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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicants’ submission filed on 24th of November 2024 has been entered.
Priority
This application was filed on the 17th of August 2023, and is a continuation of U.S. application 15/941,409, and now U.S. patent 11760975, which claims benefit to the foreign application NL2018628 filed on March 31, 2017.
Claim Status
On the 24th of November 2025, Applicant filed claims 21-33, which are pending in this application.
Claims 21-22, and 24-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 2nd of August 2024.
Currently, claims 23 and 29-33 are under examination.
Information Disclosure Statement
Applicant is reminded of 37 CFR §1.56, which details Applicant's duty to disclose all information known to be material to patentability.
The information disclosure statements (IDS) submitted on 11/24/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Applicants are reminded that disclosure statements that lists a “Search Reports”. The list of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a). Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
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 23, and 29-33 are rejected under 35 U.S.C. 103 as being unpatentable over Hematti, Peiman and Kim, Jaehyup (US8,647,678 B2, cited IDS 8/17/2023, hereinafter as “Hematti”), Schmuck, Erik and Saupe, Kurt (WO2013/028968A1, published 2013, hereinafter as “Schmuck”) Badylak et al., (Tissue Eng Part A. Nov;14(11):1835-42, 2008, hereinafter as “Badylak”), Gordana Vunjak-Novakovic, and Kara Lorraine Spiller (WO2015/031376A1, published 2015, cited IDS 8/17/2023, hereinafter as “Gordana”), and Marban et al., (WO2016/057560A1, published 2016, hereinafter as “marban”) as evidence by Schmuck, Erik and Raval, Amish (WO2016/197038A1, published 2016, hereinafter as the “Raval”).
This rejection is a new rejection necessitated by amendments to the claims. Any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 23, 29-30, and 33, Hematti discloses an anti-inflammatory population of macrophages (i.e. MSC-educated macrophages), which are produced by the method of co-culturing a population of isolated CD14+ cells with fibroblast-like cells (i.e. mesenchymal stem cells (MSCs)(see e.g. col. 1, claims 3-4, Example 1-2), which acquire an anti-inflammatory macrophage phenotype (see e.g. Example 1-2). Hematti discloses wherein the obtained anti-inflammatory macrophages have upregulated expression of CD206 (i.e.CD206 high)(see e.g. claims 1-3, Examples 2-3). Further, Hematti discloses that the composition of anti-inflammatory population of macrophages may be delivered through local or systematic injection with a carrier that is selected from the group consisting of liquid, oil, lotion, salve, cream, foam, gel, paste, powder, film, and hydrogel (see e.g. col. 5, claim 3-4, Example 5).
Hematti is silent regarding culturing with isolated cardiac fibroblast-derived extracellular matrix (CF-ECM) extracellular matrix.
However, the prior art of Schmuck discloses isolated cardiac fibroblast-derived 3-dimensional extracellular matrix (CF-ECM) that additionally comprise growth factors or cytokines(see e.g. para. 14, 44-49, 91, 184, claims 1,and 10-13, Examples 1-2). Further, Schmuck discloses culturing mesenchymal stem cells (i.e. fibroblast-like cells, MSCs) with CF-ECM to mimic the temporal aspect of cardiac healing using multiple decellularization techniques (see e.g. Example 2). Further, Schmuck discloses decellularized cardiac ECM (para. 15-19, fig. 1 and 5). Moreover, Schmuck discloses that when CF-ECM were not cross-linked they promoted infiltration and activation of anti-inflammatory macrophages (M2)(see e.g. para. 181). Additionally, the prior art of Badylak discloses mononuclear macrophages with decellularization of ECM material drives macrophages towards an anti-inflammatory phenotype (M2, CD163 high)(see e.g. page 1838-1839, fig.3).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined the anti-inflammatory macrophages (i.e. MSC-educated macrophages) as taught by Hematti with the cardiac fibroblast-derived extracellular matrix (CF-ECM), as taught by Schmuck and Badylak, with a reasonable expectation of success because one of ordinary skill in the art would know that decellularized CF-ECM (i.e. cardiac fibroblast-derived extracellular vesicles) promoted infiltration and activation of anti-inflammatory macrophages (M2)(as taught by Schmuck and Badylak, see e.g. para. 181 and 1838, respectively). Furthermore, Hematti, Schmuck, and Badylak disclose methods for obtaining a population of anti-inflammatory macrophages (i.e. M2 phenotype), as discussed above. Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation.
