DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
2. Claims 1-20 are pending and examined.
Election/Restrictions
3. Applicant’s election without traverse of SEQ ID NO: 30, as a species, claims in the reply filed on July 9, 2026, is acknowledged. All claims read on the elected species. In the process of examination, the prior art search was extended to SEQ ID NO: 62.
Information Disclosure Statement
4. The listing of references on pages 112-115 of the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, “the list may not be incorporated into the specification but must be submitted in a separate paper.” Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
5. The drawings are objected to because in Figure 33, it is unclear what numbers 1, 2, and 3, which appear in boxes at the C-terminus of the sequences, refer to: neither the figure legend nor the figure itself supply a clarification. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
6. Claims 3, 4, 10-13, and 19 is objected to because of the following informalities.
In claims 3, 4, 10, and 11, the term “cell comprises” should be amended to recite “cell is” because the types of the cells that said claims recite as specific instances of yeast and bacterial cells are coextensive with the term “cell” in the above phrase.
In claims 12, 13, and 19, the abbreviations of the cannabinoid names need not be spelled out because they are already spelled out in claims 5 and 6.
Claim Interpretation
7. As set forth in the indefiniteness rejection below, the claims have been found indefinite. The following is noted with regard to the claim interpretation for the purpose of the examination.
In claims 1, 8, and 15, the term “a genetically modified host cell comprising a microorganism” is interpreted to encompass any bacterial or yeast cell, wherein the cell expresses a glycosyltransferase of SEQ ID NO: 30 or any of the other sequences (in claims 1 and 15), or having at least 95% identity to SEQ ID NO: 30 (in claims 8 and 15), or wherein the glycosyltransferase comprises any fragment of the recited SEQ ID NO’s (in claims 1 and 15).
The “wherein” clause which recites that “one or more cannabinoids are introduced to a cell culture of said genetically modified microorganism” is interpreted as encompassing a cell culture comprising both, a plurality of the transgenic cells expressing one of the recited glycosyltransferases (or its fragment) and one or more cannabinoids.
Claim Rejections - 35 USC § 112(b)
8. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
9. Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
In claims 1, 8, and 15, the phrase “genetically modified host cell comprising a microorganism” renders the claims indefinite, because the relationship between “the host cell” and “microorganism” is unclear. Dependent claims refer to the microorganism as a yeast or a bacterial cell. It is thus unclear how a “host” cell can comprise “a microorganism” in the context of the instant claims.
The phrase “introduced to a cell culture of the genetically modified microorganism,” in each of the above three claims, renders the claims indefinite as well. Frist, the term “the genetically modified microorganism” lacks sufficient antecedent basis within the claims, because they only refer to a “genetically modified host cell” not a genetically modified microorganism. Second, it is unclear how the “cell culture” in the phrase “introduced to a cell culture” relates to the “genetically modified host cell.” The claim is drawn to “a system” comprising a genetically modified host and a cannabinoid, yet the reference to a cell culture implies that additional elements are comprised in said “system.” The metes and bounds are thus unclear.
It is noted that the combination of the term “system” in the preamble with the product-by-process term “introduced to a cell culture” introduces further ambiguity into the claims because it implies a process, yet the wording of the rest of the claim indicates a composition, a product.
Claims dependent from claims 1, 8, and 15 fail to recite additional limitations overcoming their indefiniteness, and as a result, the metes and bounds of said dependent claims are unclear as well.
Claim Rejections - 35 USC § 112(a)
10. 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.
Written Description
11. Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant claims a system for glycosylating cannabinoids comprising a genetically modified host cell, comprising (1) a microorganism, including wherein the microorganism is a yeast cell or an E. coli cell, expressing at least one of the recited glycosyltransferases, including one having 95% identity to SEQ ID NO: 30, the elected species (or the other recited SEQ ID NO’s) or any fragment of any of the recited glycosyltransferases; and (2) one or more cannabinoids, wherein the cannabinoid is introduced to a culture of said modified host cells.
