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 arguments filed 2-2-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-10, 24, 25, 27-36 have been canceled. Claims 11-23, 26, 37-43 remain pending.
Election/Restrictions
Applicants elected Group I, claims 11-14, without traverse in the reply filed on 7/19/23.
Claims 15-23 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 7/19/23.
Claims 11-14, 26, 37-43 remain under consideration.
Claim Rejections - 35 USC § 112
Enablement
Claims 39-40 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a co-culture that exhibits about 10% increased beating rate frequence as compared to cardiomyocytes alone (pg 8, para 25) and about 10% decreased conduction velocity as compared to cardiomyocytes alone (pg 9, lines 1-8), does not reasonably provide enablement for any “altered beating rate” (claim 24) or “increased beating rate” (claim 25) other than a 10% increase, any “altered impulse conduction velocity” (claim 27), “increased impulse conduction velocity” (claim 28) other than a 10% increase, “fibrillatory conduction” (claim 30; pg 20, line 8). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Withdrawn rejections
The rejection regarding making/using a co-culture with “fibrillatory conduction pattern” in claim 30 has been withdrawn because the claim has been canceled.
The rejections regarding making/using a co-culture with 10-90% or 50% GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE-7 in claims 33 and 36 have been withdrawn because the claims have been canceled.
The rejection regarding obtaining GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE7, wherein at least 90% of the cells bind antibody TE-7 in claim 38 has been withdrawn. Pg 14, para 46, says 90% of cells derived from pluripotent cells are cardiac fibroblasts. TE7 antibody is generic for binding any epithelial cell, but if 90% of the cells obtained are cardiac fibroblasts, then 90% of the cells would bind TE7 as claimed.
Pending rejections
A) The specification does not enable making/using a co-culture without steps a)-c) having a cell separation or a selection step as required in claim 39. The concept is contemplated on pg 15, line 5; however, the examples are limited to differentiating pluripotent cells into cardiomyocytes (pg 23, para 78) and cardiac fibroblasts (para 24, para 79) both of which are a selection step. The medium was separated from the cells in both processes which is “cell separation”. Pg 24-25, para 80, describes the co-culture which requires dissociating cells and replating hPSC-CFs which is “cell separation” from media and a “selection step”. Pg 25, par 81, describes performing flow cytometry which separates cells expressing different markers and is literally “cell separation” and “selection”. Para 47 (pg 15) says the method can be performed without selection or separation, but this is impossible because each step inherently IS a selection step. In some steps, the cells are centrifuged and resuspended which is a separation. All of the methods in the specification require some sort of “separation” or “selection” despite the statement on pg 15. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to perform the method without steps a)-c) having a cell separation or a selection step as required in claim 39.
Response to argument
Applicants argue paragraphs 8 and 47 provide support. Applicants’ argument is not persuasive for reasons set forth above.
B) The specification does not enable making/using a co-culture wherein GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE-7 obtained in step c) are capable of undergoing at least 10 cell divisions as required in claim 40. The specification does not contemplate or exemplify maintaining GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE-7 for at least 10 cell divisions. The specification teaches differentiating pluripotent cells into cardiac fibroblasts (para 24, para 79) but does not teach maintaining hPSC-CFs, specifically the cells claimed, for 10 cell divisions. Pg 24-25, para 80, describes the method for co-culture but does not teach maintaining hPSC-CFs, specifically the cells claimed, within the co-culture for 10 cell divisions. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to culture hPSC-CFs, specifically the cells claimed, for 10 cell divisions as required in claim 40.
Response to argument
Applicants argue the GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE-7 obtained in step c) are capable of 10 cell divisions. Applicants’ argument is not persuasive because it is unfounded.
Written Description
Support for “culturing human pluripotent cells in chemically defined culture medium comprising a Gsk3 inhibitor for about 1 day to form a population of T+ SNAI2- cells” is found on pg 24, para 79, which teaches culturing human pluripotent cells on “day 0” with CHIR99021, taken with Fig. 2B which teaches obtaining cells expressing T but not SNAI2 on day 1.
Support for “culturing the T+ SNAI2- cells in the chemically defined medium without the Gsk1 inhibitor for about 1 day to form a population of T+ MESP1+ GATA4+ SNAI1+ SNAI2+ cells” is found on pg 23, para 79, which teaches culturing the cells obtained on day 1 in the same medium without CHIR99021, taken with Fig. 2B which teaches obtaining cells expressing T, GATA4, SNAI1, and SNAI2 on day 2.
