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 .
1. Claims 14 and 19 – 23 are pending.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claim 14) in the reply filed on 12/23/2025 is acknowledged.
3. Applicant has amended the claims to cancel all claims in the Restriction Requirement mailed 09/24/2025 and added new claims 19 – 23 that depend from claim 14. Therefore, claims 14 and 19 – 23 are under consideration.
Priority
4. This application claims priority to JP 2020-162912 filed 09/29/2020.
5. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 07/02/2025, 10/31/2024, and 03/28/2023 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
6. The drawings submitted on 04/11/2023 are acknowledged.
Specification
7. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at page 16 and 43. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
8. The use of the term Matrigel, Essential 6, Essential 8, BulletKit, EGM-2, VascuLife, B27, Elplasia, iMatrix, GlutaMAX, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
9. Claim 14 is objected to because of the following informalities: in lines 2, “comprising a step of performing the culture method comprising a step of culturing” should read “comprising culturing” because “the culture method” lacks antecedent basis. 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.
10. Claims 14 and 19 – 23 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.
11. Regarding claim 14, it is unclear if “in a ratio of 50% or more” and “in a ratio of 10% or more” refers to the percentage of cells relative to the cell population, or relative to the culture medium volume, or something else. Claims 19 – 23 are also rejected as they depend from claim 14 and do not clarify the grounds of rejection. For the purpose of applying prior art, claim 14 is interpreted as a cell population comprises 100% cells and 50% or more are parathyroid gland cells and 10% or more are mesenchymal cells based on Applicant’s specification at page 19, para. 0034 – 0035.
12. Regarding claim 20, it is unclear if the cell population of claim 14 is first cultured and then embedded and further cultured, or if culturing the cell population in claim 14 occurs in an embedded matrix. Claim 21 is also rejected as it depends from claim 20 and does not clarify the grounds of rejection. For the purpose of applying prior art, claim 20 is interpreted as the cell composition of claim 14 is embedded in a matrix and cultured based on Applicant’s specification at page 15, para. 0026 and page 40, para. 0080.
Claim Interpretation
13. For the purpose of applying prior art, “parathyroid gland cells” of claim 14 is interpreted as a differentiated parathyroid gland cell or an undifferentiated parathyroid gland cell where the undifferentiated parathyroid gland cell is a cell having differentiation ability into a parathyroid gland cell including anterior foregut cell based on Applicant’s specification at page 9, para. 0014 and page 20, para. 0037 and the Example at page 38 – 40. Thus “parathyroid gland cells” is interpreted to include any undifferentiated cell having the ability to be differentiated into a parathyroid gland cell.
14. For the purpose of applying prior art, “mesenchymal cells” of claim 14 is interpreted to include a stromal cell, a mesenchymal stem cell, a differentiated mesenchymal cell, an undifferentiated mesenchymal cell (a cell destined to differentiate into a mesenchymal) cell, and a cell present in anterior foregut based on Applicant’s specification at page 10, para. 0016 and page 21, para. 0040 and 0042 and the Example at page 38 – 40. Thus “parathyroid gland cells” is interpreted to include any undifferentiated cell having the ability to be differentiated into a parathyroid gland cell.
15. For the purpose of applying prior art, “in a ratio of 50% or more” and “in a ratio of 10% or more” of claim 14 is interpreted to include 100% parathyroid gland cells and 100% mesenchymal cells, including 100% anterior foregut cells.
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.
16. Claim(s) 14, 20, and 23 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park (Park, Yoon Shin, et al. Biomaterials 65 (2015): 140-152.), hereinafter Park, which is cited on the IDS filed 03/28/2023.
Claim 14 is drawn to a method for producing a three-dimensional organ,
comprising a step of performing the culture method comprising a step of culturing, in a medium,
a cell population containing parathyroid gland cells in a ratio of 50% or more, and mesenchymal
cells in a ratio of 10% or more.
Regarding claim 14 and 20, Park teaches a method of producing a three-dimensional parathyroid organ comprising culturing tonsil-derived mesenchymal stem cells (100% parathyroid gland cells and mesenchymal cells (TMSC) of claim 14) in Matrigel (claim 20) in a culture medium comprising activin A and SHH (claim 23) (page 141, right col. para. 1 and 3; page 142, right col. last para.; page 147; page 148, left col. para. 1; page 149, left col. para. 2; Figure 7, 8).
Therefore, Park anticipates claims 14, 20, and 23.
17. Claim(s) 14, 22, and 23 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Park-2016 (Park, Yoon Shin, et al. Acta Biomaterialia 35 (2016): 215-227.), hereinafter Park-2016, which is cited on the IDS filed 03/28/2023.
Claim 14 is drawn to a method for producing a three-dimensional organ,
comprising a step of performing the culture method comprising a step of culturing, in a medium,
a cell population containing parathyroid gland cells in a ratio of 50% or more, and mesenchymal
cells in a ratio of 10% or more.
