alkaloid across the plasma membrane of S. cerevisiae, ABC transporter ScPDR5 and MATE transporter Nt-JAT1, which both transport hyoscyamine out of yeast cells wherein hyoscyamine is a condensation product and derivative of tropine. Further, Facchini teaches that purine uptake permeases are also known in the prior art to transport alkaloids out of yeast cells.
In view of the above, at the time of filing an ordinarily skilled artisan at time of filing would have been motivated to modify the engineered S. cerevisiae for producing tropine as taught by Srinivasan to further have heterologous genes or coding sequences encoding any of ABC transporter ScPDR5, MATE transporter Nt-JAT1 and/or purine uptake permeases (as taught by Facchini) with a reasonable expectation of increasing tropine production by expression of such transporters allowing for the transport/movement of tropine (tropane alkaloid product) across a cellular membrane being the outer plasma membrane of such engineered S. cerevisiae cell. Further, as indicated by Facchini, more than one transporter protein may be expressed to assist in the efflux of a produced alkaloid from S. cerevisiae such that an ordinarily skilled artisan at the time of filing would have recognized the appropriateness of expressing two (plural) of such permeases as discussed.
Regarding claim 19, Fig. 1 of Srinivasan shows that agmatine is produced in the pathway for producing tropine. Production of agmatine as an intermediate towards downstream production of tropine is considered to fall within the broadest reasonable interpretation of claim 19. The specification by working examples demonstrates production of tropine, pseudotropine, littorine, hycoscyamine, and scopolamine and certain precursors including agmatine, putrescine, etc., as shown in Figs. 2 and 3 of the specification. In the alternative, Srinivasan, Fig. 1, further shows that embodiment yeast cells producing tropine can further be extended to produce cinnamoyltropine, which is a non-natural tropane alkaloid. The teaches above for expressing plural coding sequences for plural transporters as discussed above equally apply for embodiments of Srinivasan producing cinnamoyltropine.
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.
Claims 1-5, 8, 10, 14, 19 and 24 (all non-withdrawn claims) are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 12,480,131 in view of Srinivasan et al. (Engineering a microbial biosynthesis platform for de novo production of tropane alkaloids, Nature Comm. 10, 2019, 3634) (see IDS 11/29/23, NPL 166), Szewczak et al. (Hiring cell gatekeepers, J. Biotechnol. Comp. Biol. Bionanotech. 92, 2011, 123-39), Facchini et al. (U.S. 2019/0194269 A1) (previously cited) and Morita et al. (Vacuolar transport of nicotine is mediated by a multidrug and toxic compound extrusion (MATE) transporter in Nicotiana tabacum, PNAS 106, 2009, 2447-52) (see IDS 4/16/24, NPL 2).
The reference claims recite:
1. An engineered non-plant cell that produces a precursor of a tropane alkaloid product, a tropane alkaloid product, or a derivative of a tropane alkaloid product, wherein the engineered non-plant cell comprises a heterologous coding sequences encoding hyoscyamine dehydrogenase (HDH) within a pathway for producing the precursor of a tropane alkaloid product, the tropane alkaloid product, or the derivative of a tropane alkaloid product.
15. The engineered cell of claim 1, wherein the engineered cell produces a tropane alkaloid product selected from the group consisting of a hyoscyamine, atropine, anisodamine, scopolamine, calystegine, cocaine, and a non-natural tropane alkaloid.
18. The engineered cell of claim 1, wherein transport of one or more tropane alkaloids, one or more tropane alkaloid precursors, and/or one or more tropane alkaloid derivatives across intracellular membranes or across the plasma membrane is modified in the cell.
19. The engineered cell of claim 18, wherein modified transport is enabled by one or more heterologous coding sequences encoding one or more transporters, wherein at least one of the transporters is selected from the group consisting of a multidrug and toxin extrusion transporter, a nitrate/peptide family transporter, an ATP-binding cassette transporter, and a pleiotropic drug resistance transporter.
Reference claim 19 meets the features of claims 1 and 24 except for the requirement of a plurality of heterologous coding sequences for a plurality of transport proteins as recited in reference claim 19. The rejections under 35 U.S.C. 103 set forth above are incorporated by reference.
The direct recitation in reference claim 19 of “wherein modified transport is enabled by one or more heterologous coding sequences encoding one or more transporters” is understood as an explicit teaching or suggestion to an ordinarily skilled artisan at time of filing that more than one, i.e. two, of such transporters can be expressed in forming an embodiment of reference claim 19, wherein such an embodiment of reference claim 19 meets the features of claims 1, 8, and 24 wherein such two or more transporters can include a MATE transporter.
Regarding the remainder of claims 2-5, 10, 14, 19 and 24, any embodiment of reference claim 19 requires a specific tropane alkaloid to be produced. Although reference claim 1 recites hyoscyamine dehydrogenase (HDH), as discussed, “hyoscyamine and scopolamine are derived from littorine, the product of tropine condensation with phenyllactate.” Srinivasan, page 9, right col. As such, an ordinarily skilled artisan at time of filing would have been motivated to modify embodiments of reference claim 19 to have heterologous coding sequence encoding a pathway (i.e. proteins and enzymes) for producing tropine as a precursor to hyoscyamine (presumed substrate of HDH) and other modifications (including gene deletions) for producing tropine as taught by Srinivasan, which meet the features of claims 2-5, 14, 19 and 24 as discussed above. Regarding claim 10, as discussed Facchini teach that purine uptake permease-like (PUP) transporters are known to be useful when expressed in recombinant yeast host cells to assist in increased titer production of alkaloids (i.e. movement of such alkaloids across the cell plasma membrane) as to motivate expression of heterologous coding sequences thereof to the ordinarily skilled artisan as discussed in the rejections under 35 U.S.C. 103 discussed above.
Conclusion
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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