Support for “culturing the T+ MESP1+ GATA4+ SNAI1+ SNAI2+ cells in a chemically defined culture medium free of exogenous Bone Morphogenetic Proteins (BMPs) and comprising a fibroblast growth factor for about 18 days to generate a population of human GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells” is found on:
pg 23, para 79, which teaches culturing the cells obtained on day 2 in “defined fibroblast culture medium (Table 1) [DMEM, HLL supplement, ascorbic acid, GlutaMax, hydrocortisone, and insulin] supplemented with bFGF”,
Fig. 2B which teaches obtaining cells expressing GATA4, ISL1, HAND2, TCF21, SNAI2,
Fig. 3G, described on pg 7, lines 7-11, which teaches cardiac fibroblasts obtained from hPSCs (hPSC-CF) expressed FSP1 (top panel – bottom right corner), collagen and fibronectin (bottom panel – bottom right corner),
pg 7, line 8, which teaches using “antibodies for fibroblast (clone TE-7)”, i.e. Fig. 3G shows the results of whether cells were fibroblasts as determined by whether they bound to the “fibroblast antibody” “TE-7”, and
pg 7, lines 10-11, which teaches “fibroblast [i.e. the cells bound to “fibroblast antibody” TE-7], fsp1, collagen I and fibronectin expressed in all fibroblasts” in Fig. 3G.
Claims 38-40 remain 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Withdrawn rejections
The rejection regarding making/using a co-culture with “fibrillatory conduction pattern” in claim 30 has been withdrawn because the claim has been canceled.
The rejections regarding making/using a co-culture with 10-90% or 50% GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE-7 in claims 33 and 36 have been withdrawn because the claims have been canceled.
The rejection regarding obtaining GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE7, wherein at least 90% of the cells bind antibody TE-7 in claim 38 has been withdrawn. Pg 14, para 46, says 90% of cells derived from pluripotent cells are cardiac fibroblasts. TE7 antibody is generic for binding any epithelial cell, but if 90% of the cells obtained are cardiac fibroblasts, then 90% of the cells would bind TE7 as claimed.
Pending rejections
A) The specification lacks written description for a co-culture without steps a)-c) having a cell separation or a selection step as required in claim 39. The concept is contemplated on pg 15, line 5; however, the examples are limited to differentiating pluripotent cells into cardiomyocytes (pg 23, para 78) and cardiac fibroblasts (para 24, para 79) both of which are a selection step. The medium was separated from the cells in both processes which is “cell separation”. Pg 24-25, para 80, describes the co-culture which requires dissociating cells and replating hPSC-CFs which is “cell separation” from media and a “selection step”. Pg 25, par 81, describes performing flow cytometry which separates cells expressing different markers and is literally “cell separation” and “selection”. Para 47 (pg 15) says the method can be performed without selection or separation, but this is impossible because each step inherently IS a selection step. In some steps, the cells are centrifuged and resuspended which is a separation. All of the methods in the specification require some sort of “separation” or “selection” despite the statement on pg 15. Accordingly, the specification lacks written description for performing the method without steps a)-c) having a cell separation or a selection step as required in claim 39.
Response to argument
Applicants argue paragraphs 8 and 47 provide support. Applicants’ argument is not persuasive for reasons set forth above.
B) The specification lacks written description for a co-culture wherein GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE-7 obtained in step c) are capable of undergoing at least 10 cell divisions as required in claim 40. The specification does not contemplate or exemplify maintaining GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE-7 for at least 10 cell divisions. The specification teaches differentiating pluripotent cells into cardiac fibroblasts (para 24, para 79) but does not teach maintaining hPSC-CFs, specifically the cells claimed, for 10 cell divisions. Pg 24-25, para 80, describes the method for co-culture but does not teach maintaining hPSC-CFs, specifically the cells claimed, within the co-culture for 10 cell divisions. Accordingly, the specification lacks written description for culturing hPSC-CFs, specifically the cells claimed, for 10 cell divisions as required in claim 40.
Response to argument
Applicants argue the GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCF21+ SNAI2+ cells that bind antibody TE-7 obtained in step c) are capable of 10 cell divisions. Applicants’ argument is not persuasive because it is unfounded.
Indefiniteness
The rejection of claims 29, 30 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, has been withdrawn because the claims have been canceled.
35 USC § 102
The rejection of claims 11-13 under 35 U.S.C. 102a1 as being anticipated by Campbell (“Stem Cell-derived cardiac spheroids as 3D in vitro models of the human heart microenvironment”, Methods in Molecular Biology, 2019, pg 51-59) was withdrawn because Campbell was not available at the effective time of filing (9-30-16).
Claim Rejections - 35 USC § 103
Withdrawn rejections
The rejection of claims 11-14 under 35 U.S.C. 103 as being unpatentable over Campbell (“Stem Cell-derived cardiac spheroids as 3D in vitro models of the human heart microenvironment”, Methods in Molecular Biology, 2019, pg 51-59) was withdrawn because Campbell was not available at the effective time of filing (9-30-16).
