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. This Office Action is responsive to Applicant’s Remarks, filed December 22, 2025. The Remarks, filed December 22, 2025, contain no amendment to the claims.
Claims 11 – 36 are pending in this application and are currently examined on the merits herein.
Priority
3. This application is a continuation application of PCT/CN2024/094493, filed May 21, 2024, which claims benefit of foreign priority document CN202311499958.5, filed November 10, 2023.
A Supplemental Application Data Sheet, filed December 22, 2025, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/22/2025 was filed after the mailing date of the previous Office Action on October 21, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Rejections
5. The rejection of claims 11 – 13, 17, 22 – 26, and 35 – 36 in the previous Office Action, mailed October 21, 2025, under 35 U.S.C. 103 as being unpatentable over Marcuccio et al. in view of Liu et al. has been considered and is withdrawn in view of the argument that the combination of Marcuccio et al. and Liu et al. do not teach the limitation “amorphous”.
The rejection of claims 14 – 16, 18 – 21, and 27 – 29 in the previous Office Action, mailed October 21, 2025, under 35 U.S.C. 103 as being unpatentable over Marcuccio et al. in view of Liu et al., and further in view of Li has been considered and is withdrawn in view of the argument that the combination of Marcuccio et al. and Liu et al. do not teach the limitation “amorphous”.
The following are maintained / modified / new grounds of rejection necessitated by Applicant’s Remarks, filed December 22, 2025, wherein no claims have been amended. Previously cited references are used to establish the maintained / modified / new grounds of rejection.
Maintained / Modified / New 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 17 – 20 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. The claims recite “comprises an X-ray powder diffraction (XRPD) pattern having peaks at 10 – 30 degrees 2θ”. “comprises an XRPD pattern having peaks at 0 – 10 degrees 2θ, and 10 – 30 degrees 2θ”, and “comprises an XRPD pattern having peaks at 10 – 40 degrees 2θ”. However, the specification and drawings do not sufficiently describe or support the claimed number or identity of peaks. Upon review of the disclosure, it does not appear that there are additional peaks beyond those specifically recited in the specification, nor is there sufficient description indicating the presence of more peaks than those explicitly disclosed. In the state of the art, Stachurski (Materials, 2011, Vol. 4, Issue 9, page 1564 – 1598, Reference included with PTO-892) teaches that amorphous solids do not exhibit translational symmetry and the atomic positions within them are distributed irregularly in a random sequence. This randomness makes the structure of an amorphous solid inherently unpredictable (page 1565, para. 3). It is also known in the art that amorphous materials are exhibit variable XRPD peaks depending on the method of preparation. The presence of multiple possible amorphous forms is generally unpredictable and cannot be inferred solely from the chemical structure. Without sufficient characterization data, one skilled in the art would not recognize that the specification conveys possession of the specific amorphous form claimed. The claims utilize “comprises”, which can permit the inclusion of additional unrecited elements. The specification must still provide adequate support for the claimed invention, including any embodiments that would reasonably include additional peaks or components. Therefore, the specification fails to provide sufficient written description to support the full scope of claims 17 – 20, including any embodiments with additional peaks, as would be required to demonstrate possession of the claimed subject matter at the time of filing.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed December 22, 2025, have been fully considered and are found to be not persuasive.
Regarding the rejection, Applicant argues that a person of ordinary skill in the art would understand that amorphous materials are not characterized by sharp, narrow diffraction peaks typical of crystalline forms, but instead exhibit broad, diffuse peaks (or halos) in XRPD patterns that have identifiable maxima at particular 2θ ranges. Thus, the presence of peaks in an amorphous XRPD profile does not imply crystallinity, nor does it require the same degree of peak sharpness or precise peak count expected for crystalline materials. The examiner acknowledges that amorphous materials are typically characterized by broad halos in XRPD, this general principle does not establish that the specification provides adequate written description support for the full scope of the claimed subject matter. Claims 17 – 20 recite specific XRPD peak ranges (e.g. 10 – 30 degree 2θ) using the open-ended transitional term “comprises”, which encompasses additional, unrecited peaks. However, the specification fails to provide written description support for such broadened embodiments. While Figures 1 – 4 depict particular XRPD profiles for specific amorphous forms, the specification does not describe, characterize, or otherwise demonstrate possession of amorphous calcium salt forms of reduced NMN that include additional peaks outside the recited ranges, as would be encompassed by the “comprises” language. This deficiency is particularly significant in the context of amorphous materials, whose XRPD patterns are known to vary substantially depending on the preparation conditions, solvent choice, and drying method. Absent disclosure identifying the presence and location of additional peaks, or explaining how variations in XRPD patterns would still fall within the scope of the claimed invention, a person of ordinary skill in the art would not reasonably conclude that the inventors are in possession of the full scope of the claimed XRPD patterns at the time of filing. Thus, the use of the open-ended term “comprises” impermissibly broadens the claims beyond what is described in the specification. Applicant is suggested to amend the claims to include the corresponding figures (Figures 1 – 4) to show the possession of the claimed invention.
