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 .
Claim Status
Claim listing filed on August 5, 2025 is pending. Claims 1-2, 6-9, 13, 24-26, and 28 are canceled. Claims 3-4, 10-11, 14-17, 20, 22, 27, and 29 are amended. Claims 30-33 are new. Claims 3-5, 10-12, 14-23, 27, and 29-33 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 1-2, 8-9, 13, and 25-26 have rendered all previous rejections directed to these claims moot.
Applicant’s amendments to the specification and drawings overcome the objections of record, and the specification objections and drawing objections are withdrawn. Specifically, the corrected drawings are located in the file named “721120-FBT-014US_Replacement-Figures-AS-FILED-8-5-2025.pdf” filed on August 5, 2025.
Applicant’s amendments to Claim 27 corrects the previous typographical error, and the claim objection is withdrawn.
The rejection of Claims 4-5, 10-11, and 15 under 35 U.S.C. 112(b) as being indefinite is withdrawn in view of Applicant’s amendments to Claim 4 and the remarks filed on August 5, 2025. In the remarks (page 2), Applicant defines that a sweating balloon catheter refers to a balloon catheter whose material is capable of allowing fluid to pass from the internal part to the external. Examiner interprets “sweating balloon catheter” by this definition.
The rejection of Claims 22-23 and 27 under 35 U.S.C. 112(a) as failing to comply with the written description and enablement requirements is withdrawn in view of Applicant’s amendments. It is interpreted that the amended claims are directed to reducing the potential of symptom development in patients who already have an established disease or injury. Therefore, the claims are no longer directed to preventing the onset of disease or injury.
The rejection of Claims 3-5, 11, and 14-16 under 35 U.S.C. 102(a)(1) as being anticipated by Granada et al, EuroIntervention 2016 is withdrawn in view of Applicant’s amendments. Specifically, Granada does not teach the nanoparticulate as required by amended Claim 3.
The rejection of Claims 17 and 20 under 35 U.S.C. 102(a)(1) as being anticipated by Santos et al, ACS Appl. Nano Mater. is withdrawn in view of Applicant’s amendments. Specifically, the amended claims are no longer directed to an anti-proliferative drug.
The rejection of Claims 17-22, 27, and 29 on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 12,076,417 is withdrawn in view of Applicant’s remarks filed August 5, 2025. The instant claims are directed to more specific species of biologically active agents and administration techniques, and the patented claims are directed to a broader genus. Thus, the patented genus does not anticipate the instantly claimed species (MPEP § 2131.02.I).
The rejection of Claims 17-22, 27, and 29 on the ground of nonstatutory double patenting as being unpatentable over U.S. Patent No. 11,684,678 is withdrawn in view of Applicant’s remarks filed August 5, 2025. The instant claims are directed to more specific species of biologically active agents and administration techniques, and the patented claims are directed to a broader genus. Thus, the patented genus does not anticipate the instantly claimed species (MPEP § 2131.02.I).
Claim Objections (New, necessitated by amendment)
Claim 20 is objected to because of the following informalities: “Sulindac; or wherein” does not require a semicolon as the claim is no longer directed to a list. “Sulindac or wherein” is the proper correction. Appropriate correction is required.
Note, Claims 24-28 are labeled “Cancelled” but Claim 27 is presently amended. It is interpreted that Claims 24-26 and 28 are cancelled, and Claim 27 is examined on the merits. Please correct for clarity of record.
Claim Rejections - 35 USC § 112 (New, necessitated by amendment)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 22-23, 27, and 30-33 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 27 recites the limitation "the one or more symptom of vascular injury" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim because “one or more symptom of vascular injury” has not been defined in any of the preceding claims.
Claim 22 recites “a method of reducing vascular occlusion or reducing the potential development of vascular occlusion, reducing neointimal hyperplasia or reducing the potential development of neointimal hyperplasia, or increasing the rate of re-endothelialisation in a blood vessel.” Claim 30 recites “a method of reducing one or more symptoms of vascular injury, or reducing the potential development of one or more symptoms of vascular injury.” These claims are directed to indefinite relative terminology, specifically the terms “reducing” and “increasing” (MPEP § 2173.05(b)). It is unclear what the thresholds of reducing and increasing are (a two-fold reduction? A four-fold increase? A statistically significant or non-significant reduction/increase?) The specification does not provide a definition of “reducing” and “increasing” in such a way that one of ordinary skill in the art would understand what is claimed. It is also unclear what the reduction or increase is relative to (an untreated control? a pre-treatment time point?). Due to relative terminology, Claims 22 and 30 are rejected as being indefinite, and Claims 23, 27, and 31-33 are dependent on Claims 22 and 30. For the purpose of compact prosecution, it is interpreted that the “reducing” and “increasing” encompasses any non-significant change relative to a matched-control patient that does not receive the conjugate.
Claim Rejections - 35 USC § 103 (Maintained)
Claims 3-5, 11, 14-16, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Granada et al, EuroIntervention 2016 (of record), and further in view of Santos et al, ACS Appl. Nano Mater. (of record). Note, the previous 103 rejection under Granada in view of Santos applied to Claims 22-23 and 25-26, and now applies to Claims 3-5, 11, 14-16, and 21 due to Applicant’s amendments.
