Prosecution Insights
Last updated: April 19, 2026
Application No. 18/377,942

RECRYSTALLIZATION METHOD FOR NMN PREPARATION

Non-Final OA §103§112
Filed
Oct 09, 2023
Examiner
LEE, HOI YAN NMN
Art Unit
1693
Tech Center
1600 — Biotechnology & Organic Chemistry
Assignee
Qingdao Restore Biotechnology Co. Ltd.
OA Round
1 (Non-Final)
44%
Grant Probability
Moderate
1-2
OA Rounds
3y 5m
To Grant
99%
With Interview

Examiner Intelligence

Grants 44% of resolved cases
44%
Career Allow Rate
29 granted / 66 resolved
-16.1% vs TC avg
Strong +76% interview lift
Without
With
+76.0%
Interview Lift
resolved cases with interview
Typical timeline
3y 5m
Avg Prosecution
84 currently pending
Career history
150
Total Applications
across all art units

Statute-Specific Performance

§101
2.8%
-37.2% vs TC avg
§103
40.2%
+0.2% vs TC avg
§102
17.4%
-22.6% vs TC avg
§112
17.4%
-22.6% vs TC avg
Black line = Tech Center average estimate • Based on career data from 66 resolved cases

Office Action

§103 §112
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. DETAILED ACTION 2. Claims 1 – 10 are pending in this application and are examined on the merits herein. Priority 3. This application is a domestic application, filed October 9, 2023, which claims benefit of foreign priority document CN202310983672.8 , field August 7, 2023. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action . 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application is pertinent only when interference arises. Information Disclosure Statement The information disclosure statement (IDS) submitted on 10/09/2023 was filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Claim Objections Claim s 3 – 4 are objected to because of the following informalities: Claims 3 – 4, line 3, “PH” should read “pH” . Appropriate correction is required. Claim Rejections - 35 USC § 112 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 appl icant regards as his invention. Claims 1 – 10 are 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. a. Claim 1 recites “chromatography…mixture; dialysis…osmosis of the solution” in step 5. The present phrase is not explicitly defined in the specification in such a way as to enable one skilled in the art to determine the metes and bounds of the claimed steps. In particular, it is unclear whether “chromatography” and “dialysis” are both required purification steps or are merely alternative techniques for carrying out the separation and purification. Therefore, claim 1 renders indefiniteness because the claim fails to clearly recite the purification step to be achieved. Claims 2 – 10 depends from claim 1 are also indefinite. For the purpose of examination, step 5 will be interpreted to encompass purification of NMN from the reacted mixture by any chromatography and/or dialysis technique capable of removing substrates and synthetase . b. Regarding claims 1 and 7 – 9, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention . See MPEP § 2173.05(d). Claims 2 – 6 and 10 are also indefinite because they depend from claim 1. For the purpose of examination, the phrase “such as “ will be interpreted as exemplary language, and therefore non-limiting under the broadest reasonable interpretation. 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: i . Determining the scope and contents of the prior art. ii. Ascertaining the differences between the prior art and the claims at issue. iii. Resolving the level of ordinary skill in the pertinent art. iv. 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. Claim s 1 – 7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Akiyama (US2020/0332332A1) in view of Fu et al. (US2018/0162895A1), Fu et al. (US10214552B2, hereinafter ‘552B2) , Suzuki (Machine Translation of WO2018047715A1) , and Livingston et al. (US11059847B2) . a. Regarding claims 1 – 7 and 9 , Akiyama teaches a method for producing nicotinamide mononucleotide (NMN) with excellent production efficiency. The method for producing NMN comprises the step of bringing a transformant with enhanced expression of enzymes nicotinamide phosphoribosyltransferase ( Nampt ) , phosphoribosyl pyrophosphate synthetase (Prs), and polyphosphate kinase ( Ppk ), a cell-free protein synthesis reaction solution having the three enzymes expressed, or a treated product thereof into contact with a mixture containing ribose-5-phosphate (R5P) , nicotinamide (NAM) , ATP, and polyphosphate or into contact with ribose , ATP, and polyphosphate to produce R5P (Abstract ; para. [0033] ). A buffer is used to suspend the transformant, wherein the buffer can by any buffer that substantially arrests the proliferation of the transformant and maintains