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 .
Status of the Claims
Claims 1-6, 9-11, and 36-50 are currently pending.
Claims 1, 2, 5, and 9 are amended.
Claims 7-8 and 12-35 remain cancelled.
Claims 1-6, 9-11, and 36-50 have been considered on the merits.
Withdrawn Objections/Rejections
The objections made onto claim 1 are withdrawn in light of the amendments submitted on 02/17/2026.
The 112(b) rejections made onto claims 1, 5, and 9 are withdrawn in light of the amendments made on 02/07/2026.
New and Maintained Rejections Necessitated by Amendment
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 1, 2, and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 18, and 20 of copending application number 17918933. Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 is generic to all that is recited in claim 1 (and dependent claims 2 and 20) of US 17,918,933. That is, claim 1 and 20 of ‘933 falls entirely within the scope of claim 1 of the instant application. Specifically, the invention in claim 1 and 20 of ‘933 are fully encompassed in claim 1 of the instant application. Claims 1, 2, and 20 of ‘933 meet the limitations of the instant claim 1. Claim 20 of ‘933 meet the limitations of instant claim 2. Claim 18 of ‘933 meet the limitations of instant claim 36.
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 1-6, 9-11, and 45-48 are rejected under 35 U.S.C. 103 as being unpatentable over Melton et al (US20160177267A1; reference of record), in view of Ma et al (Acta Biochem Biophys Sin, 2017), Toyoda et al (Stem Cell Reports, 2017), Wang (Commentary, The Company of Biologists, 2009), and Zorzi et al (Cell Transplant, 2015; reference of record).
With regards to claim 1, Melton teaches a method of generating insulin producing beta cells in a suspension by the steps of:
First providing a stem cell cultured in a serum free medium and contacting the stem cell with a TGFβ agonist, Activin A, and a WNT agonist, CHIR99021, to form definitive endoderm cells as required by claims 1 and 2 ([0015]).
Secondly, the definitive endoderm cells are contacted with a FGFR2b agonist, KGF, to form primitive gut tube cells as required by claim 1 and 2 (Figure 2A/B).
Next, the primitive gut tube cells are contacted with a RAR agonist, retinoic acid (RA), to form early pancreas progenitor cells as required by claims 1 and 2 (Figure 2A/B).
Next, the early pancreas progenitor cells are incubated for 5 days (i.e. at least 3). The early pancreas progenitor cells are contacted during this period with a smoothened antagonist (more specifically SANT1 ([0142]), an FGFR2b agonist (more specifically KGF ([0155]), a RAR agonist (more specifically retinoic acid ([0139]), and a protein kinase C activator (more specifically PdbU or TPB ([0163]) to form pancreatic progenitor cells as required by claims 1 and 2 (Fig. 2A/B).
Next, the pancreatic progenitor cells are contacted with an Alk5 inhibitor, Alk5i, as well as RA, T3 (thyroid hormone), betacellulin (Erbb4 agonist), and SANT1 (a smoothened antagonist) to form an endoderm cell clusters as required by claims 1 and 2 (Figure 2A/B).
Finally, Melton teaches that the cluster of endoderm cells are cultured in serum-free media to form insulin-producing beta cells as required by claim 1 ([0004]).
