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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 30, 2026 has been entered.
Note, all claims are identical to or patentably indistinct from claims in the application prior to the entry of the submission under 37 CFR 1.114, and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, this action is made final even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114.
Claim Status
Claim listing filed on March 30, 2026 is pending. Claims 1-2, 6-9, 13, 24-26, and 28 are canceled. Claims 20 and 27 are amended. Claims 3-5, 10-12, 14-23, 27, and 29-33 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s amendment to Claim 20 corrects the previous grammatical error, and the claim objection is withdrawn.
The rejection of Claims 22-23, 27, and 30-33 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments and remarks filed March 30, 2026. Amendments to Claim 27 overcome the previous insufficient antecedent basis. Applicant remarks filed March 30, 2026 state that specification page 34 defines wherein reduction in vascular occlusion or neointima formation and/or increase in the rate or re-endothelialisation is relative to a patient who has not received the conjugate described herein. Therefore, Examiner interprets that the relative terminology in Claims 22 and 30 is not indefinite as it is defined to be relative to a control patient who has not received the recited conjugate. The broadest reasonable interpretation of “reducing” and “increasing” encompasses any change in vascular occlusion, neointimal hyperplasia, re-endothelialisation, or the symptoms of vascular injury (even a non-significant change) relative to a patient that does not receive the conjugate as measured by means understood in the art prior to filing.
Claim Rejections - 35 USC § 103 (Maintained)
The rejection of Claims 3-5, 11, 14-16, and 21 under 35 U.S.C. 103 as being unpatentable over Granada et al, EuroIntervention 2016 (of record) in view of Santos et al, ACS Appl. Nano Mater. 2018 (of record) is maintained.
Applicant's arguments filed March 30, 2026 have been fully considered but they are not persuasive.
Applicant argues that the nanoparticle disclosed in Granada encapsulates sirolimus, and in contrast, the instant nanoparticles have a solid core and conjugate the biologically active agent externally. Applicant cites Granada’s teachings that sirolimus has intrinsic molecule instability and is labile in aqueous solution, yet it remains suspended at high concentrations when nano-encapsulated. Applicant asserts that nano-encapsulation of sirolimus is vital for its stability and efficacy, and there would be unpredictability in the efficacy and pharmacological effects if the nanoparticle structure was changed. Applicant’s argument is under the assumption that active agents conjugated externally to nanoparticles are more susceptible to degradation than encapsulated agents. To the contrary, it was understood in the state of the art prior to filing that immobilization of biologically active agents on the external surface of nanoparticles improves stability of the agent as evidenced by Arsalan et al. Int J Biol Macromol. 2018 (section 4 and Fig. 8). In other words, nanoparticle encapsulation is not required for agent stability. Further, it is of record that it would be obvious to one of ordinary skill to adapt the method of delivering a nanoparticle conjugate to a blood vessel as taught by Granada to use the specific nanoparticle conjugate as taught by Santos. Santos teaches that the imaging agent indocyanine green (ICG) showed significantly less degradation when conjugated to the external surface of the nanoparticles relative to unconjugated ICG (page 589 and Fig. 8g). Santos concludes that in addition to robust immobilization of cargo, the nanoparticle system can prolong the activity of some small (<1 kDa) cargoes (page 589; emphasis added). Note, sirolimus has a molar mass of 914 g/mol which is equivalent to <1 kDa, making it a “small cargo.” Further, Santos shows that luciferase bound to the nanoparticles retained proper binding and activity better than luciferase bound to alternative nanoparticles which highlights how the nanoparticle system of Santos preserves proper confirmation and efficacy of biological agents that are known to be conformationally sensitive and inactive when unfolded (page 589 and Fig. 9).
