DETAILED ACTION
All objections and rejections are withdrawn unless restated below.
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 Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 4, and 6-14 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park, Metabolic engineering of Saccharomyces cerevisiae for production of isobutanol and UVabsorbing chemical shinorine, Thesis, Seoul National University, Aug. 2018.
Park, page iv, discloses:
Lastly, S. cerevisiae was used as a host for the heterologous production of
a UV-absorbing sunscreen material shinorine. By introducing heterologous
shinorine biosynthetic genes from cyanobacteria, Nostoc punctiforme and Anabaena
variabilis, into S. cerevisiae, yeast strain capable of producing shinorine was
successfully constructed. Furthermore, to increase the pool of sedoheptulose 7-
phosphate (S7P), an intermediate in pentose phosphate pathway used for shinorine
production, xylose assimilation genes, xylose reductase (XYL1), xylitol
dehydrogenase (XYL2), and xylulokinase (XYL3) were introduced to use xylose as a
carbon source. In a fed-batch fermentation, the engineered JHYS17-1 strain
produced 64.2 mg/L shinorine with highest content (14.3 mg/gDCW) ever reported
in microbes. In addition, deletion of competing pathway producing erythrose-4-
phosphate and fructose-6-phosphate from S7P, and overexpression of transcriptional
factor (Stb5) for genes involved in pentose phosphate pathway and transketolase
(Tkl1), contributed to enhancing shinorine production.
“S. cerevisiae does not naturally produce the shinorine. To produce shinorine in S. cerevisiae, heterologous shinorine biosynthetic pathway in cyanobacteria N. punctiforme consisting of DDGS (NpR5600), O-MT (NpR5599), ATP-grasp ligase (NpR5598), and D-ala-D-ala ligase (NpR5597), was introduced into wild type yeast strain,” which are mycosporine-like amino acid biosynthesis enzymes. Park, page 155.
“In JHYS13 strain, shinorine production is still low. Therefore, to further improve shinorine production, it is critical to direct the carbon flux to the pentose phosphate pathway. So, here, xylose was used as carbon sources for shinorine production. However, S. cerevisiae does not have xylose assimilation enzymes, so xylose assimilation genes in Scheffersomyces stipitis, consisting of xylose reductase (Xyl1), xylitol dehydrogenase (Xyl2), and xylulokinase (Xyl3) were introduced into S. cerevisiae.” Park, page 161. Scheffersomyces stipitis is the same organism as Pichia stipitis.” “JHYS15 and JHYS17 genomes contains one copy of XYL1, XYL2, and XYL3 resulting from qPCR analysis.” Park, page 167.
“Shinorine is produced from S7P. Therefore, to further improve shinorine production, it is critical to increase the pool of S7P in yeast. It was chosen to be deletion of transaldolase, Tal1, which is involved in the accumulation of its substrate, S7P in pentose phosphate pathway (PPP) (Fig. 7.1).” Park, page 172. “Since S7P is a substrate of transaldolase (Tal1) in the PPP, TAL1 deletion strain (JHYS19) was constructed into JHYS17 strain as parental strain by CRISPR-Cas9 system. JHYS19 strain showed severe growth defect in xylose rich-medium containing 2 g/L glucose and 18 g/L xylose (Fig. 7.11). It has been already known that TAL1-deficient strain did not grow well in the xylose medium but JHYS19 strain promoting the consumption of S7P through the introduction of the shinorine pathway was expected to consume xylose well. The problem of defection of cell growth in JHYS19 (tal1Δ) [i.e. reduction of transaldolase by deletion of a transaldolase coding gene] can be solved by increasing the glucose ratio in the medium.” Park, page 172. Figure on page 150 of Park shows that TAL1 is a transaldolase involved in conversion reaction between sedoheptulose 7-phosphate (S7P) and glyceraldehyde 3-phosphate (G3P) as part of a pentose phosphate pathway.
“Since S7P is a substrate of transaldolase (Tal1) in the PPP, TAL1 deletion strain (JHYS19) was constructed into JHYS17 strain as parental strain by CRISPR-Cas9 system.” Park, page 172.
