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 1-6, 11, 13-17, 19-24, and 36; drawn to a method of differentiating pluripotent stem cells into thymic cells) in the reply filed on June 8, 2026, is acknowledged.
Claims 25-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II-IV), there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on October 30, 2024, have been acknowledged. Claims 7-10, 12, 18, and 32-35 were cancelled. Claims 17 and 30 were amended. Claim 36 is new. In light of the Applicant’s elected invention, claims 25-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-6, 11, 13-17, 19-24, and 36 are pending and examined on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/256,443, filed October 15, 2021, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. This provisional application does not provide information related to a method of differentiating pluripotent stem cells into thymic cells wherein differentiating anterior foregut cells into ventral pharyngeal endoderm cells comprises a first VPE medium and a seconds VPE medium. However, Application No. 63/296,251, filed on January 4, 2022, did provide the above information.
Furthermore, the disclosure of the prior-filed applications, Application No. 63/256,443, filed October 15, 2021, Application No. 63/296,251, filed January 4, 2022, Application No. 63/321,136, filed on March 18, 2022, and Application No. 63/388,407, filed on July 12, 2022, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. These provisional applications do not provide information related to a method of differentiating pluripotent stem cells into thymic cells wherein the first VPE media further comprises a WNT inhibitor. However, Application No. PCT/US2022/046551, filed on October 13, 2022, did provide the above information.
Therefore, claims 1-3, and 5-6, 11, 13-17, 19-24, and 36 receive domestic benefit from US provisional application 63/296,251, filed on January 4, 2022, while claim 4 receives domestic benefit from application No. PCT/US2022/046551, filed on October 13, 2022.
Information Disclosure Statement
The information disclosure statements (IDS) filed on April 11, 2024, December 1, 2025, and April 3, 2026, have been considered.
Claim Objections
Claim 3 is objected to because of the following informalities:
In claim 3, line 7, the phrase “comprises an, Activin A, …” should read “comprises an Activin A, …”. Appropriate correction is required.
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 1-6, 11, 13-17, 19-24, and 36 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.
Claims 1 and 6 recite the limitation "the anterior foregut cells" in line 8. There is insufficient antecedent basis for this limitation in the claim. Claims 1 and 6 previously recite anterior foregut endoderm (AFE) cells and use the AFE abbreviation to refer back to these cells later in the claims. As the claims repeatedly refer to the anterior foregut endoderm cells as the AFE cells, it is not clear whether the anterior foregut cells are meant to also be the AFE cells or a separate set of anterior foregut cells. If they are the same cells, Applicant is recommended to refer to them as the AFE cells as similarly done in part d) of claim 1.
Claims 2-5, 11, 13-17, 19-24, and 36 are also rejected because of their dependence on claim 1.
Claim 3 recites a first growth medium and a second growth medium as part of the differentiation of pluripotent stem cells to DE cells. However, subclaims a) and b) are only separated by a ; without any transitional clause or conjunction (such as and/or) to ascertain whether the first and second growth medium are both required or if only one is required. Therefore, it is unclear whether both media compositions are required for differentiating the pluripotent stem cells into DE cells or if only one is required.
Claim 11 recites the limitation “the interleukin” in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 1 does not previously refer to an interleukin. Instead, claim 2 refers to an interleukin as part of the differentiation of TEPs into TECs. As such, claim 11 is interpreted to be dependent on claim 2 and not claim 1.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 36 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 36 is dependent on claim 1 which requires culturing the VPE cells and differentiating the VPE cells by contacting or incubating the VPE cells with an ascorbic acid, an FGF, a BMP, a WNT activator, or a combination thereof. However, claim 36 recites culturing the VPE cells and differentiating the VPE cells by contacting or incubating the VPE cells with at least one of BMP4, FGF8b, EGF, SANT-1, CHIR99021, ascorbic acid, or a combination thereof. EGF (activator of the EGF pathway) and SANT-1 (SHH antagonist) could only qualify under a WNT activator as they are clearly not an ascorbic acid, an FGF, or a BMP. However, EGF and SANT-1 are not WNT activators. Therefore, if only EGF and/SANT-1 are used for culturing (as the claim allows), the media would not have an ascorbic acid, an FGF, a BMP, a WNT activator, or a combination thereof as required by claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 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.
(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 1-6, 11, 15-17, 19-23, and 36 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by United States Patent Application No. 2024/0076618 (Weinacht; Effective filing date of January 15, 2021) as evidenced by Liu et al. (Tissue Engineering: Part A 24: 1138-1147. 2018), Loh et al. (Cell Stem Cell 14: 237-252. 2014), and United States Patent Application No. 2021/0290824 (Giuseppe).
