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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 26, 2025 has been entered.
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
3. Applicant’s amendment filed October 27, 2025 and November 26, 2025 is acknowledged. Claims 1-9, 11-12, 15, 17-20 and 22-24 are cancelled. Claim 10 is amended. Claims 10, 13-14, 16, 21 and 25 are pending in this application. Election was made without traverse in the reply filed on December 27, 2023.
4. Claims 10, 13-14, 16, 21 and 25 are under examination in this office action.
5. Applicant’s arguments filed on October 27, 2025 and November 26, 2025 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
6. The rejection of claims 17 and 23-24 under 35 U.S.C. 103 as being unpatentable over Ramaswamy et al. (US2021/0180024) in view of Lewis et al. (Pharmacol. Res. 2018; 127: 33-40) and Lee et al. (US2023/0321190) and evidentiary reference: Patalano (bioRxiv. doi.org/10.1101/2022.02.04.479106) is moot because the claims are canceled.
The rejection of claims 17 and 23-24 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US11746329 in view of Ramaswamy (US2021/0180024), Lewis et al. (2018), and Lee et al. (US2023/0321190) and evidentiary reference: Patalano (2022) is moot because the claims are canceled..
Claim Rejections/Objections Maintained
In view of the amendment filed on October 27, 2025 and November 26, 2025, the following rejections are maintained.
Claim Rejections - 35 USC § 103
7. 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.
Claims 10, 13-14, 16, 21 and 25 stand rejected under 35 U.S.C. 103 as being unpatentable over Ramaswamy et al. (US2021/0180024) in view of Lewis et al. (Pharmacol. Res. 2018; 127: 33-40) and Lee et al. (US2023/0321190) and evidentiary reference: Patalano (bioRxiv. doi.org/10.1101/2022.02.04.479106). The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 10, 13-14, 16, 21 and 25 as amended are drawn to a method for producing injectable enhanced stem cell exosomes (IESCEs), comprising
seeding mesenchymal stem cells (MSCs) onto a polymeric bio-scaffold;
culturing the MSCs in a culture medium for the MSCs on the polymeric bio-scaffold under rotisserie culture;
placing the polymeric bio-scaffold in a torpedo bioreactor and culturing the MSCs under a pathological oscillatory flow condition having a shear index/oscillatory shear index (OSI) of about 0.5;
collecting IESCEs from the culture medium; and
detecting levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin in IESCEs, wherein the IESCEs comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin as compared to those of static culture and those under a physiological oscillatory flow condition having an OSI from 0.18-0.23, and
analyzing levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin released from IESCEs, wherein the IESCEs release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under the physiological oscillatory flow condition having the OSI from 0.18-0.23.
Response to Arguments
On p. 5-8 of the response, Applicant acknowledges that i) Ramaswamy teaches an OSI of 0.5 as a maximum extreme of the oscillatory flow and compares low OSI, physiological OSI and high OSI in Figures 3A-3C and concludes that the physiological OSI range for stimulating BMSCs was 0.18≤OSI≤0.23, which yield maximum phenotype benefits (para. [0153]). But Applicant argues that: i) Ramaswamy does not teach: 1) the IESCEs produced under a pathological oscillatory flow condition having an OSI of about 0.5 comprising increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23; 2) analyzing levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin released from IESCEs and wherein the IESCEs release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under the physiological oscillatory flow condition having the OSI from 0.18-023; 3) an OSI of about 0.5 as causing an increased in the recited cytokine levels in IESCEs relative to static culture or a physiological oscillatory flow condition having the OSI from 0.18-0.23 or an OSI of about 0.5 specifically induces increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin in IESCEs and release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin from the IESCEs; ii) Lewis and Lee teach several growth factors and cytokines in their exosomes but do not teach that the recited IESCEs produced under a pathological oscillatory flow condition having an OSI of about 0.5 comprising increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23 or increased release of resistin, IGF-1, IL-1a, MCP-1 and adiponectin from the IESCEs as compared to those produced under static culture and those produced under the physiological oscillatory flow condition having the OSI from 0.18-0.23; Applicant further cites KSR, Intl Co. v. Teleflex Inc.; United States v. Adams in support of the arguments; iii) the claimed method produced surprising and unexpected results of producing IESCEs that comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23 and release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under the physiological oscillatory flow condition having the OSI from 0.18-0.23 (see Table 1, and Figures 2-3 of the specification) and cites In re Rouffet, In re Sebek, In re Chupp in support of the arguments.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2141, MPEP2141-I, rationales identified by the Court in KSR (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007)), MPEP2141-II, the basic factual inquires of Graham v. John Deere Co.(Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966)),and MPEP §2141.01-2147.03, the cited references do render the claimed invention obvious because:
i. Applicant cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In this case, Ramaswamy teaches a method for producing injectable enhanced stem cell exosomes (IESCEs) from mesenchymal stem cells (MSCs) on a polymeric bio-scaffold in a torpedo bioreactor and wherein the MSCs are cultured under a pathological oscillatory flow condition having an OSI of about 0.5 (see para. [0085]; [0153]) and the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method are identical to the IESCEs obtained from the method recited in instant claims because the steps of culturing and collecting the IESCEs in the Ramaswamy’s method are identical to the steps recited in instant claims.