Melton teaches that the serum free media comprises MCBD131 ([0065]), glucose ([0065]), NaHCO3 ([0065]), BSA ([0065]), ITS-X ([0065]), Glutamax (i.e. L-glutamine) ([0065]), vitamin C ([0065]), Pen/strep ([0065]), CMRL 1066 ([0055]), trace minerals A and B ([0006]), ZnSO4 ([0006]) as required by claim 3. The pancreatic progenitor cell is not incubated with N-acetyl cysteine nor is there mention of N-acetyl cysteine in Melton as required by claim 5. The amount of time sufficient to form the insulin-producing beta cell from the endoderm cell is 24 to 31 days which is more than 9 days as required by claim 6 (Figure 2B). Further, Melton teaches that the amount of time sufficient to form the definitive endoderm cell, the primitive gut tube cell, the early pancreas progenitor cell, the pancreatic progenitor cell, the endoderm cell, or the insulin producing cell is between 1 and 15 days as shown in Figure 2B where the “amount of time sufficient to form” any of the listed cell types ranges from 3 to 14 days (i.e. between 1 and 15 days) as required by claim 38 (Figure 2B). The endoderm cell is not incubated with N-acetyl cysteine nor is there mention of N-acetyl cysteine in Melton as required by claim 9. Further, Melton teaches that the one or more insulin producing beta cells express at least one beta cell marker, at least one islet cell marker, express insulin, and undergoes GSIS response “characteristic of an endogenous mature Beta cell both in vitro and in vivo” as required by claim 10 and 47 ([0043]). Further, Melton teaches that the insulin-producing cells stably express insulin (i.e. functionality for more than 1 day) as required by claim 10 ([0174]). Melton teaches that the stem cell is a human iPSC as required by claim 11 ([0027]). Melton teaches that the insulin-producing cells are used in preparation of a medicament for the use in treating diabetes in a subject as required by claims 45 and 46 ([0178]). Melton teaches that the cells produced were able to rapidly reverse diabetes in mice within a little over a month (i.e. having persistent function for at least a month) as required by claim 47 ([0046]). Melton teaches that the insulin-producing beta cells express PDX1+ and NKX6.1+ as required by claim 48 ([0051]). Melton teaches that the early pancreas progenitor cells are further contacted with a BMP type I receptor inhibitor, more specifically LDN, to form the pancreatic progenitor cell as required by claim 49 ([0145]-[0146]).
Melton does not teach the addition of a protein kinase C activator (PKC activator) in the media which is applied to the early pancreas progenitor cell for differentiation into pancreatic progenitor cells as required by claim 1.
However, Melton does teach the application of a PKC activator in the step immediately preceding which is step involving contacting the primitive gut tube cells with factors including a PKC activator to form early pancreas progenitor cells.
Additionally, Ma et al provides a review of the current chemical strategies for pancreatic cell differentiation, reprogramming, and regeneration. Ma discloses that Melton of the current rejection and colleagues screened various molecules for the generation of pancreatic progenitors (pg. 290, col 2, last para). Ma discloses three PKC activators, TPB, PdBU, and ILV all of which promote the pancreatic specification of the cells being treated (see Table 1 and Fig. 2). Additionally, Ma provides a side by side review of three step-wise methods of differentiating functional pancreatic B-like cells (Fig. 2), which includes the method of Melton of the current rejection (method B of Fig. 2). Method A of Fig. 2 provides similar steps to that of Melton however they include a PKC activator, TPB, in both the step which differentiates primitive gut tube cells into early pancreatic progenitor cells and then the PKC activator is also included in the subsequent step of differentiating the early pancreatic progenitor cells into pancreatic progenitor cells. Ma discloses that method A of Fig. 2 employs the factors from stages 1-4 of their method “to improve pancreatic specification and enhance the generation of PDX1 and KNX6.1 double-positive cells” (pg. 296, col. 2, para 1).
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) 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.
In the present situation, rationales A, B, E, and G are applicable. The modification of Melton with the methods taught by Ma, represent combining prior methods to yield predictable results, substitution for one known element for another, and choosing from a finite number of identified, predictable results. Additionally, Ma discloses that method A of Fig. 2 employs the factors from stages 1-4 of their method “to improve pancreatic specification and enhance the generation of PDX1 and KNX6.1 double-positive cells” (pg. 296, col. 2, para 1). The teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Melton does not teach the inclusion of a cytoskeletal-modulating agent selected from the group of latrunculin A, latrunculin B, nocodazole, cytochalasin D, jasplakinolide, blebbistatin, y-15, gdc-0994, or any combination thereof in the step of contacting the pancreatic progenitor cell with multiple other claimed factors (taught by Melton above) to form a plurality of endoderm cells.
However, Toyoda et al teaches about the differentiation of iPSCs into pancreatic endoderm cells. Toyoda discloses a 4 stage process in which the last stage is the differentiation of pancreatic progenitor cells (abstract) which commit to the pancreatic endoderm fate. (abstract/Fig. 1A). Toyoda discloses the addition of a cytoskeletal modulator at this last stage (Fig. 1A). Toyoda also teaches that blebbistatin was the best cytoskeletal modulator they tested and that it was able to increase the proportion of NKX6.1+ cells (pg. 421, col 1, para 1). Additionally, Toyoda discloses that “the cells treated with Y-27632 or blebbistatin at stage 4 were able to form PDX1+ tubular structures that possess INSULIN+ and GLUCAGON+ endocrine cells, which is reminiscent of human embryonic pancreatic epithelia” (pg. 421, col. 1, para 2).