the functions of each predetermined enzyme, for example, phosphate buffer with a pH of 7.5 (para. [0130] and [0206]). The concentration of each starting material in the reaction solvent can be adjusted to the range by adjusting the amounts of these starting materials added to the reaction solvent (para. [0154]). Akiyama teaches that the concentration of enzyme can be adjusted such that it falls within an appropriate range (para. [0100] and [0152]). The concentration of NMN synthetase, such as Nampt , is 1 μg /L to 10 g/L and the concentration of NAM is 1 μg /L to 500 g/L (para. [0153 – 0154]). Conditions , other than concentration, such as temperature and time , can also be appropriately adjusted . The reaction temperature is preferably adjusted in a range that optimizes the catalysis efficiency of each enzyme (para. [0155]). The generated NMN can be recovered from the production system and appropriately concentrated and purified according to a routine method. The recovery and purification method used can be any method that can improve the purity of NMN and can efficiently recover NMN. For example, the enzyme can be removed by filtration (para. [0156]). However, Akiyama does not explicitly teach that the mixture is stirred and the reaction temperature and pH . Akiyama does not explicitly teach that the separation and purification is chromatography. Akiyama does not teach the recited steps 7 – 12 directed to the crystallization. Akiyama does not teach that the NMN dissolving solvent is deionized water. Fu et al. teach a method for preparing NMN by biocatalysis (Abstract). Fu et al. teach a stepwise feed mode wherein the raw materials are dissolved in water, to formulate a substrate solution having a composition comprising 1 – 50 mM ATP, 1 – 100 mM ribose , 1 – 30 mM MgCl2, 1 – 20 mM KCl , and 50 – 100 mM Tris-HCl buffer, which is then adjusted to pH 6.5 – 8.5. Then the catalytic enzymes are added to the substrate solution. The system is stirred until uniform and then reacted (para. [0033]). Fu et al. further teach the preferably reaction conditions are at temperature 35 – 45 ⁰C and at pH of 7.0 – 8.0 (para. [0013]). The reaction time is between 1 – 8 hours (para. [0034]). ‘552B2 teaches a method for purifying β-nicotinamide mononucleotide comprising using reverse phase high performance liquid chromatographic column and freeze-drying (Abstract). Suzuki teaches the production process for β-nicotinamide mononucleotide crystals (Abstract). The crystal production method includes a step of precipitating NMN crystals by stirring an alcohol solution in which NMN is dissolved (page 2, lines 62 – 63). The alcohol solution may be a mixture of a plurality of types of alcohols and water, wherein the alcohol is preferably an aqueous solution of ethanol (page 3, lines 9 – 12). When the alcohol solution in which NMN is dissolved contains a solid matter that hinders crystallization, the solid matter can be removed by centrifugation, filtration , or a ceramic filter. In addition, if the alcohol solution in which NMN is dissolved contains water-soluble impurities and salts that hinder crystallization, it can be dissolved in water by passing it through a column packed with an ion exchange resin or the like. Impurities and salts can be removed (page 3, lines 3 – 6). The concentration of NMN in the solution can be concentrated by a general method, such as heat concentration method (page 3, lines 17 – 18). In another embodiment, a seed crystal may be added after the solution is overlaid and before the crystals of NMN are precipitated. The time for adding the seed crystal can be within 0 to 12 hours after the alcohol solution is overlaid (page 4, lines 14 – 18). The temperature of the aqueous solution that is added to the NMN solution is most preferably 0 to 30 ⁰C (page 4, lines 23 – 24). The precipitated crystals are separated by filtration , washed with methanol, and then dried by ventilation (page 5, line 6) . A powder X-ray diffraction of crystal is obtained to observe the characteristics of the crystal (page 4, lines 57 – 58). Livingston et al. teach the preparation of β-nicotinamide mononucleotide crystals (Abstract). In one example, Livingston et al. teach synthesis of β-nicotinamide mononucleotide crystals by crystallization from water, wherein the amorphous β-nicotinamide mononucleotide is weighed into a glass vial and deionized water is added (Col. 33, lines 45 – 46). It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method for producing NMN as taught by Akiyama with the method for preparing NMN comprising the step of stirring and the explicitly stated pH conditions in view of Fu et al. because