The method disclosed by Ramaswamy comprises steps:
i) seeding mesenchymal stem cells (MSCs) including BMSCs (paragraphs [00135]-[0140], claims 5, 7-10) onto a polymeric bio-scaffold (PSIS, PGA/PLLA) (paragraphs [0077]; [0137], claim 14);
ii) culturing the MSCs in a culture medium for MSCs on the polymeric bio-scaffold under rotisserie culture for ≥8 days (paragraphs [0135]-[0140]; [0148], Example 1, claim 21);
iii) placing the polymeric bio-scaffold in a torpedo bioreactor and culturing the MSCs/BMSCs under a static and/or dynamic flow condition or a physiologically-relevant pulsatile flow condition for ≥14 days, wherein the physiologically-relevant pulsatile flow condition includes the oscillatory shear index (OSI) with a range of 0≤OSI≤0.5, with zero depicting one-directional flow and 0.5 describing maximum oscillatory flow (see Examples 4-5; para [0153]-[0155], Table 1; para.[0136]-[0139]; [0135]-[0141]; [0020]-[0021]; [0075]-[0085]) or under the shear index/OSI range at about 0.05-about 0.5, about 0.1-about 0.5, 0.1-about 0.45, 0.1-about 0.4, 0.18-0.3, or 0.1… 0.18…0.2…0.23….0.4 (see para. [0085]; [0153]);
iv) collecting IESCEs from the culture medium (para. [0140], claim21), and
v) detecting and analyzing proteomics including growth factors, cytokines and chemokines of the isolated IESCEs (para.[0144]-[0147]), wherein the growth factors, cytokines and chemokines include VEGF, IL-6, IL-10, TGF-b1, FGF2, extracellular matrix metalloprotease inducer (EMMPRIN), MMP-9, HGF and G-CSF in the IESCEs in a high shear index/OSI including OSI of about 0.5 as compared to those under a static, a physiological oscillatory flow condition at an OSI of 0.2 (see table 1; para. [0041]-[0043]; [0013]-[0015]; [0044]; [0047]; [0068]).
Ramaswamy teaches that the MSCs being cultured in the culture medium under rotisserie culture for ≥8 days (paragraphs [0135]-[0140]; [0148], Example 1, claim 21); and in the torpedo bioreactor under a physiologically-relevant pulsatile flow condition for ≥14 days, wherein the physiologically-relevant pulsatile flow condition includes the oscillatory shear index (OSI) with a range of 0≤OSI≤0.5, with zero depicting one-directional flow and 0.5 describing maximum oscillatory flow (see Examples 4-5; para [0153]-[0155], Table 1; [0136]-[0139]; [0135]-[0141]; [0020]-[0021]; [0075]-[0085]) or under the shear index/OSI range at about 0.05-about 0.5, about 0.1-about 0.5, 0.18-0.3, or 0.1… 0.18…0.2…0.23….0.4 (see para. [0085]; [0153]).
Based on the definition of “about” defined on p. 34 of the instant specification, the claimed OSI of “about 0.5” recited in instant claim 10 is equal to 0.4-0.5 or 0.45-0.5, which is taught by Ramaswamy because Ramaswamy teaches a physiologically-relevant pulsatile flow condition having the oscillatory shear index (OSI) with a range of 0≤OSI≤0.5, with zero depicting one-directional flow and 0.5 describing maximum oscillatory flow or the OSI range at about 0.05-about 0.5, about 0.1-about 0.5, 0.1-about 0.45, 0.1-about 0.4, 0.18-0.3, or 0.1… 0.18…0.2…0.23….0.4 (see para. [0085]; [0153]).
