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 .
Detailed Action
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-3 and 24-30) in the reply filed on 06/18/2025 is acknowledged.
Election of the following species on the reply filed on 06/18/2025 is acknowledged:
TGFbeta1 for type of Six2 positive regulator
administering or transplanting a therapeutically amount of SIX2-enhanced SC-beta cells.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2020/061572, filed 11/20/2020.
Applicant’s claim for the benefit of a prior-filed parent provisional application 62937825, filed on 11/20/2019, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is 11/20/2019.
Claims Status
Claims 4-23, 34-37 and 40 were previously canceled, claims 45-47 are newly added, claims 31-33, 38, 39 and 41-44 have been withdrawn from consideration as being drawn to non-elected subject matter, and claims 1-3, 24, 26-30, and 45-47 have been considered on the merits. All arguments have been considered.
Withdrawn Objections & Rejections
Applicant's response filed 01/26/2026 has been considered. Rejections and/or objections not reiterated from the previous Office action mailed 08/26/2025 are hereby withdrawn.
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application.
Claim Rejections - 35 USC § 112 (New)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The rejection is required due to the amendment to claim 1 which recites an endocrine progenitor cell.
Claims 1-3, 24, 26-30, and 45-47 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 1: The claim recites “a method of generating SIX2-enhanced stem-cell derived beta cells (SC-beta cells) comprising: providing a population of endocrine progenitor (EP) cells”.
The instant specification is silent on an explicit definition of the term “endocrine progenitor (EP) cells”.
The broadest reasonable interpretation of “endocrine progenitor (EP) cell” is any cell which can generate an endocrine cell.
Teachings of the instant specification
The instant specification teaches SC-beta cells (endocrine cells) are generated from a stem cell which is directed to form a definitive endoderm cell, which is further directed to form a primitive gut tube cell, which is further directed to form an early pancreas progenitor cell, which is further directed to form a pancreatic progenitor cell, which then forms an endocrine progenitor cell which matures to a SC-beta cell (p2 ln 7-25).
The instant specification teaches embodiments of the claimed method. Example 1 teaches human pluripotent stem cells can be induced to differentiate into insulin-producing pancreatic beta cells (p 36 ln 31-32). The instant specification teaches protocol 1 and protocol 2 which disclose media components for specific days of cell culture to generate SC-beta cells (p46 and 48). The specification further teach protocol 1 is used with HUEs8 hESCs (p58 ln 5-10) and protocol 2 is used with undifferentiated pluripotent stem cells (p58 ln15-20). The protocols teach 6 stages of culture with specific media formulations over 22 or 20 days respectively. Media components and days of treatment differ between the protocols regarding the time of media changes and components of the media. For example, for protocol 1 (HuEs8 cells) stage three of occurs at day 3 of culture and the media comprises LDN193189, KGF, SANT1, RA, PdbU, Y27632. In contrast, protocol 2 (iPSCs) stage 3 occurs at day 8-9 and the media comprises LDN193189, KGF, SANT1, RA,TPPB.
The state of the art
Rindi et al (Ann. N.Y. Acad. Sci. 1014: 1–12 (2004). © 2004 New York Academy of Sciences. doi: 10.1196/annals.1294.001) teach the endocrine system of the gut is remarkably heterogeneous and comprises as many as 14 highly specialized cells (p2 ¶4). Rindi also teach gut endocrine cells arise from the gut endoderm (p2 ¶2). Table 1 of Rindi shows 14 specific endocrine cells of the gut (p5 Table 1).
Conclusion
As discussed supra, the population of endocrine progenitor (EP) cells as recited by the instant claim 1 is broadly interpreted to encompasses any progenitor cell which can give rise to any endocrine cell.
As taught in the art, endocrine cells are diverse; Rindi teach the endocrine population in the gut comprises multiple endocrine cell types and also teaches that the differentiation of endocrine cells is complex and requires endocrine-committed multipotent cells (p9 ¶1).
Thus, while the instant specification fulfills the written description requirement for generating SC-beta cells from an endocrine progenitor derived from HUES8 cells as disclosed for protocol 1, and for generating SC-beta cells from an endocrine progenitor derived from undifferentiated pluripotent stem cells as disclosed for protocol 2, the written description requirement is not met for the generation of SC-beta cells from any endocrine progenitor cell derived from any stem cell, as recited in claim 1.