Regarding claims 23, 29-30, and 33, although Hematti is silent as to whether such derived macrophages are comprising CD163 high, CD206 high, PD-LI high, CD16 low, HLA-DR low, and CD86 low as compared to uneducated macrophages, it is well accepted that “[w]here the claimed and prior art products are…produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).” See M.P.E.P. § 2112.01(I).
However, it is noted that the recited method of claim 23 relating to co-culturing a population of isolated CD14+ cells with cardiac fibroblast-derived extracellular vesicles (which comprise exosomes) is substantially identical to the method of making macrophages having an anti-inflammatory phenotype as disclosed in Hematti. The fact that the macrophages derived by Hematti appear to be made by the same process recited presently is considered sufficient evidence to conclude that the macrophages derived by the method of Hematti are substantially identical to those claimed presently. While Hematti is silent as to the expression of other markers such as CD163 high, PD-LI high, CD16 low, HLA-DR low, and CD86 low as compared to uneducated macrophages, the instantly claimed cells are made by a process substantially identical to the methods of Hermatti, and thus, the marker expression is therefore presumed to be inherent in the absence of evidence to the contrary. Claims 29 and 30 are included herein since they require nothing more than a liquid (for example), and since the cells of Hermatti are taught either in vitro in culture or in vivo in plasma, both of which are comprised of liquid.
Regarding claim 31, as stated supra, Hematti discloses that the composition of anti-inflammatory population of macrophages may be delivered through local or systematic injection with a carrier (see e.g. col. 5, claim 3-4, Example 5). Schmuck discloses that intramyocardial injection (either epicardial or endocardial) tends to have greater cell retention rates (see e.g. para. 4 and 110). Badylak discloses mononuclear macrophages with decellularization of ECM material drives macrophages towards an anti-inflammatory phenotype (M2, CD163 high)(see e.g. page 1838-1839, fig.3).
Hematti et al. do not explicitly disclose wherein the carrier is an injectable CF-ECM.
However, the prior art of Gordana discloses an injectable extracellular matrix (ECM)(i.e. biocompatible scaffold), and cultures CD14+ monocytes to promote M2 macrophage phenotypes (i.e. CD206 high) for increase vascularization or healing (see e.g. claim 1, Example 1, Fig. 1).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have modified the anti-inflammatory macrophages (i.e. MSC-educated macrophages), as taught by Hematti, the cardiac fibroblast-derived extracellular matrix (CF-ECM), as taught by Schmuck and Badylak, with a carrier that is an injectable CF-ECM, as taught by Gordana, with a reasonable expectation of success because one of ordinary skill in the art would know that the injectability of an extracellular matrix (ECM)(i.e. biocompatible scaffold) would provide optimal distribution of the composition being delivered (as taught by Gordana, see e.g. page 19). Further, a person of ordinary skill in the art would have been able have an injectable CF-ECM as evidence by Raval, which discloses an injectable cardiac fibroblast cell-derived extracellular matrix (CF-ECM)(see e.g. abstract, claims 1 and 13). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 32, as stated supra, Hematti et al., does not explicitly disclose wherein the CF-ECM additionally comprises cardiac fibroblast-derived extracellular vesicles.
However, the prior art Marban discloses cardiac fibroblast-derived extracellular matrix (i.e. cardiosphere-derived cells, CDCs) secrete extracellular vesicles (i.e. exosomes) that mediate inflammatory processes, by, for example, shifting macrophages away from a proinflammatory M1 phenotype toward M2 healing phenotype (see e.g. abstract, fig. 23, Example 1, 33 and 36).
Accordingly, prior to the effective filing date of the instant claimed invention, it would have been prima facie to obvious for a person of ordinary skill in the art to have combined the anti-inflammatory macrophages (i.e. MSC-educated macrophages) as taught by Hematti et al., with an cardiac fibroblast-derived extracellular matrix (CF-ECM) that additionally comprises cardiac fibroblast-derived extracellular vesicles, as taught by Marban, with a reasonable expectation of success because one of ordinary skill in the art would know that the addition of extracellular vesicles from CF-ECM would help ensure the population of anti-inflammatory macrophages having a M2 phenotype (as taught by Marban, abstract). Thus, it would have been obvious for a person of ordinary skill in the art to have predictable results with a reasonable expectation of success.