Further, Although Toyoda does not provide latrunculin A as the cytoskeletal modulating agent Wang et al provides information regarding the known alternative cytoskeletal modulating agent Latrunculin A. Wang et al states “In all cases, latrunculin was found to ablate the cortical F-actin network and to permit granule redistribution to the cell periphery. Perifused rat islets treated with latrunculin show dramatic increases in insulin secretion over the course of both phases (Thurmond et al., 2003)” (pg. 895, col. 1, para 1).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating insulin-producing beta cells taught by Melton with a cytoskeletal modulator taught by Toyoda, and further with Latrunculin A as taught by Wang to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination Toyoda discloses that “the cells treated with Y-27632 or Blebbistatin at stage 4 were able to form PDX1+ tubular structures that possess INSULIN+ and GLUCAGON+ endocrine cells, which is reminiscent of human embryonic pancreatic epithelia” (pg. 421, col. 1, para 2), additionally, Wang teaches that “Perifused rat islets treated with latrunculin show dramatic increases in insulin secretion over the course of both phases” (pg. 895, col. 1, para 1). The combination of Toyoda and Wang amounts to the obviousness rationale of “Simple substitution of one known element for another to obtain predictable results” (MPEP 2143 (I)). One of ordinary skill in the art would have a reasonable expectation of success when combining Melton with Toyoda and Wang because both Melton and Toyoda teach all necessary steps to produce the insulin-producing beta cells and Wang teaches “In all cases, latrunculin was found to ablate the cortical F-actin network and to permit granule redistribution to the cell periphery. Perifused rat islets treated with latrunculin show dramatic increases in insulin secretion over the course of both phases (Thurmond et al., 2003)” (pg. 895, col. 1, para 1).
Melton does not teach resizing the cluster of endoderm cells and that the resizing comprises reducing the size of the cluster of endoderm cells as required by claim 1. Melton does not teach that the reducing the size of the clusters of endoderm cells comprises breaking apart the clusters and reaggregating prior to maturation into one of more insulin-producing beta cells as required by claim 4.
However, Zorzi teaches about the impact of size in pancreatic islet transplantation. Zorzi teaches that fragmentation (i.e. reducing the size of the cluster) was an adopted strategy to reduce the islet size and improve engraftment results as required by claims (abstract). Further, Zorzi teaches that “smaller islets were significantly superior in engraftment as compared to medium, large, and control (all sizes) groups” (abstract).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating insulin-producing beta cells taught by Melton with resizing the cluster size taught by Zorzi to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Zorzi teaches that “smaller islets were significantly superior in engraftment as compared to medium, large, and control (all sizes) groups” (abstract). One of ordinary skill in the art would have a reasonable expectation of success when combining Melton with Zorzi because Melton teaches all necessary steps to produce the insulin-producing beta cells and Zorzi teaches a successful method of resizing clusters.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1, 36, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over over Melton et al (US20160177267A1; reference of record), in view of Ma et al (Acta Biochem Biophys Sin, 2017), Toyoda et al (Stem Cell Reports, 2017), Wang (Commentary, The Company of Biologists, 2009), and Zorzi et al (Cell Transplant, 2015; reference of record), as applied to claims 1-6, 9-11, and 45-48 above, and in further view of Salvatori et al (Jour. Of Diabetes Sci. and Tech., 2014).
With regards to claim 36, the limitations of the independent claim are taught by Melton above.
Melton does not explicitly teach that the method comprises plating the early pancreas progenitor cells on a stiff substrate or on a soft substrate as required by claim 36. Melton does not teach that the stiff substrate comprises a tissue culture plastic with a layer of extracellular matrix protein (ECM) as required by claim 37.
Melton does teach that the cells are cultured on a three-dimensional support prior to implantation ([0181]), however as stated above, Melton does not teach that the support is ECM.