Applicant describes SEQ ID NO: 30 as a glycosyltransferase from tobacco, called NtGT4 (page 49). Applicant describes overexpressing tobacco glycosyltransferases, including the NtGT4 of the full-length SEQ ID NO: 30, in yeast cells and observing high levels of glycosylation of cannabinoids introduced into said yeast cell culture, particularly when the overexpressed glycosyltransferase was the tobacco NtGT4 (Examples 12-17 on pages 93-95; Figures 46-47).
Applicant describes expressing glycosyltransferase UGT76G1 from Stevia rebaudiana, which is the full-length SEQ ID NO: 62, in yeast cells, and introducing CBDA to yeast sus pension culture in acetonitrile (Examples 12 and 13). Applicant describes the transformation of tobacco BY2 cells with an expression vector encoding SEQ ID NO: 62. Applicant describes introducing CBDA, a cannabinoid, into the said cell suspension and describes observing glycosylation in both wild-type and transgenic plants (Example 17 on page 96).
Applicant does not describe the genus of compositions encompassed by the instant claims. When claims encompass a genus, an applicant can adequately describe the genus by disclosing either (1) a representative number of species falling within the scope of the genus or (2) structural features common to the members of the genus. MPEP § 2163.
In the instant case, the claims encompass a vast genus of “systems” (reasonably interpreted as “compositions”) for “glycosylating cannabinoids,” including those comprising only any “fragment” of unspecified length of any of the recited glycosyltransferases, including those of SEQ ID NO: 30, the elected species; or comprising any glycosyltransferase having 95% identity to SEQ ID NO: 30 of the other recited species.
Applicant has neither set forth a representative number of the species of said genus nor identified the structure-function relationship such that one would be able to envision which compositions are encompassed by the claims. Applicant has described only the following scenarios in which glycosylation was observed in a cell culture of the “modified microorganism” – overexpressing tobacco NtGT4 (SEQ ID NO: 30) and glycosyltransferase UGT76G1 from Stevia rebaudiana, in yeast or tobacco cells. This is not sufficiently representative of the claimed genus.
For example, the protein of SEQ ID NO: 30 is 496 amino acids long. A sequence having 95% identity to it could comprise up to 24 substitutions, insertions, or deletions anywhere along the length of SEQ ID NO: 30, which would amount to the genus of 2024 species, a number that is infinite in practical terms. Moreover, a glycosyltransferase that is recited merely as a “fragment” of SEQ ID NO: 30 could differ from it at any number of positions and would comprise a vast and undefined genus. The described species are not sufficiently representative of said genera.
Moreover, Applicant has not set forth the structure-function relationship such that one of ordinary skill in the art would be able to envision which proteins are encompassed by the claims and which ones are not. For example, the specification indicates that from among a number of glycosyltransferases screened in cell suspension cultures, including homologues from Nicotiana tabacum, only NtGT4 and UGT76G1 from Stevia showed activity towards two cannabinoids. This indicates that even the enzymes that are closely related to NtGT4 or UGT76G1 may not possess the cannabinoid glycosylation function.
This is consistent with the state of the prior art regarding cannabinoid glycosylation. For example, Hardman et al teaches that in order to identify one glycosyltransferase from Stevia (UGT76G1) and one from rice, a screening of a library of glucosyltransferases was required, as well as a screening of various cannabinoids as potential substrates (BioRxiv Preprint Server for Biology (Cold Spring Harbor), pg. 1-25; published online January 30, 2017; see page 1, 3, and 4). However, neither Hardman et al nor other available prior art provide any description of structures either that would help envision which of the naturally occurring plant glycosyltransferases possess glycosylation activity towards cannabinoids or, alternatively, which cannabinoids could act as substrates for glycosyltransferases. Moreover, glycosyltransferases are a multi-gene superfamily, which can transfer single or multiple sugars on variety of molecules, with more than 100 glycosyltransferases identified in Arabidopsis alone (See Wang et al (2009) Front Biol. China, 4:39-46).
