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 .
Applicant’s amendment and response filed on 5/8/2026 has been received and entered into the case.
Claims 4-7, 15 and 19 have been canceled, claims 1-3 and 17-18 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 8-14 and 16 have been considered on the merits. All arguments have been considered.
Response to Amendment
The claim rejections under 35 USC 112 have been withdrawn due to the instant amendment. A new 112(b) rejection was necessitated by the instant amendment (see below).
The claim rejection under 35 USC 101 has been withdrawn due to the instant amendment.
The claim rejections under 35 USC 102 have been withdrawn due to the instant amendment.
The claim rejection under 35 USC 103 has been modified from the 103 rejection presented in the previous OA mailed on 2/10/2026 because the wherein clause newly added to claim 8 has been previously addressed under claim 15, which has been canceled in the instant amendment.
Claim Rejections - 35 USC § 103 (modified)
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.
Claim(s) 8-14 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vannini et al. (US2017/0252362 A1; IDS ref.) in view of Chernyshova et al. (supra) and Verma et al. (2017, Pediatr. Blood Cancer).
Regarding claims 8 and 14, Vannini et al. teach a method of treating a decreased blood cell level in a subject comprising administering an effective amount of a mitochondrial membrane potential reducing agent in a subject by injecting or as a food supplement (para. 86). Vannini et al. teach that the condition having a decreased blood cell level is secondary to a primary or autoimmune disorder of the hematopoietic system, for example including, but not limited, to congenital bone marrow failure syndromes, idiopathic thrombocytopenia, aplastic anemia and myelodysplastic syndromes (para. 122). Vannini et al. teach that the mitochondrial membrane potential reducing agent includes nicotinamide riboside (NR) (para. 74 and 89).
Regarding the limitation directed to the subject having undergone an intervention including HSC transplant; a bone marrow transplant; myeloablative conditioning, chemotherapy, radiotherapy or surgery (claim 8), this limitation was addressed in the previous OA as the limitation of claim 15. As discussed previously, Vannini et al. teach that the subject is a hematopoietic stem cell post-transplanted subject (para. 124), and this teaching would meet the wherein clause directed to the subject having undergone an intervention.
Regarding vitamin B12, Vannini et al. do not teach the limitation.
Chernyshova et al. teach a method of preventing and/or treating anemia by using an injectable composition comprising vitamin B12 and nicotinamide, i.e. NAD+ precursor (see Abstract; para. 24; Table 2). Chernyshova et al. teach that the composition promotes hematopoiesis (Abstract).
It would have been obvious to a person skilled in the art to use the components utilized in the composition of Chernyshova et al. including vitamin B12 for the purpose of preventing and/or treating a decreased blood cell level taught by Vannini et al. for the same purpose with a reasonable expectation of success.
Regarding claim 9, Vannini et al. in view of Chernyshova et al. do not teach vitamin B12 is methylcobalamin.
However, it is well known in the art that methylcobalamin is used for vitamin B12 deficiency and forms according to Verma et al. (see entire document).
It would have been obvious to a person skilled in the art to use methylcobalamin as vitamin B12 taught by Chernyshova et al. in the method of Vannini et al. with a reasonable expectation of success.
Regarding claim 11, Vannini et al. teach that the mitochondrial membrane potential reducing agent is nicotinamide riboside (para. 89).
Regarding claim 12 directed to the combination of the NAD+ precursor and vitamin B12 being in the form of a pharmaceutical or nutritional composition, Vannini et al. teach that the mitochondrial membrane potential reducing agent is pharmaceutical formulations (para. 115). As vitamin B12 taught by Chernyshova et al. is combined with nicotinamide riboside, it would have been obvious to a person skilled in the art to form a pharmaceutical formulation comprising both nicotinamide riboside and vitamin B12.
Regarding claim 13 directed to the subject having subnormal amounts of erythrocytes, leukocytes and/or platelets, Vannini et al. teach that the subject is suffering from disease or disorders associated with a decreased blood cell level resulting from a reduction or an absence of haemopoietic function or patients at risk of developing a decreased blood cell level as compared to a control blood cell level (para. 120). As the blood cell includes erythrocytes, leukocytes and/or platelets, and neutropenia or thrombocytopenia taught by Vannini et al. indicate an abnormally low number of neutrophil or platelets, respectively, the limitation is met by the teaching of Vannini et al.
Regarding claim 16, Vannini et al. teach that the mitochondrial membrane potential reducing agent, combined with at least one co-agent useful in HSC ablative chemotherapy regimens, such as G-CSF analogues (para. 119).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
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 8-14 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 8-9, 11-13 and 16 of copending Application No. 18/246744 (reference application) in view of Verma et al. (of record). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘744 application are directed to a method and composition identical to the instant claims except the claims of the ‘744 application further disclose urolithin. The claims of the ‘744 application do not disclose methylcobalamin as vitamin B12. However, it is well known in the art that methylcobalamin is vitamin B12 utilized for treating anemia according to Verma et al. Thus, it would have been obvious to a person skilled in the art to use methylcobalamin for the method of ‘744 application.
