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 .
Priority
This application claims benefit of priority to Foreign Patent Application EP20183993.3 filed on 07/03/2020 and Foreign Patent Application EP20183991.7 filed on 07/03/2020. This application is also a 371 of PCT/EP2021/067816 filed on 06/29/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Amendments and Claim Status
In the reply filed 12/24/2025, Applicant amended claims 1-2, 4, 5-11, 14-15 and 29-30. Claims 13, 21 and 26-28 were previously canceled. Claims 17 and 23-24 remain withdrawn as they are not encompassed by the elections of Applicant.
Claims 1-12, 14-20, 22-25 and 29-30 are currently pending.
Claims 17 and 23-24 are withdrawn by the Examiner.
Claims 1-12, 14-16, 18-20, 22, 25 and 29-30 are currently pending and under examination.
Claim Objections
Claims 29-30 are objected to because of the following informalities: in vitro is recited without being italicized. Appropriate correction is required.
Maintained Rejections (with modification as necessitated by amendment)
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-12, 14-16, 18-20, 22, 25 and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Kumaran et al. (US 11230724 B2, With Priority to the filing date of 07/16/2019) in view of Vroom et al. (WO 2018144675 A1, 08/09/2018) (IDS Reference of 12/19/2022) and UniProt (A0A090NLV5_SHIDY, 11/26/2014), and further in view of Lehmann et al. (US 20150031868 A1, 01/29/2015).
Regarding claims 1, 7-9, 12, 22 and 29-30, Kumaran et al. disclose microbial cells and a method for producing advanced glycosylation products from lower glycosylated intermediates, wherein the microbial cell expresses one or more UDP-dependent glycosyl transferase enzymes (See entire reference, including the Abstract). Kumaran et al. more specifically disclose:
A method for producing a steviol glycoside product from steviol glycoside intermediates, comprising:
providing a bacterial cell, reading on in-vitro, expressing one or more UDP-dependent glycosyl transferase enzymes (UGT enzymes), reading on a first glycosyltransferase, intracellularly, wherein the UGT enzymes glycosylate steviol and steviol glycoside substrates, and wherein the bacterial cell comprises the following genetic modifications:
deletion, inactivation, or reduced activity or expression of UDP-sugar hydrolase and one or more UDP-galactose biosynthesis enzymes;
deletion, inactivation, or reduced activity or expression of glucose-6-phosphate isomerase; and
overexpression of phosphoglucomutase and UTP-glucose-1-phosphate uridylyltransferase, reading on a second glycosyltransferase;
incubating the bacterial cell with a stevia leaf extract or fraction thereof comprising the steviol glycoside intermediates thereby glycosylating the steviol glycoside intermediates to the steviol glycoside product by enzymatic transfer of one or more glucosyl groups from UDP-glucose, reading on a nucleoside diphosphate saccharide, cofactor, and
recovering the steviol glycoside product, reading on a glycosylated organic compound (Claim 1 of Kumaran et al.).
Further, the steviol glycoside intermediates comprise one or more of a group that includes rebaudioside A (rebA), reading on the elected organic compound having a nucleophilic group, (Claim 2 of Kumaran et al.) and wherein the steviol glycoside product comprises rebaudioside M (rebM), reading on the elected glycosylated organic compound (Claim 4 of Kumaran et al.). The bacterial cell also has a modification that increases UTP and/or UDP production and recycling, wherein the modification can be increased expression of pyrH, a UMP kinase, reading on the elected nucleoside monophosphate kinase (Claims 24-25 of Kumaran et al.).
While Kumaran et al. do not explicitly state the nucleoside monophosphate is UMP and the phosphate donor is ATP, Figure 8 of Kumaran et al. shows UMP as a compound within the cell of the invention and it is well known that all cells contain ATP, in some amount, as it is the primary energy molecule in cells. Also, since Kumaran et al. do disclose an increased expression of pyrH, a UMP kinase, which catalyzes the phosphorylation of UMP to UDP with ATP as the energy source, Kumaran et al. meet the limitation of ‘providing UMP and ATP’ as required by part (a) of instant claim 1.
As the cell provides the UMP and ATP, satisfying (a), and the cell is modified to have increased UMP kinase, the catalyst for the obtaining the nucleoside diphosphate, (b) is satisfied. The created nucleoside diphosphate is UDP. Glucose is the saccharide donor, satisfying (c), as evidenced by the presence of UDP-glucose, a nucleoside diphosphate saccharide, satisfying step (d). Incubating with the steviol intermediate, rebA, reads on (e) and obtaining the glycosylated organic compound, rebM, reads on (f).
