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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/24/2025 has been entered.
Claim Status
As of the Final Office Action mailed 7/28/2025, claims 8-10 and 13-17 were pending.
In Applicant's Response filed on 12/24/2025, claim 8 was amended and claims 18-19 were newly added.
As such, claims 8-10 and 13-19 are pending and have been examined herein.
Withdrawn Rejections
The rejection of record of claims 8-10, 13, and 15-17 under 35 USC § 103 as being unpatentable over Wu et al (J Biomed Mater Res Apart A, 9 June 2011; 98:442-449; Ref A21 of NPL in IDS filed 6 Aug 2021; previously cited) in view of Timmins et al (Lab Invest. 2011 Jun;91(6):955-67), Honmou et al (WO 2017111153A1, 26 Dec 2016; Published 29 June 2017; previously cited), and Shoji et al (J Atheroscler Thromb. 5 Feb 2011;18(6):464-74. doi: 10.5551/jat.6213) have been withdrawn in view of Applicant’s amendments.
The rejection of record of claim 14 under 35 USC § 103 as being unpatentable over Wu et al (J Biomed Mater Res Apart A, 9 June 2011; 98:442-449; Ref A21 of NPL in IDS filed 6 Aug 2021; previously cited) in view of Timmins et al (Lab Invest. 2011 Jun;91(6):955-67), Honmou et al (WO 2017111153A1, 26 Dec 2016; Published 29 June 2017; previously cited), and Shoji et al (J Atheroscler Thromb. 5 Feb 2011;18(6):464-74. doi: 10.5551/jat.6213) as applied to claims 8-10, 13, and 15-17 above, and further in view of Cademartiri et al (Circulation. 2003 Nov 25;108(21):e147) have been withdrawn in view of Applicant’s amendments.
New Grounds of Rejections Necessitated by Amendments
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 8-10, 13-17, and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cademartiri et al (Circulation. 2003 Nov 25;108(21):e147; previously cited) in view of Wu et al (J Biomed Mater Res Apart A, 9 June 2011; 98:442-449; Ref A21 of NPL in IDS filed 6 Aug 2021; previously cited), Timmins et al (Lab Invest. 2011 Jun;91(6):955-67; previously cited), Honmou et al (WO 2017111153A1, 26 Dec 2016; Published 29 June 2017; previously cited), and Shoji et al (J Atheroscler Thromb. 5 Feb 2011;18(6):464-74. doi: 10.5551/jat.6213; previously cited).
Cademartiri teaches that carotid artery obstructions are treated with stent implantation; however, in-stent restenosis ay occur within 6 months after stent implantation (p. 1, para 2). A 65-year-old symptomatic man with high-grade right carotid artery stenosis underwent wall stent implantation (p. 1, para 3; “wherein the stenting is carotid artery stenting” as in instant claim 14). The stent was positioned in the common carotid artery and internal carotid artery. After 11 months, the patient underwent 16-row MSCT (Figure). A rim of in-stent neointimal hyperplasia was shown, demonstrating the feasibility of using noninvasive MSCT to image in-stent neointimal hyperplasia (same para; Movie I; Fig. F and I) (“wherein the patient is a human” as in instant claim 8 in-part and 19). The density of the tissue was 75.6 +/- 5.6 Hounsfield units, which suggested the presence of fibrotic tissue (same para).
The difference between Cademartiri and the instant invention is that it does not teach administering mesenchymal stem cells to inhibit neointimal hyperplasia. It does not teach that the mesenchymal stem cells are delivered intravenously at a dose of 0.5 108 or more cells, that the stent is bare metal, or that the administering reduces an inflammatory reaction surrounding a strut of the stent (claim 8 in-part). It also does not teach that the patient who underwent stenting is a human (claim 8 in-part and 19).