Thus, the claims of the ‘744 application in view of Verma et al. render the claims of the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments with respect to the 112(a) rejections and 102 rejections have been fully considered and are persuasive. The claim rejections have been withdrawn.
Regarding the 103 rejection based on Vannini et al. in view of Chernyshova et al. and Verma et al., applicant argued that the difference between the teaching of Vannini et al. and the instant invention is at least that the invention requires the administration of NAD+ precursor and vitamin B12, which the claim rejection has acknowledged. Applicant stated that Chernyshova et al. describe pharmaceutical compositions comprising nicotinamide and vitamin B12 and other components. Applicant alleged that there is no reasonable expectation that a combination of NAD+ precursor and vitamin B12 would be therapeutically effective in treating anemia, leukopenia and/or thrombocytopenia. The Examiner respectfully disagrees with this allegation. Vannini et al. teach that the mitochondrial membrane potential reducing agent includes nicotinamide riboside (NR) (para. 74 and 89), and the mitochondrial membrane potential reducing agent would treat a decreased blood cell level as compared to a control blood cell level in a subject (para. 86). Furthermore, Vannini et al. teach that the subject can be at risk of developing a decrease in blood cell levels include patients suffering from anemia or myelodysplastic syndromes, those undergoing chemotherapy, bone marrow transplant or radiation therapy, and those suffering from autoimmune cytopenias including but not limited to immune thrombocytopenic purpura, pure red cell
aplasia and autoimmune neutropenia (para. 39). Thus, one skilled in the art would expect that NR alone can treat the anemia, leukopenia and/or thrombopenia based on the teaching of Vannini et al. Therefore, one skilled in the art would expect that the combination of NR with vitamin B12 has the same effect of NR in treating a condition having low blood cell levels. Furthermore, Chernyshova et al. teach that the composition comprising vitamin B12 and nicotinamide, i.e. NAD+ precursor promotes hematopoiesis as discussed in the claim rejection. Thus, one skilled in the art would have reasonable expectation of success in using the combination of an NAD+ precursor and vitamin B12 for treating the condition having low blood cell levels.
Applicant alleged that there is a surprising synergistic effect of the combination of an NAD+ precursor and vitamin B12. Applicant asserted that Figure 1 left panel shows that the double combination of nicotinamide riboside (NR) and vitamin B12 (MC) significantly increased the proportion of cells in the TMRMlow gate. The data shown in Fig. 1 show that the combination of NR and MC has significant better in comparison to a single treatment, however, they are not sufficient to show unexpected results from the claimed combination for the claimed method for the reasons discussed below.
First, the improvement obtained from the combination of NR and MC appears the same as the sum of single treatment of NR and the single treatment of MC. There is no clear evidence that this is a synergistic effect. Further, the evidence necessary to overcome a prima facie case of obviousness must not only be clear and convincing, but must also be commensurate in scope with the claimed subject matter. The allegation that limited data is sufficient to establish the existence of synergism from other such ingredients is without merit. It is well recognized that synergism is a highly unpredictable result that is very dependent on the ingredients used and the amounts of each. Any combination for which synergism is not clearly established would be properly rejected, because non-obviousness would not have been established.
Second, even if the date are considered synergistic, however, the date have been produced by ex vivo treatment of BM derived HSCs, and there is no evidence that the alleged synergistic effect would be produced as in the claimed method of administering the combination of NR and MC in vivo.
Third, even if the alleged synergistic effect could be produced in vivo, however, there is no information with regard to the concentrations of each components (NR and MC) in the composition would produce the alleged synergistic effect as the concentration of NR and MC for the ex vivo culturing would not be considered effective for in vivo treatment as claimed. The data in Fig. 1 are produced 500 mM NR and 100 mM of MC in a culture medium. There is no disclosure with regard to the concentration being used in vivo and no concentration to produce the alleged synergistic effect for in vivo method. As there is no evidence that any concentrations of NR and MC would produce synergistic effect in vivo, the broad disclosure of the method in claim 8 would not be commensurate with the alleged synergistic effect even if there is synergism for in vivo application of NR and MC as claimed.
Applicant is advised to provide any evidence supporting that the alleged synergism is present in vivo treatment method as claimed. Without such evidence, it is the Examiner’s position that the combined teaching of the cited references render the claimed method obvious.
Conclusion
No claims are allowed.
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 TAEYOON KIM whose telephone number is (571)272-9041. The examiner can normally be reached 9-5 EST Monday-Friday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES SCHULTZ can be reached at 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631
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