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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Status
Claims 1-9, 13, 15, and 17-19 were previously pending.
Receipt is acknowledged of the claim amendments filed 23 December, 2025. Claims 1-3, 8, 13, 15, and 17 are amended. No claims are newly added and no claims are cancelled. Therefore, claims 1-9, 13, 15, and 17-19 are currently pending.
Applicant’s election without traverse of the invention of group II (amended claims 1-9, 13, 15, and 17 in the reply filed on 01 August, 2025 was previously acknowledged. Claims 18-19 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 1-9, 13, 15, and 17 are pending and are the subject of the present Official Action.
Priority
The present application is a continuation in part of International Application No. PCT/KR2021/000276, filed 08 January, 2021, which claims priority to Republic of Korea Application No. KR10-2020-0003309, filed 09 January, 2020. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in the Republic of Korea on 09 January, 2020. It is noted, however, that applicant has not filed a certified copy of the priority application as required by 37 CFR 1.55.
Therefore, the earliest possible priority for the instant application at the present time is 08 January, 2021.
Claim Interpretation
Claim 8 is directed to the method of claim 1 wherein the composition used in the method is further defined. The recitation of “induces differentiation of adult stem cells, embryonic stem cells, and a combination thereof into insulin-producing cells” is a property of the product within the method claimed. It is noted that 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). Thus, for the purpose of applying prior art, a disclosure of an identical or substantially identical product is presumed to inherently possess the claimed properties. See MPEP 2112.01.
Withdrawn Rejections/Objections in view of Applicant’s Amendments/Arguments
Claim Objections
The objection to claims 2, and 3 for not spelling out abbreviations/acronyms upon their first encounter in the claims is withdrawn. Applicant has spelled out the abbreviations/acronyms.
Claim Rejections - 35 USC § 112
The rejection of claims 8, 13, 15 and 17 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 is withdrawn in view of Applicant’s amendments to the claims. Applicant has corrected the previously identified issues of indefiniteness.
Claim Rejections - 35 USC § 102
The rejection of claims 1, 6, 8-9, and 17 under 35 U.S.C. 102(a)(1) as being anticipated by Sun et al. Biochemical and Biophysical research communications 354.4 (2007): 919-923., hereinafter “Sun” is withdrawn in view of Applicant’s amendments to the claims. Applicant has amended claim 1 to require putrescine, glucosamine, and nicotinamide. Sun does not teach glucosamine.
Maintained Rejections in view of Applicant’s Amendments/Arguments
Claim Rejections - 35 USC § 103
Claims 1, 2-5, 7, 13, and 15 remain rejected and claims 6, 8-9, and 17 are newly rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. Biochemical and Biophysical research communications 354.4 (2007): 919-923., hereinafter “Sun” in view of Miura et al. EBioMedicine 36 (2018): 358-366., hereinafter “Miura”, of record in the IDS filed 15 July, 2022, and Jeon et al. Stem cells and development 22.22 (2013): 2975-2989., hereinafter “Jeon”. This rejection has been modified as necessitated by Applicant’s amendments to the claims.
Sun discloses a method of inducing umbilical cord blood-derived (UCB) stem cells to differentiate into islet cells by culturing the stem cells in a medium comprising DMEM/F12 supplemented with putrescine, and nicotinamide (Sun, page 920, “Materials and Methods”). The UCB stem cells are stem cells isolated from blood (Sun, page 920, “Materials and Methods”). The islet cell product produces insulin (Sun, page 922, first full paragraph).
Sun does not teach the addition of glucosamine to the culture medium.
Sun does teach that UCB stem cells are ESC-like cells and that the protocol of Sun was only slightly revised from that of a protocol developed for ESCs (Sun, page 920, first paragraph). Thus, a person having ordinary skill in the art would have understood from Sun that ESCs and UCB stem cells are at least similar enough for the application of methods for one type of cell to the other in the context of stem cell differentiation.
Jeon discloses a method of culturing embryonic stem cells in a medium comprising glucosamine (Jeon, page 2976, “mESC culture” heading, FIG. 1). Jeon teaches that the addition of glucosamine to in vitro cell culture of ESCs increases cell proliferation (Jeon, FIG. 8., page 2987, “Discussion” heading, first paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have added glucosamine as taught by Jeon to the medium of Sun for the induction of UCB stem cells into insulin-producing cells and to have arrived at the invention claimed in instant claim 1 with a reasonable expectation of success because they would have been motivated to do so to increase the proliferation of the stem cells and produce more insulin-producing cells via the combined method and they would have understood from the teachings of Sun that methods for the culture of UCB stem cells are applicable to ESCs and vice versa.
