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 .
Applicant's amendments to the claims filed on 03-04-2026 have been received and entered. Claims 1-2, 4, 6-8, 10-12, 20, 22, 25, 31, 42 have been amended. Claims 3, 5, 9, 13, 15-16, 18-19, 21, 23-24, 27-30, 32-36, 39-41, 43-45 have been canceled. Claims 1-2, 4, 6-8, 10-12, 14, 17, 20, 22, 25-26, 31, 37-38, 42 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2, 4-8, 10-12, 14, 17, 20-23,
25-26, 31, 42-43 in the reply filed on 09-09-2025 is acknowledged.
Claims 37-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09-09-2025.
Claims 1-2, 4, 6-8, 10-12, 14, 17, 20, 22, 25-26, 31, 42 are under consideration.
Priority
This application is a 371 of PCT/US2021/029457 filed on 04/27/2021 that claims priority from US provisional application no 63/147,126 filed on 02/08/2021 and US provisional application no 63/016,527 filed on 04/28/2020.
Withdrawn-Claim Rejections - 35 USC § 112
Claims 1-2, 4-8, 10-12, 14, 17, 20-23, 25-26, 31, 42-43 were 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. In view of Applicants' amendment of base claim 1, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 112 (scope of enablement)
Claims 1-2, 4-8, 10-12, 14, 17, 20-23, 25-26, 31, 42-43 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph because the specification fails to provide an enablement for the full scope of the claimed invention. Applicant's amendment to the claims limiting the scope of the claim to enabling scope obviates the basis of the rejection. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 112 (Written description)
Claims 42 – 43 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Applicant's amendments to the claim 42 specifying the signaling factors obviates the basis of the rejection. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained in modified form and New - Claim Rejections - 35 USC § 103 - necessitated by amendments
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.
Claims 1, 4, 6-8, 10-12, 14, 17, 25, 42 are rejected under 35 U.S.C. 103 as being unpatentable over Parent et al (Pub. No.: US 2016/0010055 Al, Pub. Date: Jan. 14, 2016) (Applicant own work) in view of Vizcardo et al (Pub. No .: US 2020/0270571 A1, Provisional application No. 62/560,908 , filed on Sep. 20, 2017.).
Claim interpretation:
The specification of the claimed invention teaches that the term "KGF' refers to FGF7 and functionally active fragments thereof (see [0091], page 17 ). Thus, "KGF' is interpreted as FGF7.
The specification of the claimed invention teaches that “…...Noggin is used as the inhibitor of BMP signaling …… In certain cases, the inhibitor of BMP signaling may be LDN193189 ("LDN")…... ” (see [0196], page 38-39). Thus, Noggin and LDN193189 are interpreted as inhibitor of BMP signaling.
The specification of the claimed invention teaches that “the term "activator of fibroblast growth factor" thus refers to a FGF family protein or a factor that promotes signaling of the FGF pathway” ([0182], page 35) and “the FGF may be FGF2, FGF4, FGF7 (also known as KGF or "keratinocyte growth factor"), FGF8a, FGF8b, FGF9, FGF 10, or a variant thereof.” ([0183], page 35). Thus, a FGF family protein is interpreted as activator of fibroblast growth factor.
Regarding to claim 1, Parent et al teach methods for generating thymic epithelial progenitor (TEP) cells from pluripotent stem (PS) cells in vitro (Abstract) (For the preamble).
Parent et al teach that the method includes culturing anterior foregut endodermal (AFE) cells produced by the culturing of the DE cells, wherein the culturing of the AFE cells is in a medium that includes an activator of retinoic acid receptor, an activator of BMP signaling, an inhibitor of TGF-β signaling, a Wnt family member, a FGF, and an inhibitor of Hedgehog signaling ([0009], page 1). The FGF may be FGF2, FGF4, FGF7, FGF8a, FGF8b, FGF9, FGFl0, or a variant thereof. ([0125], page 8), and the FGF may be present in a medium used for the generation of VPE cells and/or TEP cells ([0126], page 8).