Wu teaches a novel cell seeding stent to evaluate reendothelialization and anti-restenosis after implantation using percutaneous coronary intervention and mesenchymal stem cells (abstract). The reference teaches that while PCI is an important method of treating coronary heart disease, restenosis, is a major problem of therapy (“Introduction” para 1). The cell coating is helpful for accelerating reendothelialization of the stents, promoting healing injured blood vessels, and effectively preventing in-stent restenosis (same para) (“administering mesenchymal stem cells to the patient” as in instant claim 8 in-part; “wherein the administering prevents an in-stent restenosis in the patient” as in instant claim 17). The reference further teaches that MSCs contribute to the repairing of the damage of tunica intima vasorum and plays a role in reendothelialization of the impaired intima (“Introduction” para 2). The MSCs were derived from the bone marrow of New Zealand white rabbits (“wherein the mesenchymal stem cells are . . . derived from bone marrow” as in instant claim 8 in-part) and deployed in the infrarenal abdominal aorta (p. 443, para 2). The stents were introduced through the femoral artery using a steerable guide wire and implanted in the abdominal aorta using a balloon deployment and fluoroscopic guidance (p. 445-446, “Animal studies” para 2) (“wherein the stenting is . . . percutaneous transluminal angioplasty and stenting” as in instant claim 10).The MSCs seeded stents were covered and endothelialized completely and the stent surfaces were slick, which implied the appearance of endothelial cells, with no adhered blood disks and akaryocytes (“Stent morphology under SEM” para 1; Fig. 4E and F). The MSC stents accomplished intimal agglutination 4 weeks after implantation and reestablished the steady state of normal vessels (“Stent morphology under SEM” para 3). Intimal hyperplasia and in-stent restenosis were significantly inhibited by MSC implantation (“Conclusion” para 1) (“a method of inhibiting neointimal hyperplasia” as in instant claim 8 in-part; “wherein the administering reduces a degree of an in-stent restenosis in the patient” as in instant claim 16).
Timmins teaches that despite the tremendous success of vascular stent implantation, they cause excessive neointimal hyperplasia that can result in the formation of a new blockage (restenosis) (Introduction, para 1). In vivo and in vitro studies have demonstrated that arterial adventitial fibroblasts migrate to the neointima where they differentiate into myofibroblasts and secrete various extracellular matrix proteins (Introduction para 3). This migratory response is a direct result of the mechanical forces induced on the artery wall following stent implantation (same para). The reference hypothesizes that stents cause mechanical trauma on the artery wall and induce a non-favorable biomechanical environment (i.e., subjects the artery to higher non-physiologic stresses), provoking an aggressive pathobiological response of the artery wall, resulting in a higher degree of neointimal hyperplasia (Introduction, para 5). Low stress stents only induced high stress at focal regions of the intimal surface that were directly adjacent to stent struts (Results para 1). Regions of high stress were the sites of the greatest radial displacement in the stented region (i.e., the highest radial displacements occurred where the stent struts contacted the artery wall) (Results, para 2; see Fig. 3 reproduced below). Stents that subjected arteries to higher stresses had significantly more neointimal thickening at stent struts (Fig. 5). In addition, examination of the neointimal thickness at each stent strut revealed a significantly greater thickness value for the struts in the high-stress stent group when compared to the low-stress stent group (Results, para 4). This shows that, regardless of stent design, the struts of bare stents caused radial displacement where it contacted the artery wall, causing neointimal thickening and hyperplasia (i.e., inflammation around strut of stent as in instant claim 8 in-part).
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Honmou teaches a medicinal agent for treating ischemic vascular disorders containing mesenchymal stem cells, which is used in combination with recanalization therapy for occluded blood vessels (see claim 1 of Honmou). The reference teaches that the ischemic vascular disorder is ischemic cerebrovascular disorder or myocardial infarction (see claim 7 of Honmou) (“wherein the patient is a patient who suffers from . . . ischemic heart diseases including myocardial infarction, ischemic cerebrovascular diseases” as in instant claim 9). The mesenchymal stem cells are bone-marrow derived mesenchymal stem cells (see claim 9 of Honmou). The reference also teaches that the bone marrow-derived stem cells are highly migratory and can reach the target damaged tissue not only by local transplantation but also by intravenous administration, and a therapeutic effect can be expected (“Mesenchymal stem cells” para 2). The stem cells are preferably derived from the patient’s own cells (“Mesenchymal stem cells” para 3) (“wherein the mesenchymal stem cells are mesenchymal stem cells derived from bone marrow of the patient” as in instant claim 13). The reference also teaches that the medicament can be applied before, after, or simultaneously with re-opening therapy and that the medicament can easily reach the affected area by intravenous administration (see p. 4 of translation, 5th to last paragraph) (“administering mesenchymal stem cells to the patient wherein the mesenchymal stem cells are derived from human bone marrow and . . . are administered intravenously” as in instant claim 8 in-part). Furthermore, the re-opening therapy can be performed by stent treatment (i.e., bare stent) (“Physical removal of the thrombus” para 1) (“wherein the stent is a bare metal stent” as in instant claim 8 in-part). Finally the reference teaches that the larger the number of cells of MSC contained in the medicament, the better and that the number of mesenchymal stem cells is 5 x 107 or more and preferably 5 x 108 cells (overlaps with “0.5 x 108 or more cells per dose are intravenously administered” as in instant claim 8 in-part).