Regarding instant claim 2, Sun and Jeon do not disclose that the medium comprises a STAT3 inhibitor.
Miura discloses a cell culture medium comprising either the STAT3 inhibitor BP-1-102 or the STAT3 inhibitor cryptotanshinone (CPT) (Miura, page 359, “Cell Culture” heading). Miura teaches that the medium comprising 10μM BP-1-102 or 1μΜ CPT significantly enhanced cellular reprogramming into β cells, accompanied by an increased number of islet-like cells (Miura, Fig. 2, page 364, “Discussion” heading). Miura also teaches that β cells are insulin producing cells (Miura, page 358, first paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have included a STAT3 inhibitor as taught by Miura in the method of inducing stem cells to differentiate into insulin-producing cells of Sun and Jeon to have arrived at the invention claimed in instant claim 2 with a reasonable expectation of success because they would have been motivated to do so to significantly enhance the cellular reprogramming into insulin-producing cells, and Miura teaches the robustness of the effect of STAT3 inhibition on promoting insulin-producing cell differentiation. Thus, all of the elements of the claims were known to one of ordinary skill in the art at the time the invention was made and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art at the time of invention.
Regarding claim 3, the STAT3 inhibitors of Miura are CPT and BP-1-102.
Regarding claim 4, Sun does not disclose that the putrescine is present at a concentration of 1 to 20 mM. It is noted that, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). In this case, Sun discloses a medium comprising putrescine at a concentration of 100μΜ or 0.1mM (Sun, page 920, third full paragraph). The concentration of Sun and the instantly claimed concentration range are only one order of magnitude off, the putrescine of Sun is performing the same function as it is in the instant invention, and the level of ordinary skill in the art of stem cell culture encompasses the variation of the concentrations of various components to optimize culture protocols. Thus, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have optimized the concentration of putrescine of Sun and to have arrived at the invention claimed in instant claim 4 with a reasonable expectation of success because the concentration disclosed in Sun is similar to the range claimed and doing so would be a matter of routine optimization in the field of stem cell culture.
Regarding instant claim 5, Jeon teaches a concentration of glucosamine in culture of 2mM (Jeon, FIG. 1).
Regarding claim 6, the nicotinamide in the medium of Sun is at a concentration of 10mM (Sun, page 920, third full paragraph).
Regarding claim 7, Miura teaches that the medium comprises 10μM BP-1-102 or 1μΜ CPT.
Regarding claim 8, Sun and Jeon teach all of the limitations of instant claim 1, including the composition within the method of claim 1. Thus, the medium of Sun with glucosamine added as taught by Jeon is presumed to inherently possess the claimed properties (See claim interpretation above).
Regarding claim 9, the medium of Sun comprises DMEM/F12 (Sun, page 920, third full paragraph).
Regarding claim 13, Miura teaches that the cells are cultured at 37 degrees C and 5% CO2 (Miura, page 359, “Cell culture” heading), and Sun teaches to culture the cells for 5 to 7 days in the differentiation medium (Sun, page 922, first full paragraph).
Regarding claim 15, Sun teaches that the UCB stem cells are cultured for a period of days to weeks prior to inducing differentiation into insulin-producing cells (Sun, page 920, second paragraph). It is noted that, "where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). In this case, Sun discloses that the UCB cells were cultured for a minimum of 10 days utilizing T75 flasks prior to passaging and eventual differentiation, and a person having ordinary skill in the art of primary cell culture understands that cells may be cultured at lower volumes than in T75 flasks and that, under such situations, said cells will reach confluence sooner and be ready for passaging sooner. Thus, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have optimized the length of the culture of Sun and to have arrived at the invention claimed in instant claim 15 with a reasonable expectation of success because the culture length disclosed in Sun is similar to the range claimed and doing so would be within the level of ordinary skill in the art and a matter of routine optimization in the field of stem cell culture.
Regarding claim 17, the instant specification defines “Adult stem cells” as stem cells extracted from the umbilical cord (Specification, page 15, lines 17-19). Thus, the UCB stem cells of Sun are adult stem cells as required by instant claim 17.