Regarding claim 14, 22, and 23, Park-2016 teaches a method of producing a three-dimensional parathyroid organ comprising culturing tonsil-derived mesenchymal stem cells (TMSC) (100% parathyroid gland cells and mesenchymal cells of claim 14) in concave molds (“round bottom” of claim 22) in a culture medium comprising activin A and SHH (claim 23) (page 216, right col. para. 3 – 5; Figure 1; page 217, left col. para. 1; Figure 2; page 219, left col. para. 1 and right col. para. 2 – 3; Figure 4; page 221, right col. para. 2 – 3; Figure 10).
Therefore, Park-2016 anticipates claims 14, 22, and 23.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
18. Claim(s) 14, 19, 22, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Park-2016 (Park, Yoon Shin, et al. Acta Biomaterialia 35 (2016): 215-227.), hereinafter Park-2016, which is cited on the IDS filed 03/28/2023 in view of Takebe (Takebe, Takanori, et al. Cell stem cell 16.5 (2015): 556-565.), hereinafter Takebe.
Park-2016 anticipates claims 14, 22, and 23. Park-2016 does not teach the cell population further contains a vascular endothelial cell of claim 19. However, Park-2016 teaches differentiating TMSC with activin A and SHH yielded spheroids (dTMSC) that produced parathyroid hormone (PTH) (page 219, right col. para. 2; Figure 4). Park-2016 teaches hypoparathyroidism mainly occurs when parathyroid glands fail to secrete sufficient PTH as a largely unavoidable consequence of parathyroidectomy (PTX) followed by thyroidectomy (page 215, right col.). Parke-2016 teaches low PTH production and secretion leads to a lack of calcium in blood and bones and severe and chronic hypocalcemia can be fatal (page 215, left col.). Park-2016 teaches to restore damaged parathyroid function, parathyroid tissue engineering is the best option (Abstract). Park-2016 teaches implanting dTMSC spheroids in PTX rats increased survival with physiological levels of serum iPTH and ionized calcium compared to undifferentiated TMSC (cTMSC) spheroids, representing a clinically feasible strategy for hypoparathyroidism treatment (Abstract; page 220, right col.; Figure 5 and 6E; page 224, left col. para. 1). Park-2016 teaches survival rates for the rats transplanted with dTMSCs were 60% for 2 months and 50% for 3 months but survival rates significantly dropped shortly after transplantation (page 219, right col. last para; page 220, left col. para. 1; Figure 5A). Park-2016 teaches greater vascularization around implanted dTMSC spheroids compared to cTMSC (page 221, right col. para. 2; Figure 8; page 225, left col.). Park-2016 teaches differentiation induces vessel formation in an in vivo system, thereby increasing survival rates of rats transplanted with dTMSC spheroids (page 225, left col.). Park-2016 teaches it is unclear why the survival rates in PTX rats implanted with TMSC spheroids decreased rapidly and that controlling survival rates in as few as 3 – 4 days after PTX could determine the success of in vivo parathyroid regeneration (page 226, left col. para. 1).
Regarding claim 19, Takebe teaches a method of producing organ buds comprising culturing embryonic or adult organ derived whole cells with mesenchymal cells and vascular endothelial cells (Figure 3; page 562, left col. para. 1). Takebe teaches in the absence of HUVECs, no signs of functional vascularization were observed (page 562, left col.; Figure 3E – H; Figure S3B). Takebe teaches the generation of liver buds with ~1 – 2 x 106 iPSC-hepatic cells, ~8 – 16 x105 HUVECs and ~2 – 4 X 105 human mesenchymal stem cells (page 565, left col. para. 2). This is a total of 2,000,000 cells (using the lower value) and is a ratio of 50% iPSC-hepatic cells: 10% mesenchymal stem cells. Takebe teaches the same ratio of pancreatic cells: HUVECs for pancreatic buds (page 565, left col. para. 2).
Takebe teaches current stem cell therapies primarily target diseases that are treatable by cell transplantation but these approaches produce limited clinical therapeutic outcomes as well as potential side effects compared with organ-based therapy (page 557, left col.). Takebe teaches the development of innovative technologies that enable the reconstitution of 3D organs from stem cells is urgently required to potentially address the severe donor organ shortage and to lower the high medical costs incurred by the increasing numbers of waiting patients (page 557, left col. and right col. para. 1). Takebe teaches organoids generally lack complex structures such as blood vessels thus limiting their application (page 557, right col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Park-2016 regarding a method of a parathyroid organ comprising differentiating TMSCs with the teachings of Takebe regarding a method of producing organ buds with vascularization comprising culturing organ cells with mesenchymal cells and HUVECs to arrive at the claimed method wherein the cell population further comprises a vascular endothelial cell. One would have been motivated to combine the teachings of Park-2016 and Takebe in a method of producing a parathyroid organ for treating parathyroid dysfunction as Park-2016 teaches to restore damaged parathyroid function, parathyroid tissue engineering is the best option and Takebe teaches the development of innovative technologies that enable the reconstitution of 3D organs from stem cells is urgently required to potentially address the severe donor organ shortage and to lower the high medical costs incurred by the increasing numbers of waiting patients. One would have a reasonable expectation of success in combining the teachings as Park-2016 teaches dTMSCs showed vascularization in vivo thereby increasing survival rates of rats and the dTMSC spheroids in PTX rats showed physiological levels of serum iPTH and ionized calcium compared to undifferentiated cTMSC spheroids, representing a clinically feasible strategy for hypoparathyroidism treatment and Takebe teaches the method was successful with various whole organ cells andTakebe teaches in the absence of HUVECs, no signs of functional vascularization were observed.