Claims 22 – 25 and 30 – 34 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as based on a disclosure which is not enabling. The disclosure does not enable one of ordinary skill in the art to practice the invention without specifying the solvents used in the preparation, which is/are critical or essential to the practice of the invention but not included in the claim(s). See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
The Applicant’s attention is drawn to re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider where assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention;
(2) the state of the prior art;
(3) the relative skill of those in the art;
(4) the predictability or unpredictability of the art;
(5) the breadth of the claims;
(6) the amount of direction or guidance presented;
(7) the presence or absence of working examples; and
(8) the quantity of experimentation necessary.
The nature of the invention:
The claimed invention is directed to a method for preparing an amorphous calcium salt of a reduced β-nicotinamide mononucleotide comprising providing a reduced β-nicotinamide mononucleotide in different solvents. In order to be enabled for the full scope of treatment, one skilled in the art must reasonably be able to predictably ascertain the specific solvents being used in the process.
The state of the prior art:
While methods for generating amorphous forms may be known, the state of the art is not particularly advanced with predicting how to obtain a specific amorphous form of a compound. For example, Vranić (Bosnian Journal of Basic Medical Sciences, 2004, Vol. 4, Issue 3, page 35 – 39, Reference included with PTO-892) teaches that amorphous substances may be formed both intentionally and unintentionally during normal pharmaceutical manufacturing operations (Abstract), which implies that obtaining amorphous form of a compound is still unpredictable.
The breadth of the claims:
Independent claim 22 is extremely broad, requiring a first and second solvent when preparing the amorphous calcium salt of a reduced β-nicotinamide mononucleotide. Dependent claims 23 – 25 are broad even with a list of solvents provided because there could be a number of combinations based on the recited solvents. Dependent claim 30 is extremely broad. It requires a third solvent when preparing the amorphous calcium salt of a reduced β-nicotinamide mononucleotide.
The relative skill of those in the art:
The relative skill of those in the art is high.
The amount of direction or guidance presented & The presence or absence of working examples:
Applicant’s disclosure describes five examples of preparing the NMNH calcium salt amorphous solids A, B, C, and D, wherein the specific solvents used are methanol, ethanol, acetone, and water, respectively (page 9 – 10, Examples 2 – 6). There is no example to support the use of other solvents recited in claim 25 to arrive said NMNH calcium salt amorphous solids A, B, C, and D.
As mentioned above, examples 2 – 6 disclose the preparation methods for the NMNH calcium salt amorphous solids A, B, C, and D. No other examples are provided to demonstrate the use of other solvents for arriving the claimed invention. Moreover, the examples indicate that obtaining a particular amorphous form may also depends on process parameters, such as concentration, solvent-to-solution ratio, rate of adding solvent, mixing time, isolation conditions, and drying method. The specification does not provide guidance enabling a person of ordinary skill in the art to determine which combinations of these variables will reproduce the claimed amorphous forms.
Note that lack of working examples is a critical factor to be considered, especially in a case involving unpredictable art such as preparation of different amorphous forms of drug.
The predictability or unpredictability of the art & The quantity of experimentation necessary:
As discussed above, the process to obtain amorphous form of a compound is still unpredictable. Furthermore, the specification of the present application discloses that the use of different solvents, such as methanol and ethanol, will result in different amorphous forms (page 9 – 10, Examples 2 – 6). The XRPD patterns are obtained to prove that the amorphous forms obtained from using different solvents are indeed different. Therefore, it would be difficult to predict the actual amorphous forms.
In order to translate the method for preparing the NMNH calcium salt amorphous solids A, B, C, and D in Applicant’s disclosure into an actual preparation method for the NMNH calcium salt amorphous solids A, B, C, and D, one skilled in the art would have to explore the preparation of different amorphous forms of drug using different solvents. Applicant has not demonstrated the use of other solvents in the examples. Therefore, other than proposing an initial hypothesis, the entire burden of research involved in developing the method for preparing the NMNH calcium salt amorphous solids A, B, C, and D would fall on the shoulders of the skilled artisan attempting to practice the claimed invention, presenting an undue burden of unpredictable experimentation. Claims 31 – 34 depend from claim 30, wherein claim 30 depends from claim 22. The additional limitations of claims 31 – 34 do not cure the enablement deficiency discussed above. Although claim 33 limits the “third solvent” to “the third solvent comprises water”, claim 33 still does not provide the solvents needed for the first amorphous form required in step (e). Therefore, claims 31 – 34 are not enabled for the same reasons as claims 22 – 25 and 30.