Response to Arguments
Applicant argues “the present invention demonstrates that the combination of putrescine, glucosamine, and nicotinamide provide a synergistic effect for inducing differentiation into insulin-producing cells. In Example 3 of the as-filed Specification, when umbilical cord blood stem cells were treated with putrescine, glucosamine, and nicotinamide, insulin (INS) expression increased by approximately 142.5-fold compared to a control group and by at least about 14-fold compared to groups treated with glucosamine and putrescine. The expression levels of other (3- cell differentiation-related genes (MAFA, PDX1, NEUROG3) were also markedly increased in the group treated with putrescine, glucosamine, and nicotinamide compared to the other groups (Example 3, FIG. 4),” (Remarks, page 9) and “In addition, in a group in which mouse bone marrow cells were treated with putrescine, glucosamine, and nicotinamide, the expression of PDX1 (a differentiation-related gene)was markedly and synergistically increased compared to a group treated with putrescine alone, nicotinamide alone, putrescine and nicotinamide, and putrescine and glucosamine (Example 3, FIG. 5),” (Remarks, page 10) and “Sun does not mention glucosamine. That is, while Sun discloses that a composition including putrescine and nicotinamide can be used for inducing differentiation into insulin-producing cells, Sun neither discloses nor suggests the use of glucosamine for inducing differentiation into insulin-producing cells. Furthermore, Applicant submits Sun teaches that after culturing cells in a medium containing putrescine and nicotinamide for 24 hours, the medium must be replaced with high glucose DMEM. Sun discloses that without activation of a high glucose condition, no detectable insulin or C-peptide is observed… That is, according to Sun, merely culturing cells in a medium containing putrescine and nicotinamide without replacing the differentiation medium with high glucose DMEM makes it difficult to induce insulin-producing pancreatic cells.” (Remarks, page 10). These arguments have been fully considered but have not bee found persuasive for the following reasons.
At the outset, it is noted that claim 1 merely requires the production of “insulin-producing cells” and does not require any particular level of expression for MAFA, PDX1, NEUROG3, or Insulin mRNA. Moreover, claim 1 does not require umbilical cord blood stem cells. Sun teaches that the combination of putrescine and nicotinamide induces stem cells into insulin-producing cells while Jeon teaches that glucosamine increases the proliferation of stem cells in in vitro culture. Therefore, a person having ordinary skill in the art would have been motivated to add glucosamine to the culture medium of Sun to increase the proliferation of the cells and produce more insulin-producing cells. In combining the teachings of Jeon and Sun, a person having ordinary skill in the art would have understood at least that more cells equals more total RNA from an RNA extraction (which is what was performed in Example 3 (See specification, page 39, lines 5-9)) and would have expected any assay of total RNA in such a case to present the conditions which had more total cells as having higher total expression. In summary, claim 1 requires the production of insulin producing cells, Sun teaches the production of insulin producing cells, Jeon teaches the addition of glucosamine to produce more cells, and a person having ordinary skill in the art would have reasonably expected the addition of glucosamine to the medium of Sun to have produced more insulin-producing cells than either putrescine and nicotinamide in combination or glucosamine alone could produce.
Further, to the extent Applicant is relying on the examples to evidence unexpected results, it is noted that the examples on which Applicant relies require specific concentrations of putrescine, nicotinamide and glucosamine (Specification, page 38, lines 22-25), and require specific culture conditions of specific cell types (Specification, Example 1.1-1.3 and Example 3) to achieve such results. None of those specific concentrations nor conditions is claimed in instant claim 1. Applicant’s assertion that “culturing cells in a medium containing putrescine and nicotinamide without replacing the differentiation medium with high glucose DMEM makes it difficult to induce insulin-producing pancreatic cells” does not move the needle at all in this analysis as the instant claims to not specifically require the absence of a step with high-glucose DMEM, and the method of Sun in the end successfully produced insulin-producing cells. If anything, Applicant’s assertion that the production of insulin-producing cells in medium comprising just putrescine and nicotinamide is difficult provides even more motivation for a person having ordinary skill in the art to desire to improve the method of Sun by adding another component (such as glucosamine taught by Jeon) to improve the method. Accordingly, these arguments have been fully considered but have not been found persuasive.
In response to applicant's arguments against the references individually (Miura and Jeon in this case), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is acknowledged that Miura and Jeon do not individually teach a combination of putrescine, nicotinamide, and glucosamine. However, Applicant is invited to see the above 35 U.S.C. 103 rejection and response to arguments for why the combination of Sun and Jeon teaches and provides motivation for just that very combination.
Double Patenting
Claims 1-9, 13, 15, and 17 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of United States Patent No. 12527806 (reference patent). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the reference application render obvious the claims of the instant application. This rejection has been converted from a provisional rejection to a nonprovisional rejection to reflect the allowance of Application No. 17820387.
