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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 16-39, in the reply filed on 12/12/2025 is acknowledged.
Claims 40-63 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/12/2025.
Drawings
The drawings are objected to because Figures 1, 6-11 cannot be evaluated due to the use of symbols to represent different conditions that in grayscale are hard to distinguish from each other. The tSNE plots in the figures cannot be evaluated in gray scale. Correlation graphs, such as Figure 6, 7 etc., maybe corrected by identifying each condition using a different shaped symbol and/or different lined fills within the symbol. This was allow for evaluating which protocol resulted in the data points shown in these plots.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: Table 3 on page 32 is missing data for the ACVR1C gene.
Appropriate correction is required.
The incorporation of essential material in the specification by reference to an unpublished U.S. application, foreign application or patent, or to a publication is improper. "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. 37 CFR 1.57(d).
Applicant is required to amend the disclosure to include the material incorporated by reference, if the material is relied upon to overcome any objection, rejection, or other requirement imposed by the Office. The amendment must be accompanied by a statement executed by the applicant, or a practitioner representing the applicant, stating that the material being inserted is the material previously incorporated by reference and that the amendment contains no new matter. 37 CFR 1.57(g).
In example 1, the specification incorporates essential material by reference to non-U.S. patent or non-U.S. patent application publication - WO/2012/175633, WO2014/033322, WO2015/028614, WO2017/144695. These references are relied upon to teach the protocol used to generate the claimed beta like cells and are thus essential to provide a written description of the claimed invention, particularly the methods for making the claimed cells.
Claim Objections
Claims 17, 20 are objected to because of the following informalities: Claims 17 and 20 recite BASP instead of BASP1, as correctly recited in claim 16, 26 and 35. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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.
Claim(s) 16-21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Melton et al (WO 2019/217493 A2, Published November 14, 2019; IDS 2/22/2023).
Regarding claim 16-18, 20, Melton teach an in vitro population of beta cells derived from human stem cells (SC-beta cells =claimed beta like cells) that express NKX6.1 (Example 1; Figure 1A, B, E; page 80-para 2) and also express each of the markers recited – ACVR1C, MARCKSL1, BASP1, STARD10, AMBP, ST6GALNAC5, HMGCS1, SOX11, FREM2, DCC (Table 44; see Table below that shows the exact page number from Melton where each marker is identified, their expression level in the SC-beta cells and human beta cells as well as log2 fold change as shown in Melton). As can be seen from Melton’s data (copied below in the Table), each of the markers have an expression level of at least about 1 average fold change more than the expression level of each marker in native human beta cells. Melton also teaches that their SC-beta cells are functional as they produce insulin in a glucose responsive manner and stain positive for C-peptide 8 weeks after being transplanted in vivo (Figure 2, 3E). C-peptide is a fragment of insulin used as a proxy for insulin production (page 80-para 2). Thus, Melton SC-beta cells are capable of maintaining insulin expression and secretion after in vivo transplantation.
Of note, definition for “about” was provided in the specification on page 18 as “As used herein the term "about" means plus or minus 10%, such as plus or minus, 5% unless indicated otherwise”.
Regarding claims 19 and 21, Melton teaches that their SC-beta cells also express G6PC2 (Figure 35, Table 44; see Table below that shows the exact page number from Melton where G6PC2 is identified).
Therefore, Melton anticipates the claimed invention.
Marker
Page# Melton
Expression (tpm) Stage 6 SC-beta cells (all weeks, v8)
Expression (tpm) Human islet beta cells (Baron et.al)
fold change
Log2FC
NKX6.1
224
406.9
247.35
1.65
0.72
ACVR1C
92
1600.47
24.79
64.56
6.01
MARCKSL1
206
1409.75
7.25
194.45
7.60
BASP1
108
673.89
2.55
264.27
8.05
STARD10
294
205.69
102.29
2.01
1.01
AMBP
97
40.08
1.38
29.04
4.86
ST6GALNAC5
294
191.69
6.63
28.91
4.85
HMGCS1
181
227.84
17.19
13.25
3.73
SOX11
290
328.57
1
328.57
8.36
FREM2
166
5.52
1
5.52
2.46
DCC
141
67.3
1
67.30
6.07
G6PC2
167
35.59
672.7
0.05
-4.24
Claim Rejections - 35 USC § 102/103
The text of those sections of Title 35, U.S. Code not included in this section can be found above.
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.
Claim(s) 22-39 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Melton.