It is noted that a mere functional description of a genus of chemical entities is not sufficient to meet the written description requirement: “the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function. In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. In this latter case, disclosure of function alone is little more than a wish for possession; it does not satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (written description requirement not satisfied by merely providing “a result that one might achieve if one made that invention”); In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984).
For these reasons, the genus of compositions encompassed by the instant claims is not adequately described and it is unclear whether at the time of filing, Applicant was in possession of the instant invention as broadly claimed.
Claim Rejections - 35 USC § 103
12. 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 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.
13. Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Zipp et al (WIPO Publication No. 2017/053574, published March 30, 2017).
Zipp et al teach a method of producing a cannabinoid glycoside, comprising incubating a cannabinoid aglycone with a sugar donor in the presence of one or more glycosyltransferases. Zipp et al teach said method wherein the glycosyltransferase is a UGT76G1 or a UGT76G1-like transferase, including wherein the enzyme comprises SEQ ID NO: 7 (paragraphs 112-113; 119, 127, 131; 141-145). Zipp et al teach said method, wherein the production of a cannabinoid glycoside prodrug comprises expressing one or more glycosyltransferase in a cell or a plant and isolating the cannabinoid glycoside prodrug. Zipp et al teach that the methods comprise producing cannabinoid glycosides in “cell culture” (paragraphs 119-221, 224, 234; Example 1 ). Zipp et al teach that the cells of their invention, in which the enzymes of their invention may be expressed, include yeast cells, such as Pichia pastoris, or E. coli (paragraph 212). Zipp et at teach codon-optimizing the nucleic acid sequence encoding UGT76G1 for expression in P. pastoris and E. coli (paragraph 140). Zipp et al teach that the constructs of their invention include appropriate regulatory elements, such as promoters active in yeast (paragraph 0190-0191). Zipp et al teach that UGT76G1 is capable of primary, secondary or tertiary glycosylation of substrates with diverse chemical structure, including cannabinoids (paragraphs 117, 119, and 139). Zipp et al teach that UGT76G1 has the unique ability to transfer multiple glucose residues to the CBD molecule (paragraph 119). Zipp et al teach that the cannabinoids used in their invention include CBD, CBDA, and THC, among others (paragraph 50). Zapp et al teach that glycosylation of cannabinoids improves their solubility and pharmacological delivery or availability (paragraph 56).
Zipp et al teach, at SEQ ID NO: 7, the amino acid sequence of the Stevia rebaudiana TGT76G1 glycosyltransferase that has 100% sequence identity to the instant SEQ ID NO: 62. The sequence alignment is set forth below.
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AC BDU41306;
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DT 18-MAY-2017 (first entry)
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DE Stevia rebaudiana UGT76G1 protein SEQ ID NO: 7.
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CC PD 30-MAR-2017.
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CC PF 22-SEP-2016; 2016WO-US053122.
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PR 22-SEP-2015; 2015US-0222144P.
PR 23-OCT-2015; 2015US-0245928P.
PR 18-JUL-2016; 2016US-0363808P.
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CC PA (VITA-) VITALITY BIOPHARMA INC.
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CC PI Brooke RT, Hardman JM, Zipp BJ;
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DR WPI; 2017-22167W/26.
DR N-PSDB; BDU41307.
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CC PT New cannabinoid glycoside prodrug compound used for site-specific
CC PT delivery of cannabinoid drug or facilitating transport of cannabinoid
CC PT drug across blood brain barrier of subject, useful e.g. for treating
CC PT amyotrophic lateral sclerosis.
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CC PS Claim 56; SEQ ID NO 7; 165pp; English.