Salvatori teaches methods of employing ECM scaffolding for bioartificial pancreas engineering. Salvatori teaches that the native ECM have proven to be an optimal platform for recellularization and whole-organ pancreas bioengineering (abstract). Salvatori teaches culturing pancreatic islets (beta cell clusters) on porcine ECM as required by claims 36 and 37 (pg. 164, col. 2, para 1). Further, Salvatori teaches that when differentiated islets are plated on ECM they experience a promotion of glucose-mediated insulin release (pg. 164, col. 2, para 1).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating insulin-producing beta cells taught by Melton and Zorzi with the ECM culture taught by Salvatori to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Salvatori teaches that when differentiated islets are plated on ECM they experience a promotion of glucose-mediated insulin release (pg. 164, col. 2, para 1). One of ordinary skill in the art would have a reasonable expectation of success when combining Melton and Zorzi with Salvatori because Melton teaches that the cells are cultured on a three-dimensional support prior to implantation ([0181]) and Salvatori teaches the ECM as a beneficial three-dimensional support.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over over Melton et al (US20160177267A1; reference of record), in view of Ma et al (Acta Biochem Biophys Sin, 2017), Toyoda et al (Stem Cell Reports, 2017), Wang (Commentary, The Company of Biologists, 2009), and Zorzi et al (Cell Transplant, 2015; reference of record), as applied to claims 1-6, 9-11, and 45-48 above, and in further view of Mendelson et al (Development, 2014).
With regards to claim 39, the limitations of the independent claim are taught by Melton above.
Melton does not teach contacting the early pancreas progenitor cell with sphingosine-1-phosphate (S1P) as required by claim 39.
However, Mendelson teaches that S1P is known to regulate interactions during embryonic dorsal pancreas development (pg. 5, para 1). The S1P acts on the endothelium to modulate committed endodermal cells to differentiate into pancreatic tissue as required by claim 39 (pg. 5, para 1).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating insulin-producing beta cells taught by Melton and Zorzi with the S1P taught by Mendelson to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Mendelson teaches that S1P acts on the endothelium to modulate committed endodermal cells to differentiate into pancreatic tissue (pg. 5, para 1). One of ordinary skill in the art would have a reasonable expectation of success when combining Melton and Zorzi with Mendelson because Melton teaches the necessary method steps and Mendelson teaches the role of S1P in pancreatic development.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1 and 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Melton et al (US20160177267A1; reference of record), in view of Ma et al (Acta Biochem Biophys Sin, 2017), Toyoda et al (Stem Cell Reports, 2017), Wang (Commentary, The Company of Biologists, 2009), and Zorzi et al (Cell Transplant, 2015; reference of record), as applied to claims 1-6, 9-11, and 45-48 above, and in further view of Cebola et al (Nature Cell Bio., 2015).
With regards to claims 40 and 41, the limitations of the independent claim are taught by Melton above.
Melton does not teach contacting the early pancreas progenitor cell with a YAP inhibitor as required by claim 40. Melton does not teach that the YAP inhibitor is Verteporfin as required by claim 41.
However, Cebola teaches about the Yap pathway and its regulation of human embryonic pancreatic progenitors. Cebola teaches the use of Verteporfin as a YAP inhibitor applied to pancreatic multipotent progenitor cells as required by claims 40 and 41 (pg. 622, col. 1, para 2). Further, Cebola teaches that their results suggest that the YAP complex has direct effects on several known regulators of pancreatic progenitors and it required for the proliferation and growth of early embryonic pancreas epithelium (pg. 622, col. 1, para 2).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating insulin-producing beta cells taught by Melton and Zorzi with the YAP inhibitor taught by Cebola to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Cebola teaches that their results suggest that the YAP complex has direct effects on several known regulators of pancreatic progenitors and it required for the proliferation and growth of early embryonic pancreas epithelium (pg. 622, col. 1, para 2). One of ordinary skill in the art would have a reasonable expectation of success when combining Melton and Zorzi with Cebola because Melton teaches the necessary method steps and Cebola teaches the role and benefit of a YAP inhibitor in pancreatic development.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1 and 42-44 are rejected under 35 U.S.C. 103 as being unpatentable over over Melton et al (US20160177267A1; reference of record), in view of Ma et al (Acta Biochem Biophys Sin, 2017), Toyoda et al (Stem Cell Reports, 2017), Wang (Commentary, The Company of Biologists, 2009), and Zorzi et al (Cell Transplant, 2015; reference of record), as applied to claims 1-6, 9-11, and 45-48 above, and in further view of Tang et al (Regenerative Biomaterials, 2014).
