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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06-27-2025 has been entered.
Applicant’s amendment filed on 06-27-2025 has been entered. Claims 1 has been amended. Claims 11-12 have been canceled. Claims 1-10, 13-21 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10) in the reply filed on 06-20-2024 is acknowledged.
Claims 13-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.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 06-20-2024.
Claims 1-10 and species fibroblasts; a mild detergent; and Triton-X-100 are under consideration.
Priority
This application is a 371 of PCT/US19/48977 filed on 08/30/2019 that claims priority from US provisional application No 62/726,573 filed on 09/04/2018.
Withdrawn-Claim Rejections - 35 USC § 101
Claims 11-12 were rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. In view of Applicants' cancelation of claims 11-12, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
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 1-10 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.
Claim 1 recites the phrase “increased viability and increased expression of synaptopodin and nephrin,” which render the claim vague and indefinite. It is unclear the comparison is made as compared with what control or standard. It is unclear if the claimed podocytes in culture are “ increased viability and increased expression of synaptopodin and nephrin” as compared with what cells type or control in what degree of expression to be consider “increased”.
Claim 1 recites the phrase “up to at least 21 days” that is vague and indefinite because it is unclear if the claims require “up to” or “at least” which encompass lower and upper limit.
Claims 2-10 are included in the rejection because they directly or indirectly depend from the rejected base claim. Appropriate correction is required.
Maintained in modified form -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 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Ingber et al (Pub. No.: US 2016/0143949 A1, Pub. Date: May 26, 2016) in view of Leach et al (Pub. No.: US 2014/0023723 A1, Pub. Date: Jan. 23, 2014) as evidenced by May et al (Front Endocrinol (Lausanne). 2014 Oct 1:5:148. doi: 10.3389/fendo.2014.00148. eCollection 2014).
Claim interpretation:
The specification of the claimed invention teaches that Podocytes are the pivotal cells maintaining normal structure and function of the kidney glomerulus ([0005], page 1-2). Thus, Podocytes are interpreted as kidney/renal cells.
The specification of the claimed invention teaches that “FIGS. 5A-5B show immunofluorescence analysis demonstrating podocytes cultured on decellularized ECM rich substrate showed visibly higher expression of synaptopodin (FIG. 5A) and nephrin (FIG. 5B) up to 21 days under differentiation conditions” ([0026]. Page 6). Thus, the duration of 21 days is interpreted as duration for differentiation to obtain podocytes.
Regarding to claims 1, Ingber et al teaches methods, kits, and cell culture media for generation of podocytes from pluripotent stem (PS) cells (Abstract), and the method comprises culturing in a cell or tissue culture device the isolated population of podocytes ([0049], page 4) (For the preamble).
Ingber et al teaches that “decellularized matrix” refers to a composition derived from or generated by removing the cellular components of an isolated population of cells or tissues without any significant damage to the extracellular matrix, and the decellularized matrix can be derived from glomerular endothelial cells (e.g., human glomerular endothelial cells) or from podocytes or from a tissue ([0170], page 17) (For step d).
Ingber et al teaches that it can be desirable to have cell culture environment mimic the physiological microenvironment of a kidney or glomerulus, and/or to promote cell adhesion to a substrate surface, and the differentiated podocytes can be cultured on a surface coated with decellularized matrix ([0169], page 17) (For step e.).
Ingber et al does not teach producing an extracellular matrix by a. contacting a tissue culture substrate with cells; b. growing the cells on the tissue culture substrate; and c. inducing the cells to produce an extracellular matrix (ECM). However, Ingber et al does teach podocytes can be embedded in a biomaterial scaffold during the contacting step. For example, biomaterials such as... polyethylene glycol (PEG)...alginate, hyaluronic acid…. ([0172], page 17). Leach et al cure the deficiency.
Leach et al teaches methods for producing compositions of decellularized extracellular matrix (DM) tissue culture (Abstract), and the method comprises obtaining a population of cells (such as human mesenchymal stem cells) grown on a tissue culture substrate under conditions sufficient to form an extracellular matrix (ECM) ([0005]-[0006], page 1) (For step a, b, c).
