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 .
Claim Status
Claims 5 and 8 are cancelled.
Claims 4 , 7, and 10-11 are amended.
Claims 12-13 are new.
Claims 4,6-7,9-13 are pending.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/04/2026 has been entered.
Withdrawn Objections
The objection raised against claim 10 is withdrawn in light of claim amendment.
Edited rejections necessitated by amendment
Claim interpretation
The newly added claims 12-13 recite the term “subculturing” which appears to refer to the passaging of cells. The interpretation is drawn from Applicants recitation that state “ Subculture was performed when the cell density in the culture dish reached a confluency of about 80% to 90%”. ( See page 11-lines 17-18).
Claim Rejections - 35 USC § 103
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 4,6-7, and 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/143258, with a publication date of 08/09/2018 (cited on IDS), in view of Wagh et al ( Stem Cell Rev and Rep, 2011). It should be noted that the citations below have been made to the English equivalent application US 2019/0390173 A1 by Nojima et al.
Regarding claims 4,6-7,and 9, Nojima et al disclose a method for culturing pluripotent stem cells. The methods involves culturing the pluripotent stem cells in a culture medium containing β-nicotinamide mononucleotide (NMN), a pharmaceutically acceptable salt thereof, or a solvate thereof. Nojima et al’s method also involves adding the NMN to a culturing medium at concentrations of 0.01 to 5 mM. Nojima et al further disclose that the NMN is suitable for promoting the proliferation of pluripotent stem cells selected from the group consisting of embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells. (See claims 4-6). It is noted that the instant claims 4 and 7 have been amended to include the limitation wherein the NMN is included in the stem cells culturing medium “ so as to suppress or prevent chromosomal aneuploidy”, and not to promote stem cells proliferation as disclosed by prior art; however Applicants are reminded that "When the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent." See MPEP 2112.01 or In re Best, 195 USPQ430, 433 (CCPA 1997). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). In this case, Nojima et al use the same culturing medium for the same cells as the instant application. Therefore, the recitation that the NMN is specifically added to stem cell culturing medium to prevent chromosomal aneuploidy is considered an inherent property as it recites functional outcome. This functional outcome is considered inherent, because it flows from performing the active step of the method (i.e. culturing stem cells continuously in a medium containing NMN) which is taught by Nojima et al, and there is nothing in applicants' disclosure that indicates that this functional result is necessarily limited to a specific step that achieves the recited function. In conclusion, for the invention to be patentable, the claimed method must involves additional structural limitations that would account for such a difference (for example, the presence of additional constituents, or a narrow concentration range where this effect is seen).
Furthermore, the method of Nojima et al involves the step of continuously culturing stem cells in a medium containing NMN. However, Nojima et al do not teach the steps of culturing cells in a first medium, freezing them, and then culturing them in a second medium, with at least the first or second medium is supplemented with NMN.
Wagh et al supplement the method of Nojima et al by teaching a method that involves the steps of culturing stem cells in a first medium, freezing them, and then culturing them in a second medium. Specifically, Wagh et al teach a method for detecting the effect of cryopreservation on the cellular processes of human stem cells following thawing and subsequent culturing. The method of Wagh et al involves culturing H9 human embryonic stem cells ( H9 hESCs) in stem cell growth medium, which are subsequently mechanically dissociated and cryopreserved for three days. After that, the cells are thawed and re-cultured in stem cells growth medium. Wagh et al demonstrate that multiple passaging of hESCs followed by freeze-thaw cycles has a major impact on cellular health, leading to various physiological changes. For examples, Wagh et al show that freezing and thawing cells lead to low recovery and induce unwanted cell differentiation following thawing. ( See abstract, Figs.2-3, and “ hESCs Culturing and Freeze-Thawing” on page 507 ). Therefore, providing an ordinary skill in the art with the motivation to supplement the stem cell culturing medium before and /or after thawing with NMN to overcome the reduction in cell number induced by cryoinjury.
In other words, claims 4-9 would have been obvious to one with ordinary skill in the art at the time the invention was filed, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Nojima et al disclose a method for promoting the proliferation of pluripotent stem cells by continuously culturing the cells in a medium containing NMN, but it does not include the steps of freezing and thawing the cells. Wagh et al describe a method for detecting the effect of cryopreservation on different cellular processes by comparing changes in the cellular processes before and after freezing, and clearly demonstrate that cryopreservation negatively impact cell recovery. Thus, one with ordinary skill in the art who had reviewed Nojima et al could have come across the teachings of Wagh et al and immediately noticed the benefit of supplementing the culturing medium of stem cells before and after cryopreservation with NMN, as taught by Nojima et al, to induce stem cell proliferation in the attempt to overcome the low rate of recovery caused by cryopreservation.
There is a reasonable expectation of success when the cells of Nojima are cultured in a first medium, followed by freezing/thawing, and then cultured in a second medium that the medium before and/or after freezing is supplemented with NMN to induce cell proliferation.
Regarding claims 10-11, Nojima et al teach the continuous culturing of stem cells in a medium supplemented with NMN. But, they do not teach the steps of culturing cells in a first and second medium containing NMN. However, the choice of when to supplement the media with NMN and how long to expose the cells to NMN are routine practices in the art, and one with ordinary skill in the art can utilize routine experimentation to discover an optimum value of a result effective variable.
As per the MPEP "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05.
Regarding claims 12-13, as previously discussed in claim interpretation, the term subculturing refers to passaging cells. Following the discussion of claim 4 above, the method of Nojima et al involves the step of continuously culturing stem cells in a medium containing NMN. Nojima et al also state that “ The medium is replaced daily and the cells were passaged on day 5 and 6”. ( See [0065]). Thus the method of Nojima et al also involves a subculturing step, wherein the medium used for subculturing is also supplemented with NMN.