The rejection of claims 11-14 under 35 U.S.C. 103 as being unpatentable over Campbell (“Stem Cell-derived cardiac spheroids as 3D in vitro models of the human heart microenvironment”, Methods in Molecular Biology, 2019, pg 51-59) in view of Xu (Stem cells and Develop., 2006, Vol. 15, pg 931-941) was withdrawn because Campbell was not available at the effective time of filing (9-30-16).
The rejection of claims 11-14 under 35 U.S.C. 103 as being unpatentable over Campbell (“Stem Cell-derived cardiac spheroids as 3D in vitro models of the human heart microenvironment”, Methods in Molecular Biology, 2019, pg 51-59) in view of Lian (Nature protocols, 2013, Vol. 8, No. 1, pg 162-175) was withdrawn because Campbell was not available at the effective time of filing (9-30-16).
The rejection of claims 11-14, 26, 29, 30, 33, 36-43 under 35 U.S.C. 103 as being unpatentable over Rosker (Circ Res., 2011, Vol. 109, pg 1120-1131) in view of Lian (Nature protocols, 2013, Vol. 8, No. 1, pg 162-175) was withdrawn. Rosker co-cultured cardiomyocytes and cardiac fibroblasts in defined medium (pg 1122, “Actin-targeting drugs rescue MFB-induced slow conduction”). Rosker did not teach differentiating pluripotent cells into cardiac mesoderm progenitors that express T, SNA12 (step a) of claim 11) followed by differentiation into MESP1, GATA4, SNAI1, and SNAI2 using a GSK3 inhibitor (step b) of claim 11) followed by differentiation into GATA4+ FSP1+ collagen I+ fibronectin+ ISL1+ HAND2+ TCR21+ SNAI2+ cells that bind antibody TE7 in the absence of BMPs and in the presence of an FGF for about 18 days (step c) of claim 11). However, Lian differentiated human pluripotent cells into mesoderm progenitors using 12 μm CHIR99021 (pg 170, (B)(ii)) as evidenced by brachyury (pg 164, line 1, Fig. 2A); this is equivalent to (step a) of claim 11). Lian differentiated the pluripotent cells into “cardiac mesoderm” in the absence of CHIR99021 (“Induction of mesendoderm, cardiac mesoderm and cardiomyocytes” pg 163-164) which inherently MUST express T, MESP1, GATA4, SNAI1, and SNAI2 as required in step b) claim 11. This is equivalent to step b) of claim 11. After 3 days, the cells were cultured with bFGF (pg 170, C)(iv-v) “(iv) On day −3, day −2 and day −1 of differentiation, aspirate the medium and replace it with 2 ml of mTeSR1 + 1 µM CHIR99021 per well of a 12-well plate. (v) On day 0 of differentiation, add 100 ng ml− 1 activin A, 10 ng ml− 1 bFGF and 1% (vol/vol) KnockOut serum replacement into RPMI/B-27 without insulin. This medium is named GiAB d0 medium. Aspirate the old medium and then add 1 ml of GiAB d0 medium per well to the 12-well plate and record the time”) which is equivalent to culturing cardiac mesoderm progenitors in defined medium comprising FGF as required in step c) of claim 11. Lian did not teach culturing the cardiac mesoderm in the presence of FGF2 for about 18 days as required in step c) of claim 11. Lian did not teach obtaining cardiac fibroblasts or cells expressing TE7 as required in step c) of claim 11. TE7 is a marker of fibroblasts (pg 7, line 3-4, 8).
The rejection of claims 11-14 and 24-43 under 35 U.S.C. 103 as being unpatentable over Vasquez (Circ. Res., 2010, Vol. 107, pg 1011-1020) in view of Lian (Nature protocols, 2013, Vol. 8, No. 1, pg 162-175) was withdrawn because Lian did not teach culturing the cardiac mesoderm in the presence of FGF2 for about 18 days as required in step c) of claim 11. Lian did not teach obtaining cardiac fibroblasts or cells expressing TE7 as required in step c) of claim 11. TE7 is a marker of fibroblasts (pg 7, line 3-4, 8).
Double Patenting
The rejection of claims 11-13, 14, 24-43 on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11072780 was withdrawn in view of the Terminal Disclaimer filed 7-1-25.
Conclusion
Claims 11-14, 26, 37, 38, 41-43 are allowed. Claims 39-40 remain rejected. Claims 15-23 remain withdrawn.
THIS ACTION IS MADE FINAL. 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.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public.
For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199.
If attempts to reach the examiner are unsuccessful, the examiner's supervisor, Tracy Vivlemore, can be reached on 571-272-2914.
The official fax number for this Group is (571) 273-8300.
Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638