Genentech, 108 F.3d at 1366, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.” Therefore, in view of the Wands factors, as discussed above, particularly the state of art and the lack of guidance or working examples, Applicant fails to provide information sufficient to practice the claimed invention.
New 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.
Claims 11 and 35 – 36 are rejected under 35 U.S.C. 103 as being unpatentable over Garcon et al. (WO2022/263625A1) in view of Yao et al. (Pharmaceutics, 2021, Vol. 13, Issue 8, Reference included with PTO-892).
a. Regarding claims 11 and 35 – 36, Garcon et al. teach nicotinamide mononucleotide derivatives of Formula (I):
PNG
media_image1.png
100
223
media_image1.png
Greyscale
or pharmaceutically acceptable salts thereof (Abstract). In one embodiment, the nicotinamide mononucleotide derivative used is (page 32, Table 1):
PNG
media_image2.png
77
202
media_image2.png
Greyscale
or a pharmaceutically acceptable salt thereof (para. [0117]). The pharmaceutically acceptable salts include base salts, such as calcium (para. [0051 – 0052]). The compound of Formula (I) may include references to polymorphs and crystal habits (para. [0122]). The nicotinamide mononucleotide derivatives may be under the form of pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises a nicotinamide mononucleotide derivative and at least one pharmaceutically acceptable carrier (para. [0123]).
However, Garcon et al. do not teach an amorphous form.
Yao et al. teach that amorphous formulations provide a general approach to improving the solubility and bioavailability of drugs (Abstract). An amorphous drug has a higher solubility than its crystalline counterpart (page 1, para. 1).
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 modify the calcium salt of the nicotinamide mononucleotide derivative of Formula (I) in crystalline form as taught by Garcon et al. to an amorphous form of said compound in view of Yao et al. because Yao et al. teach that an amorphous formulation will provide better solubility and bioavailability compared to its crystalline form. One would have been motivated to modify the calcium salt of the nicotinamide mononucleotide derivative of Formula (I) in crystalline form as taught by Garcon et al. to an amorphous form of said compound in view of Yao et al. because of the benefits disclosed by Yao et al. regarding an amorphous formulation. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to modify the calcium salt of the nicotinamide mononucleotide derivative of Formula (I) in crystalline form as taught by Garcon et al. to an amorphous form of said compound in view of Yao et al. because Garcon et al. teach the claimed calcium salt of reduced NMN and Yao et al. provide motivation to formulate a crystalline form of claimed compound to an amorphous form for improved solubility and bioavailability.
Claims 12 – 15, 17 – 19, and 21 – 29 are rejected under 35 U.S.C. 103 as being unpatentable over Garcon et al. (WO2022/263625A1) in view of Yao et al. (Pharmaceutics, 2021, Vol. 13, Issue 8, Reference included with PTO-892) as applied to claim 11 and 35 – 36 above, and further in view of Li (Machine Translation of CN113121628A1, cited in the previous Office Action).
b. Regarding claims 12 – 15, 17 – 19, and 21 – 29, the references teach the limitations discussed above.
However, these references do not teach the preparation of the amorphous calcium salt of a reduced β-nicotinamide mononucleotide to arrive amorphous form A, B, C, and D.
Li teaches a preparation method of amorphous NMN, wherein NMN aqueous solution is mixed with a lower alcohol solvent to obtain solid, namely amorphous NMN. The preparation method provided by Li has the advantages of simple process, high yield, short production period and easiness in realization of large-scale production (Abstract). the lower alcohol may be methanol or ethanol (claim 2). In examples 3 and 6, an aqueous NMN solution mixed with aqueous sodium hydroxide solution is added to methanol and ethanol and stirred, whereby a large amount of solid is precipitated. The solution with precipitate is vacuum-filtered and vacuum-dried at 30 ⁰C to obtain the final product (page 3, lines 42 – 43; page 4, lines 5 – 6), which would necessarily result in amorphous form A and B, respectively, because the same steps are used. Li also discloses that acetone has been used in preparing amorphous form of NMN (page 2, lines 11 – 12), which would necessarily result in amorphous form C. Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
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 modify the calcium salt of the nicotinamide mononucleotide derivative of Formula (I) in crystalline form as taught by Garcon et al. to an amorphous form of said compound in view of Yao et al. and apply the amorphization method to the calcium salt of reduced NMN further in view of Li because the amorphization method of NMN is known in the art and it is obvious to apply the same amorphization method to the reduced form of NMN, which is structurally similar to NMN. One would have been motivated to modify the calcium salt of the nicotinamide mononucleotide derivative of Formula (I) in crystalline form as taught by Garcon et al. to an amorphous form of said compound in view of Yao et al. and apply the amorphization method to the calcium salt of reduced NMN further in view of Li because it is known in the art that the amorphous form of the compound has improved physiochemical properties and Li teaches the amorphization method that may be logically extended to the claimed compound. It is noted that the prior art does not expressly teach amorphous form A