Regarding claims 1, 3-6, and 36, Weinacht teaches an in vitro differentiation method for the efficient generation of TEPCs from human pluripotent stem cells (PSC) by recapitulating the sequential stages of human thymic ontogeny: Definitive Endoderm (DE), Anterior Foregut (AFG), Bipotent Third Pharyngeal Pouch Endoderm (bipotent PPEIII), Ventral Third Pharyngeal Pouch Endoderm (ventral PPEIII) and Thymic Epithelial Progenitor Cells (TEPC). These TEPCs can further mature into functional cTECs and mTECs in vitro through further signal induction. The process of differentiating pluripotent stem cells into functional TEPCs in vitro may progresses through five consecutive stages, as is shown in protocol depicted in FIG. 1 In this stepwise progression, "Stage 1" refers to the first step in the differentiation process, the differentiation of PSC into cells expressing markers characteristic of DE cells. "Stage 2" refers to the second step, the differentiation of cells expressing markers characteristic of DE cells into cells expressing markers characteristic of AFG cells. "Stage 3" refers to the third step, the differentiation of cells expressing markers characteristic of AFG cells into cells expressing markers characteristic of bipotent PPEIII cells. "Bipotent" as used herein refers to the ability of Stage 3 cells to differentiate into thymus or parathyroid. "Stage 4" refers to the fourth step, the differentiation of cells expressing markers characteristic of bipotent PPEIII cells into cells expressing markers of ventral PPEIII cells. "Stage 5" refers to the fifth step, the differentiation of cells expressing markers characteristic of ventral PPIII cells into cells expressing markers characteristic of TEPCs.
Regarding stage 1, as per the 112b above, it is unclear whether the first and second growth media compositions are required or if only one is required. For this rejection, it is interpreted that only one is required even as Weinacht teaches two media compositions that fall within the limitations of the first and second growth media. Weinacht teaches that the method of differentiating iPSCs into definitive endoderm cells comprises activation of TGFβ, WNT (e.g. CHIR99021), and FGF and inhibition of PI3K (e.g. PI-103) for 1 day in a first media composition and activation of TGFβ and FGF and inhibition of BMP4 (i.e. a BMP inhibitor) on day 2.
Regarding stage 2, Weinacht teaches that the method of differentiating definitive endoderm to anterior foregut (also known as anterior foregut endoderm) cells comprises inhibition of TGFβ and BMP signaling.
Regarding stages 3-4, Weinacht teaches that the method of differentiating anterior foregut cells into ventral third pharyngeal pouch cells (also known as ventral pharyngeal endoderm and identified as PPEIII cells by Weinacht) comprises a two-step differentiation protocol comprising culturing anterior foregut cells with a first media composition comprising a Transforming Growth Factor (TGFβ) signaling pathway inhibitor (e.g., A 83-01 at 1 nM-10 uM); a Bone Morphogenic Protein (BMP) signaling pathway inhibitor ( e.g., LDN193189 at 1 nM-10 uM); a retinoic acid (RA) signaling pathway activator (e.g., ATRA at 5 nM-5 uM); and a PI3K/AKT signaling pathway inhibitor (e.g., PI 828 at 0.05 uM-50 uM). The induction of the bipotent PPEIII stage 3 is further enhanced by addition of a Fibroblast Growth Factor (FGF) signaling pathway activators (e.g., FGF7 and/or FGFl0, at least 1 ng/ml) or a canonical WNT signaling pathway inhibitor (e.g., IWR-1 at 5 nM to 5 uM) or both to the medium to further improve conversion to bipotent PPEIII cells. For stage 4, the media comprises activators of WNT (such as CHIR00021) and BMP, optionally with one or some or all of the following: FGF/ERK/MAPK signaling pathway inhibitor, an IGF signaling pathway activator, and a Sonic Hedgehog (SHH) signaling pathway inhibitor.
Regarding stage 5, Weinacht teaches that the method of differentiating ventral third pharyngeal pouch cells (ventral PPEIII cells) into thymic epithelial progenitor cells (TEPCs) comprises culturing the ventral PPEIII cells in a medium that contains one, some or all of the followings: IFN type I and/or II signaling activators, FGF signaling pathway activators (such as an FGF), and IGF signaling pathway activators, optionally with inhibition of SHH signaling pathways and/or inhibition of the canonical WNT signaling pathway (paragraphs 0030-0074 and 0089-0107 and Figures 1-2).
Regarding claim 6, although claim 6 refers to specific compounds, such as the BMP inhibitor is LDN193189 for differentiating DE cells into anterior foregut endoderm and the BMP is BMP2 for differentiating VPE cells into thymic cells, as the specific compounds are in reference to a genus of molecules that are only identified in the alternative and not required as part of the differentiation methods, the specific compounds are also not considered to be required as the differentiation method can be performed without the genus of molecules encompassing the specific molecule.
