CTNF 18/029,028 CTNF 97490 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 07-42-04 AIA 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/28/2026 has been entered. Receipt of Applicants’ Arguments, Remarks and amended claims filed on 4/28/2026 is acknowledged. Claims 1-17 and 26-32 are pending. Claims 15,18-25 and 30 are cancelled. Claims 1 and 10 are amended. Claims 1-14, 16, 17, 26-29, 31 and 32 are pending and under examination in this application. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim (s) 1-14, 16, 17, 26-29, 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Ingber et al. (US 2013/02955012 A1) (hereinafter the reference is referred as Ingber) in view of Beard et al. (2015) – “Intracranial Pressure Elevation Reduces Flow through Collateral Vessels and the Penetrating Arterioles they Supply…” Journal of Cerebral Blood Flow & Metabolism, 35(5), 861 872 . Summary of Prior Art Teachings Ingber teaches shear-activated nanotherapeutics (SA-NTs) comprising PLGA nanoparticle aggregates that disaggregate at shear stress greater than 100 dynes/cm²; treats stroke and ischemic conditions; active agents include nimodipine and nitroglycerin; routes of administration include intravenous bolus and continuous infusion; aggregates remain intact under normal physiological flow below 10 dynes/cm²; excipients/carriers are disclosed; teaches separate administration of thrombolytics; and teaches combination with neuroprotective agents. (¶¶ 0007, 0014, 0025, 0036–0038, 0099–0100, 0122, 0171, 0186–0187, 0195, 0197, 0201–0202, 0278, 0455–0458, 0470–0482; Claims 1, 2, 4, 7, 51.) Beard (2015) is a peer-reviewed article published before Applicant's effective filing date (September 29, 2020). Beard teaches that after ischemic stroke, leptomeningeal collateral vessels experience significantly elevated shear stress due to a marked increase in blood-flow velocity driven by the pressure differential between healthy and ischemic tissue. Critically, Beard reports in Table 1 and Figure 3 that wall shear stress in collateral vessels post-stroke rises substantially – on the order of a 5–6 fold increase over baseline – reaching values well in excess of 30 dynes/cm² and within the range sufficient to trigger SA-NT disaggregation as taught by Ingber (threshold: >100 dynes/cm²). Beard explicitly states that this elevation in shear stress is independent of vessel diameter changes and that the collateral vessels remain non-occluded, serving as bypass conduits supplying the ischemic penumbra. (Beard, Abstract; Fig. 3; Table 1; Results section.) Regarding amended claim 1, requires a method of treating stroke by increasing blood supply to the penumbra via non-occluded collateral vessels, administering an SA-NT comprising a nanoparticle aggregate with a vasodilating agent (e.g., nitroglycerin), wherein the aggregate disaggregates at a shear stress greater than 30 dynes/cm² in the collateral vessel, said shear stress caused by increased blood-flow velocity independent of vessel diameter, and the aggregate remains intact under normal physiological flow conditions. Claim Limitation Prior Art Basis Treating stroke Ingber ¶¶ 0186–0187 Increasing blood supply to penumbra via non-occluded collateral vessels Beard – explicitly teaches non-occluded leptomeningeal collaterals as high-flow conduits post-stroke (Abstract; Fig. 3; Table 1; Results section) Administering SA-NT comprising aggregate of nanoparticles Ingber ¶ 0007 Aggregate contains vasodilating agent (e.g., nitroglycerin, nimodipine) Ingber ¶¶ 0014, 0171; Claims 1, 2, 4 Aggregate disaggregates at shear stress >30 dynes/cm² Ingber (threshold >100 dynes/cm² – overlapping/exceeding range); Beard (Table 1: collateral shear stress post-stroke substantially exceeds 30 dynes/cm², within Ingber's disaggregation range) Shear stress caused by increased flow velocity, independent of vessel diameter changes Beard – expressly states elevated shear in collaterals is due to increased velocity, not diameter reduction (Abstract; Results; Table 1) Aggregate remains intact under normal physiological flow Ingber ¶ 0482 (intact at normal physiological shear <10 dynes/cm²) Rationale for Combining Ingber and Beard A person having ordinary skill in the art (PHOSITA) would have been motivated to apply Ingber's SA-NTs in the collateral vessel environment identified by Beard for at least three independent reasons: (1) Both references address the same problem – improving blood delivery to ischemic brain tissue after stroke – providing a clear reason to combine their teachings. (2) Beard quantifies the shear stress values present in post-stroke collateral vessels (Table 1; Fig. 3), demonstrating that those values meet and substantially exceed Ingber's disaggregation threshold of >100 dynes/cm². A PHOSITA reading both references would immediately recognize that collateral vessels constitute a suitable environment for Ingber's