DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/18/2025 has been entered.
Status of claim rejections
The rejections of record under 35 USC 102 and 103 are maintained in view of Applicant’s arguments in the remarks filed 09/18/2025.
Claim Rejections - 35 USC §§ 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
First rejection
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Firpo et al. (US 2013/0243735; prior art of record).
Firpo teaches differentiating stem cells along the pancreatic lineage to provide pancreatic
progenitor cells, expressing Pdx-1 and Ptf1a, for transplantation to a subject (Abstract; FIG. 1, reproduced below). Firpo teaches implantation of the cells into a subject in need thereof to treat, e.g., Type 1 (T1D) and 2 diabetes (T2D), which would reasonably encompass a subject at risk of developing T2D (para 0078-0082, 0125-0126). Firpo teaches that implantation of the cells resulted in improved “glycemic control” (para 0031, 0121; FIGS 3A-3B; see also para 0039, 0121, 0125-0126). Firpo teaches that the progenitor cells mature in vivo after transplantation (para 0122-0123).
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In the alternative, it would have been prima facie obvious at the time of filing to use the method taught by Firpo to improve glycemic control in a subject with a reasonable expectation because Firpo teaches that implantation of the pancreatic precursor cells into the subject advantageously allows for improved glycemic control (para 0031, 0121; FIGS. 3A-B).
Accordingly, Firpo anticipates the claimed method or, in the alternative, renders the claimed method prima facie obvious.
Second rejection
Claims 4-5 and 7-14 are rejected under 35 U.S.C. 103 as being unpatentable over Firpo as applied to claims 1-3 above, and further in view of Hirst et al. (Diabetes Care, 35:446-454 (2012), prior art of record, hereinafter “Hirst”).
As discussed above, 1-3 were anticipated or, in the alternative, rendered prima facie obvious by Firpo. The reference does not explicitly teach the further administration of an anti-diabetic drug such as sitagliptin, metformin, or rosiglitazone.
However, it would have been prima facie obvious at the time of filing to further administer, e.g., metformin—a biguanide—to a subject in the method taught by Firpo because Hirst teaches metformin can be utilized to achieve glycemic control in diabetic patients (Abstract; Table 1; page 452, Conclusions). For example, Hirst teaches “metformin monotherapy reduced HbA1c by 1.12%, and metformin in combination with other oral antihyperglycemic treatments or insulin reduced HbA1c by 0.95 and 0.83%, respectively, for type 2 diabetes, and these effects were sustained at 24 weeks. Of particular interest is that the addition of metformin treatment to insulin treatment improves glycemic control in type 2 diabetes by a clinically significant level” (page 452, Conclusions).
One of ordinary skill in the art would have been motivated to combine the teachings of Firpo and Hurst in order to advantageously enhance glycemic control with a reasonable expectation of success. Moreover, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding instant claim 12, the references do not explicitly teach that the pancreatic endocrine progenitor cells mature in vivo to produce a population comprising at least 2% pancreatic endocrine cells. However, Firpo teaches that “the quantity of cells to be administered will vary for the subject being treated” and that “[d]osages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art” (¶ 0090). It would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal amount of pancreatic endocrine precursor cells taught by Firpo to implant into a subject to yield a desired percentage, e.g., at least 2%, of pancreatic endocrine cells in vivo with a reasonable expectation of success.
Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here 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).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Third rejection
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Firpo.
As discussed above, 1-3 were anticipated or, in the alternative, rendered prima facie obvious by Firpo. The reference does not explicitly teach that the pancreatic endocrine progenitor cells mature in vivo to produce a population comprising at least 2% pancreatic endocrine cells. However, Firpo teaches that “the quantity of cells to be administered will vary for the subject being treated” and that “[d]osages can be readily ascertained by those skilled in the art from this disclosure and the knowledge in the art” (¶ 0090). It would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal amount of pancreatic endocrine precursor cells taught by Firpo to implant into a subject to yield a desired percentage, e.g., at least 2%, of pancreatic endocrine cells in vivo with a reasonable expectation of success.
Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here 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).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Fourth rejection
Claims 1-3 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Rabinovitch et al. (US 2006/0234373, hereinafter “Rabinovitch”).