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 Ingber et al of culturing podocytes on decellularized extracellular matrix with methods for producing compositions of decellularized extracellular matrix as taught by Leach 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 Ingber et al teaches the use of decellularized matrix in culture with podocytes and Leach et al teach that the invention of decellularized extra cellular matrix (DM) has “the ability to accelerate tissue formation, improve cellular viability upon implantation, enhance biomaterial integration once implanted, and provide a platform to better model cellular behavior in vivo” ([0108], page 9). Leach et al teach the steps of producing a decellularized extracellular matrix by growing cells on a tissue culture substrate under conditions sufficient to form an extracellular matrix ([0005], page 1). One of skill in the art would have been expected to have a reasonable expectation of success because Leach et al teach the method of producing and using of decellularized extracellular matrix in cell culture with detail instruction for producing the decellularized extracellular matrix.
Ingber et al teach that in some embodiments, the pluripotent stem cells can be contacted with the podocyte induction medium until the cells differentiate into post-mitotic podocytes (e.g., Substantially incapable of proliferation). Accordingly, the contact period of time can range from about 1 day to 1 week to 1 month or longer ([0123], page 12). Thus, it is indicating that the time of “the podocytes are grown in culture” 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 podocyte culturing with different time duration out of the course of routine optimization (For the claimed: wherein the podocytes are grown in culture up to at least 21 days).
Ingber et al teach that “the methods of various aspects described herein generally can efficiently generate podocytes from the pluripotent stem cells, mesodermal cells and/or intermediate mesodermal cells. For example, the methods of various aspects described herein can induce differentiation of at least about 80% or more (up to 100%) of the pluripotent stem cells, mesodermal cells and/or intermediate mesodermal cells into podocytes” ([0177], page 17). Ingber et al teach that “Mature (post-mitotic) differentiated podocytes are ……. substantially positive for at least one or more (including, e.g., at least two, at least three or more) podocyte-specific markers described herein (e.g., but not limited to, WT1, nephrin, podocin, podocalyxin, synaptopodin, and APOL1)” ([0189], page 18). Since the art teaches that it is possible to induce differentiation 100% of the pluripotent stem cells, mesodermal cells and/or intermediate mesodermal cells into podocytes, it is possible that 100% of the induced cells can be viable and expressing podocyte-specific markers such as synaptopodin and nephrin (For the claimed: increased viability and increased expression of synaptopodin and nephrin).
Ingber et al teach FIGS. 7A-7B are images of human PS-derived podocytes exhibiting foot processes ([0073], page 6). Foot processes are inherently interdigitating as evidenced by May et al who teach that “The foot processes extend from the major processes and cover the GBM. Neighboring foot processes interdigitate, and where this occurs a modified cell to-cell junction known as the slit diaphragm is formed” (Page 2, left column, 3rd para.) (For the claimed: wherein the podocytes comprise interdigitating foot processes).
It is noted that all of the step (a) (b) (c) (d) (e) of the claimed invention are rendered obvious in view of Ingber et al and Leach et al as described above; thus, podocytes generated by methods of Ingber et al and Leach et al are expected to be the same structurally, functionally and physiologically as the claimed invention.
Regarding to claim 2, Ingber et al teaches that the podocytes can be differentiated from pluripotent stem cells that were derived from skin fibroblasts of the subject ([0219], Page 22). Additionally, Leach et al teaches ECM-expressing cells such as mesenchymal stem cells (MSCs) can be derived from fibroblasts from skin ([0072], page 5).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Ingber et al and Leach et al to grow podocytes with the use of decellularized ECM derived from cell such as Fibroblasts. One of ordinary skill in the art would be motivated to do so because both podocytes and decellularized extracellular matrix can be both generated by fibroblasts as taught by detailed instruction of Ingber et al and Leach et al, with reasonable expectation of success.