“To increase the production of shinorine by using xylose as a carbon source, it is necessary to reinforce the pentose phosphate pathway (PPP). Therefore, I overexpressed genes related to PPP, transcriptional factor Stb5 and transketolase Tkl1.” Park, page 180. “JHYS19-4 and JHYS19-5 strain, which is JHYS19 strain harboring p414ADH-STB5 and p414GPD-TKL1, respectively, showed improved shinorine production up to 26.82 mg/L and 25.14 mg/L, respectively, compared with JHY462 indicating that overexpression of STB5 or TKL1 can contribute to shinorine production by enhancing PPP. Park, page 181. Figure on page 150 of Park shows that transketolase Tkl1 produces sedoheptulose 7-phoshate (S7P) in a pentose phosphate pathway.
The JHYS19-5 strain is a S. cerevisiae microorganism having the following features: a) a xylose assimilation enzyme; and (b) a mycosporine-like amino acid biosynthesis enzyme, wherein the xylose assimilation enzyme, mycosporine-like amino acid biosynthesis enzyme, or both are exogenous proteins, wherein the xylose assimilation enzyme comprises xylose reductase (XR) derived from Pichia stipitis, xylitol dehydrogenase (XDH) derived from Pichia stipitis, and xylulokinase (XK) derived from Pichia stipitis, and wherein the microorganism is one in which a pentose phosphate pathway is further enhanced by a reduction in a transaldolase activity involved in the conversion reaction between sedoheptulose 7-phosphate and qlyceraldehyde 3-phosphate and an increase in a transketolase activity to produce sedoheptulose 7-phosphate in a pentose phosphate pathway.
Park, page 182 (Fig 7.14) show culturing of JHYS19-5 stain in a media containing xylose producing shinorine, such culture media with JHYS19-5 stain being a composition.
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.
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.
Claim(s) 1-4 and 6-14 (all pending claims) is/are rejected under 35 U.S.C. 103 as being unpatentable over Park, Metabolic engineering of Saccharomyces cerevisiae for production of isobutanol and UVabsorbing chemical shinorine, Thesis, Seoul National University, Aug. 2018 as applied to claims 1, 4 and 6-14 above, and further in view of Xiaolin et al. (Fermentation of xylose to produce ethanol by recombinant Saccharomyces cerevisiae strain containing XYLA and XKS1, Chinese Sci. Bulletin 50, 2005, 652-57) (previously cited).
Regarding claims 2 and 3, Xiaolin, abstract, states: “Saccharomyces cerevisiae, an efficient ethanol producer, cannot utilize xylose because it lacks the ability to convert xylose to its isomer xylulose. In this study, XYLA gene encoding xylose isomerase (XI) from Thermoanaerobacter tengcongensis MB4T and XKS1 gene encoding xylulokinase (XK) from Pichia stipitis were cloned and functionally coexpressed in Saccharomyces cerevisiae EF-326 to construct a recombinant xylose-utilizing strain.”
“In xylose-fermenting yeasts, xylose is first reduced to xylitol by xylose reductase (XR) and then oxidized to xylulose by xylitol dehydrogenase (XDH). In bacteria, xylose is directly isomerized to xylulose by xylose isomerase (XI) before entering pentose phosphate pathway.” Xiaolin, page 652, left col. S. cerevisiae is unable “to utilize xylose due to the absence of XR and XDH, the first two enzymes of xylose metabolism.” Xiaolin, page 652, left col.
“Xylulokinase (XK), encoded by XKS1, is the third enzyme in the xylose metabolic pathway. It catalyses the conversion of xylulose to xylulose-5-phosphate. Significant amount of xylulose observed in xylose fermentation broth of XYLA harboring S. cerevisiae indicated that xylose assimilation was limited by the native level of XK activity in S. cerevisiae although xylose could be converted to xylulose. Owing to the low activity of endogenous xylulokinase in the yeast, it is essential to introduce an endogenous or a heterologous XKS1 to increase XK activity to an optimal level for xylose uptake rate. Xiaolin, page 652, right col.
That is, xylose is converted to xylulose by either the combined action of XR and XDH or the single action of XK. But regardless of which pathway is used for xylulose production, XK is required to produce xylulose-5-phosphate that can enter the pentose phosphate pathway. These teachings of Xiaolin are consistent with the teachings of Park, discussed above, for combined expression of XR, XDH and XK to allow for S. cerevisiae producing shinorine to utilize xylose.