Finally, Shoji teaches that human mesenchymal stromal cells (i.e., mesenchymal stem cells) from bone marrow reduce neointimal hyperplasia (abstract). The reference teaches that surgical manipulation or atherosclerotic damage to arteries in the intima of the arteries activates an inflammatory cascade, causing the proliferation of smooth muscles and neointimal hyperplasia (Introduction para 1). MSCs can migrate to engraft into injured tissues and secrete a large number of cytokines (Introduction para 2). hMSC administration inhibited neointimal hyperplasia (characterized by neointimal thickening) in a carotid artery ligation model by decreasing the initial inflammatory response to the lesion (Introduction para 4; see also Fig. 3’ “wherein the administration reduces an infiltration of inflammatory cells” as in instant claim 8 in-part). At 7 days after ligation, neointimal hyperplasia was much less in the hMSC group (Results, para 1). Furthermore, administration of hMSCs decreased macrophage infiltration at the site of injury (p. 470). Finally, the systemic administration of hMSCs decreased neointimal hyperplasia without significant long-term engraftment of the cells into the lesion (only transient engraftment), however, the therapeutic benefits can be explained by the suppressing inflammatory responses and immune reactions based on the decreased macrophage infiltration and serum MCP-17 (Discussion para 1-2). The overall effect of hMSCs was to heal the vascular lesion by secreting endogenous and paracrine factors that modulated the inflammatory response (Discussion, last para). This shows that MSCs reduce inflammatory reactions in neointimal hyperplasia and inhibits neointimal hyperplasia (“administering reduces a thickness of a neointima in the patient” as in instant claim 15).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to take a human exhibiting neointimal hyperplasia due to stent implantation as taught by Cademartiri, and administer bone marrow mesenchymal stem cells to inhibit neointimal hyperplasia as taught by Wu, where the mesenchymal stem cells are administered intravenously as taught by Honmou, to arrive at the instantly claimed invention. Wu shows that mesenchymal stem cells can successfully be used to inhibit neointimal hyperplasia. Honmou shows bone marrow derived mesenchymal stem cells from a patient can be given intravenously in a dose above 5 ×107 before, during, or after stent treatment for patients with ischemic cerebrovascular disorder or myocardial infarction. One of ordinary skill would have been motivated to apply the treatment methods as taught by Wu and Honmou in combination ( i.e., intravenous administration of bone marrow mesenchymal stem cells) to the stented human patient as taught by Cademartiri with the reasonable expectation that the bone marrow-derived stem cells’ highly migratory capability and ability to target damaged tissue will create an advantageous therapeutic effect (in this case, significant inhibition of neointimal hyperplasia and preventing in-stent restenosis) both by local transplantation (e.g., stent seeding as in Wu) and intravenous administration to the human as taught by the prior art.
Furthermore, based on the disclosures of Wu, Honmou, Shoji, and Timmons in combination, one of ordinary skill would recognize that “wherein the administering reduces an inflammatory reaction surrounding a strut of the stent, thereby inhibiting the neointimal hyperplasia” as instantly claimed in claim 8 to be an inherent/intended result of the administration of the MSCs prior to the effective filing date given (1) the inflammatory response created by the introduction of stents into arterial walls, (2) the known anti-inflammatory actions of human mesenchymal stem cell, particularly in cardiac lesions, and (3) the known reduction of neointimal hyperplasia and prevention of in-stent restenosis as a result of MSC administration as taught by the prior art references, both in their individual capacity and in combination.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill prior to the time of filing, especially in the absence of evidence to the contrary.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cademartiri et al in view of Wu et al, Timmins et al, Honmou et al, and Shoji et al as applied to claims 8-10, 13-17, and 19 above, and further in view of Ishikawa et al (Exp Anim. 1 Aug 2018; 67(4):501-508).
The combined references do not state that the patient is a pig.