Independent claim 1 recites “A method for inducing differentiation into insulin-producing cells, the method comprising culturing isolated cells in a culture medium composition comprising: a) putrescine, glucosamine, and nicotinamide; and b) a culture medium.”
Reference patent claim 1 recites “A method for treating or alleviating diabetes mellitus, the method comprising: administering a composition comprising putrescine, glucosamine, nicotinamide, and a STAT3 inhibitor as active ingredients to a subject in need thereof.”. Claim 3 further limits claim 1 to adding a stem cell mobilizing factor that mobilizes bone marrow-derived stem cells to peripheral blood. Thus rendering obvious a culture medium comprising stem cells, in a culture medium composition comprising putrescine, glucosamine, nicotinamide, and a STAT3 inhibitor as active ingredients.
Claim 6 of copending application recites “6. (Original) The method of claim 1, wherein the composition promotes the differentiation of in vivo bone marrow-derived stem cells into insulin-producing cells.”
Note that MPEP 804(II)(2)(a) sets forth instances where it is acceptable to utilize the disclosure of a U.S. patent document in conjunction with its claims for ODP rejections.
In particular, the MPEP notes that the portion of the specification that supports the patent claims may be considered. The court in AbbVie Inc. v. Kennedy Institute of Rheumatology Trust pointed out that “this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined.” In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014). The court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
In this case, both claim 1 of the application and claim 1 of the reference patent recite essentially the same steps with the primary difference being in vitro vs. in vivo application of the composition. The reference specification teaches in vitro application of the composition in the working examples as experiment two of four in support of the in vivo application of the composition (Reference Specification, Example 2). Thus, claim 1 of the reference application renders obvious claim 1 of the instant application. Dependent claim limitations in instant claims 2-9, 13, 15, and 17 can be found throughout the reference application’s claims. Thus, the claims of the instant application are encompassed by, or overlap in scope significantly with, the claims of 12,527,806.
Response to Arguments
Applicant argues “Applicant submits the present invention is directed to a method for inducing differentiation into insulin-producing cells, the method comprising culturing isolated cells in a medium composition wherein a STAT inhibitor is optional. The '387 application is directed to a method for treating or alleviating diabetes mellitus comprising, in part, a STAT inhibitor. As such, the inventions are patentably distinct from each other.” (Remarks, page 12). This argument has been fully considered but has not been found persuasive for the following reasons.
While the preambles of the instant claim 1 and the reference patent claim 1 differ, the fundamental composition (putrescine, nicotinamide, and glucosamine) is the same. As well, reference patent claim 3 claims stem cell mobilizing agents rendering obvious a culture medium comprising stem cells, in a culture medium composition comprising putrescine, glucosamine, nicotinamide. Further, in a direct comparison of the independent claims, the reference patent in requiring a STAT3 inhibitor is a species of the genus claimed in instant claim 1. It is well established that a species of a claimed invention renders the genus obvious. In re Schaumann, 572 F.2d 312, 197 USPQ 5 (CCPA 1978). Even further, the disclosure of the reference patent teaches in vitro applications of the composition comprising putrescine, nicotinamide, and glucosamine (see above rejection).
Furthermore, based on the teaching disclosed in the MPEP, in vitro testing is indicative of in vivo testing.
It should be note that MPEP 2107.01 states:
It is reasonably correlated to the particular therapeutic or pharmacological utility, data generated using in vitro assays, or from testing in an animal model or a combination thereof almost invariably will be sufficient to establish therapeutic or pharmacological utility for a compound, composition or process.. See, e.g., In re Brana, 51 F.3d 1560, 34 USPQ 1436 (Fed. Cir. 1995); Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 856, 206 USPQ 881, 883 (CCPA 1980); In re Malachowski, 530 F.2d 1402, 189 USPQ 432 (CCPA 1976); In re Gaubert, 530 F.2d 1402, 189 USPQ 432 (CCPA 1975); In re Gazave, 379 F.2d 973, 154 USPQ 92 (CCPA 1967); In re Hartop, 311 F.2d 249, 135 USPQ 419(CCPA 1962); In re Krimmel, 292 F.2d 948, 130 USPQ 215 (CCPA 1961).
Therefore, the instant claims would have been obvious to a person having ordinary skill in the art over the reference patent.
Conclusion
No claim is allowed.
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 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 BRENDAN THOMAS TINSLEY whose telephone number is (703)756-5906. The examiner can normally be reached Mon-Fri 8:00-5:00.
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/BRENDAN THOMAS TINSLEY/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634