Regarding claim 2, as discussed, the prior art teaches that for xylose utilization in S. cerevisiae either a combination of XR and XDH or xylose isomerase (XI) is required to be expressed to convert xylose to xylulose, wherein xylulose is then acted upon by XK. The specification also indicates that expression of only one of XR and XDH or XI is required. Regardless, it is not inventive to express both pathways for conversion of xylose to xylulose and thereby modify embodiments of Park to further express an XI and addition to XR, XDH and XK derived from P. stipitis. As taught by Xiaolin, “A major
drawback with these recombinant strains is that the Km of XR for NADPH is an order of magnitude lower than that for NADH. This leads to accumulation of xylitol and NADH in the pathway, especially under anaerobic conditions.” Xiaolin, page 652, right col. Xiaolin proposes expression of XI in addition to a heterologous XK as a partial redress to these drawbacks. As such, an ordinarily skilled artisan would have been motivated to additionally express XI in S. cerevisiae having a xylose-utilization pathway as taught by Park to minimize the production of xylitol and NADH as taught by Xiaolin.
Regarding claim 3, Xiaolin teach a specific XI from T. tengcongensis. However, Xiaolin, page 652, right col., teaches: “The XI gene (XYLA) from several bacteria, such as Actinoplanes missouriensis, Bacillus subtilis, Clostridium thermosulfurogenes, Escherichia coli and Lactobacillus pentosus had been cloned in S. cerevisiae. But the resulting recombinant strains could not grow on xylose as a sole carbon source.” Xiaolin suggests the inability of XI to provide for growth on xylose is “Owing to the low activity of endogenous xylulokinase in the yeast, it is essential to introduce an endogenous or a heterologous XKS1 to increase XK activity to an optimal level for xylose uptake rate.” Xiaolin, page 652, right col. As such Xiaolin suggests that XI from A. missouriensis would be successful in introducing xylose utilization in S. cerevisiae when combined with expression from XK from P. stipitis such that one having ordinary skill in the art at the time of filing would have recognized and been motivated to substitute the T. tengcongensis XI with other suitable XI’s including XI from A. missouriensis.
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 1-4 and 6-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, 7, 9, 10, 12, 16-19, 21-24 and 28 of copending Application No. 16/971,209 in view of Park (Metabolic engineering of Saccharomyces cerevisiae for production of isobutanol and UVabsorbing chemical shinorine, Thesis, Seoul National University, Aug. 2018) and Xiaolin et al. (Fermentation of xylose to produce ethanol by recombinant Saccharomyces cerevisiae strain containing XYLA and XKS1, Chinese Sci. Bulletin 50, 2005, 652-57).
The rejections under 35 U.S.C. 102 and 103 set forth above are incorporated herein by reference.
Copending claims recite:
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The copending claims meet the features of the instant claims being a yeast microorganism having mycosporine-like amino acid biosynthesis enzymes for producing shinorine and increased transketolase as recited in claim 6. The copending claims do not recite expression of xylose assimilation enzymes being XR, XDH, XK and XI as recited nor deletion of a transaldolase gene as recited.
Park, as discussed above, expressly teaches that it is advantageous to express heterologous XR, XDH and XK enzymes from P. stipitis to allow for the production of shinorine from xylose that is further supported by deletion of a TAL1 gene encoding transaldolase. For these reasons, an ordinarily skilled artisan at the time of filing would have been motivated to modify embodiments of the copending claims to express heterologous XR, XDH and XK enzymes from P. stipitis to allow for the advantageous production of shinorine from xylose including further deletion of a TAL1 gene wherein the host is S. cerevisiae as taught by Park. Further, as recited in claim 2, Xiaolin et al. suggest to an ordinarily skilled artisan at the time of filing to further express XI from A. missouriensis that supports the utilization of xylose as discussed above.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4 and 6-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,384,370 B2 in view of Park (Metabolic engineering of Saccharomyces cerevisiae for production of isobutanol and UVabsorbing chemical shinorine, Thesis, Seoul National University, Aug. 2018) and Xiaolin et al. (Fermentation of xylose to produce ethanol by recombinant Saccharomyces cerevisiae strain containing XYLA and XKS1, Chinese Sci. Bulletin 50, 2005, 652-57).