The OSI of 0.4 or about 0.5 disclosed by Ramaswamy (see paragraphs [0025]; figure 8; [0041]; [0069]-[0070]; [0072]-[0076]; [0083]-[0085]; [0137]-[[0141]; [0158]; tables 1-2) is a pathological oscillatory flow condition as recited in claims 10, 14 and 21 as evidenced by Patalano because Patalano teaches that OSI of >0.2 is a high OSI and is a pathological oscillatory flow condition (p. 1 abstract). Thus, the MSCs in the Ramaswamy’s method are cultured in the torpedo bioreactor under a pathological flow condition having a OSI of about 0.5 and for ≥14 days as recited in claims 10, 14, and 21 (see paragraphs [0025]; figure 8; [0041]; [0069]-[0070]; [0072]-[0076]; [0083]-[0085]; [0137]-[[0141]). Ramaswamy teaches a physiological OSI range of 0.18-0.23 (para [0153]) or 0.2 as in claim 25 (see para [0009]; [0070]; [0137]). Ramaswamy also teaches that the polymeric bio-scaffold comprises PSIS, or PGA-PLLA as in claim 16 (see paragraphs [0010]; [0077]).
Thus, the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method are identical to those recited in instant claims.
While Ramaswamy does not teach that the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23, Lewis and Lee teach these limitations and provide motivation and an expectation of success in obtained the IESCE secreted from MSCs/BMSCs comprising the increased levels of the recited growth factors and cytokines because Lewis teaches that MSC-derived exosomes comprising different cytokines and growth factors including VEGF, IGF-1, EGF, FGF and TGF-b which can be used for treatment of cardiac repair and regeneration (see p. 33, abstract; p. 33-36; p. 36-37) and Lee teaches methods of isolating exosomes from MSCs comprising different chemokines and cytokines including MCP-1, IL-6, IL-1a, VEGF, bFGF, TNF-a, EGF, and leptin, resistin, and adiponectin and the methods of detecting these chemokines and cytokines in the exosomes/microvesicles (paragraphs [0043]-[0050]; [0053]-[0055]; [0066]-[0068]; [0165], Example 1; [0170]-[0173], Example 6; [0175], table 1; p.28; p.30; p. 40;p44; p. 44, claims 1-1-7, 11-16, 18; 42).
A person of ordinary skill in the art would have recognized that selecting and applying the known growth factors and cytokines including TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or resistin, IGF-1, IL-1a, MCP-1 and adiponectin that can be detected in exosomes secreted from MSCs and the known methods of producing these exosomes and analyzing and detecting these growth factors and cytokines disclosed by Lewis and Lee to the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method would have yielded the predictable result of producing the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5, wherein the IESCEs comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23, and resulted in an improved method of producing IESCEs for cardiac repair or regeneration because the growth factors and cytokines including TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or resistin, IGF-1, IL-1a, MCP-1 and adiponectin can be analyzed and detected in exosomes secreted from MSCs as taught by Lewis and Lee, and the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method would inherently comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23.
Detecting and analyzing the known growth factors and cytokines including TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin in the IESCEs or resistin, IGF-1, IL-1a, MCP-1 and adiponectin released from the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method would expand application of the Ramaswamy’s method and would know that the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23 because TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or resistin, IGF-1, IL-1a, MCP-1 and adiponectin can be analyzed and detected in exosomes secreted from MSCs as taught by Lewis and Lee, and the IESCE can be obtained and secreted from MSCs/BMSCs under a pathological oscillatory flow condition having an OSI of about 0.5 as compared to static culture and/or a physiological oscillatory flow condition having an OSI with a range of 0.18 ≤OSI ≤0.23 or an OSI of 0.2 as taught by Ramaswamy.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known growth factors and cytokines including TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or resistin, IGF-1, IL-1a, MCP-1 and adiponectin that can be detected in exosomes secreted from MSCs and the known methods of producing these exosomes and analyzing and detecting these growth factors and cytokines disclosed by Lewis and Lee to the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method, and yield the predictable result of producing IESCEs that comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23 for treatment of cardiovascular diseases and other diseases or for cardiac repair or regeneration.