Regarding claims 2 and 11, Weinacht teaches that the thymic epithelial cells can further mature into medullary or cortical thymic epithelial cells in vivo after transplantation. Weinacht identifies that their cells can be administered to human patients (paragraphs 0004, 0050, and 0084). Liu evidences that in vivo transplantation can be considered an incubation (whole document). As humans produce interleukins, such as IL-22, the thymic epithelial cells would be incubated in the human body with IL-22 and other factors.
Regarding claim 15, Weinacht teaches that the cells as described herein can be formed into organoids or synthetic organs. These 3D thymic organoids can be used in any of the aforementioned applications in place of TEPCs generated in 2D monolayer culture (paragraph 0088). It is well understood within the art that 3D organoids are generated through aggregation of cells in suspension culture.
Regarding claims 17 and 19-23, Weinacht teaches that they followed the protocol of Loh et al. 2014, Cell Stem Cell for differentiating pluripotent stem cells into definitive endoderm cells. Loh evidences that they used a 3 day differentiation protocol (Figure 1 and page 250, column 1, paragraph 3). The instant specification does not define about. Therefore, any definition that is used within the art represents a reasonable interpretation of the meaning of about. ±50% is considered a reasonable definition of about as evidenced by Giuseppe (paragraph 0056). Thus, 3 days would fall inside about (±50%) 5 days (2.5-7.5 days) as claimed. Weinacht teaches that they cultured DE cells in basal medium containing dual SMAD inhibition reagents to induce AFG cells with or without low concentrations of ATRA for 2 days (stage 2). Weinacht teaches that they cultured AFG cells with dual SMAD inhibition together with PI3K/AKT pathway inhibition (e.g., PI 828 at 5 uM) plus canonical WNT signal inhibition ( e.g., endo- 1 WR 1 at 250 nM) plus FGF/ERK/MAPK pathway activation (e.g., FGF 7 at 20 ng/ml and FGFl0 at 20 ng/ml) and optimal ATRA signal activation (e.g., ATRA at 50-100 nM) for 3-7 days to differentiate AFG cells into bipotent PPEIII cell stage (stage 3) (see MPEP 2131.03). The duration of differentiating bipotent PPEIII cells into ventral PPEIII cells can be 3 days (stage 4). The duration of differentiating ventral PPEIII cells into TEPCs is 5 days (stage 5) (paragraphs 0050-0074 and 0089-0107). In total this corresponds to a protocol that occurs for 16-20 days.
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, 5, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2024/0076618 (Weinacht as applied to claims 1 and 5 above, and further in view of World Intellectual Property Organization Patent Application No. 2020205859 (Gras; Referenced in IDS).
Regarding claim 5, the teachings of Weinacht are as discussed above.
Weinacht does not teach using a BMP inhibitor as part of the second VPE media.
However, Gras teaches a method of inducing differentiation of human pluripotent stem cells (hPSCs) including embryonic stem cells (ES Cs) and induced pluripotent stem cells (iPSCs) into thymic epithelial cells (TECs) or thymic epithelial cell progenitors (TEC progenitors) (TEPs) including the steps of:
1. differentiating the pluripotent stem cells into endoderm cells by culturing the pluripotent stem cells in serum-free differentiation medium and contacting or incubating the cells with human Bone Morphogenic Protein (BMP), human b Fibroblast Growth Factor (bFGF) and human Activin A;
2. differentiating the endoderm cells from the first step into anterior foregut cells by culturing the endoderm cells in differentiation medium and contacting or incubating the cells with Noggin, SB431542, retinoic scid and FGF8b;
3. differentiating the anterior foregut cells from the second step into pharyngeal endoderm cells by culturing the cells in differentiation medium, and contacting or incubating the cells with FGF8b and retinoic acid followed by FGF8b and Sonic Hedgehog (Shh);
4. differentiating the pharyngeal endoderm cells from step 3 into 3rd pharyngeal pouch specification by culturing the cells in differentiation medium and contacting or incubating the cells with Noggin;
5. further differentiating the pharyngeal endoderm cells from step 3 or step 4 into 3rd pharyngeal pouch specification cells, TEPs or TECs, by culturing the cells in differentiation medium and contacting or incubating the cells with BMP (page 3, line 32-page 4, line 17).