SA-NT mechanism. (3) The combination is simple, direct, and requires no modification of either reference's core technology. Ingber's SA-NT disaggregates based solely on reaching a shear stress threshold, regardless of whether that threshold arises from vessel stenosis or elevated flow velocity. Beard supplies the empirical confirmation that the relevant threshold is met in collateral vessels post-stroke. The expectation of success is high because Beard quantifies the precise shear environment and Ingber's disaggregation mechanism is shear-threshold-based, not location-specific or mechanism-specific with respect to the source of elevated shear. No unpredictable results would be expected; the claimed outcome follows directly from combining the two teachings. Regarding claims 2-9 and 11-14, the claims are obvious over Ingber in view of Beard for the same reasons as claim 1 above. Claims 2–5 require specific vasodilators (nitrate, ARB, CCB, nitroglycerin, nimodipine), all taught by Ingber (¶¶ 0014, 0171). Claim 6 requires disaggregation at greater than 100 dynes/cm², taught by Ingber (¶ 0482) and consistent with Beard's reported post-stroke collateral shear values (Table 1; Fig. 3). Claim 7 requires PLGA copolymers, taught by Ingber (Claim 7; ¶ 0122). Claim 8 requires encapsulation, adsorption, or covalent linkage, taught by Ingber (¶¶ 0036–0038). Claim 9 requires higher release rate/amount upon disaggregation, taught by Ingber (¶¶ 0099–0100). Claims 11–14 require intravenous administration, continuous infusion, bolus, and ischemic stroke, all taught by Ingber (¶¶ 0186, 0195, 0201–0202, 0313, 0470). Regarding claim 10 (as amended), the claim recites a method of treating stroke using a composition comprising the SA-NT of claim 1 together with pharmaceutically acceptable excipients, carriers, and/or diluents. This limitation is directly taught by Ingber (¶ 0197) and is obvious over Ingber in view of Beard for the same reasons as claim 1. Regarding claim 16, the claim requires administration of the SA-NT or composition in combination with a neuroprotective therapy. Ingber expressly teaches that SA-NTs can be combined with "other therapeutic agents" (¶ 0455) and specifically identifies agents that reduce reperfusion injury, free radical scavengers, and anti-inflammatory agents as within the scope of suitable combination therapies (¶ 0456). A PHOSITA would have found it obvious to combine Ingber's SA-NTs with a known neuroprotective agent (e.g., NXY-059, NA-1, IL-1ra, uric acid), as neuroprotection is standard adjunctive therapy in acute ischemic stroke. Ingber's ¶ 0456 neuroprotective agent listing is distinct from and not limited to thrombolytic agents; the combination is a straightforward addition of two independently known stroke therapies with predictable additive effects. Regarding claim 17, the claim recites administration of the SA-NT or composition in combination with one or more additional therapies selected from thrombolysis therapies and thrombolytic therapies, wherein the additional therapy is not administered as part of the SA-NT. Ingber explicitly teaches that SA-NTs can be administered "in combination with one or more additional therapeutic agents" that are "not physically associated with the aggregate" (¶ 0457), and specifically lists thrombolytic agents including tPA and tenecteplase as suitable for separate co-administration (¶ 0458). The prior art directly and expressly teaches the claimed feature. Regarding claims 26-29, the claims depend from claim 10 and require intravenous administration (¶¶ 0195, 0201), continuous infusion (¶¶ 0202, 0313), bolus administration (¶ 0470), and ischemic stroke (¶¶ 0186–0187), respectively. All are explicitly disclosed in Ingber. These claims add only routine, well-known administration routes and stroke types. No unexpected results are shown. Regarding claims 31 and 32, claim 31 depends from claim 10 and requires combination with neuroprotective therapy. Claim 32 depends from claim 10 and requires separate co-administration of thrombolysis or thrombolytic therapy. Both are obvious over Ingber in view of Beard for the same reasons stated above for claims 16 and 17, respectively. Response to Arguments Argument 1: Ingber and Korin teach only obstruction based targeting, not collateral flow based targeting. The Examiner has withdrawn Korin and now relies on Beard (2015), which explicitly teaches that non-occluded collateral vessels experience elevated shear stress due to increased flow velocity independent of vessel diameter. Applicant's core factual distinction – that the previous combination lacked a reference disclosing non-occluded collateral vessels as a high-shear environment – is directly overcome by Beard. The rejection is maintained on this new combination. Argument 2: The combination must be based on actual teachings and produce predictable results (KSR). The Examiner agrees