Accordingly, the rejection of claims 10, 13-14, 16, 21 and 25 under 35 U.S.C. 103 as being unpatentable over Ramaswamy in view of Lewis and Lee and evidentiary reference: Patalano is maintained.
Double Patenting
8. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 10, 13-14, 16, 21 and 25 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US11746329 in view of Ramaswamy (US2021/0180024), Lewis et al. (2018), and Lee et al. (US2023/0321190) and evidentiary reference: Patalano (2022). The rejection is maintained for the reasons of record and the reasons set forth below.
Response to Arguments
On p. 8-9 of the response, Applicant argues that the ‘329 patent, Ramaswamy, Lewis, Lee and Patalano either alone or in combination do not teach or suggest the claimed invention because the ‘329 patent claims a method for producing IESCEs under the physiological oscillatory flow condition whereas claim 10 recites a method for producing IESCES under a pathological oscillatory flow condition having an OSI of about 0.5 wherein the IESCEs comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §804, §2141, MPEP2141-I, rationales identified by the Court in KSR (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007)), MPEP2141-II, the basic factual inquires of Graham v. John Deere Co.(Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966)),and MPEP §2141.01-2147.03, the cited references do render the claimed invention obvious because:
i. While the ‘329 patent’s claims do not recite the limitations “polymeric bio-scaffold”, “torpedo bioreactor”, “under a pathological oscillatory flow condition having a OSI of about 0.5”, “increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23” in claim 10, or under rotisserie culture for ≥8 days and in the torpedo bioreactor under the pathological oscillatory flow condition for ≥14 days in claim 21, Ramaswamy, Lewis and Lee teach these limitations and provide motivation and an expectation of success for the reasons set forth above under the 103 rejection. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known polymeric bio-scaffold, the known torpedo bioreactor, the physiological oscillatory condition having an OSI of about 0.2 or the known high/pathological oscillatory flow condition having an OSI of about 0.5, and the known increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin secreted from the IESCEs obtained from MSCs under a high/pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method as compared to those produced under static culture and those produced under a physiological oscillatory flow condition having an OSI from 0.18-0.23 in claim 10 or under rotisserie culture for ≥8 days and in the torpedo bioreactor under the pathological oscillatory flow condition for ≥14 days in claim 21 and the known methods of producing and detecting these exosomes disclosed by Ramaswamy, Lewis and Lee to the method of the ‘329 patent, and yield the predictable result of producing IESCEs that comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin or release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin for treatment of cardiovascular diseases and other diseases or for cardiac repair or regeneration.
Accordingly, the rejection of claims 10, 13-14, 16, 21 and 25 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US11746329 in view of Ramaswamy, Lewis, and Lee and evidentiary reference: Patalano is maintained.
Conclusion
9. NO CLAIM IS ALLOWED.
10. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Williams et al. (J. Biomech., 2017; 65: 40-48, as in IDS) teaches a method of culturing HBMSCs (human bone marrow mesenchymal stem cells) a flow-stretch-flexure (FSF) bioreactor (i.e. a bioreactor that delivers dynamic flow conditions) (Abstract, p. 41, 1 paragraph)) and isolating exosomes from HBMSCs and optimizing and identifying the “sweet spot” of the oscillatory shear indexes (OSI) to obtain functional tissue engineered heart valves (Abstract, p. 40) and such OSI value can serve as a target for construct optimization for functional heart valve repair and/or replacement regenerative therapies (p. 47).
Gonzalez et al. (Front in Cardiovas. Med., 2020; doi:10.3389/fcvm.2020.00069, as in IDS) teaches seeding hBM-MSCs onto PGA-PLLA blend non-woven scaffolds and placing the BMSCs-scaffolds in a flow perfusion bioreactor system and subjecting the BMSCs-scaffolds to physiologically relevant pulsatile aortic flow regimens including OSI of 0.18-0.23 (Abstract, p. 3- 5).
Ramaswamy et al. (J. Biomed. Eng., 2014, 136: 121009-1- 14, as in IDS) teaches a novel bioreactor for replicating hemodynamic conditions in order to develop a method of engineering tissue engineered heart valves by seeding BMSCs onto PGA-PLLA blend non-woven scaffolds and placing the BMSC-scaffolds in the bioreactor (Abstract, p. 1; p. 5).
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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, Jeffrey Stucker can be reached at 571-272-0911. 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.
Chang-Yu Wang
April 17, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
