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 .
2. The Preliminary Amendments filed on April 2, 2024 and May 25, 2026, have been received and entered.
Restriction Requirement
3. Applicant’s election of Group III (claims 14-17, SEQ ID NO: 2) without traverse, on May 25, 2026 is acknowledged.
Claim Disposition
4. Claims 10-13 and 18 have been cancelled. Claims 19-25 have been added. Claims1-9, 14-17 and 19-25 are pending. Claims 14-17 and 19-25 are under examination. Claims 1-9 are withdrawn from further consideration pursuant to 37 CFR 1.12(b), as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Drawing
5. The drawings filed on April 2, 2024, have been accepted by the examiner.
Information Disclosure Statement
6. The Information Disclosure Statement filed on December 22, 2023, has been received and entered. The references cited on the PTO-1449 Form have been considered by the examiner and a copy is attached to the instant Office action.
Specification
7. The specification is objected to because of the following informalities:
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The following is suggested: "Method and Recombinant Microorganism for Producing Cannabigerolic Acid and Derivatives Thereof".
The specification is objected to because the priority information is missing from page 1.
The specification is objected to because trademarks are disclosed and they are not capitalized. The use of the trademark such as FLAG, has been noted in this application (see page 7, for example). It should be capitalized wherever it appears and be accompanied by the generic terminology. Although the use of trademarks is permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner, which might adversely affect their validity as trademarks.
The specification is objected to because the organism names are not consistently italicized, see E. coli on page 10, for example.
Appropriate correction of the above is required.
Abstract
8. The specification is objected to because of the following informalities:
The abstract of the disclosure is objected to because there is no clean copy, only a marked up copy. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Appropriate correction is required.
Specification
9. The specification is objected to because of the following informalities:
The specification is objected to because trademarks are disclosed and they are not capitalized. The use of the trademark such as Q-Sepharose Fast Flow, has been noted in this application (see page 103, for example). It should be capitalized wherever it appears and be accompanied by the generic terminology. Although the use of trademarks is permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner, which might adversely affect their validity as trademarks.
The specification is objected to because the organism names are not consistently italicized, see “M. col” at the top of page 102 and “M. columbinum” on page 99.
Appropriate correction of the above is required.
Information Disclosure Statement
10. To date no Information Disclosure Statement has been filed. Applicant is reminded of the duty to disclose.
Claim Objection
11. Claims 14-17 and 19-25 are objected to because of the following informalities:
For clarity and precision of claim language, it is suggested that claim 14 is amended to read, “ A method of producing cannabigerolic acid or a cannabigerolic acid derivative, comprising:
culturing a microorganism that expresses a prenyltransferase variant set forth in SEQ ID NO: 2, in a solution comprising geranyl pyrophosphate or olivetolic acid pyrophosphate”. The dependent claims hereto are also included.
For clarity it is suggested that claim 17 is amended to read, “…wherein the microorganism is transformed with a recombinant vector comprising a polynucleotide encoding the prenyltransferase variant.”
For clarity it is suggested that claim 19 is amended to recite, “….substitutions [[comprise one or more amino acid substitutions]] are selected from the group consisting of….”. See also claims 20 and 22 with similar language redundancy.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation of the first paragraph of 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.
12. Claims 14-17 and 19-25 are rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and or use the invention.
The claimed invention is directed to a method of producing cannabigerolic acid or derivatives thereof (see claim 14 in its entirety). The claimed invention broadly comprises any modification in the structure of SEQ ID NO:2 and does not safe guard any active sites. The invention is not adequately described because it encompasses a large variable genus of enzyme structures that have not been correlated with function or retention of the native function, and the language in the claim does not inform the ordinary skilled worker of the microorganism that is being cultured/transformed with a recombinant vector. The art generally establishes that several different genes can encode the same protein and no structure is provided for the polynucleotide that is contained in the vector and deemed to be the coding sequence for the enzyme variant. The invention encompasses any cannabigerolic acid derivative, any olivetolic acid derivative and any prenyltransferase variant (having one or more amino acid substitutions with no upper limit on how many). The art generally discloses that a single amino acid change can be detrimental to structure-function relationship, and the claimed invention encompasses an enormous amount of changes. The claimed invention as set forth in claim 14 encompasses fragments derivatives, analogs with the recitation of variants that are not fully described. The claimed invention also encompasses tags that are not adequately described. It is noted that some dependent claims such as claim 20 recite substitution positions, however, claim 14 is not limited by those and claim 24 provides an affinity tag, however, it does meet all the deficiencies of claim 14 and the independent claim has to stand on its own.
