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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 2, 6, 8-10 and 19-20 are cancelled. Claims 1, 3, 12 and 18 are amended. Claims 1, 3-5, 7, 11-18, and 21-24 are pending in this application. Claims 14-17 are withdrawn without traverse (filed 06/27/2025) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 27, 2025.
4. Claims 1, 3-5, 7, 11-13, 18 and 21-24 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Claim Rejections/Objections Withdrawn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 10 and 20 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 10 and 20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US11746329 or claims 1-5 of US12291725 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 1, 3-5, 7, 11-13, 18 and 21-24 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 1, 3-5, 7, 11-13, 18 and 21-24 as amended are drawn to an injectable enhanced stem cell exosome (IESCE) secreted from mesenchymal stem cells (MSCs) that are seeded onto a polymeric bio-scaffold, cultured under rotisserie culture for ≥8 days and cultured in a torpedo bioreactor under a pathological oscillatory flow condition having an oscillatory shear index (OSI) of about 0.5 for ≥14 days, the IESCE comprising increased levels of TNF-a, IGF-1, VEGF, IL-6, FGF-1, TGF-b, EGF and leptin as compared to those obtained from static culture and those obtained under a physiological oscillatory flow condition having the OSI from 0.18-0.23.
Response to Arguments
On p. 7-10 of the response, Applicant argues that: i) Ramaswamy does not teach that the IESCE produced under a pathological oscillatory flow condition having an OSI of about 0.5 comprising increased levels of TNF-a, IGF-1, VEGF, IL-6, FGF-1, TGF-b, EGF and leptin as compared to those obtained under static culture and under a physiological oscillatory flow condition having an OSI from 0.18-0.23 or that the IESCE is capable of releasing IL-1a, resistin, MCP-1 and adiponectin compared to those obtained from static culture and under a physiological oscillatory flow condition having the OSI from 0.18-0.23. ii) Lewis and Lee teach several growth factors and cytokines in their exosomes but do not teach that the claimed IESCEs obtained 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. Lewis and Lee produce exosomes through static cultures while Ramaswamy compare exosomes produced under low, physiological and high OSI conditions and thus have different contents of exosomes from different cells under different conditions. iii) Even if Ramaswamy’s exosomes express same cytokines as those in Lewis and Lee’s, there would be no expectation of success that Ramaswamy’s exosomes comprises increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin and can release increased levels 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. iv) Ramaswamy only teaches an OSI of 0.5 as a maximum extreme of the oscillatory flow and does not teach the use of an OSI of 0.5 in their culture and only showed that that the physiological OSI range for stimulating BMSCs was 0.18≤OSI≤0.23, which yield maximum phenotype benefits as compared to low OSI and high OSI conditions (para. [0153] and figures 3A-3C); v) It is surprising and unexpected that the claimed IESCEs comprise increased levels of TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin and can 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). Applicant further 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. Ramaswamy does teach the claimed IESCEs secreted from mesenchymal stem cells (MSCs) that are seeded onto a polymeric bio-scaffold, cultured under rotisserie culture for ≥ 8 days and cultured in a torpedo bioreactor under a pathological oscillatory flow condition having an OSI of about 0.5 because Ramaswamy teaches a method for producing IESCEs from MSCs onto 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]). 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.
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]).
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 1 and 12 and 18 (see paragraphs [0025]; figure 8; [0041]; [0069]-[0070]; [0072]-[0076]; [0083]-[0085]; [0137]-[[0141]). Ramaswamy teaches a physiological OSI range of 0.18-0.23as in claims 1, 3, 18 (para [0153]) or 0.2 as in claim 11 (see para [0009]; [0070]; [0137]). Ramaswamy also teaches that the polymeric bio-scaffold comprises PSIS, or PGA-PLLA as in claims 21-24 (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.
ii. 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).
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 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 method of 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 the claimed 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 product of 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 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.
Note that [T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999).