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 4,6-7, and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. US 11,634,690 B2, in view of Wagh et al ( Stem Cell Rev and Rep, 2011) . Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-3 of patent US 11,634,690 B2 are directed to a method for accelerating growth of a pluripotent stem cell, comprising culturing the pluripotent stem cell in a culture medium that comprises β nicotinamide mononucleotide, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the concentration of the β-nicotinamide mononucleotide in the culture medium is in a range from 0.1 to 2.0 mM, and the pluripotent stem cell is at least one cell selected from the group consisting of an embryonic stem cell and an induced pluripotent stem cell. It is noted that the culturing method of US 11,634,690 B2 is intended to promote stem cells growth rather than to improve the stability of stem cell chromosomes; however, this is presumed to be an inherent outcome because US 11,634,690 B2 uses the same culturing medium on the same cells as the instant application.
The claims of US 11,634,690 B2 do not teach the steps of culturing cells in a first medium, freezing them, and then culturing them in a second medium, with at least the first or second medium is supplemented with NMN.
The teachings of Wagh are set forth above.
Therefore, claims 4,6-7, and 9-10 would have been obvious to one with ordinary skill in the art at the time the invention was filed, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Because US 11,634,690 B2 disclose a method for promoting the proliferation of pluripotent stem cells by continuously culturing the cells in a medium containing NMN, but it does not include the steps of freezing and thawing the cells. Wagh et al describe a method for detecting the effect of cryopreservation on different cellular processes by comparing changes in the cellular processes before and after freezing, and clearly demonstrate that cryopreservation negatively impact cell recovery. Thus, one with ordinary skill in the art would be motivated to combine the teachings of 11,634,690 B2 and Wagh, and employ the freeze-thaw step, taught by Wagh, in the method of 11,634,690 B2. One would be motivated to do so to assess and compare the proliferative effect of NMN on stem cells before and after the freezing step. There is a reasonable expectation of success to culture the cells of 11,634,690 B2 in a first medium containg NMN, followed by freezing, thawing, and culturing in a second medium.
Claims 4,6-7, and 9-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4-8,10, and 12-15 of U.S. Patent No. US 11,814,652 B2, in view of Wagh et al ( Stem Cell Rev and Rep, 2011).
Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-2,4-8,10,12-15 of patent US 11,814,652 B2 are directed to method for differentiating pluripotent stem cell, comprising culturing the pluripotent stem cell in a culture medium that comprises β-nicotinamide mononucleotide, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein a concentration of the β-nicotinamide mononucleotide in the culture medium is in a range from 0.01-10 mM, and the pluripotent stem cell is at least one cell selected from the group consisting of an embryonic stem cell, an induced pluripotent stem cell, mesenchymal stem cells, hematopoietic stem cells, and skin stem cells. It is noted that the culturing method of US 11,814,652 B2 is intended to induce the differentiation of stem cells rather than to improve the stability of stem cell chromosomes; however, this is presumed to be an inherent outcome because US 11,814,652 B2 uses the same culturing medium on the same cells as the instant application.
The claims of US 11,814,652 B2 do not teach the steps of culturing cells in a first medium, freezing them, and then culturing them in a second medium, with at least the first or second medium is supplemented with NMN.
The teachings of Wagh are set forth above.
Therefore, claims 4,6-7, and 9-10 would have been obvious to one with ordinary skill in the art at the time the invention was filed, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Because US 11,814,652 B2 disclose a method for differentiating pluripotent stem cell by continuously culturing the cells in a medium containing NMN, but it does not include the steps of freezing and thawing the cells. Wagh et al describe a method for detecting the effect of cryopreservation on different cellular processes by comparing changes in the cellular processes before and after freezing, and clearly demonstrate that cryopreservation negatively impact cell recovery and induce unwanted cell differentiation following thawing. Thus, one with ordinary skill in the art would be motivated to combine the teachings of US 11,814,652 B2 and Wagh, and employ the freeze-thaw step, taught by Wagh, in the method of US 11,814,652 B2. One would be motivated to do so to assess and compare the effect of NMN on stem cells differentiation before and after the freezing step. There is a reasonable expectation of success to culture the cells of US 11,814,652 B2 in a first medium containg NMN, followed by freezing, thawing, and culturing in a second medium.
Response to Arguments
Applicant's arguments filed 03/04/2026 have been fully considered but they are not persuasive.
Applicants argue that the present inventers have discovered that chromosomal stabilization of stem cells can be achieved through the specific use of NMN before and/or after the freezing of stem cells, and that both Nojima and Wagh are silent regarding the issue of chromosomal instability associated with freezing and thawing of cells, as well as the protective effect of NMN on stem cells damage caused by freezing and thawing. In other words, Applicants argue that the method steps must be taught by the prior art for the same purpose.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because Applicants assertion that the method steps must be taught by the prior art for the same purpose is not accurate. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicants. In this case. the combined teachings of Nojima and Wagh render obvious the method steps of culturing stem cells in a first culturing medium, freezing them, and then subculturing in a second culturing medium wherein the first, the second, or both medium contain NMN to promote the proliferation of stem cells, thereby reversing the low rate of recovery caused by cryopreservation. It is argued that the instant method is carried to prevent chromosomal aneuploidy, not to promote cell proliferation. However, the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicants." (MPEP 2144, IV Rationale Different from Applicant's is Permissible). In other words, the recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
As per the MPEP “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Applicants use the same argument as before to argue the double patenting. As a results, the response to this argument will be the same as discussed above.
Conclusion
No claim is allowed.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638