Regarding to claims 3 and 4, Leach et al teaches method of depositing a decellularized extracellular matrix, e.g., a mesenchymal stem cell-secreted extracellular matrix, on biomaterials. This matrix is produced by cells, for example, MSCs on, e.g., tissue culture plastic (TCP) under controlled conditions ([0002], page 1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to use decellularized ECM to grow podocytes as taught by Ingber et al and apply teaching of Leach et al to generate decellularized extracellular matrix on tissue culture plastic. One of ordinary skill in the art would be motivated to do so because Ingber et al teaches the use of decellularized matrix in culture with podocytes and Leach et al teaches the steps of producing a decellularized extracellular matrix by growing cells on a tissue culture substrate under conditions sufficient to form an extracellular matrix, with reasonable expectation of success.
Regarding to claims 5 and 6, Ingber et al teach the pluripotent stem cells, mesodermal cells, intermediate mesodermal cells, and/or podocytes can be embedded in a biomaterial scaffold during the contacting step. For example, biomaterials such as... polyethylene glycol (PEG)...alginate, hyaluronic acid…. ([0172], page 17).
Regarding to claims 7, 8, 9, Leach et al teach removing the cells from the tissue culture substrate by treatment with 0.5% Triton X-100 in 20 mM ammonium hydroxide (NH4-OH) in phosphate buffered saline (PBS) for 5 minutes at 37 degrees C. to form a tissue culture substrate coated with decellularized extra cellular matrix ([0006], page 1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to use decellularized ECM to grow podocytes as taught by Ingber et al and apply teaching of Leach et al to generate decellularized extracellular matrix by removing the cells from the tissue culture substrate by treatment with 0.5% Triton X-100. One of ordinary skill in the art would be motivated to do so because Ingber et al teaches the use of decellularized matrix in culture with podocytes and Leach et al teaches the steps of producing a decellularized extracellular matrix by growing cells on a tissue culture substrate under conditions sufficient to form an extracellular matrix, with reasonable expectation of success.
Regarding to claims 10, Ingber et al teaches mechanical forces and/or shear stress can be used in conjunction with the podocyte induction media described herein to enhance differentiation of hPS cells and their derivatives into podocytes, and/or enhance interaction of differentiated podocytes with endothelial cells or any other cell type, e.g., in a co-culture ([0006], page 1).
Response to Arguments
Applicant's arguments filed on 06-27-2025 have been fully considered but they are not persuasive.
1. Applicant disagrees that at least because Ingber fails to disclose or suggest a method for growing podocytes in culture up to at least 21 days with increased viability and increased expression of synaptopodin and nephrin, wherein the podocytes comprise interdigitating foot processes. Applicant notes that Ingber does disclose using decellularized ECM proteins to coat a surface on which undifferentiated pluripotent stem cells can be cultured, see, e.g., paragraph [0403], page 33 oflngber. Ingber further indicates that the undifferentiated pluripotent stem cells can be differentiated into podocytes when the pluripotent stem cells were cultured in the podocyte induction medium on the decellularized ECM proteins, see, e.g., paragraphs [0402] and [0403], page 33 oflngber. However, Ingber fails to disclose or suggest the podocytes can be grown in culture with the decellularized extracellular matrix up to at least 21 days with increased viability and increased expression ofsynaptopodin and nephrin, wherein the podocytes comprise interdigitating foot processes. Leach fails to make up for the deficiencies of Ingber, at least because Leach fails to disclose or suggest podocytes, let alone methods of culturing podocytes (Remarks, page 7).
Response to Arguments:
As described above, Ingber et al teach that in some embodiments, the pluripotent stem cells can be contacted with the podocyte induction medium until the cells differentiate into post-mitotic podocytes (e.g., Substantially incapable of proliferation). Accordingly, the contact period of time can range from about 1 day to 1 week to 1 month or longer ([0123], page 12). Thus, it is indicating that the time of “the podocytes are grown in culture” 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 podocyte culturing with different time duration out of the course of routine optimization (For the claimed: wherein the podocytes are grown in culture up to at least 21 days).
