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 .
Claim Status
Claims 1-6 are pending and examined.
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 1-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for systems for producing glycosylated CBD or THC or both comprising Picha pastoris expressing a nucleotide sequence encoding a UDP-glucosyltransferase (UGT) according to the amino acid sequence having SEQ ID NO: 8963, does not reasonably provide enablement for the systems as broadly claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
In In re Wands (8 USPQ2d 1400 (CAFC 1988)), the CAFC considered the issue of enablement in molecular biology. The CAFC summarized eight factors to be considered in a determination of "undue experimentation". These factors include: (a) the quantity of experimentation; (b) the amount of guidance presented; (c) the presence or absence of working examples; (d) the nature of the invention; (e) the state of the prior art; (f) the predictability of the prior art; (g) the breadth of the claims; and (h) the relative skill in the art. The factors are analyzed in turn for the instant case as follows:
Here, the claims are broadly drawn to systems for producing glycosylated CBD, THC or both comprising yeast cells expressing a nucleotide sequence encoding a UDP-glucosyltransferase (UGT) according to the amino acid sequence having SEQ ID NO: 8963 or a sequence having at least 95% sequence identity to SEQ ID NO: 8963.
Meanwhile, the specification teaches the identification of putative UGT enzymes with the amino acid sequence of SEQ ID NO: 8963 having a GT-B structural fold (see Example 1 and 2).
However, the specification fails to teach the critical motifs or domains that confer UGT functionality as claimed, and further fails to provide any working examples of the expression of said UGT in yeast as broadly claimed to predictably glycosylate CBD, THC, or both.
Appropriate guidance is essential because a a polynucleotide encoding a polypeptide with at least 95% identity to SEQ ID NO: 8936 would have 48 amino acid substitutions relative to SEQ ID NO: 8936 and would encompass 1948 distinct protein variants.
However, in the absence of guidance indicating where in the sequence of SEQ ID NO: 8936 such variations can be sustained, undue trial and error experimentation would be required to make the polypeptide which would retain the activity of SEQ ID NO: 8936, and lead to a functional UGT that glycosylates both CBD and THC.
This guidance is also critical in light of the state of the art, which teaches that mutational studies of plant UGTs have identified specific amino residues involved in substrate recognition with some mutations resulting in UGTs with altered substrate specificity (Hansen et al, 2009, Phytochemistry, 70:473-482; see p. 474, col. 1, ¶ 1).
Therefore, in light of the breadth of the claims, the lack of guidance and working examples and the state of the art which teaches single amino acid changes can alter functionality, the skilled practitioner would resort to systematic screening and testing to predictably practice the method as claimed which is tantamount to excessive and unduly burdensome impermissible experimentation.
Claim 1-6 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.
Instant claims 1-6 are broadly drawn to systems for producing glycosylated CBD, THC or both comprising yeast cells expressing a nucleotide sequence encoding an UGT according to the amino acid sequence having SEQ ID NO: 8963 or a sequence having at least 95% sequence identity to SEQ ID NO: 8963.
Meanwhile, the specification describes the identification of putative UGT enzymes with the amino acid sequence of SEQ ID NO: 8963 having a GT-B structural fold (see Example 1 and 2).
The written description requirement may be satisfied through sufficient description of a representative number of species by disclosing relevant and identifying characteristics such as structural or other physical and/or chemical properties, by disclosing 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 invention as claimed. See Eli Lilly,119 F.3d at 1568, 43 USPQ2d at 1406.
However, the specification fails to describe the critical motifs or domains that confer UGT functionality as claimed, and further fails to provide any working examples of the expression of said UGT in yeast as broadly claimed to predictably glycosylate CBD, THC, or both. The specification fails to describe, in fact, a representative number of species from the genus of polynucleotides encoding polypeptides with at least 95% identity to SEQ ID NO: 8936.
This description is essential because a polynucleotide encoding a polypeptide with at least 95% identity to SEQ ID NO: 8936 would have 48 amino acid substitutions relative to SEQ ID NO: 8936 and would encompass 1948 distinct protein variants.
However, in the absence of describing where in the sequence of SEQ ID NO: 8936 such variations can be sustained, the skilled practitioner would not be led to believe that Applicant possesses the genus of polypeptides as claimed that retain the activity of SEQ ID NO: 8936, and lead to a functional UGT that glycosylates both CBD and THC.
This description is also critical in light of the state of the art, which describes that mutational studies of plant UGTs have identified specific amino residues involved in substrate recognition with some mutations resulting in UGTs with altered substrate specificity (Hansen et al, p. 474, col. 1, ¶ 1).
Therefore, in light of the breadth of the claims, the failure of the specification to describe a structure function correlation for the claimed UGT, the failure of the specification to describe a representative number of species from the genus of amino acid sequences as claimed, and the state of the art which describes single amino acid changes can alter functionality, the skilled practitioner not believe Applicant posses the methods as claimed.
Conclusion
No claim is allowed.