It is noted, a ‘Leloir glycosyltransferase system’ simply refers to a catalyst system comprising at least a first glycosyltransferase and a second glycosyltransferase. For the purpose of the specification, all glycosyltransferases are preferably to be regarded as sugar nucleotide-dependent (Leloir) glycosyltransferases, i.e. enzymes which are able to catalyze the transfer of a glycosyl moiety of a phosphor-containing nucleotide sugar substrate to a nucleophilic group of an acceptor (Instant Specification, Paragraph [0019]. Thus, as the prior art discloses glycosyltransferases that catalyze the transfer of a monosaccharide from a sugar nucleotide donor to an acceptor molecule to form a glycosidic bond, the prior art reads on a ‘Leloir glycosyltransferase system.’
Kumaran et al. do not disclose wherein the saccharide donor is sucrose or wherein the nucleoside monophosphate kinase instant SEQ ID NO. 1.
However, Vroom et al. disclose a method for producing rebaudioside M, comprising providing a stevioside substrate comprising at least one stevioside and/or a mixture of steviosides and rebA, NDP, sucrose, a sucrose synthase and at least one ADP-glycosyltransferase (Claim 168 of Vroom et al.).
Additionally, UniProt discloses A0A090NLV5_SHIDY, a uridylate kinase, a species of UMP kinase, with 100% sequence identity to instant SEQ ID NO. 1. Sequence alignment provided below. It is noted UniProt indicates the function of this protein, uridylate kinase, is to catalyze the reversible phosphorylation of UMP to UDP (UniProt A0A090NLV5_SHIDY, Function Section).
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“A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties. In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).” Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used sucrose as the saccharide donor in the method of Kumaran et al. as sucrose has similar properties and utility to glucose and was used in a similar method for producing rebaudioside M as taught by Vroom et al.
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention have to have used A0A090NLV5_SHIDY, a uridylate kinase, as the kinase in the method of Kumaran et al. as it was a known and effective kinase for catalyzing the conversion of UMP to UDP as taught by UniProt.
Regarding the new limitation of claim 1 wherein the process is cell-free, Kumaran et al. do not disclose the process being cell-free.
However, Lehmann et al. disclose recombinant microorganisms comprising nucleotide sequences that encode multiple enzymes, including glycosyltransferases, that make the microorganism capable of producing one or more steviol glycosides (See entire document, Abstract), including multiple species of rebaudioside (Paragraph [0017]). Lehmann et al. further disclose a method for converting a first glycosylated diterpene into a second glycosylated diterpene, which comprises: contacting a first glycosylated diterpene with a microorganism according to the invention, a cell free extract derived from such a microorganism or an enzyme preparation derived from either thereof, to convert the first glycosylated diterpene into the second glycosylated diterpene (Paragraphs [0025] – [0027]). Rebaudioside A and M, the elected species, are both glycosylated diterpenes. Lehmann et al. go on the disclose the preparation of a cell free extract that contains the enzymes necessary to facilitate the conversion of diterpenes into glycosylated diterpenes and the use of the cell free extracts to make the glycosylated diterpenes (Paragraphs [0307] – [0322]).
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized a cell free extract derived from the cell of Kumaran et al. because Lehmann et al. disclose a similar method, a method for producing rebaudioside, from a cell free extract because it is known the cell of Kumaran et al. contains the necessary enzymes, and Lehmann et al. disclose an effective means of producing rebaudioside utilizing the enzymes produced from the cell but in an extract. Exemplary rationales that may support a conclusion of obviousness include applying a known technique to a known method ready for improvement to yield predictable results. See MPEP 2143(I)(D). It would have been obvious, and within the skill set of an ordinary artisan, to create a cell free extract containing the enzymes from the cell of Kumaran et al. because the enzymes of the cell of Kumaran et al. provide the necessary components to produce advanced glycosylation products from lower glycosylated intermediates, and Lehman et al. disclose a similar method utilizing a cell free extract with the enzymes from the cell to do the same. Thus, it would have been obvious to utilize a cell free extract in the method of Kumaran et al. as it amounts to applying a known technique to a known device ready for improvement to yield predictable results.
Regarding claim 2, Kumaran et al. do not disclose wherein the UMP and ATP are employed in a molar ratio within the range of 0.5 to 1.5.
However, UniProt shows the reaction of UMP + ATP = ADP + UDP wherein 1 UMP and 1 ATP are used to make 1 ADP and 1 UDP (Catalytic Activity).
Thus, the limitation of claim 2 appears, absent evidence to the contrary, to be intrinsic to Kumaran et al.
Regarding claim 3, as the nucleoside monophosphate is UMP, having one phosphate, and the phosphate donor is ATP, having three phosphates, the phosphate donor and nucleoside monophosphate differ in number of phosphate groups.
