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 .
Status of Claims
Claims 56-76 are currently pending and under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/GB2022/053385 filed on December 23, 2022 and claims priority to international applications GB2209590.5 and GB2204252.7, filed on 06/29/2022 and 03/25/2022, respectively. Acknowledgment is made of applicant' s claim for foreign priority and papers submitted under 35 U.S.C. 119 (a)-(d). The present application and all claims are being examined with an effective filing date of March 25, 2022. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 09/23/2024 and 04/01/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 112(a)
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 56-76 is 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.
It is noted that MPEP 2111.01 states that ''[d]uring examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 56 and 57 encompass a genus of methods employing, inter alia, enzymes having the amino acid sequences of SEQ ID NOS: 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, and 88, as well as genera of enzymes having amino acid sequences with at least 80% sequence identity to the respective SEQ ID NOS. Claims 58-76 depend directly or indirectly from claims 56 or 57 and therefore encompass these sequence-identity genera.
MPEP 2163 states that, to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. MPEP 2163.II.A.3 further provides that possession may be shown by actual reduction to practice, by a clear depiction of the invention, or by disclosure of sufficient relevant identifying characteristics such that one skilled in the art would recognize that the inventor had possession of the claimed invention.
With respect to a claimed genus, satisfactory disclosure of a representative number of species depends on whether one skilled in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by members of the genus in view of the species disclosed. Where a genus encompasses substantial structural variation, the disclosure must adequately reflect the structural diversity of the claimed genus through disclosure of sufficient species representative of the full variety or scope of the genus, or through establishment of a reasonable correlation between structure and function.
In the instant case, the specification provides the particular amino acid sequences recited in the claims and expressly describes enzymes having various percentages of sequence identity thereto (e.g., para [0094]-[0125]). However, merely identifying a percentage of sequence identity does not, by itself, identify which structural variations retain the particular enzymatic activities required by the claimed methods. Although the specification generally discusses conservative amino acid substitutions and states that enzymes defined by sequence identity “typically retain” the corresponding enzymatic function, the specification does not identify the residues or regions that are critical/essential to the respective catalytic activities, does not identify which positions may be substituted, inserted, or deleted while retaining such activity, and does not otherwise establish a structure-function correlation sufficient to define the members of the claimed ≥80% sequence-identity genera.
Further, the experimental disclosure does not provide a representative number of species commensurate with the breadth and structural diversity of the claimed genera. With respect to the carboxyl CoA ligases of SEQ ID NOS: 54, 56, 58, 60, 62, and 64, Example 3 evaluates six particular Q. saponaria CCL candidates. The experimental results demonstrate differences in activity among the candidates. For example, 3CCL exhibited significantly greater activity than other candidates, 1CCL, 2CCL, 3CCL, and 4CCL showed activity under certain tested conditions, while 5CCL and 6CCL did not, and the candidates further exhibited differences in substrate utilization. See paragraphs [0255]-[0259]. Thus, even among the specifically identified CCL species, related enzymes did not uniformly exhibit the same activity or substrate preference. The disclosure therefore does not establish that the much broader genus of proteins having at least 80% sequence identity to any of SEQ ID NOS: 54, 56, 58, 60, 62, or 64 possesses the required CCL activity.
Similarly, with respect to the chalcone synthase-like enzymes of SEQ ID NOS: 66, 68, 70, 72, 74, and 76, Example 4 evaluates six particular ChS candidates and demonstrates differing contributions to downstream product formation. The specification reports, for example, that omission of ChSE substantially reduced product formation and that different combinations of ChS candidates produced differing amounts of product. See paragraphs [0260]-[0266]. These results demonstrate functional variability among the disclosed candidate enzymes rather than a disclosed structural feature common to all enzymes falling within the much broader ≥80% sequence-identity genera.