The claimed invention is not commensurate in scope with the disclosure in the specification and applicant has not demonstrated possession of the entire genus encompassed in the claims. The specification fails to provide any additional representative species of the claimed genus to show that applicant was in possession of the claimed genus. A representative number of species means that the species which are adequately described are representative of the entire 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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. The claimed genus of polypeptides could include non-functional proteins or proteins with a different function than the one described. Therefore, the genus of claimed polypeptides encompasses widely variant species. Based on the unlimited variations contemplated one skilled in the art would at best expect a protein that is different or at worst a protein that is not functional. Moreover, Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir.1991), states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed" (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed" (See Vas-Cath at page 1116). The skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993).
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
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.
13. Claims 24-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 24 and 25 contains the trademark/trade name MISTIC. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112, second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an assay with regard to the selection of the patient population for the method of treatment, and accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 103
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.
14. 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.
15.Claim(s) 14 and 16-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019173770 A1 in view of WO2019183152 (file too large to import but abstract cited herein).
The primary reference teaches that prenyltransferases including non-natural variants thereof having at least one amino acid substitution as compared to its corresponding natural or unmodified prenyltransferases and that are capable of at least two-fold greater rate of formation of cannabinoids such as cannabigerolic acid, cannabigerovarinic acid, cannabigerorcinic acid, and cannabigerol, as compared to a wild type control. Prenyltransferase variants also demonstrated regioselectivity to desired cannabinoid isomers such as CDBA (3-GOLA), 3-GDVA, 3-GOSA, and CBG (2-GOL). The prenyltransferase variants can be used to form prenylated aromatic compounds, and can be expressed in an engineered microbe having a pathway to such compounds, which include 3-GOLA, 3-GDVA, 3-GOSA, and CBG. 3-GOLA can be used for the preparation of cannabigerol (CBG), which can be used in therapeutic compositions (see abstract and the entire document). The sequence of SEQ ID NO:2 is not expressly taught by the reference however is known in the art. WO2019183152 is one such reference (see the below alignment) and they teach substitution mutations in the sequence. The secondary reference also teaches the biosynthesis of cannabinoids and related prenylated phenolic compounds using recombinant enzymes. In particular, the disclosure provides recombinant mutant ORF2 enzymes engineered to produce a greater amount of a desired product, or to have a greater ability to catalyze a reaction using a desired substrate, as compared to WT ORF2. The disclosure also provides methods of preparing such ORF2 mutant enzymes; as well as methods of use thereof in improving the biosynthesis of cannabinoids and related prenylated phenolic compounds (see abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed invention as a whole because the combined teaching of the references renders the claimed invention as obvious. One of ordinary skill in the art would be motivated to combine the teaching of the references because they are analogous art. Moreover, the Supreme Court pointed out in KSR, “a patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 127 S. Ct. at 1741. The Court thus reasoned that the analysis under 35 U.S.C. 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the “inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 1741. The Court further advised that “[a] person of ordinary skill is…a person of ordinary creativity, not an automation.” Id. at 1742. Therefore, the claimed invention was obvious to make and use at the time the invention was made and was prima facie obvious.
RESULT 8
BGU00550
(NOTE: this sequence has 4 duplicates in the database searched.
See complete list at the end of this report)
ID BGU00550 standard; protein; 307 AA.
XX
AC BGU00550;
XX
DT 14-NOV-2019 (first entry)
XX
DE Streptomyces sp. CL190 NphB mutant A232S, SEQ 254.