Parent et al teach production of TEP cells from PS cells is provided in FIG. 1, Panel A. Production of TEP cells from PS cells involve four stages of differentiation: Stage 1: Culturing of PS cells under conditions suitable to produce DE cells. Stage 2: Culturing of DE cells under conditions suitable to produce AFE cells. Stage 3: Culturing of AFE cells under conditions suitable to produce VPE cells. Stage 4: Culturing of VPE cells under conditions suitable to produce TEP cells. Culturing at each stage is conducted under culture conditions and for a time sufficient to produce the product of that stage, where the product may be characterized by expression of one or more markers and/or by functional characterization ([0070]-[0075], page 5).
PNG
media_image1.png
385
875
media_image1.png
Greyscale
It is noted that Parent et al (applicants’ own work) teach “the TEP cells may be generated within about 15 days …. from the start of the culturing of the PS cells” ([0108], page 7). The specification of the claimed invention teaches that “the population of cells to induce further maturation of the TEP cells in vitro can comprise further culturing the population of cells for up to 14 days” (see the instant disclosure [0013], page 2) and Figure 8 of the claimed invention show maturation start at day 13 (see Figure 8 of the claimed invention below). Thus, Parent et al teach mature TEP cells. Furthermore, there is no guidance/teaching from the claimed invention to distinguish the difference between TEP and mTEP. The specification of the claimed invention only teaches that “Culturing of TEP cells under conditions suitable to produce matured TEP (mTEP) cells. The mTEP upon in vivo transplantation may produce TECs” (see the instant disclosure [0161], page 28). Parent et al also teach that “functional TEP cells that mature into thymic epithelial cells in vivo” (abstract). Parent et al also teach “culturing at each stage is conducted under culture conditions and for a time sufficient to produce the product of that stage” ([0075], page 5). Thus, it is indicating that the time for culturing of TEP cells was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to perform the culturing of TEP cells in vitro for a time sufficient to produce functional mature TEP cells that can mature into thymic epithelial cells in vivo out of the course of routine optimization, in order to improve the differentiation function of TEP cells in vivo.
PNG
media_image2.png
526
901
media_image2.png
Greyscale
Although Parent et al teach the use of FGF7 (KGF) for the generation of TEP cells ([0125]-[0126], page 8), Parent et al do not teach heparin and hydrocortisone. Vizcardo et al cure the deficiency.
Vizcardo et al teach “in vitro generation of thymic organoid from human pluripotent stem cells” (Title). Vizcardo et al demonstrated the generation of early thymic epithelial progenitor-like cells (TEPLC) from human iPSCs in xeno-free culture ([0109], page 9), and provided media compositions comprising keratinocyte growth factor (KGF), heparin, and hydrocortisone that were used to generate thymic organoids ([0119], page 10, see below).
PNG
media_image3.png
549
458
media_image3.png
Greyscale
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Parent et al by using heparin, and hydrocortisone to generate thymic organoids as taught by Vizcardo et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Vizcardo et al teach that “addition of BMP4 , Wnt3a, and FGF7 to the TEC media allows the spheroids to continue growing for 7 additional days, resulting in discrete iPS derived thymic organoids, as shown in FIGS . 5A-5B .” ([0119], page 10). Vizcardo et al demonstrated the generation of early thymic epithelial progenitor-like cells (TEPLC) from human iPSCs in xeno-free culture ([0109], page 9) and stated that “ …… Embodiments of the invention may provide any one or more of a variety of advantages. For example, human iPS (induced pluripotent stem cell) derived thymic organoids (hiTO) produced by the inventive methods may produce cells of the T -cell lineage (e.g., thymic emigrant cells) which may be useful for treating or preventing a condition in a mammal, e.g., cancer. Alternatively, or additionally, the inventive methods may provide an organoid that can mimic the positive selection processing that takes place in the thymus ….” ([0042], page 2). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Vizcardo et al were successful in generation of early thymic epithelial progenitor-like cells (TEPLC) from human iPSCs in xeno-free culture ([0109], page 9), with working example and data.
Regarding to claim 4, Parent et al teach that the medium or cell culture medium may be modified by adding one or more additives. Additives may include serum, such as, fetal bovine serum and/or serum replacement agents, such as, B27, N2, KSR, and combinations thereof ([0056], page 4).
Regarding to claim 6, Parent et al teach that the TEP cells may be generated within about 15 days (e.g., within 15 days-10 days, within 14 days-10 days, ….) from the start of the culturing of the PS cells” ([0108], page 7).