With respect to KR11 and KR23’ of SEQ ID NOS: 78 and 80, the specification states that twenty genes were selected as candidate reductases and that KR11 and KR23’ were particularly strong candidates. The experimental results show that KR11 alone produced relatively small amounts of the relevant product, whereas relatively high levels of the C9 and C18 products were obtained when both reductases were present. See paragraphs [0267]-[0268]. The specification therefore provides particular functional species but does not identify structural characteristics sufficient to establish possession of the full genera of enzymes having at least 80% sequence identity to SEQ ID NO: 78 or SEQ ID NO: 80.
With respect to DMOT9 and DMOT4 of SEQ ID NOS: 82 and 84, respectively, the specification states that thirty-six acyltransferase candidates were selected for cloning and testing, from which DMOT9 and DMOT4 showed the relevant activities. The experiments further demonstrate that these two enzymes perform distinct sequential acyl-transfer reactions, with DMOT9 transferring a first acyl unit and DMOT4 ligating a second acyl unit. See paragraph [0269]. However, the specification does not identify the structural characteristics responsible for these respective activities or demonstrate that the broad genera encompassing all enzymes having at least 80% sequence identity to SEQ ID NO: 82 or SEQ ID NO: 84 retain the respective claimed transferase functions.
With respect to UGT-L-short and UGT-L-long of SEQ ID NOS: 86 and 88, the specification identifies two closely related forms of UGT-L, with the short form lacking the initial fourteen amino acids present in the long form. Both forms were shown to transfer arabinofuranose to the QS-21 acyl-chain substrate. See paragraphs [0270]-[0272]. Disclosure of these closely related forms, however, does not reflect the structural diversity encompassed by the genera of all enzymes having at least 80% sequence identity to SEQ ID NO: 86 or SEQ ID NO: 88, nor does the specification identify structural features sufficient to predict which members throughout those genera would retain the required arabinofuranosyltransferase activity.
Accordingly, while the specification identifies and experimentally characterizes particular enzyme species falling within the scope of the claims, the claimed ≥80% sequence-identity limitations encompass substantially broader genera of structurally variant proteins. The specification does not disclose a sufficient variety of species representative of the full scope of these genera and does not identify conserved or critical residues, domains, motifs, permissible sequence variations, or another reasonable structure-function correlation that would permit one skilled in the art to recognize the members of the genera as enzymes possessing the respective claimed activities. Indeed, the differing activities observed among the candidate enzymes tested in the specification further demonstrate that enzymatic function is not shown to follow merely from sequence-family membership or percentage sequence identity.
Therefore, the disclosure does not reasonably convey to one skilled in the art that the inventors were in possession of the full scope of the claimed genera of enzymes having at least 80% sequence identity to SEQ ID NOS: 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, and 88, as required by 35 U.S.C. 112(a).
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 56-60, 62-69 and 72-76 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18751380 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘380 claims anticipate and/or make obvious the instant claims.
Claim 1 of copending application ‘380 claims, inter alia:
PNG
media_image1.png
103
516
media_image1.png
Greyscale
PNG
media_image2.png
184
520
media_image2.png
Greyscale
PNG
media_image3.png
589
522
media_image3.png
Greyscale
PNG
media_image4.png
130
522
media_image4.png
Greyscale
It is noted that SEQ ID NOs: 178, 181, 187, 193, and 196 of ‘380, as recited in “J)” above, have 100% sequence identity to instant SEQ ID NOs: 58, 72, 78, 82, and 84, respectively (see application file for sequence alignments). While SEQ ID NO: 232 (i.e., QsArafT2) does not satisfy the recited sequence identity requirement for UGT-L, ‘380 identifies a QsArafT2 in “I)” set forth in SEQ ID NO: 229, having 100% sequence identity to instant SEQ ID NO: 86 (see application file for sequence alignments). It would have been obvious to a person of ordinary skill in the art to substitute the alternatively claimed QsArafT2 enzyme of SEQ ID NO: 229 for QsArafT2 of SEQ ID NO: 232, and expect predictable results (see MPEP 2144.06, “Substituting equivalents known for the same purpose”). There is a reasonable expectation of success since both are identified as QsArafT2 enzymes for the corresponding glycosylation of the C18-containing derivative.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Pertinent Art
Osbourn et al. (WO2022136563, published on 06/30/2022, effectively filed on 12/24/2020, cited in PTO-892) teaches biosynthetic production of QS-21 intermediates and, specifically, enzymatic construction of the C-28 linear tetrasaccharide of quillaic acid derivatives. Osbourn et al. teaches sequentially adding D-fucose, L-rhamnose, D-xylose, and either D-xylose or D-apiose to produce QA-FRXX or QA-FRXA derivatives and identifies the glycosyltransferases responsible for these transformations. Osbourn et al. further teaches engineering biological systems to express the enzymes required for the pathway and specifically identifies yeast as a suitable engineered host. Therefore, Osbourn et al. demonstrates that complex QS-21 intermediates could be biosynthetically assembled through sequential enzymatic transformations, but does not teach the particular enzymatic construction of the C18 acyl chain required by claims 56 and 57, including the claimed combination of carboxyl-CoA ligase, chalcone-synthase-like enzyme, keto reductase, DMOT9, DMOT4, and UGT-L enzymes.