The rejections under 35 U.S.C. 102 and 103 set forth above are incorporated herein by reference.
The patented claims recite:
1. A microorganism for producing a mycosporine-like amino acid, wherein an activity of 3-dehydroquinate dehydratase is inactivated as compared to a corresponding non-modified microorganism and wherein the microorganism comprises a heterologous mycosporine-like amino acid biosynthesis gene comprising a 2-demethyl 4-deoxygadusol synthase gene from a Cyanobacterium.
2. The microorganism of claim 1, wherein the mycosporine-like amino acid biosynthesis gene further comprises a gene encoding at least one protein selected from the group consisting of O-methyltransferase and C—N ligase.
4. The microorganism of claim 1, wherein an activity of at least one protein selected from the group consisting of 2-dehydro-3-deoxyphosphoheptonate aldolase, phosphoenolpyruvate synthetase, transketolase I/II, and 3-dehydroquinate synthase is further enhanced as compared to a corresponding non-modified microorganism.
5. The microorganism of claim 1, wherein the microorganism is a microorganism of the genus Corynebacterium, a microorganism of the genus Escherichia, or a yeast.
7. The microorganism of claim 1, wherein the mycosporine-like amino acid is at least one selected from the group consisting of deoxygadusol, shinorine, and mycosporine-glycine.
The patented claims meet the features of the instant claims being a yeast microorganism having a mycosporine-like amino acid biosynthesis enzymes for producing shinorine and increased transketolase as recited in claim 6. The patented claims do not recite expression of xylose assimilation enzymes being XR, XDH, XK and XI as recited nor deletion of a transaldolase gene as recited.
Park, as discussed above, expressly teaches that it is advantageous to express heterologous XR, XDH and XK enzymes from P. stipitis to allow for the production of shinorine from xylose that is further supported by deletion of a TAL1 gene encoding transaldolase. For these reasons, an ordinarily skilled artisan at the time of filing would have been motivated to modify embodiments of the patented claims to express heterologous XR, XDH and XK enzymes from P. stipitis to allow for the advantageous production of shinorine from xylose including further deletion of a TAL1 gene wherein the host is S. cerevisiae as taught by Park. Further, as recited in claim 2, Xiaolin et al. suggest to an ordinarily skilled artisan at the time of filing to further express XI from A. missouriensis that supports the utilization of xylose as discussed above.
Response to arguments
Applicant argues:
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The declaration under 37 CFR 1.132 filed 06/05/2026 is insufficient to overcome the rejection of claims based upon 35 U.S.C. 102(a)(1) and 103 as set forth in the last Office action because:
The declaration sets forth:
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The referenced “true copy of the Thesis Service Confirmation issued by the Director of Seoul University Library” referenced cannot be identified in the electronic file wrapper.
The RISS International database available at https://www.riss.kr/link?id=T14953573 is a database wherein the Park Thesis can be downloaded. The entry from the RISS database retrieved on 08/25/2026 is attached as an OA appendix and indicates that the Park Thesis was downloaded once in 2018 and seven times in 2019, which are dates prior to 09-01-2021. Further, the RISS database indicates “Year of Publication” as 2018.
As such, in considering the following:
A statement unsupported by documentation that the Park Thesis was not publicly available until 09/01/2021; and
Documentary evidence that the Park thesis was available for download as early as 2018 as indicated in the RISS database,
the information from the RISS database along with the cover date of the Park thesis is more convincing regarding the availability date of the Park thesis. Further, it is noted that the declaration does not directly state personal knowledge of the declarant that the Park thesis was not available publicly prior to 09/01/2021, but only that the same is the content of a document being “Thesis Service Confirmation issued by the Director of Seoul University Library.” However, the best evidence of the content of “Thesis Service Confirmation issued by the Director of Seoul University Library” is the document itself and not the declarant’s statement regarding the contents of the document.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TODD M EPSTEIN whose telephone number is (571)272-5141. The examiner can normally be reached Mon-Fri 9:00a-5:30p.
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/TODD M EPSTEIN/Primary Examiner, Art Unit 1652
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