Ingber et al teach that “the methods of various aspects described herein generally can efficiently generate podocytes from the pluripotent stem cells, mesodermal cells and/or intermediate mesodermal cells. For example, the methods of various aspects described herein can induce differentiation of at least about 80% or more (up to 100%) of the pluripotent stem cells, mesodermal cells and/or intermediate mesodermal cells into podocytes” ([0177], page 17). Ingber et al teach that “Mature (post-mitotic) differentiated podocytes are ……. substantially positive for at least one or more (including, e.g., at least two, at least three or more) podocyte-specific markers described herein (e.g., but not limited to, WT1, nephrin, podocin, podocalyxin, synaptopodin, and APOL1)” ([0189], page 18). Since the art teaches that it is possible to induce differentiation 100% of the pluripotent stem cells, mesodermal cells and/or intermediate mesodermal cells into podocytes, it is possible that 100% of the induced cells can be viable and expressing podocyte-specific markers such as synaptopodin and nephrin (For the claimed: increased viability and increased expression of synaptopodin and nephrin).
Ingber et al teach FIGS. 7A-7B are images of human PS-derived podocytes exhibiting foot processes ([0073], page 6). Foot processes are inherently interdigitating as evidenced by May et al who teach that “The foot processes extend from the major processes and cover the GBM. Neighboring foot processes interdigitate, and where this occurs a modified cell to-cell junction known as the slit diaphragm is formed” (Page 2, left column, 3rd para.) (For the claimed: wherein the podocytes comprise interdigitating foot processes).
It is noted that all of the step (a) (b) (c) (d) (e) of the claimed invention are rendered obvious in view of Ingber et al and Leach et al as described above; thus, podocytes generated by methods of Ingber et al and Leach et al are expected to be the same structurally, functionally and physiologically as the claimed invention.
2. Applicant argue that based on paragraph [0170], a person skilled in the art would understand that podocytes cannot be cultured on a surface coated with decellularized matrix, as in paragraph [0170], Ingber specifically fails to disclose or suggest that podocytes or differentiated podocytes can be cultured on a surface coated with decellularized matrix ….. Applicant notes that paragraph [0403] states that the decllularized ECM proteins can be used to coat a surface on which undifferentiated pluripotent stem cells can be cultured. Paragraph [0403] does not state that the podocytes can be cultured on decellularized matrix, and it certainly does not state that podocytes can be cultured on decellularized matrix for extended periods of time. (Remarks, page 8)
Response to Arguments:
Applicant essentially cited [0170] and [0403] to argue that Ingber et al teach culturing pluripotent stem on decellularized matrix but fails to disclose or suggest that podocytes or differentiated podocytes can be cultured on a surface coated with decellularized matrix. This is not persuasive because of the following reasons:
Ingber et al teach methods, kits, and cell culture media for generation of podocytes from pluripotent stem (PS) cells (Abstract); thus, this culturing pluripotent stem (PS) cells on decellularized matrix would lead to podocytes that would be in the same culture containing decellularized matrix. The [0170] even suggested to use “the decellularized matrix can be derived from podocytes.” (see [0170], page 17). The [0403] stated “decellularized ECM proteins can be used to coat a surface on which undifferentiated pluripotent stem cells are cultured. FIG. 12 shows that podocytes were generated by differentiating and culturing human pluripotent stem cells on decellularized matrix,” (see [0403], page 33).
Ingber et al teach “FIG. 12 is a set of fluorescent images showing that decellularized ECM supports adhesion and differentiation of human PS cells into podocytes” ([0078], page 7).
Further, Ingber et al teach [0169] that stated “the pluripotent stem cells, mesodermal cells, intermediate mesodermal cells, and/or differentiated podocytes can be cultured on a surface coated with at least one or more (e.g., at least two or more, including, at least three, at least four or more) extracellular matrix proteins. Non-limiting examples of extracellular matrix include, but are not limited to, laminin, collagen, fibronectin, vitronectin, hyaluronic acid, peptides, gelatin, matrigel, decellularized matrix” (see [0169], page 17). Thus, it is apparent that differentiated podocytes can be cultured on a surface coated with decellularized matrix.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KHOA NHAT TRAN whose telephone number is (571)270-0201. The examiner can normally be reached M-F (9-5).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, PETER PARAS can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632