Rabinovitch teaches a method of treating Type-1 diabetes (T1D) or Type-2 diabetes (T2D), which would reasonably encompass a subject at risk of developing T2D, comprising implantation of undifferentiated progenitor cells into a host animal and providing pancreatic differentiation in vivo alone or in combination with a cell expansion agent (para 0009, 0025, 0117).
Rabinovitch teaches that the “invention offers advantages over existing treatment regimens for diabetic patients. By providing a means to stimulate adult pancreatic cells to regenerate not only is the need for traditional drug therapy (Type 2) or insulin therapy (Type 1 and Type 2) reduced or even eliminated, but the maintenance of normal blood glucose levels” i.e., improved glycemic control. (para 0025).
In the alternative, it would have been prima facie obvious at the time of filing to use the method taught by Rabinovitch to improve glycemic control in a subject with a reasonable expectation because Rabinovitch teaches that implantation of the precursor cells into a subject advantageously reduces or even eliminates the need for traditional drug therapy or insulin therapy, and also maintains normal blood glucose levels (para 0025).
Accordingly, Rabinovitch anticipates the claimed method or, in the alternative, renders the claimed method prima facie obvious.
Fifth rejection
Claims 4-5 and 7-14 are rejected under 35 U.S.C. 103 as being unpatentable over Rabinovitch as applied to claims 1-3 above, and further in view of Hirst.
As discussed above, 1-3 were anticipated or, in the alternative, rendered prima facie obvious by Rabinovitch. The reference does not explicitly teach the further administration of an anti-diabetic drug such as sitagliptin, metformin, or rosiglitazone.
However, it would have been prima facie obvious at the time of filing to further administer, e.g., metformin—a biguanide—to a subject in the method taught by Rabinovitch because Hirst teaches metformin can be utilized to achieve glycemic control in diabetic patients (Abstract; Table 1; page 452, Conclusions). For example, Hirst teaches “metformin monotherapy reduced HbA1c by 1.12%, and metformin in combination with other oral antihyperglycemic treatments or insulin reduced HbA1c by 0.95 and 0.83%, respectively, for type 2 diabetes, and these effects were sustained at 24 weeks. Of particular interest is that the addition of metformin treatment to insulin treatment improves glycemic control in type 2 diabetes by a clinically significant level” (page 452, Conclusions).
One of ordinary skill in the art would have been motivated to combine the teachings of Rabinovitch and Hurst in order to advantageously enhance glycemic control with a reasonable expectation of success. Moreover, “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding instant claim 12, the references do not explicitly teach that the pancreatic endocrine progenitor cells mature in vivo to produce a population comprising at least 2% pancreatic endocrine cells. It would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal amount of pancreatic endocrine precursor cells taught by Rabinovitch to implant into a subject to yield a desired percentage, e.g., at least 2%, of pancreatic endocrine cells in vivo with a reasonable expectation of success.
Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here 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).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Sixth rejection
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Rabinovitch.
As discussed above, 1-3 were anticipated or, in the alternative, rendered prima facie obvious by Rabinovitch. The reference does not explicitly teach that the pancreatic endocrine progenitor cells mature in vivo to produce a population comprising at least 2% pancreatic endocrine cells. However, it, would have been a matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal amount of pancreatic endocrine precursor cells taught by Rabinovitch to implant into a subject to yield a desired percentage, e.g., at least 2%, of pancreatic endocrine cells in vivo with a reasonable expectation of success.
Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. “[W]here 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).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 09/18/2025 have been fully considered but they are not persuasive.
