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 OFFICE ACTION
This Office Action is in response to the papers filed on 21 July 2026.
ELECTION
Applicants’ election with traverse of Group I (Claims 1 and 3-16; drawn to a method of generating hPSC-islets) in the reply filed on 21 July 2026 is acknowledged. Claim 1 has been amended to recite “hPSC-islets”. The claim has been amended to recite the second culture medium is supplemented with ISX9 and Wnt-C59. The Applicant argues Tsakamaki does not teach the technical feature recited in the claims.
In response: Invention V (directed to a kit) does not require a second medium comprising ISX9 and Wnt-C59. Invention V only requires one of a first to seventh culture medium. Therefore the sixth culture medium is the shared technical feature shared technical feature. Pagliuca US20210403876A1 teaches a medium to obtain cells expressing markers characteristic of definitive endoderm (see rejection below). The medium taught by Pagliuca reads on the sixth medium.
The requirement is still deemed proper and is therefore made FINAL.
Claims 17-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
CLAIMS UNDER EXAMINATION
Claims 1 and 3-16 have been examined on their merits.
PRIORITY
PCT/CN2021/134632, filed on 30 November 2021 is acknowledged. A certified translation has not been provided.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 3-16 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1: step (1) recites “the hPSCs”. While the preamble of the claim recites “hPSC-islets” there is a lack of antecedent basis for “the hPSCs”. The metes and bounds of the claim are unclear. Appropriate correction is required. All dependent claims are included in this rejection.
Claim 3 recites “T3”. The metes and bounds of T3 are unclear. If the Applicant means liothyronine sodium, the claim should be rewritten to recite “liothyronine sodium (T3)”. Appropriate correction is required. All dependent claims are included in this rejection.
Claim 13 recites “the seventh culture medium”. There is a lack of antecedent basis for a seventh culture medium in claim 1. The metes and bounds of the claim are unclear. Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
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.
Claims 1, 4-6, 9, 12 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Pagliuca et al. (Stem cell derived differentiation. US20210403876A1 with benefit of 17/171497 filed on 09 February 2021 and PCT/US2019/045985 filed on 09 August 2019) in view of D’Amour et al. (Production of pancreatic hormone–expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24, 1392–1401 (2006) and Karp et al. (Production of Differentiated Enteroendocrine Cells and Insulin Producing Cells. US20170349884).
Pagliuca et al. is directed to stem cell islet differentiation (Title and Abstract). Culture media is used ([0232]).
The art teaches a staged differentiation process comprising (see Figure 39; and [0161]):
differentiating human pluripotent stem cells to produce definitive endoderm (DE);
producing primitive gut tube cells (PGT);
producing Pdx1-positive pancreatic progenitor cells (PP1);
producing Pdx1-positive, NKX6-1-positive pancreatic progenitor cells (PP2);
producing endocrine progenitor cells (EN); and
producing insulin secreting stem cell derived β cell (SC β)
The art teaches the protocol can be modified to produce SC-islets from endocrine progenitor cells ([0141]] Figure 19).
Pagliuca teaches definitive endoderm cells express makers characteristic of definitive endoderm ([0197]). Pagliuca teaches primitive gut tube cells express at least one of HNP1-β, HNF3-β or HNF4-α ([0199]; hence, markers characteristic of primitive gut).
PP1 and PP2 (pancreatic progenitors) express markers characteristic of pancreatic progenitor cells (supra, PDX and NKX6-1). Pagliuca teaches “pancreatic endocrine progenitor” can express at least one of the following markers: Ngn3, NKX2.2, NeuroD, ISL-1, Pax4, Pax6, or ARX (markers characteristic of said cells [0183]). At [0141] Pagliuca teaches markers associated with SC-islets (SC-β cells (NKX6.1+/ISL1+), SC-α cells (GCG+; ARX+; NKX6.1−/ISL1+)).
Pagliuca teaches posterior foregut associated cells expressing PDX1 are differentiated into Pdx1 expressing, NKX6.1 (PP2) expressing pancreatic progenitor cells ([0084]).
Pagliuca differentiates Pdx1+ NKX6.1+ pancreatic progenitor cells to pancreatic endocrine progenitor with a WNT signaling inhibitor ([0034] [0269]). Wnt-059 (C59) is a Wnt signaling inhibitor ([0266]).
The deficiencies are:
Pagliuca teaches primitive gut cells and posterior foregut as intermediates to produce endocrine progenitor cells. The art does not explicitly teach differentiating primitive gut cells to produce posterior foregut.
Pagliuca does not teach Wnt-059 with sufficient specificity to anticipate the claim.
The art does not teach ISX9.
D’Amour et al. differentiate hPSC to produce pancreatic endocrine cells (Abstract; see Figure 1). D’Amour produces the following intermediates using culture mediums: definitive endoderm, primitive gut tube and posterior foregut and pancreatic precursors (progenitors). The following is also taught:
In vivo, the pancreas develops from the definitive endoderm (DE), which forms a primitive gut tube. The pancreas develops from the posterior foregut, emerging as buds from the gut tube (see page 1392, ;eft column, second paragraph). D’Amour teaches the disclosed method is based on developmental biology (page 1393, left column, first paragraph).