Regarding to claim 7, Parent et al teach “cells may be induced to adhere to the container …. the wall of the container to which it is desirable to promote adhesion may be coated with a composition to which the cells may adhere …, matrigel ….” ([0053], page 4).
Regarding to claim 8, Parent et al teach that “the culturing methods described herein may be carried out in adherent conditions or in non-adherent conditions (e.g., suspension cultures) ([0109], page 7).
Regarding to claim 10, Parent et al teach that “the TEP cells may be transplanted into a subject in need of TE cells. In certain cases, the TEP cells may be transplanted into a target site in a subject that provides appropriate differentiation conditions for the TEP cells to differentiate into TE cells ….” ([0218], page 14).
Regarding to claim 11, Parent et al teach that “Thymic epithelial progenitor (TEP) cells give rise to two populations of mature thymic epithelial cells in the thymus: cortical thymic epithelial cells and medullary thymic epithelial cells” ([0004], page 1), and “hESC-derived TEPs mature into TECs in vivo: …. Cytokeratin 8 (KS) (green) and cytokeratin 5 (K5) (red) staining identify cortical and medullary TECs, respectively, …. ” ([0255], page 18).
Regarding to claims 12 and 17, Vizcardo et al teach reaggregating the TEP cells to form a reaggregate that comprise mesenchymal cells (MSC) (See Figure 8 below).
PNG
media_image4.png
686
978
media_image4.png
Greyscale
Regarding to claim 14, Parent et al teach “cell populations or cell cultures enriched in cells of interest, such as, TEP cells, by at least about 2- to about 1000-fold as compared to un-enriched cell populations are produced.” ([0159], page 11) and “the TEP cells produced by the methods provided herein express …., EpCAM ….” ([0103], page 7) and “Monitoring of generation of TEP cells may be carried out by determining …. EpCAM.” ([0150], page 10).
Regarding to claim 25, Parent et al teach “Cell compositions produced by the above-described methods include cell cultures that include AFE cells and cell populations enriched in AFE cells. In certain cases, the cell composition comprising AFE cell may include one or more of an activator of RA receptor, an activator of BMP signaling, an inhibitor of TGF-β signaling, a Wnt family member, a fibroblast growth factor, and an inhibitor of hedgehog signaling. In general, the AFE cells present in the cell populations are capable of differentiating into VPE cells, and TEP cells, when cultured according to the methods disclosed herein” ([0173], page 12). Thus, adding activator of retinoic acid receptor is optional for AFE cells culture , one of ordinary skill in the art would be able to select other factors without using activator of retinoic acid receptor.
Furthermore, Parent et al teach Figure 1B showing factor combinations (conditions 1-7) with condition 3 is not supplemented with an activator of retinoic acid receptor signaling for all of the stages (without retinoic acid (RA)). Thus, it is indicating that including or excluding an activator of retinoic acid receptor signaling such as retinoic acid (RA) was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to include or exclude an activator of retinoic acid receptor signaling for the processes of generation of TEP cells in vitro out of the course of routine optimization, in order to control the differentiation processes of TEP cells from pluripotent stem cells.
PNG
media_image5.png
313
895
media_image5.png
Greyscale
Regarding to claim 42, Parent et al teach “the culturing of the AFE cells is in a medium that includes an activator of retinoic acid receptor, an activator of BMP signaling, an inhibitor of TGF-β signaling, a Wnt family member, a FGF, and an inhibitor of Hedgehog signaling” ([0009], page 1, and Fig 1A), and “the culturing of the VPE cells is in a medium comprising an activator of retinoic acid receptor and an activator of BMP signaling” ([0010], page 1 and Fig 1A). Parent et al teach one or more Wnt/β- catenin pathway agonists (e.g., Wnt ligands, DSH/DVL-1, -2, -3, LRP6N, WNT3A, WNT5A, and WNT3A, 5A) ([0134], page 9).
Additionally, Vizcardo et al teach the use of BMP4 , Wnt3a, and FGF7 in addition of Hidrocortisone and heparin ([0119], page 10). Thus, the prior arts teach the use of one or more factors as claimed invention for generating thymic epithelial cells via differentiation.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Parent et al (Pub. No.: US 2016/0010055 Al, Pub. Date: Jan. 14, 2016) (Applicant own work) in view of Vizcardo et al (Pub. No .: US 2020/0270571 A1, Provisional application No. 62/560,908 , filed on Sep. 20, 2017.) as applied to claims 1, 4, 6-8, 10-12, 14, 17, 25, 42 above, and further in view of Zhang et al (WO 2020/041065 A1, International Publication Date: 27 February 2020).
