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 .
Election/Restrictions
Applicant’s election without traverse of Group III, claims 21-24, 26, 27 and 29-31 and the following species: SEQ ID NO:2 for claims 1 and 6, bacterium for claims 10 and 11 and option (i) for claim 26 in the reply filed on 06/22/2026 is acknowledged.
Election of species of sequences with SEQ ID NOs is withdrawn.
Claims 1-20, 25 and 28 are cancelled by Applicant. Claims 30 and 31 are new.
Claims 21-24, 26, 27 and 29-31 are pending (claim set filed 06/22/2026) and are examined on the merits herein.
Priority
This application is 371 of PCT/US2022/081510 filed 12/14/2022. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d) based on application CN2021/137842 filed 12/14/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/04/2024 complies with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 21-24, 26, 27 and 29-31 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.
Claim 21 recites the limitation for a protein to comprise an amino acid sequence having at least 70%, 80%, 90%, 95%, 99% or 100% sequence identity to 13 alternative sequences with SEQ ID NOs and to have epimerase activity. Claim 21 is interpreted as directed to a protein wherein 30% or less of which vary from the sequences identified by SEQ ID NOs numbers and the protein has activity of epimerase.
Thus, claim 21 broadly encompasses genera of the proteins with 70% or more sequence identity to the corresponding sequences identified by SEQ ID NOs. This would represent large pools of variant amino acid sequences encoding the respective proteins which are functional. At the same time proteins can have 30% or less of sequences that can differ from the corresponding sequences identified by SEQ ID NOs. The Specification does not provide structure function correlation for the epimerase proteins and does not describe domains and/or amino acid residues essential for the function of epimerase proteins and domains and/or amino acid residues which can be modified without loss of epimerase function. Further, applicants have not shown possession of a representative number of species for the functional epimerase proteins as the specification only provides examples of the wild-type proteins with 100% identity to the corresponding SEQ ID NOs. The specification does not describe any variants of proteins with epimerase activity having less than 100% identity to the corresponding SEQ ID NOs. The prior art of Zhang (Zhang et al. J. Agric. Food Chem., 2018, 66, 5593-5603) teaches epimerase from Dorea species producing allulose (Abstract) and shows that mutation of single amino acid residues, for instance N187C I193A or C212Q, results in significant reduction of epimerase activity (p. 5596, Table 1). Thus, modification of a single amino acid residue of epimerase protein can lead to significant functional change.
Therefore, one of ordinary skill in the art would not be able to identify which protein sequences that have 70% or more identity to protein sequences identified by SEQ ID NOs encode for functional epimerase proteins. One of ordinary skill in the art would conclude based on the lack of representative number of species and the lack of describing the domains or amino acid residues of epimerase protein critical for its function, that the Applicant was not in possession of the claimed genera and that the specification fails to satisfy the requirements of written description under 35 U.S.C. 112 (a).
Therefore, claim 21 is rejected.
Claims 22-24, 26, 27 and 29-31, dependent on claim 1, do not resolve the issue mentioned above and are rejected.
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.
Claim 24 is 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.
Claim 24 recites: “an amount of metal cofactor that is less than a metal cofactor concentration needed for epimerase activity”. The specification does not define “needed for epimerase activity” metal cofactor concentration. The specification describes that in “some embodiments the baseline activity is an activity measured in the presence of a metal cofactor in a concentration range of about 0.1 to about 2 mM … In some embodiments, the epimerase retains a percentage of activity as described in this paragraph and/or herein when an amount of metal cofactor that is less than the concentration of metal cofactor present for the baseline activity is added”. (paragraph 0066). Therefore, it is not clear what concentration of metal cofactor is needed for epimerase activity and whether the “needed concentration” is the concentration for the baseline activity. It is also unclear how epimerase can have any activity if certain concentration of a metal cofactor is needed for that activity as recited in claim 24 indicating that without metal cofactor there would be no activity. The scope and boundaries of claim 24 are not certain, making claim 24 indefinite.
For examination purposes claim 24 is interpreted as requiring the metal cofactor concentration to be less than 0.1-2 mM.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
First Rejection
Claims 21-23 and 29 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated by Zhang 1 (Zhang et al. J. Agric. Food Chem., 2018, 66, 5593-5603 on record in IDS) as evidenced by GenBank CDD09088.1 (GenBank CDD09088.1, 2013 [retrieved on 08/18/2026]. Retrieved from the Internet: <https://www.ncbi.nlm.nih.gov/protein/CDD07088.1>).
