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
Claims 1-13 are pending in the instant application. Applicant’s election without traverse of Group I, Claims 1-10 in the reply filed on 15 December 2025 is acknowledged. Claims 11-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 15 December 2025.
Claims 1-10 are being examined on the merits.
Claim Rejections - 35 USC § 112(a)
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 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
The specification, while being enabling for a method for improving bioavailability of NAD+ derivative comprising administration of the specific controlled-release nicotinamine mononucleotide (NMN) microspheres (prepared by the processes of and having the identifying features according to Example 1 ([00103-00115])) - the administering according to Examples 2 ([00116]-[00120]), 7 ([00140]-[00150]), and 13 ([00182]-[00192]), corresponding to controlled-release NMN microsphere groups 1, 2, 3, 5, 6, 9 and 10; or administration of the specific controlled-release NR microspheres of Examples 4 ([00126]-[00130]), 10 ([00161]-[00171]), and 16 ([00203]-[00213]) corresponding to controlled-release NR microsphere groups 4, 7, 8, 11, and 12; however, does not reasonably provide enablement for a method of improving bioavailability of an NAD+ derivative comprising any arrangement of any CD38 inhibitor and NAD+ derivative in a same preparation and controlling the CD38 inhibitor and NAD+ derivative to release stepwise in such a manner that the CD38 inhibitor releases first and then the NAD+ derivative releases. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112(a) (AIA ), or 35 U.S.C. 112, first paragraph (pre-AIA ), have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary (see MPEP 2164.01(a)).
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a method for improving bioavailability of an NAD+ derivative comprising arranging a CD38 inhibitor and the NAD+ derivative in a same preparation, and controlling the CD38 inhibitor and the NAD+ derivative to release in a stepwise manner such that the CD38 inhibitor releases first and then the NAD+ derivative releases. Thus, the claims imply that any composition comprising any NAD+ derivative and any CD38 inhibitor in any arranged dosage form release in a stepwise manner to improve bioavailability of the NAD+ derivative.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
Vora (US 2021/0077514 A1) discloses nutraceutical compositions comprising 15.28-66.67 w/w% nicotinamide mononucleotide (NAD+ derivative) and 23.47-81.45 w/w% resveratrol (CD38 inhibitor) that provides efficient cell absorption and can be prepared in a controlled-release dosage form such as microcapsules, microparticulates, nanoparticulates, and slowly degenerating matrices (Vora, [0024]). Neither improved bioavailability of nicotinamide mononucleotide nor stepwise release of the resveratrol and then the nicotinamide mononucleotide are disclosed.
Nandra et al. (US 2021/0008010 A1) disclose administration of compositions comprising compounds effective to increase the level of NAD+ in a subject wherein the composition comprises one or more NAD+ precursor selected from nicotinic acid, nicotinamide, nicotinamide mononucleotide, nicotinamide riboside, or a salt thereof (NAD+ derivative; [0037]) or an activator of AMP activated kinase selected from a group comprising resveratrol and quercetin (CD38 inhibitor; [0040]). The composition can be in the form of microspheres ([0047]). Neither a composition comprising both an NAD+ derivative and a CD38 inhibitor nor sequential controlled release are disclosed.
Wang (CN 112089705 A, Translation, 9 pages) discloses a nicotinamide mononucleotide microcapsule comprises a capsule core comprising nicotinamide mononucleotide (NAD+ derivative) and resveratrol (CD38 inhibitor), and capsule material (Abstract). The microcapsule slowly releases the active ingredients in the core (page 4) and allows for a slow speed of absorption (page 4) and prolong effective blood concentration time of nicotinamide mononucleotide (e.g., increase bioavailability; page 7). Stepwise release of resveratrol and then nicotinamide mononucleotide is not disclosed.
Kuang et al. (CN 114762732 A, Translation, 16 pages) disclose controlled release microspheres comprising nicotinamide adenine dinucleotide (NAD) content (NAD+ derivative) selected from nicotinic acid nucleoside, nicotinamide riboside (NR), nicotinic acid mononucleotide, nicotinamide mononucleotide (NMN), and combinations thereof; and a compound for reducing NAD consumption (CD38 inhibitor) selected from resveratrol and quercetin (page 2). Stepwise release of the CD38 inhibitor and NAD+ derivative, however, is not disclosed.