would result when NMN is mixed with methanol. However, the prior art exemplifies mixing NMN in methanol, which is the same exact steps as recited in the instant claim 26. This would necessarily result in amorphous form A. The prior art does not expressly teach amorphous form B would result when NMN is mixed with ethanol. However, the prior art exemplifies mixing NMN in ethanol, which is the same exact steps as recited in the instant claim 27. This would necessarily result in amorphous form B. The prior art also does not expressly teach amorphous form C would result when NMN is mixed with acetone. However, the prior art exemplifies mixing NMN in acetone, which is the same exact steps as recited in the instant claim 28. This would necessarily result in amorphous form C. It is expected that the product obtained will have the same XRPD with the same peaks. Therefore, one of the ordinary skill in the art would have had a reasonable expectation of success to modify the calcium salt of the nicotinamide mononucleotide derivative of Formula (I) in crystalline form as taught by Garcon et al. to an amorphous form of said compound in view of Yao et al. and apply the amorphization method to the calcium salt of reduced NMN further in view of Li because Garcon et al. teach the calcium salt of reduced NMN, Yao et al. provide the motivation to formulation the calcium salt of reduced NMN to an amorphous form, and Li provides the preparation of amorphous forms of NMN that may be logically extended to the claimed compound for the improved solubility and bioavailability.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed December 22, 2025, have been fully considered and are found to be not persuasive.
Regarding Marcuccio et al., Applicant argues that Marcuccio et al. do not disclose or suggest an amorphous salt, let alone an amorphous calcium salt of a reduced β-nicotinamide mononucleotide. Regarding Liu et al., Applicant argues that Liu et al. only teach a reduced form of NMN without suggesting any salt form. Regarding Li, Applicant argues that Li is not relevant because it discloses an NMN analog containing a cyclopentane substructure, rather than the tetrahydrofuran ring of NMN and NMNH, and thus cannot reasonably be relied upon to support the preparation of the claimed amorphous form. However, the arguments are not persuasive because the new rejection relies on Garcon et al. in view of Yao et al. and Li. Garcon et al. teach the claimed compound, Yao et al. provide motivation for one skilled in the art to modify the compound Garcon et al. taught to an amorphous form, and Li supports the formation of an amorphous form by disclosing the amorphization method of NMN using different solvents. The combination of references renders the claimed invention obvious. Moreover, the key teachings of Li is not related to the specific structure of the compound, but the general method of forming amorphous pharmaceutical salts using known techniques such as solvent selection and freeze drying. The teaching that different alcohol solvents can be substituted to influence the resulting solid form is not limited to the specific compound disclosed by Li and would be readily recognized by a person of ordinary skill in the art as broadly applicable to structurally related compounds, including NMN and NMNH derivatives. Furthermore, the formation of amorphous forms by in-situ freeze drying is a routine and predictable technique in pharmaceutical formulation is well within the skill of the art. Accordingly, Li is properly relied upon not for its specific compound, but as evidence that solvent selection and freeze drying are predictable variables that a person of ordinary skill in the art would consider when obtain an amorphous calcium salt of NMNH
Applicant argues that the claimed amorphous calcium salt of reduced NMN exhibits unexpected improvement in stability, reduced hygroscopicity, and higher purity compared to NMNH disodium salts and refers to experimental data in Tables 1 and 2. However, the experimental design incorporates two simultaneous variables (a) the identity of the counterion (calcium vs. sodium), and (b) the solid state form (amorphous vs. crystalline). The data presented in Example 7 compare amorphous calcium salts of NMNH to disodium NMNH salts (both crystalline and amorphous), but do not include a comparison to a crystalline NMNH calcium salt. As a result, the data demonstrate only that changing the salt form affects stability. The data do not isolate or establish that the amorphous nature of the claimed calcium slat provides any unexpected advantage over the crystalline form of the same salt, which is the critical distinction recited in the claims. Accordingly, Example 7 does not demonstrate unexpected results commensurate with the claimed invention.
Allowable Subject Matter
Claims 16 and 20 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: Claims 16 and 20 have been indicated as being allowable or as containing allowable subject matter because these claims require the recitations of “amorphous form D” and of the steps “adding the first amorphous form of the amorphous calcium salts into a third solvent to form a third mixture; and drying the third mixture to provide the second amorphous form of the amorphous calcium salt”. There is no available prior art that teaches these subject matter.
Conclusion
THIS ACTION IS MADE NON-FINAL.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOI YAN LEE whose telephone number is 571-270-0265. The examiner can normally be reached 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, SCARLETT GOON can be reached at 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