With regards to claims 42-44, the limitations of the independent claim are taught by Melton above.
Melton does not teach that the culture is planar (i.e. attached as defined in the specification) culture as required by claim 42. Melton does not teach that the surfaces change hydrophobicity with an external cue as required by claim 43. Melton does not teach that the external cue is temperature as required by claim 44.
However, Tang teaches developments in temperature responsive surfaces for cell sheet engineering. Tang teaches that the temperature responsive cell culture allows attached culture to be released from the culture surface by altering the temperature from 37 C to 20°C as required by claims 42-44 (abstract). Further, Tang teaches that pancreatic islet cells have been successfully cultured on temperature-responsive cell culture surface and formed cell sheets (pg. 99, col. 2, para 2).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating insulin-producing beta cells taught by Melton and Zorzi with the temperature-responsive surfaces taught by Tang to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Tang teaches that pancreatic islet cells have been successfully cultured on temperature-responsive cell culture surface and formed cell sheets (pg. 99, col. 2, para 2). One of ordinary skill in the art would have a reasonable expectation of success when combining Melton and Zorzi with Cebola because Melton teaches the necessary method steps and Tang teaches that pancreatic islet cells have been successfully cultured on temperature responsive surfaces.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1 and 50 are rejected under 35 U.S.C. 103 as being unpatentable over over Melton et al (US20160177267A1; reference of record), in view of Ma et al (Acta Biochem Biophys Sin, 2017), Toyoda et al (Stem Cell Reports, 2017), Wang (Commentary, The Company of Biologists, 2009), and Zorzi et al (Cell Transplant, 2015; reference of record), as applied to claims 1-6, 9-11, and 45-48 above, and in further view of Czysz et al (PLOS one, 2015).
With regards to claims 50, the limitations of the independent claim are taught by Melton above.
Melton does not teach that the stem cell is further contacted with DMSO for an amount of time to sufficiently form a definitive endoderm cell as required by claim 50.
However, Czysz teaches about the differentiation from stem cells into definitive endoderm cells (abstract). Czysz teaches that the addition of DMSO to Activin A based culture medium, when culturing stem cells “resulted in rapid down regulation of the pluripotency genes OCT4 and NANOG, accompanied by an increase expression of the DE genes SOX17, CXCR4 and GATA4” (abstract). Further, Czysz teaches that “These initial studies indicate that the inability to rapidly down regulate pluripotency genes at the initiation of cellular specification prevents cells from efficiently responding to the differentiating signals and that this key hurdle may be overcome by appropriate potentiation of gene expression with DMSO” (pg. 13, para 2).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of generating insulin-producing beta cells taught by Melton and Zorzi with the differentiation from stem cells to definitive endoderm cells using DMSO taught by Czysz to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Czysz teaches that “These initial studies indicate that the inability to rapidly down regulate pluripotency genes at the initiation of cellular specification prevents cells from efficiently responding to the differentiating signals and that this key hurdle may be overcome by appropriate potentiation of gene expression with DMSO” (pg. 13, para 2). One of ordinary skill in the art would have a reasonable expectation of success when combining Melton and Zorzi with Czysz because Czysz teaches that the addition of DMSO to Activin A based culture medium when culturing stem cells “resulted in rapid down regulation of the pluripotency genes OCT4 and NANOG, accompanied by an increase expression of the DE genes SOX17, CXCR4 and GATA4” (abstract).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments, see Remarks, filed 02/17/2026, with respect to the rejection(s) of claim(s) 1-6, 9-11, and 45-48, the rejections of claims 1, 36, and 37, the rejections of claims 1 and 39, the rejections of claims 1, 40, and 41, the rejections of claims 1 and 42-44, and the rejections of claims 1 and 50 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made Employing Melton in view of Ma, Toyoda, Wang, and Zorzi.
Applicants argue (Remarks, pg. 8) that the double patenting should be withdrawn due to having an earlier patent term filling date.
This is not found persuasive because both applications are currently pending.
Conclusion
No claims are 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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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