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 with traverse of Group I (Claims 1-4, 7-18, and 20-21; drawn to a method for producing insulin-producing cells by differentiating pluripotent stem cells into insulin-producing cells) in the reply filed on February 3, 2025, is acknowledged.
Claims 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II and III), there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on July 24, 2026, have been acknowledged. Claims 5-6, 19, and 22 were cancelled. Claim 1 was amended. Claims 25-26 are new. In light of the Applicant’s elected invention, claims 23-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-4, 7-18, 20-21, and 25-26 are pending and examined on the merits.
Applicant’s response has been considered. Rejections and/or objections not reiterated from the previous office action mailed April 13, 2026, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).The applicant claims foreign priority from JP2019-126861 filed on July 8, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received January 6, 2022. A certified English translation of said foreign patent application was provided on July 9, 2025. Claims 1-4, 7-18, 20-21, and 25-26 find support in JP2019-126861 filed on July 8, 2019.
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.
Claim 1-4, 7-18, 20-21, and 25-26 are rejected under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, as based on a disclosure which is not enabling. The disclosure does not enable one of ordinary skill in the art to practice the invention without the identifying the individual culture steps, including the concentration of the components in the media used in each culture step and the timing of each culture step, involved in the step-wise differentiation of pluripotent stem cells into insulin-producing cells, which is/are critical or essential to the practice of the invention but not included in the claim(s). See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976). This is a new rejection that is substantially similar to a previous rejection of record made in response to Applicant’s amendments to claim 1 and addition of new claims 25-26. Applicant’s traversal is addressed below.
The factors to be weighed to evaluate whether a disclosure satisfies the enablement requirement and whether any necessary experimentation is undue are set forth in MPEP 2164.01(a).
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Although all the factors have been considered, the relevant factors will be addressed below.
Breadth of the claims: Claim 1 recites the following claim language, “A method for producing insulin-producing cells by differentiating pluripotent stem cells into insulin-producing cells, steps 1 to 5 below, and at least one step selected from the group consisting of step 3, step 4 and step 5 comprises culturing cells in a medium containing the compound represented by formula (I) or a salt thereof: step 1 of inducing definitive endoderm cells from pluripotent stem cells; step 2 of inducing primitive gut tube cells from the definitive endoderm cells; step 3 of inducing pancreatic progenitor cells from the primitive gut tube cells; step 4 of inducing pancreatic endocrine progenitor cells from the pancreatic progenitor cells; and step 5 of inducing insulin-producing cells from the pancreatic endocrine progenitor cells, in a medium containing a compound represented by formula (I)”. The broadest reasonable interpretation is that this method could be done with any culturing steps and media that are used for each individual culture step.
Nature of the invention: The subject matter of the invention relates to a method to differentiate pluripotent stem cells into insulin-producing cells by culturing cells with a compound of Formula (I).
State of the prior art: The prior art teaches that a multi-step procedure is required for generating insulin-producing cells from pluripotent stem cells and that the media composition and timing of the culture are important considerations for achieving differentiation of stem cells to insulin-producing cells.
