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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. JP2020-080760, filed on 04/30/2020.
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.
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 8, 10, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Raghunath et al. (US 2012/0322152 A1) view of Maiese et al. (Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain, 2003) as evidenced by Nadeeshani et al. (Nicotinamide mononucleotide (NMN) as an anti-aging health product – Promises and safety concerns, 2022)
Regarding Claim 8: Raghunath teaches a method of increasing cellular proliferation using macromolecular crowding via carbohydrate-based macromolecules to promote the growth of stem cells while preserving their multipotentiality. (57) In addition, Raghunath teaches use of human mesenchymal stem cells to be used in culture. (0006) Specifically, Raghunath teaches that macromolecules when used in culture exert an excluded volume effect (EVE) which speeds up specific enzymatic steps required for collagen deposition, thus resulting in a 20-30 fold increase of collagen-specific ECM deposition. (0011) in addition, Raghunath states that when used in vitro, macromolecular crowding is a tool which can recapitulate the in vivo physiological environment and cause enhanced deposition of key ECM proteins. (0078) One specific embodiment of the invention uses polyvinylpyrrolidone as the macromolecule (0099) and figure 21 demonstrates use of polyvinylpyrrolidone at both 100 ug/mL (0.1% mg/mL) and 500 ug/mL (0.5% ug/mL), which reads on the claimed range of use of polyvinylpyrrolidone at a concentration between 0.2-0.6 mg/mL. (pg. 24, Fig. 21) As demonstrated in the figure below, use of PVP at both concentrations significantly increased cellular proliferation when compared to the control which used no macromolecules.
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Raghunath fails to teach use of ß-nicotinamide mononucleotide in the culture medium.
Maiese teaches that nicotinamide is an essential cellular nutrient for cell growth and maintenance (pg 228, Introduction), protects cells by maintaining DNA integrity and preventing acute cellular degeneration (pg 229, Nicotinamide and apoptosis), and prevents degradation of poly(ADP-ribose) polymerase which allows for DNA repair by direct inhibition of caspase-3-like activity. (Pg 230, Nicotinamide, poly(ADP-ribose) polymerase (PARP) and cellular energy) Maiese further teaches that nicotinamide acts as a broad spectrum cytoprotectant and when used in culture, resulted in increased survival of cells in culture, DNA fragmentation was decreased, and PARP cleavage decreased. (Pg 231, Concluding remarks and Table 2) While Maiese does not specify use of ß-NMN, it is known throughout the art that ß-NMN is simply the biologically active form of NMN as evidenced by Nadeeshani, who teaches that NMN exists as α and ß anomeric forms and that the ß form is the active anomer. (Pg 268, What is nicotinamide mononucleotide (NMN)?) This reads on the claimed method of the medium further comprising ß-nicotinamide mononucleotide.
Regarding claims 10 and 11: Raghunath teaches use of the media comprising polyvinylpyrrolidone for the culture of adult mesenchymal stem cells. (0006)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the culture method taught by Raghunath of use of polyvinylpyrrolidone in a medium for mesenchymal stem cells with the teachings of Maiese (use of NME) to create a culture system for stem cells comprising carboxymethyl cellulose at 0.1-0.5 mg/mL and ß-nicotinamide mononucleotide. One would have had motivation and a reasonable expectation of success at doing so based on the teachings of Maiese who teaches that NMN acts as a broad spectrum cytoprotectant by means of maintaining DNA integrity, prevents acute cellular degeneration, and allows for DNA repair.
Claims 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Raghunath et al. (US 2012/0322152 A1) in view of Maiese et al. (Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain, 2003), Keenan et al. (Recombinant Human Albumin in Cell Culture: Evaluation of Growth-Promoting Potential for NRK and SCC-9 Cells In Vitro, 1997), and Sargent (Expansion of Mesenchymal Stem Cells in Blood-free, Chemically Defined Media, 2018).
The teachings of Raghunath and Maiese are set forth above. Both fail to teach use of the claimed concentration of recombinant albumin.
Regarding Claim 9: Sargent teaches a method of culture for mesenchymal stem cells (MSC) in media comprising recombinant albumin as compared to serum-derived albumin and transferrin with FBS as a control. (Pg 2, Mesenchymal Stem Cell Culture Performance) The MSCs in culture with recombinant albumin showed equivalent or superior performance when compared to serum-derived albumin (pg 2, Mesenchymal Stem Cell Culture Performance) and it is advantageous to use recombinant albumin as opposed to serum-derived due to the chemically defined nature of recombinant albumin. Serum-derived albumin is variable from batch to batch and risks introducing biological contaminants to culture. (Pg 1, Stem Cell Media) This reads on the claimed method of culturing stem cells in a medium comprising recombinant albumin.
Sargent fails to teach use of recombinant albumin at a final concentration of 0.05-1 mg/mL.
Keenan teaches use of recombinant albumin in the culture of both NRK and SCC-9 cells at a range of between 0-11 mg/mL of rHA. (Pg 245-246, Figures 1 and 2) This reads on the claimed range of recombinant albumin being present in the medium at a final concentration of 0.05-1 mg/mL.
Regarding Claims 10 and 11: Sargent teaches a method of culturing mesenchymal stem cells in a media comprising recombinant albumin. (Pg 2, Mesenchymal Stem Cell Culture Performance)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Raghunath of use of polyvinylpyrrolidone in a stem cell culture media with the culture method taught by Sargent (use of recombinant albumin) and Keenan (the specified final concentration of rHA at 0-11 mg/mL) to incorporate rHA at 0.05-1 mg/mL in the claimed medium. One would have had motivation and a reasonable expectation of success at doing so based on the teachings of Sargent who states use of recombinant albumin for mesenchymal stem cell culture is advantageous to serum-derived albumin and Keenan who demonstrates successful culture of NRK and SCC-9 cells within the claimed range of 0.05-1 mg/mL.
Response to Arguments
Applicant's arguments filed 10/01/2025 have been fully considered but they are not persuasive.
Applicant argues that, due to submitted amendments, none of the aforementioned references (Abe, Maiese, Nadeeshani, Keenan, or Sargent) disclose or suggest use of polyvinylpyrrolidone. Examiner recognizes this as true. However, as amended, claims 8-11 now teach strictly use of polyvinylpyrrolidone as opposed to use of polyvinylpyrrolidone or carboxymethyl cellulose, as was encompassed previously in the prior art.
As necessitated by amendments, incorporation of the teachings of Raghunath (US 2012/0322152 A1) in the place of Abe fully read on claims 8-11 when combined with the teachings of Maiese, Nadeeshani, Keenan, and Sargent (as discussed above) as Raghunath teaches use of polyvinylpyrrolidone (PVP) at a concentration of either 100 ug/mL (0.1% mg/mL) and 500 ug/mL (0.5% ug/mL) and that it significantly increases cellular proliferation, reading on the claimed range of 0.2-0.6 mg/mL. (Fig 21) Raghunath further teaches use of PVP specifically for the culture of mesenchymal stem cells (0006) due to its ability to recapitulate the in vivo physiological environment and cause enhanced deposition of key ECM proteins. (0078)
Based on the above discussion, the arguments regarding claims 8-11 are unpersuasive.
Conclusion
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 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.
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/HANNA MARIE THUESON/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638