19. Claim(s) 14, 20, 21, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Park (Park, Yoon Shin, et al. Biomaterials 65 (2015): 140-152.), hereinafter Park, which is cited on the IDS filed 03/28/2023in view of Takebe (Takebe, Takanori, et al. Cell stem cell 16.5 (2015): 556-565.), hereinafter Takebe.
Park anticipates claims 14, 20, and 23. Park does not teach the matrix composition containing the cell population embedded therein is cultured in a state suspended from a breathable membrane of claim 21. However, Park teaches loss of parathyroid cells results in hypoparathyroidism and consequent low-turnover bone disease (Abstract; page 140, right col. para. 1). Park teaches hypoparathyroidism is characterized by low serum calcium levels and the absence of PTH (page 140, right col. para. 2). Park teaches implantation of differentiated TMSC (dTMSC) embedded in Matrigel (dTMSC-MA) restored serum levels of PTH and calcium in PTX rats (page 141, right col. para. 1; Figure 5; page 148; Figure 6). Park teaches in dTMSC-MA retrieved from PTX rats, significant vascularization was detected in dTMSC-MA and PTH protein was detected (page 149, left col. para. 2; Figure 7). Park teaches dTMSC-MA are likely to be a potential biocompatible cell source for in vitro and in vivo parathyroid cell regeneration (page 149, right col. para. 2). Park teaches the use of the dTMSC-MA will enhance our understanding of parathyroid pathophysiology at the molecular level as investigations of parathyroid cells at the cellular, molecular, and physiological levels are greatly limited owing to difficulty in isolating pure primary parathyroid cells mainly due to their small size (page 151, left col. para. 1).
Regarding claim 21, Michael teaches a method of producing cell spheroids by hanging drop on a paper filter (“breathable membrane”) (Figure 3A; Abstract). Michael teaches the method allows for in-site analysis including drug testing, time-dependent detection of secreted protein and fluorescence staining without disturbing the spheroids (Abstract; page 33840, left col. para. 1). Michael teaches three-dimensional spheroids have an architecture that closely mimics in vivo microphysiology and hanging drop culture has been widely adopted because of single spheroid formation and high reproducibility (page 33839, right col. para. 1). Michael teaches culturing 3D spheroids on the paper by hanging drop was stable for more than 10 days because of the enhanced mass transport of nutrients and oxygen by undisturbed periodic medium exchange through the porous paper substrate (page 33840, left col. para. 1). Michael teaches the paper-based hanging drop system for 3D spheroid culture is simple and inexpensive to fabricate and feasible for the culture of spheroids for more than 10 days without serious protein adsorption (page 33845, left col. last para.). Michael teaches easy liquid exchange through the porous paper and effortless transfer of 3D spheroids allowed complex 3D cell-based assay to be performed with minimal complexity (page 33845, left col. last para.).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Park regarding a method of producing a three-dimensional parathyroid organ embedded in Matrigel with the teachings of Michael regarding a method of producing 3D cell spheroids by hanging drop culture on paper to arrive at the claimed method wherein the matrix composition containing the cell population embedded therein is cultured in a state suspended from a breathable membrane. One would have been motivated to combine the teachings of Park and Michael in a method to study parathyroid spheroids at the cellular, molecular, and physiological levels as Park teaches investigations of parathyroid cells at the cellular, molecular, and physiological levels are greatly limited owing to difficulty in isolating pure primary parathyroid cells mainly due to their small size and Michael teaches three-dimensional spheroids have an architecture that closely mimics in vivo microphysiology. One would have a reasonable expectation of combining the teachings as Park teaches the dTMSC embedded in Matrigel are functional because they restored serum levels of PTH and calcium in PTX rats and Michael teaches the method allows for in-site analysis including drug testing, time-dependent detection of secreted protein and fluorescence staining without disturbing the spheroids and hanging drop culture has been widely adopted because of single spheroid formation and high reproducibility.
Conclusion
No claims allowed.
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/Z.M.B./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632