Silva et al. (Stem Cell Research & Therapy 13: 1-24. 2022) discloses that protocols to differentiate pluripotent stem cells into insulin-producing cells have been designed using consecutive cytokines or signaling modulators treatments, in specific doses, to activate or inhibit the main signaling pathways that control the differentiation of iPSCs into pancreatic β-cells, namely Wnt; Nodal/Activin A; BMPs; FGF; EGF (epidermal growth factor); Hedgehog; retinoid; and Notch. Obtaining mature insulin-producing cells in vitro depends on a refined control of concentration, time and duration of treatment with the defined growth and differentiation factors (page 8, column 2, paragraph 3). Silva discloses that the differentiation protocol must undergo a step-by-step process of differentiating pluripotent stem cells into definitive endoderm, differentiating definitive endoderm into a pancreatic precursor, differentiating a pancreatic precursor into an endocrine precursor, and differentiating an endocrine precursor into an insulin-producing cell (page 8, column 2, paragraph 4-page 12, column 2, paragraph 2 and Figure 2). Each differentiating step requires specific differentiation factors to ensure the cells differentiate into the proper cell type (Table 3). Table 3 identifies the differentiation protocols from 16 different studies that differentiated pluripotent stem cells into insulin-producing cells. As can be seen in Table 3, each of the 16 studies used a different protocol for differentiating stem cells into insulin-producing cells with a range of outcomes. All 16 studies performed multistep differentiation protocols to generate insulin-producing cells with distinct differentiation steps, media compositions at each step, and timing for each step (Table 3). Many of the protocols generated immature mixed populations of cells at different developmental stages, displaying polyhormonal properties and, additionally, IPCs-transplanted mice usually maintain euglycemia for only a short period of time or present a compromised GSIS dynamics. As part of this, Silva identifies that a standardized differentiation protocol is still lacking, and the final differentiation stages also need to be better understood (page 8, column 2, paragraph 4-page 17, column 2, paragraph 3).
Schroeder et al. (Nature Protocols 1: 495-507. 2006) identifies that some pancreatic differentiation protocols promote the differentiation of pancreatic and neuronal cells and that this can lead to unsuccessful controlled insulin release and functional parameters, such as insulin-positive secretory granules, in the differentiated cells. Some differentiation protocols have used retinoic acid (RA, alone or in combination with activin A), activin A alone or soluble factors from conditioned medium of fetal pancreatic buds. RA, a strong teratogen, has been shown to induce ES cells — dependent on the concentration and treatment time — to differentiate into various cell types, including neuronal, cardiac and smooth muscle cells. Furthermore, D’Amour found that endodermal differentiation by activin A apparently requires a sophisticated application scheme as flow-cytometry sorting to obtain definitive endoderm progenitor cells failed to show that this population can differentiate into insulin-producing cells (page 495, column 1, paragraph 1-page 496, column 1, paragraph 4).
Wong et al. (Experimental Diabetes Research 2011: 1-15. 2011) identifies that there is a wide variation between media compositions and induction periods with each media composition for different protocols (see Table 2), For example the Segev protocol differentiates human embryonic stem cells into insulin-producing cells over 25 days or longer while the Jiang protocol also differentiates human embryonic stem cells into insulin-producing cells over 18 days using different media compositions and induction periods compared to the Segev protocol. There have also been varying results between protocols that use the same compound. Low concentrations of EGF and bFGF are used in the culture of stem cells. High concentrations of EGF and bFGF, either used alone, or in combination, have been shown to be useful in IPC differentiation in some studies. On the contrary, Dalvi demonstrated that when human pancreatic islets were exposed to medium containing a high concentration of EGF (50 ng/mL), such populations demonstrated a high degree of proliferation. Removal of EGF from the medium resulted in the formation of islet-like cell aggregates. This phenomenon was also supported by Cras-Meneur et al. who demonstrated that EGF increased undifferentiated pancreatic embryonic cells in vitro. Therefore, a careful use of EGF may be important in successful IPC differentiation and will be dependent on the protocol being used. The wide variations in induction techniques and sources of stem cell used may be a challenge to researchers as there is no standard method for IPC generation. A careful choice of stem cell and induction method is necessary for successful IPC differentiation (page 5, column 2, paragraph 3-page 12, column 2, paragraph 1).
As such, the prior art shows that a careful consideration of the media components, concentration, and induction time associated with each differentiation step is important for successful differentiation of stem cells into insulin-producing cells.
Level of predictability in the art: The prior art has successfully reduced to practice that a multistep differentiation protocol with refined control of media components, concentration, and duration of treatment with defined growth and differentiation factors is required to generate insulin-producing cells from pluripotent stem cells. As such, this results in unpredictability about how someone can use this method to differentiate stem cells without defining the concentration of the defined growth and differentiation factors and induction times associated with each step of the multistep differentiation protocol of claim 1.