Guzman et al. (In vitro evaluation and molecular docking of QS-21 and quillaic acid from Quillaja saponaria Molina as gastric cancer agents. Sci Rep. 2020 Jun 29;10(1):1053, cited in PTO-892) teaches QS-21 and it’s quillaic acid (QA) aglycone and describes QS-21 as an acylated 3,28-bidesmodic triterpene glycoside of QA. Guzman et al. describes the biological activity of QS-21 but does not teach the engineered biosynthetic pathway or combination of enzymes required by claims 56 and 57.
Xu et al. (Characterization of the Formation of Branched Short-Chain Fatty Acid:CoAs for Bitter Acid Biosynthesis in Hop Glandular Trichomes, Jul 2013, Molecular Plant, Vol 6, No 4, p. 1301–1317, cited in the IDS) teaches that carboxyl-CoA ligases (CCLs) activate carboxylic acids to their corresponding CoA thioesters and characterizes plant CCLs involved in specialized-metabolite biosynthesis. In particular, Xu et al. identifies HlCCL2 and HlCCL4 as CoA ligases capable of activating branched short-chain fatty acids and demonstrates their function in a reconstructed biosynthetic pathway in yeast.
Mugford et al. (Modularity of plant metabolic gene clusters: a trio of linked genes that are collectively required for acylation of triterpenes in oat. Plant Cell. 2013 Mar;25(3):1078-92, cited in the PTO-892) teaches the enzymatic acylation of triterpenoid saponins, specifically avenacins, and identifies a three-enzyme biosynthetic module involved in forming and transferring the acyl group. Mugford et al. demonstrates that coordinated enzyme modules can be used to generate acylated triterpenes and expressly discusses their potential utility for heterologous modification of triterpenes.
Li et al. (Characterization of a Group of UDP-Glycosyltransferases Involved in the Biosynthesis of Triterpenoid Saponins of Panax notoginseng. ACS Synth Biol. 2022 Feb 18;11(2):770-779, cited in PTO-892) teaches UDP-glycosyltransferase-mediated glycosylation of triterpenoid saponins, identifying six UGTs capable of catalyzing numerous glycosylation reactions. Of particular relevance, UGTPn87 accepts both UDP-glucose and UDP-xylose and catalyzes extension of sugar chains on triterpenoid saponins, demonstrating both UGT-mediated sugar-chain elaboration and sugar-donor promiscuity in saponin biosynthesis.
Conclusion
No claim is in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NAGHMEH NINA MOAZZAMI whose telephone number is (703)756-4770. The examiner can normally be reached Monday-Friday, 9:00-5:00.
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, Robert Mondesi can be reached at 408-918-7584. 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.
/NAGHMEH NINA MOAZZAMI/ Examiner, Art Unit 1652
/ROBERT B MONDESI/ Supervisory Patent Examiner, Art Unit 1652
Prosecution Insights