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, consisting of claims 1-3 & 6, in the reply filed on 4 Jun 2026 is acknowledged. Claim 26 is added for purposes of examination. Applicant has elected the species of SEQ ID NO.7 for examination.
Claim Status
Claims 1, 3, 6 & 26 are under examination on the merits.
Claims 2, 7, 9-15, 17-19, 21 and 23-25 are withdrawn as non-elected subject matter.
Claims 4-5, 8, 20 & 22 are canceled.
Priority
Claims 1, 3, 6 & 26 receive the U.S. effective filing date 11 Mar 2022.
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.
Claims 1, 3, 6 & 26 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 claims contain 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.
Claims 1 & 26, encompass functional analogs of the THCA and CBDA synthase genes having as little as 80% sequence identity to SEQ ID NO.7 & 8, respectively.
A review of sequence search information reveals that there appear to be no reports of genes involved in cannabinoid synthesis in Helichrysum of similar identity to that claimed in SEQ ID NO.7 & 8. Thus, prior art does not provide structural description of sequences encoding enzymes involved in cannabinoid biosynthesis or modification, active in Helichrysum, with less than 100% identity to SEQ ID NO.7 & 8. Furthermore, there appear to be no reports even from Cannabis sativa which indicate functional analogs of THCA synthase sequences of <95% identity to Applicant’s SEQ ID NO.7 [See attached ‘Sequence search SEQ ID NO.7 results entries 1-41.pdf’’]. There appear to no reports from C. sativa which indicate functional analogs of CBDA synthase sequences of <89% identity to Applicant’s SEQ ID NO.8 [See attached ‘Sequence search SEQ ID NO.8 results entries 1-31.pdf’].
Nucleic acids with 80% identity to the 1638-nucleotide long SEQ ID NO.7 encompass genes with approximately 327 base pair substitutions from the described sequence. This corresponds to approximately 109 amino acid substitutions within any position of the encoded cannabinoid synthase enzyme. Describing a genus of alleles with all such possible single amino acid substitutions relative to the gene identified as SEQ ID NO.7 would require describing a large number of variant encoded enzymes; a representative number of which were not described by the Applicant at the time of filing.
Nucleic acids with 80% identity to the 1635-nucleotide long SEQ ID NO.8 encompass genes with approximately 327 base pair substitutions from the described sequence. This corresponds to approximately 109 amino acid substitutions within any position of the encoded cannabinoid synthase enzyme. Describing a genus of alleles with all such possible single amino acid substitutions relative to the gene identified as SEQ ID NO.8 would require describing a large number of variant encoded enzymes; a representative number of which were not described by the Applicant at the time of filing.
Applicant is claiming a broad range of structurally variable nucleic acids as a result of requiring only 80% identity to SEQ ID NO.7 & 8. No structural information is described beyond that of SEQ ID NO.7 & 8 identifying such functional sequences. Without further guidance in the written description, such proposed structural modification(s) would amount to making random mutational changes in the THCA and CBDA synthase genes.
Making random changes in protein encoding sequences is unpredictable, and thus one would not be enabled to isolate or derive such functional analogs conferring the claimed function(s). One would not have any reasonable certainty that such mutant or variant forms of encoded enzymes would function properly, or be effective functional analogs as claimed.
It has been shown within the art that highly similar cannabinoid biosynthesis alleles can have different functionality owing to even small sequence changes. It has been demonstrated that mutation of a single SNP within a THC synthase gene can impact production of cannabinoids [See p.10, ¶3 – p.11, ¶2 in Garfinkel et al., Genes 2021, 12, 228; Published 4 Feb 2021].
Because of this, claim 1 and its dependents are rejected, as is claim 26. Such variable genes that are only 80% identical to SEQ ID NO.7 and involved in cannabinoid synthesis within Helichrysum are not described in the specification, nor taught by the existing art. Even with numerous reports directed to the biosynthesis of THC and other cannabinoids [See attached ‘Sequence search SEQ ID NO.7 results entries 1-41.pdf’ & ‘Sequence search SEQ ID NO.8 results entries 1-31.pdf’] no variants of THCA synthase have been described with less than 95% identity to SEQ ID NO.7 and no variants of CBDA synthase of <89% identity to SEQ ID NO.8 have been described, even within C. sativa.