If claim 1 were amended to incorporate the limitations of claim 2, which provides guidance for culture stages 1-5 to generate the endocrine progenitor cell from a stem cell, this would overcome this the rejection as written.
Note claims 3, 24, 26-30, and 45-47 depend from rejected claim 1 and fail to remedy the deficiency.
Claim Rejections - 35 USC § 102
(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.
Claims 1, 3, 24, 29 and 45-47 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Rieck et al (US 2017/0362572 A1, cited in the IDS filed 04/10/2023; cited previously).
This is a new rejection to address the new limitation introduced into claim 1 which changes the scope of claim 1 (e.g. endocrine progenitor cells).
Regarding claim 1: The claim recites “endocrine progenitor cells”. The instant specification is silent on an explicit definition of “endocrine progenitor cell”. The term is broadly interpreted to encompass any cell which can develop into an endocrine cell, such as an embryonic stem cell. Rieck teach methods of differentiating pluripotent stem cells into functional pancreatic beta cells (p1 [0002]). Example 2 teaches human embryonic stem cells are differentiated SC-beta cells (p31 [0229]). This reads on providing a population of endocrine progenitor cell per the claim interpretation above.
Rieck teach the pluripotent cells (endocrine progenitor cells) are treated with a glycogen synthase kinase-3 beta inhibitor (p12 [0109]). This reads on providing a Six2 positive regulator as required by claim 1, which recites a GSK-3 inhibitor as a Six2 positive regulator.
Rieck teach that the method generates cells for which Six2 expression is increased (Fig 3J). Thus Rieck teach a method which reads on the active steps and structures as disclosed by the instant claim 1.
Regarding claim 3: The teachings of Rieck are discussed supra. Rieck also disclose SC-beta cells have increased metabolic respiration (oxygen consumption) compared to SC-beta cells not incubated with a SIX2 positive regulator (Fig8B; p5 0048)
Regarding claim 24: Rieck disclose Example 2 in which cells treated with the SIX2 positive regulator are assessed for gene expression (p29 0221). Figures 3A-3M demonstrate an increase in the gene expression of a set of maturation markers due to Six2 upregulation. This reads on promoting maturation of the SC-beta cell transcriptome (p30 0225).
Regarding claim 29: The teachings of Rieck are discussed supra. Rieck also teach the population of cells are capable of glucose-stimulated insulin secretion (claim 14).
Regarding claim 45-47: As discussed supra, claim 1 does not recite a stage 6 media. Therefore the components of a stage 6 media are not considered limiting to the invention.
Claim Rejections - 35 USC § 103 (New)
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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Rieck et al as applied to claims 1, 3, 24, 29 and 45-47 above, and further in view of Tan et al (Cytotherapy (2015) 17:1152-1165).
Claims 1, 3, 24, 29 and 45-47 are anticipated by Rieck and thus also rendered obvious, see above.
Regarding claim 2: The claim recites “pancreatic progenitor cell”. The instant specification is silent on an explicit definition of the term. Thus a pancreatic progenitor cells is broadly interpreted to be any cell that can differentiate into a pancreatic cell. Because the method of Rieck is drawn to generating the pancreatic SC-beta cell, any cell that is a progenitor to the SC-beta cell is considered a pancreatic progenitor cell.
The teachings of Rieck are discussed supra. Rieck also teach the EP cells are generated by providing a stem cell (embryonic stem cells) and contacting (culturing) the stem cells with stage 1 media which comprises the GSK-3 inhibitor (p31/32 [0232]). Rieck further teach that during stage 1 the pluripotent stem cells are cultured to induce formation of definitive endoderm cells (p11 [0097]).
Rieck teach a stage 2 medium in which in which the definitive endoderm is cultured to induce formation of primitive gut tube cells (p11 [0098]). Rieck further teach stage 2 medium comprises the FGFR2b agonist FGF7 (p32 [0232]).
Rieck also teach a stage 3 in which the primitive gut tube cells are differentiated into foregut endoderm cells (p11 [0099]). A foregut endoderm cell is considered an early pancreas progenitor cell because it further differentiated into a pancreas cell (SC-beta cell) as discussed in the claim interpretation supra. The stage 3 media comprises the RAR agonist retinoic acid and cells are cultured for two days (p32 [0234]).