Amount of direction provided by the inventor and existence of working examples: The Applicant discloses that they used defined protocols for differentiating different pluripotent stem cell types into insulin producing cells.
The SK7 mouse ES cells were differentiated into β cells basically according to the previous report (Nakashima et al., 2015). Briefly, the cells were seeded at 5,000 cells per well in CellBIND 384-well cell culture plate or at 20,000 cells per well in a 96-well plate coated with 0.2% gelatin.
Then, the cells were cultured in medium 1 from days 1 to 5. Medium 1 consisted of DMEM (high glucose) supplemented with 0.1 mM NEAA, 2 mM L-glutamine, 100 U/mL penicillin-streptomycin, 0.01 mM β-mercaptoethanol, 1% insulin-transferrin-selenium supplement (ITS), 0.25% Albumax, and 10 ng/mL recombinant human activin-A.
Subsequently, the cells were cultured for 1 day in medium 2 which consisted of medium 1 supplemented with 10 μM retinoic acid.
On day 6, the medium was replaced with medium 3, and the culture was continued until day 12 in order to induce differentiation into β cells. Medium 3 consisted of DMEM (low glucose) supplemented with 0.1 mM NEAA, 2 mM L-glutamine, 100 U/mL penicillin-streptomycin, 0.1 mM β-mercaptoethanol, 1% ITS, 0.25% Albumax, and 3 mM nicotinamide.
The Toe human iPS cells were seeded in CellBIND 6- well cell culture plate coated with synthemax II, and differentiated into primitive gut tube cells by the previously described method (Shahjalal et al., 2014). The cells were dissociated with TrypLE Select and cryopreserved in BamBanker at a density of 1.0 to 2.0 x 107 cells/mL until use.
One day before compound addition, the cells were thawed in a medium for stage 3 (DMEM (high glucose), 0.25 M SANT1, 0.1 μM LDN193189, 10 pMSB431542, 2 μM retinoic acid, 1% B27-free serum supplement, and seeded at 150,000 cells per well in CellBIND 96-well cell culture plated coated with synthemax II. The cells were cultured for 1 day in a medium for stage 3 containing a test compound or a negative control (0.01% DMSO). The cells were further cultured for 2 days and 1 day in media for stages 4 (DMEM high glucose, 0.1 μM LDN193189, 5 μM TGF-3 type I receptor kinase inhibitor II, 0.3 μM (-)-indolactam V, 1% B27 serum free supplement) and 5 (GLP-1 receptor agonist and nicotinamide-free; Knockout DMEM/F-20, 1% B27 serum free supplement), respectively, containing the test compound or the negative control.
The RPChipS771 cells were differentiated according to protocol #1. Briefly, on day 0, the cells were dissociated with TrypLE Select, transferred at a concentration of 1 x 106 cells/mL in Essential 8 medium to a low-attachment 6-well plate, and cultured on a rotary shaker (95 rpm). On day 1, the medium was replaced with methionine-depleted medium KA01, and the cells were cultured for 5 hours.
The medium was replaced with differentiation medium 1 (DMEM (high glucose), L-Gln, NEAA, 0.01 mM β-mercaptoethanol, 100 ng/mL activin A, B27 supplement, 3 μM CHIR99021), and the cells were cultured for 1 day (stage 1-1).
Then, the medium was replaced with medium 1 free from CHIR99021, and the cells were cultured for 2 days (stage 1-2).