The teachings from Melton, as detailed in the U.S.C. 102 rejection above, are relied upon for the instant rejection.
Melton teaches an in vitro population of beta cells derived from human pluripotent stems with each of the markers recited in the claims (Example 1, Figure 1, Table 44).
Regarding the average fold change recited in claims 23, 25, 29, Melton teaches that ACVR1C, MARCKSL1 and AMBP markers are expressed at least 2 average log fold change more in their SC-beta cells in comparison to human beta cells (Table 44; see Table above that shows the exact page number from Melton where each marker is identified, their expression level in the beta like cells and human beta cells as well as log2 fold change as shown in Melton).
Regarding claims 22, 24, 26-28, 30-39, each of these recite the percent of cells within the population of beta like cells that express each marker. Claims 23, 25, 29 depend from claims 22, 24 and 28 respectively.
Melton is silent regarding the percentage of cells within their population of SC-beta cells that express each marker. The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not the SC-beta cells of Melton are patentable distinct, and if so to what extent, from applicant’s beta like cells.
Melton teaches that their in vitro population of SC-beta cells was derived from step-wise differentiation of human pluripotent stem cells using protocols known in the art (page 52, 53; Figure 13). They performed two variants of the step wise protocols known in the art (Figure 13), each of which resulted in SC-beta cells with similar gene expression profile albeit a different amount/percent of SC-beta cells were produced (page 81, 82- bridging para; Figure 6). They performed single cell RNA sequencing on the cells differentiated using these protocols and identified a SC-beta cell population (page 67-68, bridging para). They provide a detailed transcriptional profile of these SC-beta cells using their single cell RNA sequencing and teach that this data can be used to identify markers for SC-beta cells (Table 44; page 68, para 1; page 71, para 1). Finally, Melton teach that their SC-beta cells express each of the claimed markers at expression levels claimed.
In comparison to Melton’s SC-beta cells and methods for producing SC-beta cells, Applicant also produces their beta like cells using step-wise differentiation of human pluripotent stem cells using protocols known in the art (Example 1; page 28-last page). Same as Melton, Applicant also show that each protocol variant produced beta like cells albeit at different amount/percent (Figure 1, page 29-para 1). Applicant show that the amount of human C-peptide produced in vivo after transplantation was positively correlated with the amount of beta like cells produced by each protocol variant – in other words if a protocol produced more beta like cells then it produced cells that produce more C- peptide (Figure 6). Similar to Melton, Applicant performed single cell RNA sequencing on the cells differentiated using these protocols in the prior art and identified a beta like cell population, in clusters 14, 15 and 26, by comparing their transcriptional profile to human beta cells (Figure 2). Unlike Melton, Applicant do not provide the data set produced by their single cell RNA sequencing. A summary Table 3 of Genes unique to their beta like cells is provided in which the Applicant teach the claimed markers. In example 4, Applicant state that ACVR1C was expressed in more than 99% of beta like cells (page 34, para 1). In example 6, Applicant state that G6PC2 was expressed in native human beta and alpha cells, and a subset of cells within beta like cells (exact % not disclosed; page 35, para 3). Applicant do not provide data showing the % cells in beta like cells (clusters 14, 15 and 26) that express any of the markers claimed, other than ACVR1C. Melton also teaches ACVR1C and G6PC2 as specific markers for their SC beta cells (Figure 35).
Taken together, Melton’s SC beta cells and claimed beta like cells appear patentably indistinct.
Where an examiner cannot determine whether or not the reference inherently possesses properties which anticipate, or render obvious, the claimed invention a rejection under §§102/103 is appropriate. See MPEP §§ 2112-2112.02.
The cited art taken as a whole demonstrates a reasonable probability that Melton’s SC-beta cells is either identical or sufficiently similar to the claimed beta-like cells that whatever differences exist, they are not patentably significant. Therefore, the burden of establishing novelty or non-obviousness by objective evidence is shifted to applicants. See MPEP § 2112(v). Clear evidence that SC-beta cells of the cited prior art does not possess a critical characteristic that is possessed by the claimed beta like cells would advance prosecution and might permit allowance of claims to applicant’s claimed product. Applicant is requested to specifically point out the support for any amendments made to the disclosure and arguments in response to this Office Action, including the claims. See MPEP §§ 714.02 and 2163.06. Applicant is also requested to refer to pages and line numbers in the as-filed specification. It is noted that other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Therefore, the invention as a whole was either anticipated or 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.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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/MATASHA DHAR/Examiner, Art Unit 1632