Claim 3 recites a method comprising conjugating a biologically active agent to a nanoparticle to produce a conjugate wherein the conjugate comprises a nanoparticulate polymer with a mean diameter of about 1 nm to about 50 nm and formed from a plasma comprising at least one monomer selected from: an alkene, an alkyne, a cycloalkene, a cycloalkyne, or a mixture thereof; or an aggregate comprising two or more of the nanoparticulate polymers, wherein the aggregate has a mean diameter of about 5 nm to about 500 nm; wherein the biologically active agent is selected from the group consisting of: an anti- inflammatory cytokine; anti-inflammatory drug; a statin drug and an anti-proliferative drug. The method of Claim 3 further comprises delivering the conjugate to a region of a blood vessel to regulate inflammation and promote healing. Claims 4-5 recite wherein the conjugate is retained in the blood vessel longer than a biologically active agent unconjugated to the nanoparticulate, and the conjugate is retained for at least 1 day. The biologically active agent can be paclitaxel or sirolimus (Claims 11 and 21). The conjugate is delivered to the blood vessel using a sweating balloon catheter (Claims 14-15). The patient has received an endovascular intervention (Claim 16).
Granada teaches nanoparticles formulated with sirolimus (a biologically active anti-proliferative agent) that are delivered to regions of porcine arteries and swine models of in-stent restenosis using a porous balloon catheter to treat vascular injury (abstract). Note, a porous balloon catheter reads on “sweating balloon catheter” based on Applicant’s definition in the remarks filed on August 5, 2025. The sirolimus nanoparticles were administered following stent implantation in swine models (abstract) as required by Claim 16. Granada teaches that the use of sirolimus has been limited because of its inability to achieve long-term tissue retention when delivered into local arterial tissue (introduction paragraph 2). However, by formulating sirolimus with a nanoparticle, tissue retention increased up to 14 days when delivered to porcine coronary arteries (introduction paragraph 3).
Granada fails to teach the nanoparticle formulation as required by Claims 3 and 21.
Santos teaches carbon-activated plasma-polymerized nanoparticles (abstract) that can be formed spontaneously through reactive plasma polymerization of particular precursors such as acetylene (a type of alkyne) (page 581, col. 2, par. 2 and Figure 1). During the first phase of synthesis, primary carbonaceous nanoclusters (PCN) form that are ~10nm in size (page 582, col. 1, par. 2-3), comparable to the nanoparticulates of Claims 3 and 21. In the second phase of synthesis, the PCN aggregate to form nanoparticles (Figure 1) that range from about 80nm to 200nm in size (page 584, col. 1, par. 2 and Figures 4-5). To characterize the ability of the nanoparticles to conjugate to biologically active agents, Santos used representative conjugate classes with wide-ranging molecular weights and structures including an antibody (IgG, 150 kDa), enzyme (luciferase, 62 kDa), ribonucleic acid (small interfering RNA, 15 kDa), fluorescent dye (cardiogreen, 0.78 kDa), and an anti-proliferative drug (paclitaxel, 1.3 kDa) (page 587, col. 1, par. 1). Santos teaches that the covalent binding between the nanoparticle and the cargo prevents the cargo from being released once inside the cell (page 591, col. 1, paragraph 2) which indicates that the nanoparticle causes a higher retention rate than the cargo would have unconjugated. Santos does not teach a specific number of days the conjugate is retained at the delivery site, but it is understood that structure dictates function. Because Santos teaches the nanoparticle structure of Claim 3, the nanoparticles inherently have the functional properties as recited in Claims 4-5 (MPEP § 2112.01.I-II). Santos further teaches that the nanoparticles have negligible toxicity and have valuable potential for broad clinical applications (page 591, col. 2, paragraph 1).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to adapt the method of delivering a nanoparticle conjugate to a blood vessel as taught by Granada to comprise the specific nanoparticle conjugate as taught by Santos. The motivation to use the nanoparticle platform taught by Santos is because it can bind and carry a wide variety of biologically active agents, it is non-toxic, and it has clinical applications. It would have been obvious to substitute a nanoparticle conjugate known to be safe for clinical use into a known method of promoting healing in a blood vessel using nanoparticles with a reasonable expectation of success.
Claims 10, 12, 17-19, 22-23, 27, and 29-33 are rejected 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. (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). Note, the previous 103 rejection under Granada in view of Santos, Kamaly, and Boehler applied to Claims 8-10, 12, and 29, and now applies to Claims 10, 12, 17-19, 22-23, 27, and 29-33 due to Applicant’s amendments.
The teachings of Granada and Santos as they apply to Claims 3-5, 11, 14-16, and 21 are outlined in the rejection above and encompass administering a nanoparticle conjugated to an anti-proliferative agent to a region of a blood vessel to treat vascular injury. Granada and Santos fail to teach: wherein the biologically active agent is the anti-inflammatory cytokine IL-10 (Claims 10, 17-19, and 29); wherein the regulation of inflammation is through macrophage polarization (Claim 12); and administering the conjugate comprising an anti-inflammatory cytokine to reduce vascular occlusion or atherosclerosis, both of which are symptoms of vascular injury (Claims 22, 27, and 30-33).