The cell culture was continued for 2 days in medium 2 (RPMI, L-Gln, NEAA, 0.01 mM β-mercaptoethanol, insulin-depleted B27 supplement, 50 ng/mL FGF10, 0.25 pM SANT1) (stage 2),
for 6 days in medium 3 (DMEM (high glucose), L-Gln, NEAA,
0.01 mM β-mercaptoethanol, 0.15 pM SANT1, 2 pM retinoic acid, 0.1 pM LDN193189, B27 supplement) (stage 3),
for 2 days in medium 4 (DMEM (high glucose), L-Gln, NEAA, 0.01 mM 0-mercaptoethanol, 5 μM ALK5 inhibitor (Calbiochem, 616452), 0.3 μM indolactam V, 0.1 μM LDN193189, B27 supplement) (stage 4),
and for 13 days in medium 5 (KO DMEM/F12, L-Gln, NEAA, 0.01 mM β-mercaptoethanol, 50 ng/mL exendin 4, 10 mM nicotinamide, 10 pM ZnSO4, 1 mM N- acetyl-L-cysteine, B27supplement) (stage 5).
The FfI-01s01 cells were differentiated according to protocol #2. Briefly, the cells were dissociated with TrypLE Select, transferred at a concentration of 1 x 106 cells/mL in AK03N medium to a low-attachment 6- well plate, and cultured for 24 hours on a rotary shaker (95 rpm). Then, the medium was replaced with AK03N-based methionine-depleted medium KA01, and the cells were cultured for 5 hours. Then, the medium was replaced with M1-1 AKM medium, and the cells were cultured for 24 hours (stage 1-1). The cells were cultured for 2 days in M1-2 AKM medium (stage 1-2), subsequently cultured for 2 days in M2 AKM medium (stage 2-1), cultured for 2 days in S2 medium (stage 2-2), cultured for 2 days in S3 medium (stage 3), cultured for 5 days in S4 medium (stage 4), cultured for 4 days in 55-1 medium (stage 5-1), and cultured for 3 days in 55-2 medium (stage 5).
AKM medium is insulin- and Zn2+-depleted StemFit Basic 03 medium.
M1-1 AKM medium: AKM (100 ng/mL IGF1, 0.5 μM Zn) medium supplemented with 100 ng/mL activin A and 3 pMCHIR990221
M1-2 AKM medium: AKM (100 ng/mL IGF1, 0.5 μM Zn) medium supplemented with 100 ng/mL activin A
M2 AKM medium: AKM (0.5 μM Zn) medium supplemented with 50 ng/mL FGF10 and 250 nM SANT1
S2 medium: StemFit Basic 03 supplemented with 50 ng/mL KGF and 44 μg/mL vitamin C
S3 medium: StemFit Basic 03 supplemented with 50 ng/mL KGF, 50 nM indolactam V, 2 pM retinoic acid, 250 nM SANT1, and 44 μg/mL vitamin C
S4 medium: StemFit Basic 03 supplemented with 50 ng/mL KGF, 100 nM retinoic acid, 250 nM SANT1, 44pg/mL vitamin C, and 100 nM LDN193189
S5-1 medium: StemFit Basic 03 supplemented with 10 μM ALK5 inhibitor, 10 μM DAPT, 33.3 ng/mL EGF, 100 nM retinoic acid, 1 μM T3, and 44 μg/mL vitamin C
S5-2 medium: StemFit Basic 03 supplemented with 10 μM ALK5 inhibitor, 10 μM DAPT, 33.3 ng/mL EGF, 25 nM retinoic acid, and 1 μM T3 (paragraphs 0312-0334).
As can be seen in Applicant’s examples, each of the 4 stem cell lines used a different multi-stage differentiation protocol with specific differentiating compounds and time frames that are essential to producing insulin-producing cells.
As such, the method of differentiating pluripotent stem cells into insulin-producing cells of the instant application requires a defined step-wise differentiation protocol associated with each cell line that is not disclosed in claim 1.
Quantity of experimentation needed: In light of the above factors, the prior art and the Applicant disclose several multi-step differentiation protocols and that the media composition and timing of each step is an important consideration for each cell line. Therefore, a defined differentiation protocol is necessary to generate insulin-producing cells from pluripotent stem cells. As such, these essential steps are considered to be missing from claim 1. There would be undue experimentation related to any culturing method that does not have a defined multistep differentiation protocol in line with the prior art and the Applicant’s specification to practice the full scope of the claim.