Rieck teach culturing the cells for three additional days (Stage 4 of Rieck) (p32 [0234]). Rieck teach stage 4 in which the foregut endoderm cell is differentiated into pancreatic endoderm cells, which is considered a pancreatic progenitor cell (p12 [0100]).
Rieck teach stage 5 in which the media comprises an ALK5 inhibitor (p12 [0101]). Rieck teach stage 5 generates pancreatic endoderm/endocrine precursor cells which are considered endocrine progenitor cells (p12 [0103]).
Rieck do not teach that the media is a serum free media. Rieck do not teach that the stage three media is used for the fourth stage of cell culture.
Tan teach serum-free medium for cells for cell therapies offers advantages compared to serum-supplemented medium such as fewer potential contaminants and less batch-to-batch variability (abstract, p1 col2 ¶2).
It would have been obvious to modify the method of Rieck, drawn to differentiation of stem cells into pancreatic beta cells by using serum free medium as taught by Tan.
One would have been motivated to use serum free medium because Tan teach serum free medium has fewer potential contaminants and more consistency from batch to batch.
One would have had a reasonable expectation of success because Tan teach most serum-free formulations claim equivalent cell population doubling time compared with serum-containing media in monolayer culture and stem cell characteristics such as expression of cell surface markers and differentiation are similar or improved in the serum free medium (p1153 col1 ¶1).
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Rieck as applied to claims 1-3, 24, 27 and 29 above, and further in view of Pagliuca et al (Cell(2014)159;428-439, as cited in the IDS filed 04/10/2023; cited previously).
Claims 1, 3, 24, 29 and 45-47 are anticipated by Rieck and thus also rendered obvious, see above.
Regarding claim 27: The teachings of Rieck are discussed supra. Rieck do not teach the stem cell is an HUES8 embryonic stem cell.
Pagliuca teach use of HUES8 embryonic stem cells in the SC-B differentiation method (p429 Fig1b).
It would have been prima facie obvious to substitute the embryonic stem cells of Rieck with the HUES8 embryonic stem cells taught by Pagliuca because both methods are drawn to generating pancreatic beta cells from embryonic stem cells and both protocols generate SC-beta cells that express SC-beta cell maturation markers that are derived from embryonic stem cells.
There would have been a reasonable expectation that the method of Pagliuca would work equivalently to the method of Rieck due to similarities in the methods which both generate SC-beta cells from embryonic stem cells, and these results would have been predictable.
Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Rieck as applied to claims 1, 3, 24, 29 and 45-47 above, and further in view of Abdelalim et al (World Journal of Stem cells (2015) 7(1) 174-181).
Claims 1, 3, 24, 29 and 45-47 are anticipated by Rieck and thus also rendered obvious, see above.
Regarding claim 26: The teachings of Rieck are discussed supra. Rieck do not teach the GSK-3 inhibitor is CHIR9902.
Abdelalim teach methods of differentiation of pluripotent stem cells into pancreatic beta cells (p313 col1 ¶3). Abdelalim further teach that CHIR99021 improves the percentage of definitive endoderm cells (beta cell precursors) is potente (p313 col2 ¶2). Abdelalim also teach GSK2beta inhibitors have a similar effect (p314 col1 ¶1).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to adapt the method of producing functional beta cells taught by Rieck to use the GSK inhibitor CHIR99021, as taught by Abdelalim, in place of the GSK3beta inhibitor taught by Rieck.
One would have been motivated to use CHIR9921 in place of the GSK3 beta inhibitor because Abdelalim teach CHIR99021 is potent and improves the progenitor population.
One would have had a reasonable expectation of success because both Abdelalim further teach that both CHIR99021 and a GSK3beta inhibitor have similar effects.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Rieck as applied to claims 1, 3, 24, 29 and 45-47 above, and further in view of Millman et al (WO 2019/222487 A1, as cited in the IDS filed 04/10/2023 and cited previously).
Claims 1, 3, 24, 29 and 45-47 are anticipated by Rieck and thus also rendered obvious, see above.
Regarding claim 28: The claim recites “single cell dispersion”. The instant specification is silent on an explicit definition of the term.
Millman teach cells are passaged single cell dispersion are treated with enzymatic digestion (Accutase), counted and seeded at a specific cell density (45 ln10-21). In view of the method disclosed by Millman, single-cell dispersion as recited in the instant claim is interpreted as disruption of cell-cell contacts in cell aggregates to generate single cells and is considered equivalent to a single cell suspension and a suspension containing individual cells.