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicants’ asserts nonobviousness with respect to the rejection of US20110045071 ("Hematti") in view of Ti et al., J Translational Med, 2015 ("Ti"), Humeres et al., J Mol Cell Cardiol, 2016 ("Humeres"), and Kim et al., Exp. Hem., 2009, ("Kim") as evidenced by Wei et al., Frontiers in Pharmacology, 2021 ("Wei").
Applicant’s arguments with respect to the previous rejection of claims as being rejected under 35 U.S.C. §103 as being unpatentable over Hematti in view of Ti et al., Humeres et al., Kim et al., as evidenced by Wei et al., have been fully considered and are persuasive in view of the amendments to the claims. Therefore, the rejection has been withdrawn.
However, upon further consideration, a new ground(s) of rejection is made in view of Hematti, Peiman and Kim, Jaehyup ( “Hematti”), Schmuck, Erik and Saupe, Kurt (“Schmuck”) Badylak et al., (“Badylak”), and Gordana Vunjak-Novakovic, and Kara Lorraine Spiller (“Gordana”), and Marban et al., (“Marban”) as evidence by Schmuck, Erik and Raval, Amish (“Raval”).
Applicant asserts that claim 23 is a composition claim not a method claim (Remarks, p. 5-6). Applicant argues that the skilled artisan could not have had the required reasonable expectation of success in producing the claimed population of anti-inflammatory macrophages having phenotypic characteristics of CD 163 high, CD206 high, PD-LI high, CD16 low, HLA-DR low, and CD86 low as compared to uneducated macrophages (Remarks, p. 7-9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants’ argument regarding the claimed composition is not a method, it is not persuasive because 103 rejections for product-by-process claims has been approved by the courts. “[T]he lack of physical description in a product-by-process claim makes determination of the patentability of the claim more difficult, since in spite of the fact that the claim may recite only process limitations, it is the patentability of the product claimed and not of the recited process steps which must be established. We are therefore of the opinion that when the prior art discloses a product which reasonably appears to be either identical with or only slightly different than a product claimed in a product-by-process claim, a rejection based alternatively on either section 102 or section 103 of the statute is eminently fair and acceptable. As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972). As discussed above, it is well accepted that “[w]here the claimed and prior art products are…produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).” See M.P.E.P. § 2112.01(I). M.P.E.P. § 2113 reads, “Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps.” Definition by derivation, or product-by-process, (e.g. anti-inflammatory macrophages derived from co-culturing) is not considered a limiting feature unless it can be demonstrated that it imparts detectable technical features.
Applicant argues that the combination of the teachings of the Hematti and Ti reference would not express such a phenotype and that a skilled person would recognize the difference between the effects of co-culturing with exosomes and cardiac fibroblast-derived extracellular matrix (CF-ECM)(see Naba, Nat Rev Mal Cell Biol. 2024 Nov;25(1l):865-885, and Kalluri et al., Science. 2020 Feb 7;367(6478):eaau6977, cited IDS 11/24/2025)(Remarks, p. 7).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the references individually, one 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 regards to Applicants’ argument regarding Hematti, as Ti is no longer cited, it is not persuasive because Hematti discloses an anti-inflammatory population of macrophages (i.e. MSC-educated macrophages), that have upregulated expression of CD206 (i.e.CD206 high)(see e.g. claims 1-3, Examples 2-3), as discussed above. It is noted that Applicants cites the reviews of Naba, which discloses a review on the extracellular matrix complex, and Kalluri, which discloses a review on exosomes and their potential on biomedical applications (see abstracts, respectively). However, as stated supra, the prior art of Marban discloses compositions and methods related to use of cardiosphere-derived cells (i.e. cardiac fibroblast) and their extracellular vesicles, such as exosomes and macrovesicles (see e.g. abstract and background). Thus, a person of ordinary skill in the art would know that exosomes are a type of extracellular vesicles. Furthermore, the claims read on “comprising” which does not exclude other embodiments, such as exosomes being present in the CF-ECM as claimed (see MPEP 2111.03).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPHINE GONZALES whose telephone number is (571)272-1794. The examiner can normally be reached M-Th: 10AM - 5:00PM (EST).
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Josephine Gonzales PhD
Examiner
Art Unit 1638
/JOSEPHINE GONZALES/ Examiner, Art Unit 1638
/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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