Kamaly teaches nanoparticles incorporating the anti-inflammatory cytokine IL-10 for targeted delivery to atherosclerotic plaques in the blood vessels of mice (abstract). Atherosclerosis can trigger vascular occlusion (page 5285, last paragraph). The administration of IL-10 nanoparticles stabilized, repaired, and remodeled pre-existing atherosclerotic plaques, which are key features of the resolution of inflammation (page 5287, last paragraph of results). Kamaly does not speak to the exact mechanism by which IL-10 resolves inflammation, but Boehler teaches “lentiviral delivery of IL-10 to macrophages represents a promising strategy for directing and sustaining macrophage polarization towards an M2 phenotype in order to promote local immune responses that facilitate tissue engineering” (abstract). Together, these references teach that IL-10 nanoparticles can be administered to blood vessels to regulate inflammation through macrophage polarization and treat symptoms of vascular injury, specifically atherosclerosis and vascular occlusion.
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to adapt the method of delivering an anti-proliferative nanoparticle conjugate to a blood vessel as taught in Granada and Santos to instead deliver an IL-10 nanoparticle conjugate as taught in Kamaly and Boehler. It would have been obvious to substitute the biologically active agents because Kamaly teaches that the administration of IL-10 nanoparticles to blood vessels treats atherosclerosis and vascular occlusions. Further, Santos teaches that the nanoparticle platform can deliver a wide variety of cargo. It would have been obvious to substitute a known therapeutic agent into an established nanoparticle platform that is capable of carrying different cargo. The motivation to combine these teachings is to create an IL-10 therapy that regulates inflammation in blood vessels that is stable, non-toxic, and site-specific.
Response to Arguments
Applicant's arguments filed August 5, 2025 have been fully considered but they are not persuasive.
Applicant argues that the claims are not obvious over Granada, Kamaly, and Boehler because none of the references teach the nanoparticles as described in Claim 3. Santos is relied upon to teach the nanoparticles as described in Claim 3, and one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references (MPEP § 2145.IV).
Applicant argues that the claims are not obvious over Santos and Kamaly because the instant application demonstrates for the first time the surprising retention of biologically active agents loaded on the claimed nanoparticulate conjugates within the high flow environment of a blood vessel, and such a positive outcome could not be predicted based on the teachings of Santos and Kamaly. Note, Claims 22-23, 25-26, and 29 were previously rejected in view of Granada, Santos, and Kamaly. Granada teaches a prolonged retention of a biologically active agent conjugated to a nanoparticle in the high flow environment of a blood vessel (of record), and Santos teaches the specific nanoparticulates of the instant claims. Therefore, the outcomes of the instant claims are predictable from the prior art. Further, MPEP § 2112.I teaches: "[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). Thus, a newly discovered property of a known nanoparticulate is not patentable.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
Claims 17 and 20 are rejected 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. (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.
The teachings of Granada and Santos as they apply to Claims 3-5, 11, 14-16, and 21 are outlined in the rejection above and encompass administering a nanoparticle conjugated to an anti-proliferative agent to a region of a blood vessel to treat vascular injury. Granada and Santos fail to teach: wherein the biologically active agent is a statin (Claim 17), specifically simvastatin (Claim 20).
Imanparast teaches formulating simvastatin as a nanoparticle and administering the conjugate in vitro to human umbilical cord vascular endothelial cells to treat endothelial dysfunction, a critical aspect of atherosclerosis (abstract).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to adapt the anti-proliferative agent nanoparticle conjugate taught by Granada and Santos to instead comprise the statin agent simvastatin taught by Imanparast. Imanparast teaches that simvastatin formulated as a nanoparticle is therapeutic in vascular injury and disease which is the same application as the nanoparticle conjugate taught by Granada and Santos. Further, Santos teaches that the nanoparticle platform can deliver a wide variety of cargo. It would have been obvious to substitute a known biologically active agent in an established nanoparticle platform that is capable of carrying different cargo. The motivation to combine these teachings is to create a simvastatin therapy that has favorable blood vessel targeted delivery and retention time due to the established nanoparticle/balloon catheter delivery platform.
Double Patenting (Maintained)
3. Claims 17-19 and 21 are provisionally rejected 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. Note, the previous rejection applied to Claims 17-22, 26-27, and 29 and now applies to Claims 17-19 and 21 due to Applicant’s amendments in both the instant and copending claims.
Applicant's arguments filed August 5, 2025 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.
Applicant argues that in double patenting analysis, no part of the reference patent or application may be used as if it were prior art, and instead the analysis is solely by the claims. However, the applicant cited the MPEP without distinctly and specifically pointing out the supposed errors in the Examiner’s action as is required in a complete response (MPEP § 714.02). Therefore, these arguments do not warrant a complete response and are not persuasive.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675