DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Request for Reconsideration
Applicant's reply filed 8/17/2026 has been entered. The claims were not amended. Claims 1, 19, 24, 34, 35, and 38-55 remain pending, of which claims 34, 35, 38, and 39 are being considered on their merits. Claims 1, 19, 24, and 40-55 remain withdrawn from consideration. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 34, 35, 38, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Pagliuca et al. (Cell (2014), 159, 428-439) in view of Cebola et al. (Nature Cell Biology (2015), 17(5), 615-626 plus appended Methods and Supplementary Data) and Zhang et al. (Cellular Physiology and Biochemistry (2013), 32:1808-1817).
Pagliuca teaches a differentiation medium comprising XXI (i.e. a species of gamma-secretase inhibitor, Betacellulin (i.e. a species of EGF family member), T3 (i.e. a species of thyroid hormone signaling pathway activator), and Alk5i II (i.e. a species of TGF-beta signaling pathway inhibitor) (page 437, subheading “Cell Culture”), and being useful to differentiate pluripotent stem cells into intermediate PDX1+ and NKX6.1+ pancreatic progenitor cells and then PDX1+ and NKX6.1+ beta cells (Fig. 1A, “PP2”; and, the paragraph spanning pages 429-430; Fig. 3A and 3B, and the last two paragraphs in the right column of page 430), reading in-part on claim 34, 38, and 39.
Regarding claim 34, Pagliuca does not teach a composition comprising verteporfin at 0.3-0.4 µM. Regarding claim 35, Pagliuca is silent regarding any NGN3 expression.
Cebola teaches a composition comprising pancreatic multipotent progenitor cells (MPCs) contacted with verteporfin (VP), wherein verteporfin disrupts the TEAD-YAP complex and the pancreatic multipotent progenitor cells are PDX1+ and NKX6.1+ (2nd page of the Methods, right column, paragraph starting “VP experiments in….”; p616, left column, paragraph starting “To study the genomic…”; page 622, paragraph starting “To study YAP-dependent TEAD function…”), reading on claim 34. Cebola further teaches the pancreatic multipotent progenitor cells are NGN3+ (Fig. 6d, “NGN3”), reading on claim 35. In a separate embodiment, Cebola teaches contacting E11.5 mouse embryonic pancreatic bud explants with 0.1 µM verteporfin (2nd page of the Methods, right column, paragraph starting “Pancreatic explant experiments…”), reading in-part on claim 34. Cebola teaches that verteporfin treatment of human in vitro MPCs and pancreatic bud explants dissected from E11.5 mouse embryos and grown ex vivo caused decreased expression of a subset of genes associated with TEAD1-bound enhancers (p622, left column, paragraph starting “To study YAP-dependent TEAD function…”), reading in-part on claim 34.
Zhang teaches that YAP1 is necessary for the proliferation of pancreatic progenitor cells, as measured by YAP1 inhibition by miR-375(Abstract). Zhang teaches YAP1 is highly expressed in pancreatic progenitor cells and that YAP1 expression is repressed during pancreatic progenitor cell differentiation into β-cells (paragraph starting “YAP1 was highly expressed…” on page 1815), reading on claim 34.
Regarding the verteporfin of claim 34, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the verteporfin of Cebola to the pancreatic progenitor cell composition of Pagliuca in view of Zhang. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Pagliuca and Cebola are in-part directed towards PDX1+ and NKX6.1+ pancreatic progenitor cell compositions, and because Cebola teaches contacting the PDX1+ and NKX6.1+ pancreatic progenitor cells with an effective concentration of verteporfin. The skilled artisan would have been motivated to do so because Zhang as a whole teaches that YAP inhibition would inhibit pancreatic progenitor cell proliferation and drive differentiation of the pancreatic progenitor cells into beta cells, and so the addition would predictably improve upon Pagliuca’s methods of differentiating PDX1+ and NKX6.1+ pancreatic progenitor cells into PDX1+ and NKX6.1+ beta cells.
Regarding the verteporfin concentration of claim 34, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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). Also see M.P.E.P. § 2144.05 (II) and (III). In the instant case, Cebola teaches that the verteporfin concentration is a results-effective variable to decrease expression of a subset of genes associated with TEAD1-bound enhancers in either pancreatic multipotent progenitor cells or in mouse embryonic pancreatic buds. Thus, the burden is shifted back to establish criticality of the claimed verteporfin concentration range by objective evidence.