The teachings of Parent et al and Vizcardo et al above are incorporated herein in their entirety.
Parent et al and Vizcardo et al do not teach a triiodo-L-thyronine (T3) supplement. Zhang et al cure the deficiency.
Regarding to claim 2, Zhang et al teach methods of producing epithelial cell spheroids (title). Epithelial cells can comprise keratinocyte epithelial (KE) cells or non-keratinocyte epithelial (NKE) cells (Page 10, lines 32-33). Non-keratinocyte epithelial (NKE) cells described herein can be of any type or tissue of origin. Examples of NKE cells include thymus epithelial cells (Page 11, lines 11-20). Zhang et al teach “additional ingredients may be added to a cell culture medium herein. For example, … heparin …. Hydrocortisone …. triiodothyronine (T3) …... (Page 52, lines 9-15)
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Parent et al and Vizcardo et al by using Triiodothyronine (T3) in cell culture medium as taught by Zhang et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Zhang et al teach Fig. 8 that shows pre-aggregating airway epithelial cells expressing GFP improved cell survival (page 7, lines 10-11), and Zhang et al stated that “Epithelial cells may be expanded under any suitable expansion culture conditions, such as, for example, expansion culture conditions described herein” (Page 16, line 30-32). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Zhang et al were successful in generation of epithelial cell spheroids, with detailed instructions, working example and data.
Claims 20, 22, 26, 31 are rejected under 35 U.S.C. 103 as being unpatentable over Parent et al (Pub. No.: US 2016/0010055 Al, Pub. Date: Jan. 14, 2016) (Applicant own work) in view of Vizcardo et al (Pub. No .: US 2020/0270571 A1, Provisional application No. 62/560,908 , filed on Sep. 20, 2017.) as applied to claims 1, 4, 6-8, 10-12, 14, 17, 25, 42 above, and further in view of Snoeck et al (Pub. No.: US 2016/0168535 A1, Pub. Date: Jun. 16, 2016).
The teachings of Parent et al and Vizcardo et al above are incorporated herein in their entirety.
Parent et al teach “DE cells in a medium containing one or more of an activator of RA receptor, an activator of BMP signaling, an inhibitor of TGF-β signaling for a period of 1 day to 6 days” ([0106], page 7) . However, Parent et al and Vizcardo et al do not specifically teach DE cells are differentiated into AFE cells in a culture medium comprising an inhibitor of bone morphogenetic protein (BMP) signaling. Snoeck et al cure the deficiency.
Regarding claims 20, 22, Snoeck et al teach “in vitro methods of inducing differentiation of anterior foregut endoderm and the enriched populations of anterior foregut endoderm produced by such methods” (Abstract). Snoeck et al teach “culturing the definitive endoderm cells in the presence of an inhibitor of BMP, e.g., Noggin or Chordin or follistatin, and/or an inhibitor of TGF-beta signaling, e.g., SB-431542, and in the absence of Activin A, to induce the definitive endoderm cells to form anterior foregut endoderm cells.” ([0015], page 1). Anterior foregut endoderm induced by Noggin/SB431542 may be further induced to form ventralized anterior foregut endoderm by treatment with one or more agonists of the Wnt signaling, FGF signaling, BMP signaling, and EGF signaling pathways ([0052], page 4).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Parent et al and Vizcardo et al by using an inhibitor of BMP for vitro methods of inducing differentiation of anterior foregut endoderm from definitive endoderm cells as taught by Snoeck et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Snoeck et al teach efficient endoderm generation of anterior foregut endoderm from Human Embryonic and Induced Pluripotent stem cells (Example 1, [0082]-[0087], page 7). Snoeck et al teach “cells, e.g., thymic epithelial cells (TECs) derived from ES or iPS cells by a method described herein could also improve humanized mouse models (FIG. 1e)” ([0080], page 6). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Snoeck et al were successful in generation of anterior foregut endoderm from definitive endoderm cells, with detailed instructions, working examples and data.