However, Ishikawa teaches a swine model of in-stent stenosis in the iliac artery (title). It teaches that pig and rabbit models have been widely used to evaluate in-stent stenosis by pathological analysis as well as simultaneous “one-shot” angiography and/or intravascular ultrasound (IVUS) (Introduction para 1). Göttingen minipigs were used for the study (see Materials and Methods). The reference teaches that the aim of this study was to propose a new animal model evaluating the serial time course of in-stent stenosis by repeated carotid artery catheterization in the same animal. 16 bare-metal stents were implanted in the normal external and internal iliac artery of 8 miniature pigs. Repeated measurements were performed in the same animal every 2 weeks for 12 weeks through carotid artery catheterization. The time course and peak neointimal proliferation were evaluated by intravascular ultrasound. Health of all animals was assessed by clinical and hematological examinations. As a result, 7 times of carotid artery catheterization was performed per pig, but all animals remained healthy without both any complications and hematological inflammatory abnormalities. The time course of neointimal proliferation of each stent was observed from the stage of hyperplasia to partial regression. The reference concludes that the serial analysis of in-stent stenosis in the iliac arteries of minipigs is feasible through repeated carotid artery catheterization (see conclusion). Using this method, the time course and peak neointimal proliferation can be evaluated without compromising the health of the animals.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to administer bone marrow mesenchymal stem cells to inhibit neointimal hyperplasia in a patient that underwent stenting as taught by Cademartiri, Wu, Honmou, Timmons, and Shoji in combination, where the patient is a pig model of neointimal hyperplasia as taught by Ishikawa, to arrive at the instantly claimed invention. Ishikawa shows pig and rabbit models have been widely used to evaluate in-stent stenosis by pathological analysis. It would have been a matter of routine optimization using standard laboratory techniques for one of ordinary skill to apply the method as taught by Cademartiri, Wu, Honmou, Timmons, and Shoji in combination to the hyperplasia mini-pig model as taught by Ishikawa to obtain the predictable result of advantageously using a model that has consistently been used to evaluate in-stent restenosis due to stenting as taught by the prior art.
Response to Arguments
Applicant’s arguments and the Declaration submitted by Osamu Honmou (referred to herein as the “Honmou declaration”) have been fully considered but are not persuasive. The examiner notes that Applicant did not argue the substantive teachings (and combinations thereof) of the Wu, Honmou, Timmons, or Cademartiri references previously cited and utilized herein. The examiner addresses the arguments related to the Shoji reference below.
On p. 4-6 of Remarks, Applicant argues that the pig model used in the examples of the specification is a more relevant model for humans than the mouse model utilized by Shoji because “pigs are more anatomically similar to humans . . . [and] are widely recognized by those of ordinary skill in the art as a model with high human extrapolation potential in cardiac research.” The Honmou declaration attests to this argument and offers FDA guidance on animal testing for medical devices (draft issued Oct 14, 2015), Lunney et al (2021; discusses pigs as advantageous model to study heart disease compared to mice, dog, and sheep), Lee et al (Nov 2013; discussing porcine coronary artery models as being the standard for preclinical evaluation of endovascular devices), Perkins et al (Apr 2019; discusses porcine model as principal model to evaluate safety of devices for coronary and endovascular treatment), and Galon et al (2013; discusses porcine model as being anatomically and physiologically similar to the human heart and useful to test new stent and balloon generations) as support for Applicant’s contentions.
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). Applicant’s arguments are not directed to the specific combination of references rendering the claims prima facie obvious. Rather, the arguments are directed to whether mice are an adequate model of human stenting as in Shoji. These arguments are not commensurate in scope with the instant claims because the claims are not drawn to the relevancy of a particular animal model for neointimal hyperplasia due to stenting. Regardless, as shown in the Ishikawa reference newly cited due to Applicant’s amendment to the claims, pig (in this case, mini-pigs) and rabbit (as seen in the Wu reference previously cited) models have been widely used to evaluate in-stent stenosis by pathological analysis. The examiner also notes that Applicant has also conceded on the record that prior to the effective filing date, one of ordinary skill would have contemplated and substituted other animal models of neointimal hyperplasia due to stenting for a pig model because pig coronary artery models are standard models of preclinical evaluation of endovascular devices (see, e.g., p. 713 of Lee reference provided by Applicant; published in 2013). The Galon reference (provided by Applicant; 2013) states that the experimental porcine model is anatomically and physiologically similar to the human heart and is used for benchmark tests to evaluate the effectiveness of new devices (see, e.g., p. 382). Thus, Applicant’s arguments are not persuasive.
Conclusion
No claim is allowed.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632