The teachings of Rieck are discussed supra. Rieck also teach cells may be seeded as droplets of the cell suspension containing individual cells (p19 0166). This reads on single cell dispersion based on the claim interpretation discussed supra.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Rieck as applied to claims 1-3, 24, 27 and 29 above, and further in view of Rickels et al (Endocrine Review(2019)40(2):1-38).
Claims 1, 3, 24, 29 and 45-47 are anticipated by Rieck and thus also rendered obvious, see above.
Regarding claim 30: : The teachings of Rieck are discussed supra. Rieck also teach that a shortage of transplantable islets of Langerhans have focused interest on developing sources of insulin-producing cells, or beta cells, appropriate for engraftment (p1 003).
Rickels teach pancreatic islet transplantation has become an established approach to beta cell replacement therapy for the treatment of insulin-deficient diabetes (abstract).
It would have been obvious for one of ordinary skill in the art at the time of the effective filing date to combine the method of Rieck, to produce beta cells developed from pluripotent stem cells as a source of transplantable islets of Langerhans for therapy for Type I diabetes with the disclosure of Rickels, transplantation of beta-cells to treat insulin-deficient diabetes because it would have been obvious to combine prior art elements according to known methods to yield predictable results.
Combining the method of Rieck of differentiation of SC-beta cells from pluripotent stem cells with the teaching of Rickels, that SC-beta cells represent a source of transplantable islets of Langerhans, and thus would be transplanted into a subject in need thereof would have led to predictable results with a reasonable expectation of success because the method of Rieck is drawn to developing engraftable islets of Langerhans for therapy and Rickels teach that beta-cells such as those developed by Rieck are an established approach to treat insulin-deficient diabetes. One having ordinary skill in the art would understand that differentiation of functional beta-cells from stem cells as taught by Rieck represents a potential method of generating autologous islets of Langerhans for the stem cells of a patient in need thereof.
Response to Arguments
The responses are directed to the Arguments filed 01/26/2026, all arguments have been considered.
Regarding the objections to the drawings:
Replacement sheets 1/19-19/19 are acknowledged. The objection is withdrawn.
Regarding the objections to the claims:
Claim 1 is amended to comprise a full description of the abbreviation "SC-beta cells" at its first occurrence which overcomes the objection. The objection is withdrawn.
Regarding Arguments directed to 35 USC § 112:
Applicant submits claim 1 is amended and complies with the written description requirement. The argument is persuasive; claim 1 has been amended to recite a specific SIX2 positive regulator and this overcomes the rejection as written. The rejection is withdrawn.
Regarding Arguments directed to 35 USC § 102:
Claim 1 has been amended to recite specific SIX2 positive regulators which were previously recited in claim 25 and thus overcomes the rejection as written. The rejection is withdrawn.
Regarding Arguments relevant to the instant rejection:
Applicant submits Rieck fails to disclose a SIX2 positive regulator is
designedly added to EP cells to enable differentiation, maturation, and SIX2-
enhancement of stage 6 product cells (i.e., SIX2-enhanced SC-13 cells).
The independent claim 1 has been amended to require endocrine progenitor cells which, as discussed above, are broadly interpreted to read on any cell which can generate an endocrine cell. Thus method as disclosed by claim 1 is not considered to be limited to a cell of a specific developmental stage as long as the population of cells is an endocrine progenitor (can generate an endocrine cell).In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., stage 6 product cells) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding Arguments directed to 35 USC § 103:
The amendment to the claims overcome the rejection as written and the rejection is withdrawn.
In response to arguments relevant to the instant rejection that the combination of Rieck, Pagliuca, Miralles, Millman, and/or Rickels do not teach or suggest a stage 6 incubation with a SIX2 positive regulator, applicant's argument is that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., stage 6 incubation with a SIX2 positive regulator) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
As discussed above, the independent claim 1 has been amended to require endocrine progenitor cells which, as discussed, are broadly interpreted to read on any cell which can generate an endocrine cell. Thus method as disclosed by claim 1 is not considered to be limited to a cell of a specific developmental stage as long as the population of cells is an endocrine progenitor (can generate an endocrine cell).
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.
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/ANDREA LYNNE MORRIS SPENCER/Examiner, Art Unit 1631
/TAEYOON KIM/Primary Examiner, Art Unit 1631
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