both Akiyama and Fu et al. teach the methods for preparing NMN. It would have been obvious for one of ordinary skill in the art to do this because both methods are known separately in the prior art for the purpose of preparing NMN, and it would have been obvious to combine them for the same purpose. Although Akiyama teaches polyphosphate rather than phosphoric acid, it would have been obvious to substitute polyphosphate used in the known NMN production as taught by Akiyama with phosphoric acid because both are known phosphate-containing reagents, and Akiyama already teaches the use of such phosphate-containing components in the known NMN production system. The substitution would have been a routine optimization of a known reaction component. One of ordinary skill in the art would have had a reasonable expectation of success to combine the method for producing NMN as taught by Akiyama with the method for preparing NMN comprising the step of stirring and the explicitly stated pH conditions in view of Fu et al. because both Akiyama and Fu et al. teach methods for preparing NMN and it is well known to optimize known methods for producing the same compound by combining known process, and it is well known in the art to optimize known NMN production methods by adjusting the reaction parameters. It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method for producing NMN as taught by Akiyama and Fu et al. with the method for purifying NMN in view of ‘552B2 because each of the references is directed to NMN and addresses different aspects of NMN preparation, which are preparation and purification. ‘552B2 teaches that NMN can be purified using chromatographic technique, which is well-known to isolate molecules from reaction mixtures. Therefore, it would have been obvious to incorporate the purification method disclosed by ‘552B2 into the method of producing NMN to obtain purified NMN. One of ordinary skill in the art would have had a reasonable expectation of success to combine the method for producing NMN as taught by Akiyama and Fu et al. with the method for purifying NMN in view of ‘552B2 because it is known in the art that chromatographic technique has been used to successfully separate NMN from the reaction mixture. It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the method for preparing and purifying NMN as taught by Akiyama, Fu et al., and ‘552B2 with the method for preparing NMN crystals in view of Suzuki and Livingston et al. because each of the references is directed to NMN and addresses different aspects of NMN preparation, such as synthesis, purification, and crystallization. Crystallization is a well-known and routinely used technique for isolating and purifying molecules from solution and both Suzuki and Livingston et al. teach the crystallization of NMN. Therefore, it would have been obvious to incorporate the crystallization techniques of Suzuki and Livingston et al. into the known NMN production and purification processes to obtain crystalline NMN. Moreover, it would have been obvious to adjust the stirring speed , temperature, and pH during crystallization because these are the routine crystallization parameter s affecting crystal growth and purity. One would have been performed routine experimentation to discover the best parameters for optimal crystal characteristics. For packaging and storing, it would have been obvious to package and store the dried crystals because packaging and storing are conventional post-production handling steps performed after a crystalline product has been isolated and dried. One of ordinary skill in the art would have had a reasonable expectation of success to combine the method for preparing and purifying NMN as taught by Akiyama, Fu et al., and ‘552B2 with the method for preparing NMN crystals in view of Suzuki and Livingston et al. because crystallization is a well known and routinely used technique for isolating and purifying molecules from solution and the cited references demonstrate that NMN can be successfully prepared and crystallized under the claimed conditions. Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Akiyama (US2020/0332332A1) in view of Fu et al. (US2018/0162895A1), Fu et al. (US10214552B2, hereinafter ‘552B2), Suzuki (Machine Translation of WO2018047715A1), and Livingston et al. (US11059847B2) as applied to claim s 1 – 7 and 9 above, and further in view of Atsukawa et al. (Journal of Industrial and Engineering Chemistry, 2022, Vol. 106, page 69 – 73, Reference included with PTO-892) . b. Regarding claim 8, the references teach the limitation discussed above. However, these references do not teach the aeration crystallization method. Atsukawa et al. teach an aeration-based crystallization technique . In particular, Atsukawa et al. teach that the aeration method enhances nucleation in solution systems and aeration is promising for improving the quality distributions in crystalline materials (Abstract). Atsukawa et al. further teach that the quality of the solid phase can be improved by simply adding bubbles without drastically changing the existing crystallizer (page 69, Right Col., para. 2). It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the template crystallization method of NMN as taught by Suzuki with the aeration crystallization method in view of Atsukawa et al. because both methods are directed to crystal formation and Atsukawa et al. teach that aeration provides an effective way to improve nucleation and crystal quality. One would have been motivated to substitute the template crystallization method of NMN as taught by Suzuki with the aeration crystallization method in view of Atsukawa et al. because Atsukawa et al. teach that aeration crystallization is promising for improving the quality distributions in crystalline materials. One of ordinary skill in the art would have had a reasonable expectation of success to substitute the template crystallization method of NMN as taught by Suzuki with the aeration crystallization method in view of Atsukawa et al. because crystallization techniques are routinely selected and optimized to control nucleation and improve crystal quality under conventional crystallization conditions. Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Akiyama (US2020/0332332A1) in view of Fu et al. (US2018/0162895A1), Fu et al. (US10214552B2, hereinafter ‘552B2), Suzuki (Machine Translation of WO2018047715A1), and Livingston et al. (US11059847B2) as applied to claim s 1 – 7 and 9 above, and further in view of Srinivasakannan (Particulate Science and Technology, 2005, Vol. 23, Issue 2, page 159 – 167, Reference included with PTO-892) . c. Regarding claim 10, the references teach the limitation discussed above. However, these references do not teach the gradual cooling crystallization method. Srinivasakannan teaches that large crystals can be obtained by reducing temperature slowly in the early stages of the process and more rapidly as the temperature of the solution decreases (page 160, para. 3). It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the template crystallization method of NMN as taught by Suzuki with the gradual cooling crystallization method in view of Srinivasakannan because both methods are directed to crystal formation and Srinivasakannan teaches that large crystals can be obtained by reducing temperature slowly during crystallization. One would have been motivated to substitute the template crystallization method of NMN as taught by Suzuki with the gradual cooling crystallization method in view of Srinivasakannan because Srinivasakannan teaches that controlling the rate of temperature reduction improves crystal size, which is a desired outcome in crystallization processes. One of ordinary skill in the art would have had a reasonable expectation of success to substitute the template crystallization method of NMN as taught by Suzuki with the gradual cooling crystallization method in view of Srinivasakannan because crystallization techniques are routinely selected and optimized by adjusting temperature to control crystal growth and Srinivasakannan demonstrates that gradual cooling can effectively produce larger crystals under conventional crystallization conditions. Conclusion No claim is found to be allowable. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT HOI YAN LEE whose telephone number is FILLIN "Phone number" \* MERGEFORMAT 571-270-0265 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday - Thursday 7:30 - 17:30 . 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, FILLIN "SPE Name?" \* MERGEFORMAT SCARLETT GOON can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-270-5241 . 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. /H.Y.L./ Examiner, Art Unit 1693 /SCARLETT Y GOON/ Supervisory Patent Examiner, Art Unit 1693
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Prosecution Timeline

Oct 09, 2023
Application Filed
Mar 25, 2026
Non-Final Rejection — §103, §112 (current)

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Prosecution Projections

1-2
Expected OA Rounds
44%
Grant Probability
99%
With Interview (+76.0%)
3y 5m
Median Time to Grant
Low
PTA Risk
Based on 66 resolved cases by this examiner. Grant probability derived from career allow rate.

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