The teachings of Arsalan and Santos are cited solely in response to Applicant’s arguments and not as a new ground of rejection. These teachings support that one of ordinary skill could substitute the nanoparticle of Granada with the nanoparticle of Santos with a reasonable expectation of success in maintaining sirolimus structure and efficacy. While the exact pharmacokinetics of sirolimus conjugated to the Santos nanoparticle are not recited in the art, Applicant is reminded that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007). MPEP § 2145. The nanoparticle conjugate platform of Santos is understood to maintain structure and activity of the cargo and could be applied to the method of promoting healing in a blood vessel taught by Granada with an expectation of success that one of ordinary skill would have found to be reasonable.
Applicant argues that the therapeutic effect of sirolimus demonstrated in Granada was minimal with a slight stenosis reduction and modest neointimal thickness reduction. Applicant argues that the present application demonstrated a significant treatment effect achieved using the particular nanoparticle delivery vehicle claimed. The only examples of sirolimus in the instant specification are in Figs. 7-8 wherein sirolimus conjugated to the nanoparticle has reduced occlusion (~40%) as compared to free sirolimus (~60%), and sirolimus conjugated to the nanoparticle has increased re-endothelialisation (~70%) as compared to free sirolimus (~10%) in a rat carotid injury model. Similarly, Granada teaches a decrease in neointimal thickness and injury score in porcine vessels treated with sirolimus-eluting angioplasty balloons as compared to plain old balloon angioplasty (page 744, Table 1, and Fig. 5). Therefore, Examiner maintains that the instant results are not unexpected in view of the teachings of Granada and Santos, because one of ordinary skill would have expected the treatment to promote vascular healing by reducing occlusion and neointimal hyperplasia. See UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 693, 2023 USPQ2d 448 (Fed. Cir. 2023): "A difference of degree is not as persuasive as a difference in kind – i.e., if the range produces ‘"a new property dissimilar to the known property,’" rather than producing a predictable result but to an unexpected extent." (MPEP § 716.02). Therefore, a difference in degree of blood vessel healing is not persuasive because there is no difference in the kind of response (i.e. promotes blood vessel healing).
Applicant argues that Santos does not disclose how long the nanoparticle is able to be retained in a blood vessel. The nanoparticles of Granada (100-400 nm in diameter as evidenced by Fig. 1) were effectively retained in a blood vessel after administration with a balloon catheter (of record). The nanoparticles of Santos are ~200 nm in diameter (of record). Because the two nanoparticles are similar sizes, the Santos nanoparticles prolong activity of their cargo (as discussed above), and the Santos nanoparticles maintain the structure and function of their cargo (as discussed above), one of ordinary skill could apply the Santos nanoparticle to the method of Granada with a reasonable expectation of success that the nanoparticle would be retained in the blood vessel. There is no evidence in the art nor argument made by Applicant that specifically details why the Santos nanoparticle would not be expected to be retained in the blood vessel. Applicant’s arguments are not persuasive, and the rejection is maintained.
The rejection of Claims 10, 12, 17-19, 22-23, 27, and 29-33 under 35 U.S.C. 103 as being unpatentable over Granada et al, EuroIntervention 2016 (of record) in view of Santos et al, ACS Appl. Nano Mater. 2018 (of record) as applied to Claims 3-5, 11, 14-16, and 21 above, and further in view of Kamaly et al. ACS Nano. 2016 (of record) and Boehler et al. Biotechnol Bioeng 2014 (of record) is maintained.
Applicant's arguments filed March 30, 2026 have been fully considered but they are not persuasive.
Applicant argues that the nanoparticles of Kamaly have significant structural differences from the nanoparticles of Granada. Kamaly is relied upon to teach wherein the biologically active agent is IL-10 – not to teach the nanoparticle platform (of record). Examiner maintains that it would be obvious to one of ordinary skill to substitute the biologically active agent to IL-10 on the nanoparticles taught by Santos, especially considering that Santos teaches that the nanoparticle platform can deliver a wide variety of cargo (of record). Therefore, this argument is not persuasive because Kamaly was not relied upon to teach the structure of the nanoparticles.