Therefore, without guidance from the specification as to which nucleotide sequences of 80% identity to SEQ ID NO.7 or 8 confer analogous function(s) in the cannabinoid synthesis pathway of Helichrysum, this would require undue experimentation to find these functional variants of encoding sequence <100% identical to SEQ ID NO.7 or 8, if it is even possible to do so.
For these reasons, the written description does not reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention. Their disclosure does not support that they are or were able to generate functional analogs of THCA or CBDA synthases within Helichrysum with as little as 80% identity to SEQ ID NO.7 & 8, respectively.
Claims 1, 3, 6 & 26 recite a transgenic H. umbraculigerum cell, tissue or plant. Claims are drawn to recombinant forms of Helichrysum comprising SEQ ID NO.7, which is a THCA synthase [Specification, p.15, Table 1].
Review of Applicant’s specification does not indicate they have successfully produced a transgenic Helichrysum plant, or any form of genetically modified Helichrysum possessing exogenous DNA sequences. Review of Applicant’s example describes the transgenic production of enzymes including those from both C. sativa (i.e. CsOAC & CsOLS) and Helichrysum (i.e. HuCoAT6, HuTKS4, & HuCBGAS4) in Nicotiana but they do not indicate any use of transgenic Helichrysum plants or cells in such a system [Specification, p.32, ¶153].
Helichrysum belongs to the Asteraceae family; research reports have indicated within the Asteraceae there is a wide variability in the ability of species to be successfully transformed [see Daqui et al., Front. Plant Sci. 12:767459; Published 26 Nov 21]. Several species in the family, including sunflower, are known to be recalcitrant to transformation procedures and it is established those which work successfully in models like Nicotiana do not necessarily work in Asteraceae species [p.2, col.2, ¶3; p.3, col.1, ¶2-3;p.7, col.1, ¶4].
No description of tissue culture, transformation via Agrobacterium or biolistics, or any other procedure reasonably considered critical to the ability to successfully generate transgenic Helichrysum plants are described in the specification. No reference is provided or incorporated indicating it is possible to tissue culture, transform, or otherwise reliably manipulate the genus Helichrysum using standard transformation protocols.
While Applicant describes transgenesis in the well-known model Nicotiana, it is unclear if it is actually possible to generate transgenic forms of Helichrysum. As such, the written description does not reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention.
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.
Claims 1, 3, 6 & 26 are rejected under 35 U.S.C. 103 as being unpatentable over Russo [Front. Plant Sci. 9:1969; Published 9 Jan 2019] in view of Williams [U.S. Patent 11,085,047; Published 10 Aug 2021] and Geissler et al. [Biotechnol Lett (2018) 40:981–987; Published 4 Apr 2018].
Claims are drawn to a transgenic H. umbraculigerum plant which has a recombinant, functional analog of THCA synthase combined with a promoter. The THCA synthase (e.g., SEQ ID 7) converts CBG into THC or other cannabinoids. Claim 26 includes the CBDA synthase gene (e.g., SEQ ID NO 8).
Russo teaches that H. umbraculigerum produces cannabinoids, including CBG (i.e. THC precursor). They teach species other than Cannabis which produce cannabinoid compounds, and that H. umbraculigerum specifically produces the CBG precursor [p.3, col.2, ¶2]. They teach conversion of CBG precursor to both THCA and CBDA via the action of THCA synthase (i.e. SEQ ID NO.7) and CBDA synthase (i.e. SEQ ID NO.8) [Specification, p.5, Table 1]. They depict this process in the natural species H. umbraculigerum and in genetically modified Nicotiana [Russo, p.3, Fig.1].
Russo does not teach methods of genetic modification of THCA synthase, or analogs thereof, to modulate or increase the production of cannabinoids in plants.