Karp et al. form enteroendocrine cells (EECs) by treating with small molecules that are capable of activating and/or deactivating pathways and mechanisms that lead to differentiation into EECs ([0144]). “Enteroendocrine cells” are specialized endocrine cells of the gastrointestinal tract and pancreas ([0086]).
Karp teaches ISX-9, a NeuroD1 activator, promotes insulin and Nkx6.1 expression (see Figure 51; [0014]). Karp teaches Wnt-C59, a Wnt inhibitor, promotes insulin and Nkx6.1 expression (see Figure 52 [0135]). Karp teaches “the combination of Wnt-C59 and ISX-9, increase EEC differentiation” ([0031]).
It would have been obvious to differentiate the primitive gut tube cells taught by Pagliuca to produce the posterior foregut cells. Pagliuca teaches both cells as intermediates and D’Amour teaches culturing primitive gut tube cells in a medium to produce posterior foregut cells. One would have been motivated to do so since D’Amour teaches using differentiation steps which occur in vivo. One would have had a reasonable expectation of success since D’Amour teaches primitive gut tube cells can be differentiated to posterior foregut cells as an intermediate in the same pancreatic development pathway taught by Pagliuca. One would have expected similar results since Pagliuca and D’Amour are both directed to methods of differentiating cells of the pancreatic lineage.
It would have been obvious to culture the pancreatic progenitors taught by Pagliuca in a medium comprising Wnt-C59 and ISX9. Pagliuca treats pancreatic progenitor cells with a Wnt inhibitor and Karp explicitly teaches Wnt-C59 drives progenitor cells toward an endocrine fate. Pagliuca teaches pancreatic endocrine progenitors express NeuroD and Karp teaches ISX-9 is a NeuroD activator. The skilled artisan would use Wnt-C59 and ISX-9 since Karp explicitly teaches combining Wnt-C59 and ISX-9 to increase endocrine differentiation. One would have had a reasonable expectation of success since Karp teaches Wnt-C59 and ISX9 can be combined to enhance endocrine differentiation. One would have expected similar results since Pagliuca and Karp are both directed to endocrine differentiation. Therefore claim 1 is rendered obvious.
Pagliuca teaches contacting Pdx1+ NKX6.1+ pancreatic progenitor cells with a bone morphogenic protein (BMP) signaling pathway inhibitor to produce
pancreatic endocrine progenitor cells ([0269]). Therefore claim 4 is included in this rejection.
Pagliuca contacts primitive gut tube cells with a protein kinase C (PKC) activator to produce Pdx1 expressing pancreatic progenitor cells ([0251]). Therefore claim 5 is included in this rejection.
D’Amour teaches culturing primitive gut tube cells in a medium comprising retinoic acid to produce posterior foregut (Figure 1). Therefore claim 6 is included in this rejection.
Pagliuca teaches primitive gut tube cells are produced by contacting said cells a fibroblast growth factor (FGF) family member (hence, an activator of FGF signaling) ([0250]). Therefore claim 9 is included in this rejection.
Pagliuca teaches definitive endoderm can be produced by culturing in a medium comprising a Wnt signaling pathway activator ([0249]). Therefore claim 12 is included in this rejection.
Pagliuca teaches induced pluripotent stem cells ([0241]). Therefore claim 14 is included in this rejection.
Pagliuca teaches PP2 cells were produced in spinner flask (suspension culture) ([0325]). Therefore claim 15 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claims 7-8 and 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Pagliuca in view of D’Amour and Karp as applied to claims 6 and 9 above, and further in view of Funa et al. (TGF-β modulates cell fate in human ES cell-derived foregut endoderm by inhibiting multiple endogenous signaling pathways. bioRxiv 2021.07.15 pages 1-37).
Claims 6 and 9 are rejected on the grounds set forth about. Differentiating primitive gut tube cells to posterior foregut cells is rendered obvious in view of D’Amour. While Pagliuca teaches Wnt inhibitors, the art is silent regarding their use to differentiate primitive gut tube cells to posterior foregut cells (claims 7-8). Pagliuca does not teach culturing definitive endoderm in a medium comprising a Wnt inhibitor to produce primate gut tube cells (claims 10-11).
Funa et al. determine how exogenously provided factors modulate endogenous signaling events during specification of foregut endoderm lineages (Summary on page 2). Funa teaches TGF-β1 antagonizes endogenous Wnt signaling and suppresses liver- and promotes pancreas fate (same section). Funa teaches TGF-β1 are potent inducers of pancreatic fate when present during development of foregut endoderm and early pancreatic progenitors (see page 4, lines 77-79). The art also teaches blocking Wnt secretion via Porcupine inhibition promoted pancreas differentiation, while suppressing liver differentiation (page 15, lines 404-405).