with the legal standard. Ingber teaches SA-NTs that disaggregate at a defined shear stress threshold (>100 dynes/cm²). Beard teaches, with quantitative data, that post-stroke leptomeningeal collateral vessels experience shear stress that substantially meets and exceeds that threshold (Table 1; Fig. 3). The combination is therefore based on actual, explicit teachings of both references. The result – SA-NT disaggregation occurring in collateral vessels post-stroke – is directly and predictably expected from the combination. Applicant has not shown unexpected results that would overcome this prima facie case. Argument 3 : The combination would render Ingber unsatisfactory for its intended purpose (In re Ratti, 270 F.2d 810 (C.C.P.A. 1959)). The Examiner respectfully disagrees. Ingber's intended purpose is to deliver therapeutic agents via SA-NT disaggregation at high-shear vascular sites in the treatment of ischemic conditions including stroke. The proposed combination does not remove, negate, or alter that purpose – it identifies an additional vascular environment (post-stroke collateral vessels) where Ingber's already-disclosed mechanism operates as designed. Expanding the recognized set of environments in which a mechanism functions does not render the reference unsatisfactory for its intended purpose. In re Ratti applies where a proposed modification would undermine the primary function or purpose of the reference; that is not the case here. Argument 4 : The references teach away from the claimed combination (In re Gurley, 27 F.3d 551 (Fed. Cir. 1994)). Applicant argues that because Ingber and Korin characterize elevated shear as exclusively a function of vessel narrowing, they implicitly teach away from a velocity-based, non-occluded mechanism. The Examiner respectfully disagrees for two independent reasons. First, and most fundamentally, Ingber's SA-NT disaggregation mechanism is shear-threshold-based, not source-of-shear-based. The aggregate disaggregates when the local shear stress exceeds the threshold (>100 dynes/cm²). The SA-NT has no capacity to distinguish whether that threshold was reached due to vessel narrowing or elevated flow velocity. Neither Ingber nor Korin states that the SA-NT would fail to disaggregate in a high-velocity, non-occluded vessel. Silence on a specific environment is not a teaching away. A reference teaches away only when it affirmatively indicates that the proposed modification would be undesirable or would not work – neither reference does so here with respect to velocity-driven shear in non-occluded vessels. Second, Beard affirmatively points toward collateral vessels as a high-shear environment, directly supplying what Ingber and Korin do not address. The Beard reference is expressly directed to the relevant biological phenomenon. Its inclusion in the combination remedies the gap Applicant identifies. Argument 5 : Example 4 (free nitroglycerin fails) shows non obviousness. The Examiner does not rely on free nitroglycerin as an element of the prior art combination. The rejection is directed to the obviousness of administering Ingber's SA-NT – a nanoparticle aggregate formulated to release its payload upon shear-triggered disaggregation – in the collateral vessel environment identified by Beard. Free nitroglycerin's failure to enhance collateral perfusion and its induction of systemic hypotension (Example 5) are entirely consistent with the claimed invention's premise: targeted SA-NT delivery is designed to release the vasodilator locally at the high-shear collateral site, not systemically. That free nitroglycerin behaves differently from an SA-NT formulation does not render the SA-NT approach non-obvious. A PHOSITA would have predicted this difference, which is precisely why encapsulating the vasodilator in a shear-responsive SA-NT (as Ingber teaches) would have been motivated. Example 4's data support the efficacy of the SA-NT approach; they do not render it non-obvious. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A Wax can be reached at 571-272-0323. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /ANDRE MACH/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615 Application/Control Number: 18/029,028 Page 2 Art Unit: 1615 Application/Control Number: 18/029,028 Page 3 Art Unit: 1615 Application/Control Number: 18/029,028 Page 4 Art Unit: 1615 Application/Control Number: 18/029,028 Page 5 Art Unit: 1615 Application/Control Number: 18/029,028 Page 6 Art Unit: 1615 Application/Control Number: 18/029,028 Page 7 Art Unit: 1615 Application/Control Number: 18/029,028 Page 8 Art Unit: 1615 Application/Control Number: 18/029,028 Page 9 Art Unit: 1615 Application/Control Number: 18/029,028 Page 10 Art Unit: 1615 Application/Control Number: 18/029,028 Page 11 Art Unit: 1615 Application/Control Number: 18/029,028 Page 12 Art Unit: 1615
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