Applicant argues that Kamaly teaches weekly administration of drug in mice which is not a realistic solution for real-world patient treatment. Again, Examiner relies on Kamaly to teach that IL-10 as biologically active cargo is capable of treating atherosclerosis and vascular occlusions - not to teach the nanoparticle delivery platform (of record). Granada teaches how nanoparticle delivery of cargo via one-time balloon catheter administration provides long-term drug retention and therapeutic effects (of record). Examiner maintains that it would be obvious to substitute sirolimus for IL-10 in the method of treating taught by Granada and Santos with a reasonable expectation of success considering that IL-10 was known to treat atherosclerosis and vascular occlusions and that the Santos nanoparticles can deliver a wide variety of cargo. Therefore, the specific pharmacokinetics of the nanoparticles of Kamaly are not applicable to the instant obviousness rejection. Further, frequency of administration is not recited in the instant claims.
Applicant argues that Boehler teaches the lentiviral delivery of IL-10 for sustaining macrophage polarization towards an M2 phenotype which is an entirely different treatment paradigm to that of the present application. Examiner relies on Boehler to teach the mechanism of action of IL-10, specifically wherein IL-10’s regulation of inflammation is through macrophage polarization (of record). One of ordinary skill would understand that regardless of the delivery platform (nanoparticle vs lentivirus), the mechanism of action of IL-10 is the same because function is an inherent property of the structure of IL-10.
The rejection of Claims 17 and 20 under 35 U.S.C. 103 as being unpatentable over Granada et al, EuroIntervention 2016 (of record) in view of Santos et al, ACS Appl. Nano Mater. 2018 (of record) as applied to Claims 3-5, 11, 14-16, and 21 above, and further in view of Imanparast et al. Microvasc Res. 2017 (of record) is maintained.
Applicant's arguments filed March 30, 2026 have been fully considered but they are not persuasive.
Applicant argues that Imanparast does not provide in vivo data to determine whether simvastatin is effective in treating atherosclerosis, and it would not have been obvious to a person skilled in the art to expect simvastatin to treat vascular injury based on the disclosures in Imanparast. It is of record that Imanparast teaches that simvastatin can treat endothelial dysfunction in vitro which is a critical aspect of atherosclerosis. It is important to understand Imanparast in light of the state of the art at the time it was published (2017). It was well-understood in the art that statins treat atherosclerosis by lowering cholesterol, and simvastatin was the second statin to be used clinically as early as 1988 (as evidenced by Hajar Heart Views. 2011; pages 124-125). Therefore, the ability of simvastatin to effectively treat atherosclerosis is not unpredictable simply because the teachings of Imanparast were in vitro rather than in vivo. Examiner notes that the instant application does not teach in vivo administration of simvastatin either and also relies on the state of the art prior to filing for proper enablement. Further, Examiner relies on Imanparast to teach simvastatin as the biologically active agent, and does not rely on Imanparast to teach the nanoparticle system. Applicant’s arguments are not persuasive, and the rejection is maintained.
Double Patenting (Maintained)
The provisional rejection of Claims 17-19 and 21 on the ground of nonstatutory double patenting as being unpatentable over claims 39, 51, 55-56 of copending U.S. App. No.18/787,371 is maintained.
Applicant's arguments filed March 30, 2026 have been fully considered but they are not persuasive. Applicant argues that the claims of the ‘371 application are directed to a biologically active agent comprising interleukin 10 and the instant claims recite an anti-inflammatory cytokine. However, this is not persuasive because the instant claims define interleukin 10 as a species of anti-inflammatory cytokine. Therefore, both the instant claims and the copending claims recite wherein the biologically active agent is interleukin 10.
Applicant argues that the copending claims do not teach nanoparticles decorated with agents suitable for the treatment of blood vessels, specifically reducing vascular occlusion, neointimal hyperplasia, and/or increasing rate of re-endothelialisation. Examiner maintains that the rejection pertains to instant Claims 17-19 and 21 which are directed to a conjugate and not a method of treating. Therefore, the recited functions (reducing vascular occlusion, neointimal hyperplasia, and/or increasing rate of re-endothelialisation) are not required to be taught by the copending claims. Applicant’s arguments are not persuasive, and the provisional rejection is maintained.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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