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SQ Sequence 466 AA;
Query Match 100.0%; Score 2377; Length 466;
Best Local Similarity 100.0%;
Matches 458; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MENKTETTVRRRRRIILFPVPFQGHINPILQLANVLYSKGFSITIFHTNFNKPKTSNYPH 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MENKTETTVRRRRRIILFPVPFQGHINPILQLANVLYSKGFSITIFHTNFNKPKTSNYPH 60
Qy 61 FTFRFILDNDPQDERISNLPTHGPLAGMRIPIINEHGADELRRELELLMLASEEDEEVSC 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 FTFRFILDNDPQDERISNLPTHGPLAGMRIPIINEHGADELRRELELLMLASEEDEEVSC 120
Qy 121 LITDALWYFAQSVADSLNLRRLVLMTSSLFNFHAHVSLPQFDELGYLDPDDKTRLEEQAS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LITDALWYFAQSVADSLNLRRLVLMTSSLFNFHAHVSLPQFDELGYLDPDDKTRLEEQAS 180
Qy 181 GFPMLKVKDIKSAYSNWQILKEILGKMIKQTRASSGVIWNSFKELEESELETVIREIPAP 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 GFPMLKVKDIKSAYSNWQILKEILGKMIKQTRASSGVIWNSFKELEESELETVIREIPAP 240
Qy 241 SFLIPLPKHLTASSSSLLDHDRTVFQWLDQQPPSSVLYVSFGSTSEVDEKDFLEIARGLV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 SFLIPLPKHLTASSSSLLDHDRTVFQWLDQQPPSSVLYVSFGSTSEVDEKDFLEIARGLV 300
Qy 301 DSKQSFLWVVRPGFVKGSTWVEPLPDGFLGERGRIVKWVPQQEVLAHGAIGAFWTHSGWN 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 DSKQSFLWVVRPGFVKGSTWVEPLPDGFLGERGRIVKWVPQQEVLAHGAIGAFWTHSGWN 360
Qy 361 STLESVCEGVPMIFSDFGLDQPLNARYMSDVLKVGVYLENGWERGEIANAIRRVMVDEEG 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 STLESVCEGVPMIFSDFGLDQPLNARYMSDVLKVGVYLENGWERGEIANAIRRVMVDEEG 420
Qy 421 EYIRQNARVLKQKADVSLMKGGSSYESLESLVSYISSL 458
||||||||||||||||||||||||||||||||||||||
Db 421 EYIRQNARVLKQKADVSLMKGGSSYESLESLVSYISSL 458
Zipp et al do not expressly teach a composition comprising a microorganism genetically modified to express one of the recited glycosyltransferases or a fragment thereof, and a cannabinoid, where the cannabinoid was introduced into a cell culture of said microorganism.
At the time the invention was made, it would have been prima facie obvious to one of ordinary skill in the art to modify the teachings of Zipp et al and genetically modify a microorganism, including a Pichia pastoris yeast cell, or an E. coli cell using a nucleic acid encoding SEQ ID NO: 7 of Zipp. It would have been obvious to grow said cells in a culture and introduce a cannabinoid, including a CBD, CBDA, or THC to said culture. The resultant composition would read on the “system” of the instant claims 1-6, 8-13, and 15-19. With regard to claims 7, 14, and 20, given the teachings of Zipp regarding the properties of UGT76G1, one would have reasonably expected that a cell culture of said modified cells would comprise a glycosylated cannabinoid having between 1 and 4 glycosylation moieties. It would have been also obvious to select for the presence of such glycosylated cannabinoids.
One would have been motivated to modify the teachings of Zipp et al, given the express suggestion in the reference regarding the expression of UGT76G1 in various microorganisms, and given the desirability of obtaining glycosylated cannabinoids, as also taught by Zipp et al. Given that Zipp et al reduced their invention to practice and the properties of the UGT76G1 glycosyltransferase from Stevia, as taught by Zipp et al, one would have had reasonable expectation of success.
Conclusion
14. Mo claims are allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MYKOLA V KOVALENKO whose telephone number is (571)272-6921. The examiner can normally be reached Mon.-Fri. 9:00-5:30 PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, BRATISLAV STANKOVIC can be reached at (571)270-0305. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MYKOLA V. KOVALENKO/Primary Examiner, Art Unit 1662
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