Williams teaches transgenic approaches to increase cannabinoid content of Cannabis plants via modulation or up-regulation of the THCA synthase gene [col.3, line 45 – col.4, line 45]. Thus, they teach one can increase production of THC or other related molecules in Cannabis. They teach increased expression of THCA synthase via transgenesis catalyzes increased conversion of CBGA to THCA [col4, ¶2, lines 9-17].
Geissler teaches transgenic approaches to generate or increase cannabinoid content in plant cells via modulation or up-regulation of the THCA synthase gene in plant cells or species which do not endogenously produce cannabinoids. They teach production of recombinant vectors including the THCA synthase gene linked to promoters, transformation into Nicotiana and production of recombinant proteins for cannabinoid production [p.982, col.2, ¶4 – p.983, col.1, ¶1].
Before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to modify the production of cannabinoids in Helichrysum species taught by Russo to a transgenic model, or plant, as was described in Cannabis by Williams and in transgenic plant systems (i.e. Nicotiana) by Geissler.
One of ordinary skill in the art would have been motivated to combine these teachings because cannabinoids, both THC & CBD, are known to be valuable secondary metabolites with global interest for medical and recreational markets. One would be motivated to breed or genetically modify plants that produce cannabinoids to increase their concentrations, or yield, as a commercially valuable secondary metabolite. One would be motivated to cross-apply known methods of increasing or producing cannabinoids via transgenic manipulation of THCA synthase as was known in Cannabis. This approach was previously described [Williams; col.3, line 45 – col.4, line 45] as well as similarly reported in exogenous (i.e. Nicotiana) cannabinoid production systems [Giessler; p.982, col.2, ¶4 – p.983, col.1, ¶1].
Regarding claim 1; this includes the limitation of SEQ ID NO.7, and analogous sequences of as little as 80% identity to it. Referring to the specification, SEQ ID NO.7 is the THCA synthase gene from Cannabis [Specification, p.15, Table 1]. Modulation of the THCA synthase gene via transgenic methods to increase or alter cannabinoid content is taught by Williams [col.3, line 45 – col.4, line 45]. Russo graphically depicts the relationship between the precursor molecules in Helichrysum, the relevant synthase enzymes, and production of THCA [p.3, Figure 1].
Regarding claim 3; this includes the limitation of SEQ ID NO.7 operably linked to a promoter. Geissler teaches the linking of THCA synthase to a promoter to modulate production of cannabinoids in transgenic systems [p.982, col.2, ¶4 – p.983, col.1, ¶1].
Regarding claim 6; this includes the limitation of having an artificial DNA molecule wherein the THCA synthase gene is linked to at least one other sequence encoding a protein or enzyme involved in cannabinoid synthesis. Production of such recombinant proteins, and transgenic production of cannabinoids via recombinant THCA synthase is taught by Geissler [p.982, col.2, ¶4 – p.983, col.1, ¶1].
Regarding claim 26; this includes the limitation of the transgenic Helichrysum plant having functional analogs of both SEQ ID NO.7 and SEQ ID NO.8 with as little as 80% sequence identity. Referring to the specification, SEQ ID NO.8 is the CBDA synthase gene from Cannabis [Specification, p.15, Table 1]. Modulation of the cannabinoid synthase genes via transgenic methods to increase or alter cannabinoid content is taught by Williams [col.3, line 45 – col.4, line 45]. Russo graphically depicts the relationship between the precursor molecules in Helichrysum, the relevant synthase enzymes, and production of CBDA [p.3, Figure 1].
At the time of filing, both the production of cannabinoids in H. umbraculigerum and transgenic approaches to modulating or up-regulating cannabinoid production in endogenous cannabinoid producing species (i.e. Cannabis) and non-cannabinoid producing species such as Nicotiana were known. Because of this, claims 1,3, 6 & 26 are obvious in view of prior art, and rejected.
Conclusion
No claims are allowed.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEITH R WILLIAMS whose telephone number is (571)272-3911. The examiner can normally be reached Mon - Fri, 9:30 - 5:30 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amjad Abraham can be reached on (571)270-7058. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KEITH R. WILLIAMS/Examiner, Art Unit 1663
/Amjad Abraham/SPE, Art Unit 1663
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