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 method of generating thymic epithelial progenitor cells from iPSCs of Weinacht by performing the differentiation of anterior foregut cells into third pouch pharyngeal cells/ventral pharyngeal endoderm cells using the two step protocol of Gras 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 Gras teaches that Noggin is a BMP4 antagonist and/or inhibitor expressed throughout the mesenchyme of the 3rd PA at E9.5 in mice, immediately adjacent to the early 3rd PP endoderm while BMP4 expression begins at E10.5 in cells of the 3rd PP endoderm. It was hypothesized that Noggin may diffuse from the mesenchyme to the 3rd PP endodermal cells right before BMP4 signaling arises in this area. To mimic this event, BMP4 was substituted with Noggin from day 16 to day 22 in protocols #3c and #4c (Figure 2A). PAX9 expression (a VPE marker) was significantly increased in both protocols with the addition of Noggin and this lead to increased FOXN1 expression (a TEC marker) at the end of the differentiation protocol (Example 3). Therefore, it would have been obvious to modify the method of Weinacht to use Noggin in the second VPE media as this produces a higher number of PAX9+ VPE cells which results in producing more thymic epithelial progenitor cells or thymic epithelial cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 13, Noggin and LDN193189 are known BMP inhibitors, as identified by Weinacht (paragraph 0060). As Gras already reduces to practice that the BMP inhibitor Noggin successfully increases the rate of PAX9+ and FOXN1+ cells as part of their method, it would have been obvious that other known BMP inhibitors, such as LDN193189, could also be used as part of the method with similar results. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1, 5, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2024/0076618 (Weinacht as applied to claims 1 and 5 above, and further in view of World Intellectual Property Organization Patent Application No. 2020220040 (Russ).
The teachings of Weinacht are as discussed above. As stated supra, Weinacht teaches that for stage 4 (i.e. second VPE media, the media comprises activators of WNT (such as CHIR00021) and BMP, optionally with one or some or all of the following: FGF/ERK/MAPK signaling pathway inhibitor, an IGF signaling pathway activator, and a Sonic Hedgehog (SHH) signaling pathway inhibitor (paragraphs 0030-0074 and 0089-0107 and Figures 1-2)
Although Weinacht identifies a multitude of exemplary SHH inhibitors (paragraph 0073), Wienacht does not teach SANT-1 as one of the exemplary inhibitors.
However, Russ teaches that a method for generating patient-specific thymic epithelial cells (TECs), the method comprising: isolating a cell from the patient; administering one or more factors to the cell to reprogram the cell and create an induced pluripotent stem cell (iPSC); culturing the patient-specific iPSC for 9-14 days in a differentiation media to create a thymic epithelial progenitor (TEP) cell; and transferring at least one TEP into a recipient; and allowing the TEP cell to differentiate into a TEC. Russ teaches that SANT-1 can be used as part of their differentiation protocol (claims 1 and 14).
As SANT-1 is a known SHH and inhibitor and Russ identifies that it can be used as part of a method of differentiating iPSCs into thymic epithelial cells, which is the same goal as Weinacht, it would have been well understood to one of ordinary skill in the art that SANT-1 could be used as the SHH inhibitor in the second VPE media of Weinacht’s stage 4 step. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1-2 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 2024/0076618 (Weinacht as applied to claims 1 and 2 above, and further in view of World Intellectual Property Organization Patent Application No. 2010143529 (Isobe).
The teachings of Weinacht are as discussed above. Weinacht teaches that TEPCs can further mature into functional cTECs and mTECs in vitro through further signal induction. (paragraph 0050).
Weinacht is silent regarding what in vitro method can be used to differentiate the TEPs into TECs.
However, Isobe teaches a method of inducing medullary thymic epithelial cells (mTEC). In order to induce differentiation into medullary thymic epithelial cells, the cells were cultured in a medium supplemented with RANK ligand (10 ng / ml) and LiCl (5 mM) from day 12 of culture (FIG. 7). As a result, the expression of FoxN1, which had not changed in the expression so far, markedly increased on the 16th day of culture, and the expression of keratin 5 also increased similarly (FIG. 8). Regarding AIRE, Crp, and Sap1, which are genes involved in self-tolerance, the expression of Crp and Sap1 was increased (FIG. 8). In addition, regarding Dll1 and Dll4 involved in thymic T cell differentiation, the expression of Dll4 increased with time (FIG. 8). As a result of detecting the expression of Pax1, FoxN1 and K5 by real-time PCR, FoxN1 and K5 were highly expressed on the 16th day of culture, and differentiation into thymic epithelial cells was confirmed (FIG. 9) (page 16, paragraph 4 of Machine Translation).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the method of generating thymic epithelial progenitor cells from iPSCs of Weinacht with the method of differentiating thymic epithelail progenitor cells into medullary thymic epithelial cells of Isobe to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Weinacht specifically identifies that their thymic epithelial progenitor cells can be further differentiated into medullary thymic epithelial cells in vitro and Isobe reduces to practice that their method successfully generates medullary thymic epithelial cells from thymic epithelial progenitor cells. Therefore, it would have been obvious to combine the two methods to generate medullary thymic epithelial cells. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
As identified by Isobe above, the culture media comprises RANKL and the culture step occurs for four days.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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