XX
KW NphB protein; ORF2 protein; cannabinoid; enzyme engineering;
KW enzyme production; mutein; prenylation; prenyltransferase; screening.
XX
OS Streptomyces sp. CL190.
OS Synthetic.
XX
CC PN WO2019183152-A1.
XX
CC PD 26-SEP-2019.
XX
CC PF 19-MAR-2019; 2019WO-US023046.
XX
PR 19-MAR-2018; 2018US-0645081P.
XX
CC PA (RENE-) RENEW BIOPHARMA INC.
XX
CC PI Mendez M, Noel J, Burkart M, Lanoiselee J, Botsch K, Saunders M;
XX
DR WPI; 2019-82328R/80.
DR N-PSDB; BGU00850.
XX
CC PT Recombinant polypeptide for producing a prenylation product, comprises an
CC PT amino acid sequence with identity to amino acid, where amino acid
CC PT sequence substitution does not comprise alanine substitution at amino
CC PT acid positions of 47 and 64.
XX
CC PS Example 9; SEQ ID NO 254; 374pp; English.
XX
CC The present invention relates to a novel Streptomyces sp. strain CL190
CC prenyltransferase (NphB or ORF2) recombinant polypeptide comprises an
CC amino acid sequence with 95\% identity to amino acid sequence of SEQ ID
CC NO:1 (see BGU00297), useful for producing a prenylation product. The
CC invention also provides: a nucleic acid molecule encoding the recombinant
CC polypeptide; a cell vector, construct or expression system comprising the
CC nucleic acid molecule; a cell comprising the cell vector, construct or
CC expression system; a plant comprising the cell; a method for producing a
CC prenylation product; a composition comprising a prenylation product and
CC the recombinant polypeptide; a method for screening for an ORF2 mutant;
CC and a method for preparing a prenyltransferase mutant. The recombinant
CC polypeptide is useful the biosynthesis of cannabinoids and related
CC prenylated phenolic compounds. Note: The present sequence is derived from
CC a parent sequence (see BGU00297).
XX
SQ Sequence 307 AA;
Query Match 99.8%; Score 1581; Length 307;
Best Local Similarity 99.7%;
Matches 306; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSEAADVERVYAAMEEAAGLLGVACARDKIYPLLSTFQDTLVEGGSVVVFSMASGRHSTE 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSEAADVERVYAAMEEAAGLLGVACARDKIYPLLSTFQDTLVEGGSVVVFSMASGRHSTE 60
Qy 61 LDFSISVPTSHGDPYATVVEKGLFPATGHPVDDLLADTQKHLPVSMFAIDGEVTGGFKKT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 LDFSISVPTSHGDPYATVVEKGLFPATGHPVDDLLADTQKHLPVSMFAIDGEVTGGFKKT 120
Qy 121 YAFFPTDNMPGVAELSAIPSMPPAVAENAELFARYGLDKVQMTSMDYKKRQVNLYFSELS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 YAFFPTDNMPGVAELSAIPSMPPAVAENAELFARYGLDKVQMTSMDYKKRQVNLYFSELS 180
Qy 181 AQTLEAESVLALVRELGLHVPNELGLKFCKRSFSVYPTLNWETGKIDRLCFAVISNDPTL 240
|||||||||||||||||||||||||||||||||||||||||||||||||||:||||||||
Db 181 AQTLEAESVLALVRELGLHVPNELGLKFCKRSFSVYPTLNWETGKIDRLCFSVISNDPTL 240
Qy 241 VPSSDEGDIEKFHNYATKAPYAYVGEKRTLVYGLTLSPKEEYYKLGAYYHITDVQRGLLK 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 VPSSDEGDIEKFHNYATKAPYAYVGEKRTLVYGLTLSPKEEYYKLGAYYHITDVQRGLLK 300
Qy 301 AFDSLED 307
|||||||
Db 301 AFDSLED 307
Conclusion
16. No claims are presently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOPE A ROBINSON whose telephone number is (571) 272-0957. The examiner can normally be reached 9-5pm on Monday to Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HOPE A ROBINSON/Primary Examiner, Art Unit 1652
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