On pg. 6-11 of the remarks, Applicant argues that Firpo (similar to previously cited Xu reference) uses streptozotocin (STZ) to mimic T1D and not T2D in mice, but the present application teaches a model system for T2D using low dose STZ to mimic slow progression of beta-cell destruction in T2D and use of high dose to generate a T1D model is markedly different than the mouse model of the application. Applicant concedes that Firpo alleges treatment of both T1D and T2D as well as “improved glycemic control”, but that the model system utilized is a T1D model and the data presented in Firpo doesn’t support improved glycemic control because Fig. 3A of Firpo shows only one mouse with blood glucose level <180 mg/dl, Fig. 4 shows wide fluctuations in glucose levels, and Fig. 11A demonstrates hypoglycemia. Applicant further urges, inter alia, that this data does not permit predictions or treatment of T2D, and that improved glycemic control depends on whether a person of ordinary skill would interpret Firpo as teaching that implantation of pancreatic endocrine progenitor cells would provide at least de minimis improvement of glycemic control in T2D subjects. Applicant cites to Kalra et al and LeRoith et al for support to evidence importance of effective glycemic control in diabetic patients, Fig. 4A-E, 1C, and 9A-B of the application to compare with the data from Firpo, and asserts that because Firpo doesn’t report HbA1c, FBG, PPZG or response to glucose challenge, it doesn’t present an indication of glycemic control.
In response, the examiner disagrees with Applicant’s arguments. Applicant’s arguments are not commensurate with the scope of the instant invention. The instant invention is drawn to, inter alia, a method for improving glycemic control in a subject having or at risk of having Type 2 Diabetes comprising implanting a population of pancreatic endocrine progenitor cells into the subject to produce pancreatic endocrine cells. The instant claims are not drawn to the model utilized for such a method, which seems to be the crux of Applicant’s arguments. The Kalra et al and LeRoith et al references were fully considered but are not persuasive. While the examiner appreciates the data on why improved glycemic control is important in diabetic patient populations, Firpo explicitly teaches implantation of the cells into a subject in need thereof to treat, e.g., Type 1 (T1D) and 2 diabetes (T2D) (para 0078-0082, 0125-0126). Firpo also explicitly teaches that implantation of the cells resulted in improved “glycemic control”, de minimis or otherwise (para 0031, 0121; FIGS 3A-3B; see also para 0039, 0121, 0125-0126). Thus, one of ordinary skill would have reasonably understood the teachings of Firpo to encompass the instantly claimed method of improving glycemic control.
On pg. 11-16 of the remarks, Applicant argues the Firpo reference. Specifically, Applicant argues that to have “improved glycemic control” as claimed, there is a requirement that a correction can be made when a patient is hypoglycemic as well as hyperglycemic, to respond appropriately and to do so without too much delay and cell transplants in a T2D model would work to do so. Applicant urges that Firpo does not anticipate or render obvious the instant method. Applicant then argues the frequent testing of blood glucose in the present application (citing to Fig. 1C, 4B and 4E) versus the infrequent testing by Firpo with no relationship to a glucose challenge provides no information about the amplitude of glucose excursions, time to return to baseline, or resulting HbA1c. Applicant cites to Bastyr et al (Fig. 1A-D) as to the efficacy of different treatment strategies to uncontrolled T2D to emphasize importance of quality and interpretation of data with regards to whether or not improved glycemic control was achieved. Applicant further argues that simply lowering blood glucose at random time periods would not have enabled authors to make any conclusions related to improved glycemic control.
In response, as stated above, Firpo provides one of ordinary skill explicit teaching, suggestion, and motivation to utilize pancreatic endocrine progenitor cell implantation as a treatment for T2D and to improve glycemic control (para 0078-0082, 0125-0126; para 0031, 0121; FIGS 3A-3B; see also para 0039, 0121, 0125-0126). The instant method merely requires implantation of pancreatic endocrine progenitor cells to treat T2D in a subject, and Firpo does not need to disclose increased or frequent testing as argued by Applicant, nor the information about the amplitude of glucose excursions, time to return to baseline, or resulting HbA1c. Furthermore, while the examiner appreciates the data provided in the Bastyr reference (which was fully considered), the examiner finds Applicant’s arguments regarding the reference unpersuasive for the same reasons as set forth above.
On pg. 16-17, Applicant argues that euglycemic blood glucose levels may not be an indication of glycemic control because various medications utilized for management of T2D can cause euglycemic diabetic ketoacidosis. Applicant also argues that insulin use, decreased caloric intake, heavy alcohol use, chronic liver disease, pregnancy, and glycogen storage disorders can also lead to euDKA. Thus, if Applicant had not measured glycemic control in non-challenged glucose responses, they would have incorrectly concluded that diabetes drugs in combination with the cells cannot improve glycemic control in T2D. Applicant further cites to Fig. 6A of the application and argues much of the same as it relates to the combination of the Hirst reference with Firpo to render obvious treatment of diabetes known anti-diabetic drugs with progenitor cells.