Regarding to claim 26, Parent et al teach that the method includes culturing definitive endodermal (DE) cells obtained from pluripotent stem cells ([0088], page 6).
Regarding to claim 31, Parent et al teach “DE cells may be obtained from PS cells by culturing PS cells in a medium …… where the culturing without the Wnt family” ([0085], page 6) and “the medium or cell culture medium may be modified by adding one or more additives. Additives may include serum, such as, fetal bovine serum and/or serum replacement agents, such as, …… activators of RA receptor, …… , Wnt family members, …. inhibitors of hedgehog signaling, and the like, and combinations thereof” ([0056], page 4). Thus, the prior art teaches embodiments that do not use activators of RA receptor, Wnt family members, inhibitors of hedgehog signaling.
Response to Arguments
Applicant's arguments filed 03-04-2026 have been fully considered but they are not persuasive. The 35 USC § 103 rejections necessitated by amendments have been rewritten as described above. Relevant arguments will be discussed below:
1. Applicant argue that
Parent does not teach or suggest a method of generating mTEP cells in vitro. Rather, the methods described in Parent rely on in vivo transplantation of TEPs to induce their maturation, with Parent clearly noting that although differentiated cells express genes important for thymic identity such as FOXN1, HOXA3, and EYA1, marker genes characteristic of mature TECs such as HLA-DRA (MHC class II molecule) and AIRE were not detected (see Parent at paragraph [0253]) (remarks, page 14).
Response to Arguments:
Applicants cited [0253] of Parent to argue that marker genes characteristic of mature TECs such as HLA-DRA (MHC class II molecule) and AIRE were not detected. However, mature TECs are mature thymic epithelial cells (TECs) not thymic epithelial progenitor (TEP) cells that are recited in the claim. Paragraph [0253] of Parent stated that “Although differentiated cells in our cultures express genes important for thymic identity such as FOXN1, HOXA3, and EYA1, marker genes characteristic of mature TECs such as HLA-DRA (MHC class II molecule) and AIRE were not detected (data not shown). This was not surprising since interactions of TEPs with developing T cell progenitors are necessary to stimulate maturation into functional TECs”; thus Paragraph [0253] of Parent teaches maturation into functional thymic epithelial cells (TECs) not thymic epithelial progenitor (TEP) cells.
It is noted that Parent et al (applicants’ own work) teach “the TEP cells may be generated within about 15 days …. from the start of the culturing of the PS cells” ([0108], page 7). The specification of the claimed invention teaches that “the population of cells to induce further maturation of the TEP cells in vitro can comprise further culturing the population of cells for up to 14 days” (see the instant disclosure [0013], page 2) and Figure 8 of the claimed invention show maturation start at day 13 (see Figure 8 of the claimed invention below). Thus, Parent et al teach mature TEP cells. Furthermore, there is no guidance/teaching from the claimed invention to distinguish the difference between TEP and mTEP. The specification of the claimed invention only teaches that “Culturing of TEP cells under conditions suitable to produce matured TEP (mTEP) cells. The mTEP upon in vivo transplantation may produce TECs” (see the instant disclosure [0161], page 28). Parent et al also teach that “functional TEP cells that mature into thymic epithelial cells in vivo” (abstract). Parent et al also teach “culturing at each stage is conducted under culture conditions and for a time sufficient to produce the product of that stage” ([0075], page 5). Thus, it is indicating that the time for culturing of TEP cells was recognized in the prior art to be a result-effective variable. A person of ordinary skill in the art would have been motivated to perform the culturing of TEP cells in vitro for a time sufficient to produce functional mature TEP cells that can mature into thymic epithelial cells in vivo out of the course of routine optimization, in order to improve the differentiation function of TEP cells in vivo.