Regarding claim 21, Zhang 1 teaches D-allulose 3-epimerase from Dorea sp. CAG317 and its mutagenesis to increase thermostability (Abstract). Zhang 1 uses epimerase with NCBI identification CDD07088.1 (p. 5594, left column, 4th paragraph) the sequence of which is 100% identical to instant SEQ ID NO:20 as evidenced by GenBank CDD07088.1. Zhang 1 discloses production of D-allulose from D-fructose in the reaction comprising purified epimerase in the presence of D-fructose (p. 5595, left column 3rd paragraph). Thus, Zhang 1 teaching anticipates claim 21.
Regarding claims 22 and 23, Zhang 1 teaches that production of allulose by epimerase is performed at 70°C and in phosphate buffer with pH 6.0 (p. 5595, left column 3rd paragraph) that reads on limitations of claims 22 and 23. Additionally, Zhang 1 describes that the wild-type epimerase is active at 40-80°C and has optimum temperature of 70°C (p. 5595, right column, last paragraph). Zhang 1 measured activity of epimerase at pH range of 4.5-9.0 and determined the optimal pH to be 6.0 (p. 5596, right column, last paragraph). Thus, Zhang 1 teaching anticipates claims 22 and 23.
Regarding claim 29, Zhang 1 teaches that epimerase is expressed in E. coli and purified from lysed cells (p. 5594, left column 5th and 6th paragraphs and right column, 1st paragraph). The specification defines “a cultured cell material comprising an epimerase” as a cell lysate or supernatant that includes epimerase as a component (paragraph 0052). Therefore, epimerase of Zhang teaching is comprised in cultured cell material. Thus, Zhang teaching anticipates claim 29.
Second Rejection
Claims 21-24 are rejected under 35 U.S.C. 102 (a) (1) as being anticipated Zhang 2 (Zhang et al. J. Sci. Food Agric., 2017, 97, 3420-3426) as evidenced by GenBank CDD09088.1 (GenBank CDD09088.1, 2013 [retrieved on 08/18/2026]. Retrieved from the Internet: <https://www.ncbi.nlm.nih.gov/protein/CDD07088.1>).
Regarding claim 21, Zhang 2 teaches production of D-allulose from D-glucose by E. coli cells co-expressing glucose isomerase and D-psicose 3-epimerase (Abstract). Zhang 2 uses epimerase with NCBI identification CDD07088.1 (p. 5594, left column, 4th paragraph) the sequence of which is 100% identical to instant SEQ ID NO:20 as evidenced by GenBank CDD07088.1. Zhang 2 discloses production of D-allulose by incubation of washed cells containing expressed glucose isomerase and epimerase and D-glucose (p. 3422, left column, 4th paragraph). Zhang 2 describes that glucose isomerase converts D-glucose to D-fructose and epimerase immediately isomerizes D-fructose to D-allulose (p. 3421, left column, 1st paragraph). Since fructose is present in the reaction mixture, epimerase can contact fructose. Thus, Zhang 2 teaching anticipates claim 21.
Regarding claims 22 and 23, Zhang 2 teaches that production of allulose by epimerase is performed at 65°C and in phosphate buffer with pH 6.5 (p. 3422, left column 4th paragraph) that reads on limitations of claims 22 and 23. Thus, Zhang 2 teaching anticipates claims 22 and 23.
Regarding claim 24, Zhang 1 teaches production of allulose at different concentrations of added metal cofactors. In the control reaction metal cofactors were not added, however epimerase activity of allulose production was detected (p. 3423, Table 1). Thus, Zhang 2 teaching anticipates claim 24.
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.
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 26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang 1 (Zhang et al. J. Agric. Food Chem., 2018, 66, 5593-5603 on record in IDS) as evidenced by GenBank CDD09088.1 (GenBank CDD09088.1, 2013 [retrieved on 08/18/2026]. Retrieved from the Internet: <https://www.ncbi.nlm.nih.gov/protein/CDD07088.1>) in view of Vessels (WO 2021146134 A1 on record in IDS).
The teaching of Zhang 1 has been set forth above.
Zhang 1 does not teach production of fructose by contacting a substrate comprising glucose with glucose isomerase prior to contacting with epimerase (elected species) and does not teach purification of allulose.