In response, the examiner disagrees with Applicant’s arguments for much of the same reasons as set forth above. The instant claims do not require examination or interpretation of measurement of euglycemic blood glucose levels or how the use of known anti-diabetic treatment modalities may cause euDKA in diabetic patients. Firpo provides one of ordinary skill explicit teaching, suggestion, and motivation to utilize pancreatic endocrine progenitor cell implantation as a treatment for T2D and to improve glycemic control. Hirst explicitly teaches that administration of commonly used anti-diabetic drugs are successful in treatment of T2D. The combination of Firpo and Hirst renders prima facie obvious the claimed invention because “[i]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
On pg. 17-19 of the remarks, Applicant argues that Rabinovich teaches methods of treatment by transplanting undifferentiated precursor cells and providing pancreatic differentiation agent either alone or in combination with a cell expansion agent in vivo or transplanting functional pancreatic islet beta cells to provide a source of functioning pancreatic islet beta cells versus implantation of pancreatic endocrine precursor cells as claimed by Applicant. Applicant argues that the claimed cells are not “undifferentiated precursor cells” or “functioning pancreatic islet beta cells” as taught by Rabinovich. Applicant also points to paragraph 0025 and 0117 to demonstrate that while Rabinovich teaches some type of glycemic control through maintenance of normal blood glucose levels, Rabinovich concludes that the findings support a therapeutic role of TGF-a and gastrin in T1/T2D. Applicant then argues that this suggests the teachings are less about implantation of cells and all about the role of TGF-a and gastrin as treatments for diabetes. Applicant concedes that Rabinovich teaches use of a T2D model but argues again that Rabinovich does not teach implanting pancreatic endocrine progenitor cells. Applicant then argues that the manner in which Rabinovich treats the rats results in chemical mediated destruction of beta cells not seen in T2D and Rabinovich is silent to insulin resistance or weight gain typical of T2D.
In response, the examiner disagrees with Applicant’s arguments. Rabinovich explicitly teaches the implantation of islet precursor pancreatic cells (i.e., pancreatic endocrine progenitor cells) for the treatment of T2D (see abstract, claim 1), providing pancreatic differentiation in vivo alone or in combination with a cell expansion agent (para 0009, 0025, 0117) which results in glycemic control through maintenance of normal blood glucose levels (para 0025 and 0117). Paragraph 0029 of Rabinovich also explicitly states “Treatment of diabetes also can be effected by transplantation of purified islets or pancreatic islet precursor cells into a patient in need thereof” (i.e., the method as instantly claimed by Applicant). Thus, Applicant’s argument runs contrary to the explicit teachings of Rabinovich regarding implantation of pancreatic progenitor cells for treatment of T2D. Second, the extrapolation of the experimental results of Rabinovich as it relates to TGF-a and gastrin as treatment modalities for T2D does not negate the explicit teachings of the reference regarding implantation of pancreatic endocrine progenitors to treat T2D and improve glycemic control as instantly claimed for the same reasons as set forth above. Third, the mouse models, treatment of Rabinovich’s mouse models, and the reference being silent on insulin resistance or weight gain typical of T2D also does not negate the explicit teachings of the reference for the same reasons as set forth above. Thus, the rejections are maintained as set forth above.
Conclusion
NO CLAIMS ALLOWED.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Rezania et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32, 1121–1133 (2014): discusses transplantation of pancreatic progenitors or insulin-secreting cells derived from human embryonic stem cells (hESCs) has been proposed as a therapy for diabetes. We describe a seven-stage protocol that efficiently converts hESCs into insulin-producing cells. Stage (S) 7 cells expressed key markers of mature pancreatic beta cells, including MAFA, and displayed glucose-stimulated insulin secretion similar to that of human islets during static incubations (see abstract; throughout document).
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672