Detecting 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 the known 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 know that the IESCE secreted from MSCs/BMSCs under a pathological oscillatory flow condition having an OSI of about 0.5 disclosed by Ramaswamy comprise increased TNF-a, IGF-1, FGF-1, VEGF, IL-6, EGF, TGF-b and leptin in the IESCEs and release increased levels of resistin, IGF-1, IL-1a, MCP-1 and adiponectin 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, and expand application of the Ramaswamy’s product and method, and would increase the use and production of IESCEs for treatment of cardiovascular diseases or cardiac repair or regeneration, and for treatment of other diseases 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 method of 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.
iii. The limitation “MSCs that are seeded onto a polymeric bio-scaffold….under a pathological oscillatory flow condition having an oscillatory sheer index (OSI) of about 0.5 for ≥14 days…….under a physiological oscillatory flow condition” recited in claim 1, the limitation “the physiological oscillatory flow condition having an OSI with a range of 0.18≤OSI≤0.23” recited in claims 10 and 20, the limitation “the physiological oscillatory flow condition having an OSI of 0.2” in claim 11, the limitation “seeding MSCs…culturing the MSCs…placing…collecting….and detecting…” recited in claims 12 and 18, the limitation “the polymeric bio-scaffold comprising PSIS….PLLA” recited in claims 21-24 are product-by-process limitations.
“The determination of patentability in a product-by-process claim is based on the product itself, even though the claim may be limited and defined by the process. That is, the product in such a claim is unpatentable if it is the same as or obvious from the product of the prior art, even if the prior product was made by a different process. In re Thorpe, 777 F.2d 695, 697, 227 USPQ 964, 966 (Fed. Cir. 1985). A product-by-process limitation adds no patentable distinction to the claim, and is unpatentable if the claimed product is the same as a product of the prior art. See MPEP 2113
In this case, the IESCEs obtained from MSCs under a pathological oscillatory flow condition having an OSI of about 0.5 in the Ramaswamy’s method 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.
iv. In response to Applicant’s arguments related to unexpected results, note that evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978). See MPEP 716.02(c)-I. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. See: MPEP §716.02. In addition, “A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). See MPEP 716.02(a)-I. Further, evidence of unexpected results is frequently in the form of a direct comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See: e.g., In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980).
In this case, the claimed IESCEs that are obtained and secreted from MSCs/BMSCs 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 and capable of releasing 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 are not unexpected because the IESCEs that are obtained or produced from MSCs/BMSCs cultured under a pathological oscillatory flow condition having an OSI of about 0.5 are taught by Ramaswamy’s method. 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 for the reasons set forth above.
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.
Note that [T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999).
Accordingly, the rejection of claims 1, 3-5, 7, 11-13, 18 and 21-24 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 1, 3-5, 7, 11-13, 18 and 21-24 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US11746329 or claims 1-5 of US12291725 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. 10-11 of the response, Applicant argues that the ‘329 patent, the ‘725 patent, Ramaswamy, Lewis, Lee and Patalano either alone or in combination do not teach or suggest the claimed invention under a pathological flow condition with an OSI of about 0.5 wherein the IESCE comprises 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 claims of the ‘329 patent or the ’725 patent do not recite the limitation “polymeric bio-scaffold”, “torpedo bioreactor”, “under rotisserie culture for ≥8 days and in the torpedo bioreactor under the pathological oscillatory flow condition having a OSI of about 0.5 for ≥14 days” recited in claims 1, 12 and 18, or ““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” recited in claims 1, 3, 12 and 18, Ramaswamy, Lewis, Lee and Patalano 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 or the product of the ‘725 patent, and yield the predictable result of the claimed IESCEs for treatment of cardiovascular diseases and other diseases or for cardiac repair or regeneration.
Accordingly, the rejection of claims 1, 3-5, 7, 11-13, 18 and 21-24 on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of US11746329 or claims 1-5 of US12291725 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) 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.
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Chang-Yu Wang
April 17, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