Claims 2-4, 7-18, 20-21, and 25-26 are also rejected because of their dependency on claim 1.
Response to Arguments
Applicant's arguments filed July 24, 2026, are acknowledged.
Applicant argues that the amendments to claim 1 to specify the media components in each of steps 1-5 overcome the rejection (page 24, paragraph 6-page 25, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
Although Applicant has identified the media components, the claims still lack the concentration of the components and the timing for each step which are considered essential to the practice of the invention but not included in the claims. Therefore, the amendments fail to overcome the rejection as newly written.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 7-17, 20-21, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11530211. Although the claims at issue are not identical, they are not patentably distinct from each other. This is a new rejection that is substantially similar to a previous rejection of record made in response to Applicant’s amendments to claim 1 and addition of new claim 25. Appilicant’s traversal is addressed below.
‘211 teaches the same genus of compounds that fall within Formula (I) in claims 1-14 of ‘211. ‘211 does not disclose that the compounds are cultured in a media for generating insulin-producing cells from pluripotent stem cells. However, MPEP 804(II)(B)(1) states that those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). The court pointed out that "this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined." In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
In this regard, the specification of ‘211 discloses that as a result of diligent studies, the inventors have found that a compound represented by formula (I) or a salt thereof has a remarkable effect of promoting induction of differentiation from pluripotent stem cells into insulin-producing cells, and further the compound or a salt thereof is useful for producing insulin-producing cells, thereby accomplishing the present invention. The compound of the present invention has a new structure that is completely different from known differentiation inducers and exerts an effect of further enhancing the efficiency of the induction of differentiation in the later steps of the differentiation process more than known differentiation-promoting compounds and growth factors (column 6, line 60-column 7, line 9). As such, this represents the utility of the compound of ‘211 and is allowed to be considered for non-statutory double patenting. Therefore, in light of the utility information from the specification of ‘211, claims 1-16 are rejected for non-statutory double patenting.
Experimental Example 1 of ‘211 discloses that they differentiated induced pluripotent stem cells into insulin-producing cells. ‘211 discloses that they used the method of Nakashima (NPL document 6) to differentiate iPSCs into pancreatic β cells. As part of this process, they used a 5 step differentiation process wherein the five stages are: stage 1 in which Sox17-positive definitive endoderm cells are induced from pluripotent stem cells, stage 2 in which Foxa2-positive primitive gut tube cells are induced from the definitive endoderm cells, stage 3 in which PDX1-positive pancreatic progenitor cells are induced from the primitive gut tube cells, stage 4 in which Ngn3-positive pancreatic endocrine progenitor cells are induced from the pancreatic progenitor cells, and stage 5 in which insulin-producing cells are finally induced from the pancreatic endocrine progenitor cells. In Experimental Example 1, the compound is added at stages 3-5. ‘211 discloses that the medium used in each differentiation stage was also produced with reference to known information (differentiation media A to E (Media A to E) described in Non Patent Document 6 (Nakashima et al. Neural cells play an inhibitory role in pancreatic differentiation of pluripotent stem cells. Genes Cells, 20: 1028-1045, 2015) were used respectively for stages 1 to 5; however, a medium free from GLP-1 receptor agonist and nicotinamide was used as differentiation medium E). Nakashima identifies that embryonic stem cells were first exposed to an activin-containing Medium 1 for 4 days to trigger definitive endoderm differentiation. The medium was switched to retinoic acid (10 μM)-containing Medium 2 on day 5 (page 1029, column 2, paragraph 1). ‘211 discloses that post stage 2 cells were suspended in differentiation medium C for stage 3 (DMEM high glucose (Life technologies, 11965092), 0.25 μM SANT-1, 0.1 μM LDN193189 (Stemgent, 04-0074), 10 μM SB431542, 2 μM Retinoic acid (Stemgent, 04-0021), 1% B27 serum free supplement (Life technologies, 17504044) and thereafter seeded in a 96-well plate (Corning, #3340) coated with Synthemax II (Corning, #5656) at 1×105 cells/well. After culturing for 2 days, the medium was removed, and new differentiation medium C for stage 3 with the compound. After culturing for 2 days, the medium was removed, and new differentiation medium D for stage 4 (DMEM high glucose, 0.1 μM LDN193189, 5 μM TGF-β type I receptor kinase inhibitor II (Calbiochem 616452), 0.3 μM (−)-indolactam V (Enzo life science ALX-420-011-C300), 1% B27 serum free supplement) with the compound or only DMSO added was added thereto at 100 μL/well. In stage 5, a medium containing GLP-1 receptor agonist or nicotinamide is generally used for culture (Experimental Example 1 and column 43, line 46-column 44, line 24).