The closest prior art is Zirpel et al (2015, Biotechol Lett, 37:1869-1875) which teaches the production of THC in Pichia pastoris expressing THCAS (e.g., see Abstract). The closest prior art is also McKernan et al (2020, bioRxiv, 1-56, doi: https://doi.org/10.1101/2020.01.03.894428), which teaches Accession no. A0A7J6GJ42 having 85% sequence identity to SEQ ID NO: 8963 of the instant invention:
Query Match 85.1%; Score 3583; Length 806;
Best Local Similarity 83.5%;
Matches 669; Conservative 67; Mismatches 63; Indels 2; Gaps 1;
Qy 5 LTRVPSLKERLDETLTAQRNEIISFLSKIASHGKGILQPHEVLSEFEAV--ADKHKLADG 62
|||| ||:|||||||:| ||||:: ||:| : ||| ||||::::||||: :: || ||
Db 6 LTRVHSLRERLDETLSAHRNEIVALLSRIEAKGKGFLQPHQIIAEFEAIPEVNRKKLLDG 65
Qy 63 PFGEVLRHTQETIVLPPWITLAVRPRPGIWEYIRVNVDALAVEELTPSQFLHVKEELVDG 122
|||||| ||| | ||||: ||||||||:|||||||| || :||| |::|| |||||||
Db 66 AFGEVLRATQEAICLPPWVALAVRPRPGVWEYIRVNVHALVIEELQVSEYLHFKEELVDG 125
Qy 123 STNGNFVLELDFEPFTASFPRPTLSKSIGNGVEFLNRHLSAKMFHDKESMRPLLDFLRMH 182
| ||||||||||||| ||||||||||||||||||||||||||:||||||| |||:|||:|
Db 126 SANGNFVLELDFEPFNASFPRPTLSKSIGNGVEFLNRHLSAKLFHDKESMHPLLEFLRVH 185
Qy 183 HYKGKTIMLNDRIQNLDSLQAVLRKAEEFLTTIPADTPYSEFDHKFQEIGLERGWGDNAE 242
|||| :|||||| ||: || |||||||:||:: :|||:||:|||||||||||||| ||
Db 186 CYKGKNMMLNDRIHNLNGLQHVLRKAEEYLTSLAPETPYAEFEHKFQEIGLERGWGDTAE 245
Qy 243 RVMDMIQLLLDLLEAPDSCTLEKFLGRIPMVFNVVILTPHGYFAQANVLGYPDTGGQVVY 302
||::||||||||||||| |||||||||||||||||||:||||||| ||||||||||||||
Db 246 RVLEMIQLLLDLLEAPDPCTLEKFLGRIPMVFNVVILSPHGYFAQDNVLGYPDTGGQVVY 305
Qy 303 ILDQVRALEHEMLLRIKQQGLDIIPRILIVSRLLPDAVGTTCGQRLEKVFGTEHSHILRV 362
|||||||||:||||||||||||| |||||::||||||||||||||||||: |||:|||||
Db 306 ILDQVRALENEMLLRIKQQGLDIKPRILIITRLLPDAVGTTCGQRLEKVYDTEHTHILRV 365
Qy 363 PFRTEKGIVRRWISRFEVWPYLETYTEDVANEIAGELQAKPDLIIGNYSDGNIVASLLAH 422
||| |||:||:|||||||||||||||||||:|:| ||| |||||||||||||||||||||
Db 366 PFRDEKGMVRKWISRFEVWPYLETYTEDVAHELAKELQGKPDLIIGNYSDGNIVASLLAH 425
Qy 423 KLGVTQCTIAHALEKTKYPNSDIYWKSFEEKYHFSCQFTADLIAMNHTDFIITSTFQEIA 482
|||||||||||||||||||:|||||| ||||||||||||||||||||||||||||||||
Db 426 KLGVTQCTIAHALEKTKYPDSDIYWKKLEEKYHFSCQFTADLIAMNHTDFIITSTFQEIA 485
Qy 483 GNKDTVGQYESHMAFTLPGLYRVVHGIDVFDPKFNIVSPGADLSIYFNYTEEKKRLTALH 542
|:|||||||||| |||||||||||||||||||||||||||||:|||| ||| :|||| |
Db 486 GSKDTVGQYESHTAFTLPGLYRVVHGIDVFDPKFNIVSPGADMSIYFPYTETEKRLTYFH 545
Qy 543 PEIEELLFSETQNEEHICVLKDRKKPIIFSMARLDRVKNMTGLVEWYGKNKKLRELVNLV 602
|||||||:|: :||||||||||| |||||:|||||||||:||||||||||||||||||||
Db 546 PEIEELLYSDVENEEHICVLKDRNKPIIFTMARLDRVKNITGLVEWYGKNKKLRELVNLV 605
Qy 603 VVAGDRRKESKDTEEKEEMKKMYSLIEEYNLNGQFRWISAQMNRVRNGELYRYIADTRGA 662
|||||||||||| ||| || ||| ||| | |||||||||:|||||||||||||| ||:||
Db 606 VVAGDRRKESKDIEEKAEMAKMYGLIETYKLNGQFRWISSQMNRVRNGELYRYICDTKGA 665
Qy 663 FVQPAYYEAFGLTVVEAMTCGLPTFATCHGGPAEIIVHGKSGFHIDPYHGDKAADLLVDF 722
||||| |||||||||||||||||||||| |||||||||||||:||||||||:||: ||:|
Db 666 FVQPAVYEAFGLTVVEAMTCGLPTFATCKGGPAEIIVHGKSGYHIDPYHGDRAAETLVEF 725
Qy 723 FEKSTADPSYWENISKGGLQRIEEKYTWKIYSDRLLTLAGVYGFWKYVSNLDRREARRYL 782
||| |||:|: ||:|||||| |||||||||:||||| |||||||:||||| :|:||||
Db 726 FEKCKVDPSHWDKISEGGLQRIYEKYTWKIYSERLLTLTGVYGFWKHVSNLDHQESRRYL 785
Qy 783 EMFYALKYKKLAESVPLAIED 803
||||||||:|||||||||:::
Db 786 EMFYALKYRKLAESVPLAVDE 806
However, neither Zirpel et al nor McKernan et al reasonably teach, suggest or provide motivation to arrive at the methods as claimed using an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 8963 of the instant invention.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JASON DEVEAU-ROSEN whose telephone number is (571)272-2828. The examiner can normally be reached 7:30am - 4pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JASON DEVEAU ROSEN/Primary Examiner, Art Unit 1662
Prosecution Insights