Regarding claim 4, as Kumaran et al. never disclose transferring the cell or reaction components to another place, absent evidence to the contrary, the method of Kumaran et al. is performed in a single reactor. Regarding the reactor being a ‘pot,’ absent a definition of a pot, a pot can be anything that contains the reactions components. Thus, the disclosure of Kumaran et al. reads on a pot.
Regarding claim 5, as UMP and ATP are already present in the cell and the saccharide donor, sucrose, is introduced, (a) and (c) are performed simultaneously.
Regarding claim 6, as discussed above regarding claims 1, 7-9, 12, 22 and 29-30, the UMP and ATP are already present in the cell, along with UMP kinase as it was disclosed the cell has enhanced expression of pyrH, a UMP kinase, fulfilling (b). The sucrose and sucrose synthase, reading on a glycosyl transferase, were introduced, to the cell, fulfilling (c) and (d). Therefore, (b), (c) and (d) are performed simultaneously.
Regarding claims 10 and 11, Applicant indicated the election of SEQ ID NO. 1 read on claims 10 and 11. Therefore, as the uridylate kinase of UniProt has 100% sequence identity to instant SEQ ID NO. 1, it meets this limitation.
Regarding claim 14, as discussed above regarding claims 1, 7-9, 12, 22 and 29-30, Vroom et al. disclose sucrose synthase.
Regarding claim 15, as discussed above regarding claims 1, 7-9, 12, 22 and 29-30, Kumaran et al. disclose one or more UDP-dependent glycosyl transferases (Claim 1 of Kumaran et al.). UDP-dependent glycosyl transferases are a species of uridine diphosphate glycosyltransferases.
Regarding claim 16, as discussed above regarding claims 1, 7-9, 12, 22 and 29-30, Kumaran et al. disclose one or more UDP-dependent glycosyl transferase enzymes . UDP-dependent glycosyl transferase enzymes are a species of nucleotide sugar-dependent glycosyltransferase.
Kumaran et al. do not explicitly disclose using a UDP-dependent glycosyl transferase enzyme in (f).
However, as Kumaran et al. do disclose one or more UDP-dependent glycosyl transferase enzymes, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized a UDP-dependent glycosyl transferase enzyme in (f) as the species is a known and effective glycosyltransferase and it was already disclosed as being used in the method.
Regarding claim 18-20, as discussed above regarding claims 1, 7-9, 12, 22 and 29-30, Kumaran et al. disclose a bacterial cell expressing one or more UDP-dependent glycosyl transferase enzymes (UGT enzymes) intracellularly, wherein the UGT enzymes glycosylate steviol and steviol glycoside substrates, and wherein the bacterial cell comprises the following genetic modifications: deletion, inactivation, or reduced activity or expression of UDP-sugar hydrolase and one or more UDP-galactose biosynthesis enzymes. Under the broadest reasonable interpretation, the disclosure of the bacterial cell with deletion of UDP-sugar hydrolase reads on an enzyme provided being produced in a genetically modified organism because one single cell is an organism.
Regarding claim 25, as disclosed regarding claims 1, 7-9, 12, 22 and 29-30, Kumaran et al. disclose a method for producing rebaudioside M, wherein rebaudioside M is produced, reading a composition comprising rebaudioside M. Additionally, as the method of Kumaran et al. can be continuous, the composition comprising rebaudioside M, absent evidence to the contrary, would comprise unreacted nucleoside monophosphate kinase and glycosyltransferase. It is noted this is a product by process claim, with the product being simply rebaudioside M and a glycosyltransferase or nucleoside monophosphate kinase.
Response to Arguments
Applicant's arguments filed 12/24/2025 have been fully considered but they are not persuasive.
Applicant argued on Page 16 that Kumaran’s method is carried out in vivo while the claimed method is in vitro as well as that Kumaran’s process cannot be modified to be in vitro or cell free.
The Examiner respectfully disagrees. It is the Examiner’s position, as set forth in the Non-Final Rejection mailed 09/29/2025, that the method of Kumaran was carried out in vitro (See above and Page 6 of the Non-Final). In vitro simply means the process is performed inside a test tube, a culture dish and etc., the disclosure of Kumaran meets this limitation.
Applicant further argued on Page 17 that Kumaran requires different steps than those defined in instant claim 1 and pointed to Figure 8 of Kumaran.
The Examiner respectfully disagrees. It is the Examiner’s position that this an overgeneralization of the teachings of Kumaran. Figure 8 of Kumaran is a general depiction of genetic modifications to increase the native E.coli flux to UDP-glucose (Column 4, Lines 60-61 of Kumaran).
The remainder of Applicant’s arguments are addressed in the modified rejection set forth above as necessitated by amendment.
Conclusion
Claims 1-12, 14-16, 18-20, 22, 25 and 29-30 are rejected.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/A.T.W./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653