Response to Arguments
Applicant's arguments filed July 24, 2026, are acknowledged.
Applicant argues that the claims of the reference patent are directed solely to compounds and related composition and not all to a method for producing insulin-producing cells. Moreover, the reference patent fails to teach the specified five step process with the identified media components (page 27, paragraphs 2-3).
Applicant's arguments have been fully considered but they are not persuasive.
As stated in double patenting rejection above, ‘211 teaches the same genus of compounds that fall within Formula (I) in claims 1-14 of ‘211. ‘211 does not disclose that the compounds are cultured in a media for generating insulin-producing cells from pluripotent stem cells. However, MPEP 804(II)(B)(1) states that those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). The court pointed out that "this use of the disclosure is not in contravention of the cases forbidding its use as prior art, nor is it applying the patent as a reference under 35 U.S.C. 103, since only the disclosure of the invention claimed in the patent may be examined." In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003).
In this regard, the specification of ‘211 discloses that as a result of diligent studies, the inventors have found that a compound represented by formula (I) or a salt thereof has a remarkable effect of promoting induction of differentiation from pluripotent stem cells into insulin-producing cells, and further the compound or a salt thereof is useful for producing insulin-producing cells, thereby accomplishing the present invention. The compound of the present invention has a new structure that is completely different from known differentiation inducers and exerts an effect of further enhancing the efficiency of the induction of differentiation in the later steps of the differentiation process more than known differentiation-promoting compounds and growth factors (column 6, line 60-column 7, line 9). As such, this represents the utility of the compound of ‘211 and is allowed to be considered for non-statutory double patenting. Therefore, in light of the utility information from the specification of ‘211, claims 1-4, 7-17, 20-21, and 25 are rejected for non-statutory double patenting based on the disclosures of ‘211 outlined above.
Therefore, the non-statutory double patenting rejection is considered proper as the proposed utility of the ‘211 compound makes obvious the method of the instant application.
Regarding the amendments to the claims and the identified media compositions, this has been addressed in the rejection above.
Claims 1 and 18 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11530211 as applied to claim 1 above and further in view of Nakashima et al. (Genes to Cells 20: 1028–1045. 2015; cited in IDS). Although the claims at issue are not identical, they are not patentably distinct from each other. This rejection is repeated with regards to the Final Office action mailed on September 23, 2025. Applicant’s traversal has been addressed above.
The teachings of ‘211 are as discussed above.
‘211 does not disclose that low-adhesive or non-adhesive culture containers are used.
Nakashima teaches that as part of the process of differentiating embryonic stem cells into pancreatic β-cells (i.e. insulin-producing cells), they formed embryoid bodies in liquid suspension culture (page 1041, column 1, paragraph 4-column 2, paragraph 1). As such, a liquid suspension culture would be performed in low-adhesive or non-adhesive culture containers to maintain the cells in suspension and not cause adherent culture.