Regarding claims 26 and 27, Vessels teaches method of production of allulose from corn syrup. Method comprises separation of allulose, fructose, glucose and glucooligosaccharides using moving bed chromatography (paragraph 0006) and recovering of allulose at a high purity and yield. Vessels discloses that allulose is synthesized from fructose by immobilized epimerase (paragraph 0009) derived from Burkholderia multivorans (paragraph 0064) and glucose is converted to fructose by immobilized glucose isomerase (paragraph 0038). Vessels describes that chromatography process separates allulose from fructose and glucose and separates fructose from glucose. Vessels discloses that if glucose and fructose are recycled to glucose isomerase process, glucose isomerase productivity decreases due to high concentration of fructose, and it reduces the effectiveness of allulose production (paragraph 0076). To increase the productivity fructose is separated into the fructose enriched stream and recycled to epimerase reaction (paragraph 0077) while only glucose enriched stream is recycled to glucose epimerase reaction (paragraph 0076). Vessels describes that the allulose enriched stream may be subjected to further processing to obtain allulose, including evaporation and ion exchange (paragraph 0067). Vessels mentions that allulose is purified to at least 95% wt/wt of dissolved solids (paragraph 0038).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Vessels teaching and add glucose isomerase to convert glucose to fructose which can be further supplied to epimerase reaction converting fructose to allulose and apply that to Zhang 1 process of allulose production. One would have been motivated to do that since Zhang 1 teaches optimal conditions for epimerase reaction and provides mutants with improved thermostability and Vessels describes allulose production involving glucose isomerase providing fructose, substrate for epimerase, that allows to produce allulose from low cost supply (corn starch) reducing the cost of allulose production and Vessels describes addition of fructose produced in the glucose isomerase reaction to epimerase allowing to avoid inhibition of glucose isomerase by high fructose. A skilled artisan would have reasonably expected success in this combination because Zhang 1 and Vessels teach production of allulose by purified epimerase derived from bacteria.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to follow Vessels teaching and purify allulose produced based on the combination of Zhang 1 and Vessels teachings. One would have been motivated to do that since Vessels describes purification of allulose to at least 95% purity from corn syrup. A skilled artisan would have reasonably expected success in this combination because Zhang 1 and Vessels teach production of allulose by epimerase reaction. Thus, Zhang 1 and Vessels teachings render claims 26 and 27 obvious.
Claims 30 and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang 1 (Zhang et al. J. Agric. Food Chem., 2018, 66, 5593-5603 on record in IDS) as evidenced by GenBank CDD09088.1 (GenBank CDD09088.1, 2013 [retrieved on 08/18/2026]. Retrieved from the Internet: <https://www.ncbi.nlm.nih.gov/protein/CDD07088.1>) in view of Iyappan (WO 2018116266 A1 on record in IDS).
The teaching of Zhang 1 has been set forth above.
Zhang 1 does not teach soluble or immobilized epimerase comprised in a reactor and adding fructose to the reactor.
Regarding claims 30 and 31, Iyappan teaches production of allulose with mutant D-psicose-3-epimerase with increased thermostability and operational stability and providing high yield of allulose (Abstract). Iyappan describes process of production of D-allulose from D-fructose comprising steps of preparing reaction mixture with D-fructose solution and contacting D-psicose-3-epimerase mutant with the reaction mixture in a bioreactor and harvesting of D-allulose from the solution (p. 3, lines 15-18). The reaction is performed at 40-80°C and at pH 4.0-9.5 (p. 3, lines 21-23). Iyappan used D-psicose 3 epimerase derived from Agrobacterium tumefaciens (p. 6, lines 18-19). Iyappan discloses expression of mutant epimerase in bacterial system and its partial purification (p. 3, lines 7-11). Iyappan describes that the partially purified epimerase can be used as free enzymes or can be immobilized on solid matrices for effective and efficient conversion of D-fructose to D-allulose (p. 18, lines 11-12). Iyappan mentions that immobilization imparts higher temperature optima to the enzyme reaching optima at 74°C (p. 18, lines 20-21). Iyappan provides examples of comparison of allulose production by free and immobilized epimerase in a packed bed reactor to which fructose solution is added and mentions that immobilized enzyme is equally effective as compared to the free enzyme (p. 28, Example 14 and p. 31, Example 20, Figure 23).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Zhang 1 and Iyappan teachings and use epimerase of Zhang 1 teaching in industrial process of allulose production in bioreactor as taught by Iyappan with allulose in a soluble or immobilized form. One would have been motivated to do that since Zhang 1 describes mutant epimerases with increased thermostability and having activity in the same range of temperature and pH as in Iyappan teaching and Iyappan teaches production of high yield of allulose in a bioreactor, describes similar effectivity for epimerase in a soluble and immobilized form and mentions that immobilization further increases temperature optima for epimerase. A skilled artisan would have reasonably expected success in this combination because Zhang 1 and Iyappan teach production of allulose from fructose by purified epimerase derived from bacterial species. Thus, Zhang 1 and Iyappan teachings render claims 31 and 32 obvious.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIOUBOV G KOROTCHKINA whose telephone number is (571)270-0911. The examiner can normally be reached Monday-Friday: 8:00-5:30.
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/L.G.K./Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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