It would have been obvious to try using TGF-β1 when culturing primitive gut tube cells to produce posterior foregut cells. One would have been motivated to do so since Funa teaches TGF-β1 antagonizes endogenous Wnt signaling to specify pancreatic fate during development of foregut endoderm and early pancreatic progenitors. One would have had aa reasonable expectation of success since Pagliuca, D’Amour and Funa are all directed to pancreatic differentiation. Therefore claim 7 is rendered obvious.
It would have been obvious to use Wnt-C59 to inhibit Wnt. KSR B teaches that it is rational to substitute one known, equivalent element for another to obtain predictable results. Funa teaches a porcupine Wnt inhibitor while Pagliuca and Karp teach Wnt-C59 (a porcupine inhibitor) inhibits Wnt. One would have had a reasonable expectation of success since both porcupine inhibitors suppress Wnt. One would have expected similar results since the references are directed to endocrine cell differentiation. Therefore claim 8 is included in this rejection.
It would have been obvious to try using TGF-β1 when culturing primitive gut tube cells. One would have been motivated to do so since Funa teaches TGF-β1 antagonizes endogenous Wnt signaling to specify pancreatic fate during development of foregut endoderm and early pancreatic progenitors. One would have had aa reasonable expectation of success since Pagliuca, D’Amour and Funa are all directed to pancreatic differentiation. Therefore claim 10 is rendered obvious. Claim 11 is rejected on the same grounds as claim 8.
Therefore Applicant’s invention is rendered obvious as claimed.
Claims 3, 13 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Pagliuca in view of D’Amour and Karp as applied to claims 1 and 15 above, and further in view of Pagliuca et al. (Generation of Functional Human Pancreatic β Cells In Vitro. Cell. 2014 Oct 9;159(2):428-39).
Claims 1 and 15 are rejected on the grounds set forth above. The teachings of the prior art are reiterated. Pagliuca teaches pancreatic endocrine progenitors can be cultured to produce islets.
The art does not teach culturing in a media comprising an ALK5 inhibitor or T3 (instant claim 3).
Pagliuca teaches the disclosed method can use the following routine tissue culture components: basal medium, glucose, L-glutamine and B27 ([0232]). Pagliuca teaches the use of Actin A ([0249]) to produce definitive endoderm cells ([0249]). The reference is silent regarding vitamin C (instant claim 13).
Pagliuca teaches a spinner culture (suspension). The art does not teach suspension culture for the steps recited in instant claim 16.
Pagliuca (2014) teaches a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro (Summary section). It is noted Figure 1 discloses the same differentiation steps as Figure 39 of the Pagliuca Patent (see pathway marked “New Differentiation”). Pagliuca treats pancreatic endocrine progenitors (EN) with T3 and Alk5i to produce SC-β cells.
It would have been obvious to culture pancreatic endocrine progenitors in a medium comprising Alk5i and T3. Pagliuca (‘876) differentiates pancreatic endocrine progenitors to produce islets and Pagliuca (2014) cultures pancreatic endocrine progenitors with Alk5i and T3. One would have been motivated to do so since Pagliuca (2014) teaches the disclosed method increases glucose-responsive β cells from hPSC in vitro. One would have had a reasonable expectation of success since Pagliuca (2014) teaches endocrine progenitors can be cultured with Alk5i and T3. One would have expected similar results since both Pagliuca references differentiation HPSCs using the same pathway. Therefore claim 3 is rendered obvious.
Pagliuca (2014) teaches vitamin C is used at each differentiations stage (see “Extended Experimental Procedures, page 13 section following the first paragraph).
It would have been obvious to combine vitamin C with the media components taught by Pagliuca (‘876). One would have been motivated to do so since Pagliuca (2014) teaches vitamin C is used at each stage of differentiating hPSCs to pancreatic cells in vitro. One would have had a reasonable expectation of success since Pagliuca (2014) teaches vitamin C can be used to culture cells at all stages. One would have expected similar results since both references are directed to methods of making pancreatic cells in vitro. Therefore claim 13 is rendered obvious as claimed.
Pagliuca (2014) teaches a suspension-based culture system that can generate >108 hPSCs and later differentiated cell type (first paragraph of Results section on page 3). Clusters of human pluripotent stem cells were induced into definitive endoderm and subsequently early pancreatic progenitors in Figure 1A (first paragraph of Results section on page 3). This reads on steps 1-3.
It would have been obvious to perform steps 1-3 in suspension culture. Pagliuca (‘876) differentiates human pluripotent stem cells into definitive endoderm and subsequently early pancreatic progenitors and Pagliuca (2014) teaches each of the steps can be performed in suspension culture. One would have been motivated to do so since Pagliuca (2014) teaches doing so to produce a large number of cells. One would have had a reasonable expectation of success since Pagliuca (2014) the steps can be performed in suspension. One would have expected similar results since both references are directed to methods of making pancreatic cells in vitro. Therefore claim 16 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 270-8439.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
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