PNG
media_image2.png
526
901
media_image2.png
Greyscale
2. Applicants argue that
Vizcardo does not teach or suggest generating mature thymic epithelial progenitor (mTEP) cells in vitro by culturing a population of TEP cells in a culture medium comprising keratinocyte growth factor (KGF), heparin, and hydrocortisone, as is presently claimed. That is at least because (i) Vizcardo does not teach or suggest any method in which KGF, heparin and hydrocortisone are used concurrently, and (ii) Vizcardo describes the use of hydrocortisone, Cholera Toxin, and hEGF, or of B27, HC, hEGF, insulin, hbFGF and heparin in the context of the differentiation of stem cells into the spherical structures ("early TEPCs"), less differentiated lower levels of cells (TEPLCs), and early TEPCs, e.g., not for the culture of mature TEPs, with the mere speculation that the TEPC will grow and differentiate into medullary and cortical TECs, which are the cells that mainly give function to the thymus (see Vizcardo at paragraph [0120]) (Remarks, Page 15).
Zhang does not teach or suggest the maturation of TEPs in vitro in general, is also completely silent about the claimed differentiation factor to generate the mTEP cells from TEP cells and does not teach or suggest generating mTEP cells having the characteristics of the claimed cells and therefore fails to cure the deficiencies in Parent and Vizcardo (Remarks, Page 16).
Response to Arguments:
It appears that Applicant is arguing that the cited references do not expressly suggest the claimed invention. However, it is well established in case law that a reference must be considered not only for what it expressly teaches, but also for what it fairly suggests. In re Burkel, 201 USPQ 67 (CCPA 1979). Furthermore, in the determination of obviousness, the state of the art as well as the level of skill of those in the art are important factors to be considered. The teaching of the cited references must be viewed in light of these factors. It also appears that applicant is attempting to attack each reference individually. However, in a 103 rejection the references must be considered as a whole. In the instant case, Vizcardo et al teach “in vitro generation of thymic organoid from human pluripotent stem cells” (Title) and provided media compositions comprising keratinocyte growth factor (KGF), heparin, and hydrocortisone that were used together to generate thymic organoids ([0119], page 10, see below). Given that different factors such as KGF (FGF7), heparin, and hydrocortisone were commercially available and were routinely used in different combination for culturing thymic epithelial cells, it would have been prima facie obvious for one of ordinary skill in the art to combine different factors each of which is taught by the prior art to be useful for the same purpose in order to culturing thymic epithelial cells for the very same purpose. In the instant case the idea of combining them flows logically from there having been taught in the prior art. One of ordinary skill in the art would have been motivated to do so because Vizcardo et al teach that “addition of BMP4 , Wnt3a, and FGF7 to the TEC media allows the spheroids to continue growing for 7 additional days, resulting in discrete iPS derived thymic organoids, as shown in FIGS . 5A-5B .” ([0119], page 10). Vizcardo et al demonstrated the generation of early thymic epithelial progenitor-like cells (TEPLC) from human iPSCs in xeno-free culture ([0109], page 9) and stated that “ …… Embodiments of the invention may provide any one or more of a variety of advantages. For example, human iPS (induced pluripotent stem cell) derived thymic organoids (hiTO) produced by the inventive methods may produce cells of the T -cell lineage (e.g., thymic emigrant cells) which may be useful for treating or preventing a condition in a mammal, e.g., cancer. Alternatively, or additionally, the inventive methods may provide an organoid that can mimic the positive selection processing that takes place in the thymus ….” ([0042], page 2).
PNG
media_image3.png
549
458
media_image3.png
Greyscale
Zhang et al teach methods of producing epithelial cell spheroids (title). Epithelial cells can comprise keratinocyte epithelial (KE) cells or non-keratinocyte epithelial (NKE) cells (Page 10, lines 32-33). Non-keratinocyte epithelial (NKE) cells described herein can be of any type or tissue of origin. Examples of NKE cells include thymus epithelial cells (Page 11, lines 11-20). Zhang et al teach “additional ingredients may be added to a cell culture medium herein. For example, … heparin …. Hydrocortisone …. triiodothyronine (T3) …... (Page 52, lines 9-15). One of ordinary skill in the art would have been motivated to combine the references because Zhang et al teach Fig. 8 that shows pre-aggregating airway epithelial cells expressing GFP improved cell survival (page 7, lines 10-11), and Zhang et al stated that “Epithelial cells may be expanded under any suitable expansion culture conditions, such as, for example, expansion culture conditions described herein” (Page 16, line 30-32).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
The examiner has required restriction between product or apparatus claims and process claims. Where applicant elects claims directed to the product/apparatus, and all product/apparatus claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product/apparatus claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product/apparatus claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product/apparatus claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
Prosecution Insights