Regarding claim 35, this dependent claim only describes the inherent properties of the PDX1+ and NKX6.1+ cells of claim 34, as Cebola makes clear that pancreatic progenitor cells inherently express NGN3. See M.P.E.P. § 2112.01 recites, "Products of identical chemical composition can not have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” See In re Spada 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, Pagliuca as evidenced by Cebola reads on claim 35.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 34, 35, 38, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Millman et al. (WO 2019/222487) in view of Cebola et al. (Nature Cell Biology (2015), 17(5), 615-626 plus appended Methods and Supplementary Data).
Millman teaches methods and compositions for generating endodermal lineage cells and beta cells (Abstract). Millman teaches beta cells derived from stem cells (SC-β) that are PDX1+, NKx6.1+, and NGN3+ (p37, paragraph starting “Combining these modifications…”; also, p7, lines 23-27), reading in-part on claim 34 and 35. In a separate embodiment, Millman teaches adding verteporfin to methods of differentiating stem cells into beta cells because verteporfin is a YAP inhibitor and YAP inhibition enhances differentiation of human pluripotent stem cells to cells of endodermal lineage, pancreatic progenitors, and insulin-producing beta-cells (paragraph spanning p19-20), reading on claims 34 and 36. Millman teaches adding ALk5 inhibitor II during the last stage of culture to mature the stem cell-derived beta cells (p19, lines 4-10), reading on the embodiment of Alk5 inhibitor II for the TGF-beta signaling pathway inhibitor of claim 34, and reading on claims 38 and 39. Millman teaches adding XXI, Betacellulin, Alk5i II, and T3 (as species of gamma-secretase inhibitor, a growth factor from the EGF family, TGF-beta signaling pathway inhibitor, and a thyroid hormone signaling pathway activator, respectively) to differentiate pluripotent stem cells into beta cells (the paragraph spanning pages 73-74), alternatively reading on claim 34.
Regarding claim 34, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the verteporfin of Millman to the stem cell differentiation methods and composition of Millman. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because Millman expressly considers the addition of verteporfin. The skilled artisan would have been motivated to do so because Millman teaches that adding verteporfin is predictably advantageous to improve differentiation of human pluripotent stem cells to cells of endodermal lineage, pancreatic progenitors, and insulin-producing beta-cells.
Regarding claim 34, Millman does not teach adding 0.3-0.4 µM of verteporfin.
Cebola teaches a composition comprising pancreatic multipotent progenitor cells (MPCs) contacted with 10 µM verteporfin (VP), wherein the pancreatic multipotent progenitor cells are PDX1+ and NKX6.1+ (2nd page of the Methods, right column, paragraph starting “VP experiments in….”; p616, left column, paragraph starting “To study the genomic…”), reading in-part on claim 34. Cebola further teaches the MPCs are NGN3+ (Fig. 6d, “NGN3”). In a separate embodiment, Cebola teaches contacting E11.5 mouse embryonic pancreatic bud explants with 0.1 µM verteporfin (2nd page of the Methods, right column, paragraph starting “Pancreatic explant experiments…”), reading in-part on claim 34. Cebola teaches that verteporfin treatment of human in vitro MPCs and pancreatic bud explants dissected from E11.5 mouse embryos and grown ex vivo caused decreased expression of a subset of genes associated with TEAD1-bound enhancers (p622, left column, paragraph starting “To study YAP-dependent TEAD function…”), reading in-part on claim 34.
Regarding the verteporfin concentrations of claim 34, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature 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). Also see M.P.E.P. § 2144.05 (II) and (III). In the instant case, Cebola teaches that the verteporfin concentration is a results-effective variable to decrease expression of a subset of genes associated with TEAD1-bound enhancers in either pancreatic multipotent progenitor cells or in mouse embryonic pancreatic buds. Thus, the burden is shifted back to establish criticality of the claimed verteporfin concentration range by objective evidence.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 6-9 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
On pages 6-7 of the reply, Applicants urge that Pagliuca is deficient by not teaching every element of independent claim 34. Similarly, on pages 7-8 of the reply Applicants urge that Millman is deficient by not teaching every element of independent claim 34. However, neither Pagliuca nor Millman is not applied alone, but in combination with Cebola and Zhang with Pagliuca and with Cebola with Millman. And, the claimed invention becomes prima facie obvious when the references are considered together as a whole rather than each alone. None of Applicant’s arguments address the specific rationale and motivation to combine the verteporfin of Cebola with the methods of Pagliuca in view of Zhang or with the methods of Millman. Nor do the arguments rebut the prima facie case that any differences in the claimed verteporfin concentration is the mere routine experimentation and/or optimization of Cebola’s verteporfin concentration.
Conclusion
No claims are allowed. No claims are free of the art.
THIS ACTION IS MADE FINAL. 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 SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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