As such, it would have been obvious that the three-dimensional culturing could be performed in a low-adhesive or non-adhesive culture container to generate embryoid bodies in suspension culture for differentiating pluripotent stem cells into insulin-producing cells.
Claims 1 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11530211 as applied to claim 1 above and further in view of Pagliuca et al. (Cell 159: 428–439. 2014), Agulnick et al. (Stem Cells Translational Medicine 4: 1214-1222. 2015), and Kim et al. (Scientific Reports 6: 1-13. 2016). Although the claims at issue are not identical, they are not patentably distinct from each other. This rejection is a new rejection.
The teachings of ‘211 are as discussed above.
‘211 does not disclose that a medium comprising an FGF receptor agonist as part of the media of stage 2 and 4 nor a medium comprising a TGFβ receptor inhibitor as part of the media of stage 5.
Regarding the stage 2 media, however, Pagliuca teaches a method of differentiating pluripotent stem cells into SC-β insulin producing cells using a multistep differentiation protocol (see Figure 1). As part of this protocol, they differentiate definitive endoderm cells into primitive gut tube cells by culturing the definitive endoderm cells in a media comprising KGF (an FGF receptor agonist) (Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the differentiation protocol identified in ‘211 to use a media comprising KGF as part of the stage 2 differentiation of definitive endoderm cells into primitive gut tube cells to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because both media involve differentiating definitive endoderm into primitive gut tube cells and are successful. As KGF is known to successfully differentiate definitive endoderm into primitive gut tube cells, it would have been well understood by one of ordinary skill in the art that KGF could also be used for differentiating definitive endoderm into primitive gut tube cells as part of the media composition. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the stage 4 media, Agulnick teaches a method of differentiating pluripotent stem cells into insulin producing cells using a multistep differentiation protocol (see pages 1-3 of Supplementary Information (Stages 1-7)). As part of this protocol, stage 5 (days 13–15), was designed to maximize induction of NGN3 (as identified in ‘211 and stated above, stage 4 in which Ngn3-positive pancreatic endocrine progenitor cells are induced from the pancreatic progenitor cells) (page 1216, column 1, paragraph 2-column 2, paragraph 1). As part of the stage 5 media, Agulnick identifies that they use KGF (an FGF receptor agonist) (Supplementary Information page 2 (stage 5)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the differentiation protocol identified in ‘211 to use a media comprising KGF as part of the stage 4 differentiation of pancreatic progenitor cells into NGN3-positive endocrine progenitor cells to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because both media involve differentiating pancreatic progenitor cells into NGN3-positive endocrine progenitor cells and are successful. As KGF is known to successfully differentiate pancreatic progenitor cells into NGN3-positive endocrine progenitor cells, it would have been well understood by one of ordinary skill in the art that KGF could also be used for differentiating pancreatic progenitor cells into NGN3-positive endocrine progenitor cells as part of the media composition. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the stage 5 media, Kim teaches a method of differentiating pluripotent stem cells into insulin producing cells using a multistep differentiation protocol (Figures 1-3 and page 3, paragraphs 4-7). As part of this protocol, stage 4 (endocrine progenitor cells (EP) to endocrine cells (EC)) uses a medium comprising SB431542 (a TGFβ receptor inhibitor) (as identified in ‘211 and stated above, stage 5 in which insulin-producing cells are finally induced from the pancreatic endocrine progenitor cells).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the differentiation protocol identified in ‘211 to use a media comprising SB431542 as part of the stage 5 differentiation of pancreatic endocrine progenitor cells into insulin-producing cells to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because both media involve differentiating pancreatic endocrine progenitor cells into insulin-producing cells and are successful. As SB431542 is known to successfully differentiate pancreatic endocrine progenitor cells into insulin-producing cells, it would have been well understood by one of ordinary skill in the art that SB431542 could also be used for differentiating pancreatic endocrine progenitor cells into insulin-producing cells as part of the media composition. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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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/KEENAN A BATES/Examiner, Art Unit 1631
