DETAILED ACTION
Applicant’s amendment to the claims in the Response filed on 09/02/2025 is acknowledged.
The objection to the Drawings is withdrawn in view of the approved petition for color drawings under Rule 1.84(a)(2) filed on 09/02/2025.
The objection to the claims is maintained and modified as set forth below.
The rejection of record under 35 U.S.C. § 112(a) is maintained and modified in view of Applicant’s amendment to the claims in the Response filed on 09/02/2025 as set forth below.
Claim Objections
Claims 9-12 are objected to because they have been improperly renumbered. It is noted that a claim numbered “9” was omitted in the claims filed on 12/06/2021. In response, Applicant renumbered claim 10 as claim 9, claim 11 as claim 10, etc. The numbering of claims is not accordance with 37 CFR 1.126, which requires the original numbering of the claims to be preserved throughout the prosecution. See also MPEP 714(II)(C)(B), all claims being currently amended must be presented with markings to indicate the changes that have been made relative to the immediate prior version. The changes in any amended claim must be shown by strike-through (for deleted matter) or underlining (for added matter).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-12 and 24-29 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, the enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
Nature of the Invention and Breadth of the claims:
The claims, as amended, are drawn to a method of producing a mature stem cell-derived β cell by contacting an immature stem cell-derived β cell with an mTOR inhibitor to produce a mature stem cell-derived β cell. Claim 6 recites that the mTOR inhibitor is Torin1. Therefore, the claims together with the specification imply that mature β cells exhibiting increased glucose-stimulated insulin secretion as compared to an immature β cell can be produced from immature β cells by treating the immature β cells with an mTOR inhibitor and specifically, Torin1.
State of the Art and Predictability of the Art:
The state of the art before the effective filing date of the claimed invention describes the role of mTORC in β cell maturation. Ni et al. (Nature Communications, 2017, 8:15755) generated a β cell specific Raptor knockout mice (βRapKO) to investigate the role of mTORC1 in mature β cells (pg. 2, left col., par. 3; right col., par. 2) and found that crucial pathways required for physiologic insulin secretion were preferentially decreased in βRapKO transcriptome (pg. 4, left col., par. 2), thus concluding that loss of Raptor as an essential component of MTORC1 results in a defect in protein/insulin production, reduced GSIS (glucose stimulated insulin secretion) response and secretory vesicle formation/maturation (pg.4, right col., par. 1). Ni discloses that 8-week-old βRapKO islets shared properties with fetal β cells, such as decreased expression of key metabolic genes Glut2 and Pcx, enhanced expression of glycolytic genes Ldha, AldoB and Hk1, as well as reduced ATP production and GSIS (glucose responsiveness) (pg. 6, left col., par. 2). Therefore, ablation of Raptor in adult β cells resulted in a loss of functional maturation, reduced insulin secretion, and such characteristics described above resemble those of poorly responsive neonatal islets.
Sinagoga et al. (Development, 2017, 144, pp. 2402-2414) performed loss-of-function studies of mTOR in the developing endocrine pancreas of a mouse model to study the impact of inactivating mTOR on postnatal islet development (abstract; pg. 2403, left col., par. 3). Sinagoga teaches that mTOR activity is required for normal morphogenesis of the postnatal islet (pg. 2407, right col., par. 5) and observed that mTOR-deficient islets became dysmorphic, β cell maturation and function were impaired and mice lost islet mass (abstract). Sinagoga concluded that mTORC1 and mTORC2 are required for different aspects of islet maturation/function (pg. 2410, right col.).
Therefore, since the state of the art teaches that mTORC1 and mTORC2 mediate the maturation and function of β cells, there is a high level of unpredictability.
The relative skill of those in the art:
The relative skill of those in the art is high.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification describes growing differentiated human induced pluripotent stem cell-derived beta cells on two different conditions, an earlier version which produces stem cell-derived beta cells that secrete insulin in a glucose non-responsive manner and a more recent version which produces insulin-secreting stem cell-derived beta cells in response to high concentrations of glucose compared to low concentrations of glucose (Example 1- pg. 86, lines 15-19). The specification describes enhanced mTORC1 signaling in the non-responsive stem cell-derived beta cells, and the cells were treated with Torin1 for 48 hours to test if mTORC1 activity negatively affects glucose responsiveness of the glucose non-responsive stem cell-derived beta cells (pg. 86, lines 30-34 to pg. 87, lines 1-5). Pathway inhibition with Torin1 in the glucose non-responsive stem cell-derived beta cells by reducing mTORC1 activity induced insulin secretion in response to glucose.
The specification does not describe producing a mature β cell by contacting immature stem cell-derived β cells with an mTOR inhibitor, since working example 1 describes enhancing glucose-responsive insulin secretion in non-responsive β cells, and not immature β cells, by treating the cells with Torin1.
The quantity of experimentation necessary:
Considering the state of the art as discussed above and the high unpredictability and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to use the claimed invention within the broad scope as instantly claimed.
It is the examiner’s position that one skilled in the art could not use the invention commensurate in the scope of the claims without undue experimentation. Therefore, claims 1-13 and 24-29 are rejected under 35 U.S.C. 112(a) for a lack of enablement.
Response to Arguments
Applicant’s arguments filed 09/02/2025 have been fully considered but they are not persuasive. On page 6 of the Response, Applicant urges that “a more mature β cell may be evidenced by its GSIS response” and that the “Application describes treating glucose nonresponsive SC-beta cells with an exemplary mTOR inhibitor, Torin1, thereby increasing the cells GSIS response.”
As discussed above, the Specification demonstrates pathway inhibition with Torin1 in glucose non-responsive stem cell-derived β cells (NR-SC-β-cells) by reducing mTORC1 activity induced insulin secretion in response to glucose. The results do not reasonably demonstrate that Torin1 shifted the NR-SC-β-cells from an immature to mature state; rather, the results suggest that reducing mTORC1 activity via Torin1 increased glucose responsiveness in the mature NR-SC-β-cells. NR-SC-β-cells are nonresponsive cells—not immature cells. Torin1 affected the responsiveness of the NR-SC-β-cells to glucose as opposed to the maturation/differentiation of the NR-SC-β-cells. This is evidenced by the fact that the state of the art, discussed in detail above, teaches that mTORC1 and mTORC2 positively mediate the maturation of β cells.
As such, the rejection of record is maintained.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THOMAS J VISONE whose telephone number is (571)270-0684. The examiner can normally be reached Monday-Thursday, 8:30 AM to 6:30 PM.
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/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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