Conlon et al. (WO 2019/175587 A1) disclose compositions comprising a NAD precursor (NAD+ derivative) such as nicotinamide riboside (NR), nicotinic acid adenine dinucleotide (NaAD), nicotinamide (NAM), and nicotinamide mononucleotide (NMN; page 8, lines 19-24) and NAMPT upregulators such as apigenin, resveratrol, and quercetin (CD38 inhibitor; page 9, lines 5-15). The composition may be provided as a controlled, modified, or extended release formulation (page 15, lines 29-34). Stepwise release of the NAD precursor and NAMPT upregulator is not disclosed.
Wu et al. (RSC Advances, 2020, 8 pages) and He et al. (Crys Grow Desig, 2017, 3989-3996) disclose quercetin-nicotinamide and resveratrol-nicotinamide cocrystals (CD38 inhibitor-NAD+ derivative), respectively. While these cocrystals improve bioavailability of poorly soluble compounds such as quercetin and resveratrol, the cocrystals are homogenous (see e.g., He et al., Figure 2, page 3992) and therefore stepwise release of the CD38 inhibitor and then the NAD+ derivative is not disclosed.
Since the method for stepwise release of the CD38 inhibitor and then the NAD+ derivative to improve bioavailability of NAD+ remains largely unsolved, means for success is highly unpredictable.
(5) The relative skill of those in the art:
The relative skill of those in the art is high, with respect to compositions improving bioavailability of NAD+ and CD38 inhibitors in general. However, methods wherein there is stepwise release of the CD38 inhibitor and then the NAD+ derivative to improve bioavailability of NAD+ remained unresolved as evidenced by the lack of disclosure of stepwise release in the prior art, as discussed above, and beyond the purview of one of skill. Accordingly, one would have turned to the instant disclosure for additional direction and guidance.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided data indicating that the specific controlled-release NMN microsphere groups 1, 2, 3, 5, 6, 9 and 10 and the controlled-release NR microsphere groups 4, 7, 8, 11, and 12 not only allow for stepwise release of the CD38 inhibitor followed by the NAD+ derivative, but also that levels of NAD+ are increased relative to control groups comprising NMN or NR alone, quercetin or apigenin alone, and NMN+quercetin or NR+apigenin. However, the specification does not provide a method for producing microspheres comprising any NAD+ derivative with any CD38 inhibitors or the corresponding data regarding controlled, stepwise release and resulting increased NAD+ levels.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the prior art described above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to determine a specific combination of ingredients (NAD+ derivative, controlled release excipients, foaming agents, CD38 inhibitor, filler, disintegrant, and binder; see e.g., [00103]-[00107]) and specific steps (see e.g., [00103]-[00107]) necessary to make the stepwise controlled release microspheres which increase NAD+ bioavailability.
It is the Examiner’s position that one skilled in the art could not practice the invention commensurate in the scope of the claims without undue experimentation.
Claim Rejections - 35 USC § 112(b)
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.
Claims 2, 3, and 8-10 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.
Regarding Claims 2 and 3, the limitation “a peak of the releasing” is indefinite because it is unclear what “peak” is being referenced and intended by the claims; e.g. is it a peak measured using a particular method? The maximum of such peak? or any peak? Accordingly, one would not be apprised as to what applicant intends by the phrasing as presently claimed.
Regarding Claim 3, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 3 recites the broad recitation 0.5-4 hours and the claim also recites 0.5-2 hours and 2-4 hours, which are the narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding Claims 3 and 8-10 the phrases "optionally" and “preferably” render the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05.
Appropriate clarification is necessary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER L CAIN whose telephone number is (703)756-1318. The examiner can normally be reached M-Th 11:00am to 5:00pm EST.
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, Anand Desai can be reached at (571)272-0947. 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.
/J.L.C./Examiner, Art Unit 1655
/AARON J KOSAR/Primary Examiner, Art Unit 1655