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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/11/2026 has been entered.
Claims 29, 60, 61, 63-73 are pending.
Claims 1-28, 30-62, 66 and 69-70 are cancelled.
Claims 29, 65 and 67 are amended.
Claims 74-81 are new.
Claims 29, 63-65, 67, 68, 71-81 are pending and are included in the prosecution.
Maintained Rejections
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.
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 29, 63-65, 67, 68, 71-81 are rejected under 35 U.S.C. 103 as being unpatentable over Woodworth et al. (WO 2013/081835 A2 - cited in IDS filed 04/08/2022) hereinafter the reference is referred as Woodworth, in view of Surface-Modified PLGA Nanoparticles for targeted drug delivery to neurons (hereinafter the master thesis is referred as Li) and further in view of Effects of Surface Modification on Delivery Efficiency of Biodegradable Nanoparticles Across the Blood-Brain Barrier (hereinafter the article is referred as Kulkarni).
Woodworth teaches pharmaceutical compositions formulated for delivery to the brain directed to methods for treating disease or disorder of the brain (e.g., glioblastoma, neurological disorder, neurodegenerative disease, brain injury, or trauma) (¶ 0009), brain cancer (¶ 0043), and epilepsy (¶ 0080). Woodworth teaches delivery via intravenous, intra-arterial, intra-thecal, stereotactic injection, and convection-enhanced delivery routes (¶ 0010), and a pharmaceutical composition comprising a nanoparticle, a PEG polymer coating, a targeting moiety, and a biologically active agent to enhance a desired response intracellularly or extracellularly (abstract), with a nucleic acid as the therapeutic agent (¶¶ 0043, 0099). Woodworth further discloses receptor-mediated transport across the BBB (¶ 0004) and PLGA as the biodegradable polymer (claim 14, ¶ 0174).
Regarding claim 29 (as amended), Woodworth teaches a method of delivering a brain therapeutic agent to a subject having a physical disorder of the brain comprising intravenous administration, NPs comprising a nucleic acid as the brain therapeutic agent, biodegradable polymer PLGA, wherein the NPs cross the blood-brain barrier (¶¶ 0004, 0009–0010, 0043, 0099, 0174). Thus, the limitations of (i) a nucleic acid therapeutic agent, (ii) PLGA, intravenous administration, BBB crossing, and treatment of a physical brain disorder are taught by Woodworth.
Woodworth does not specifically teach polysorbate 80 (PS80) as the surfactant component (iii). Li teaches surface-coated PLGA NPs for brain uptake using polysorbate 80 (T80) and/or TPGS (page 52, ¶ 2.3.2.2; Table 2.1, pages 15–20), and demonstrates that PS80-coated PLGA NPs showed enhanced cellular uptake (21%) versus unmodified NPs, and that PS80 displays a specific role in brain targeting (page 23, top; page 22, 2nd ¶). Kulkarni further teaches PLGA NPs surface-modified with PS80 (Tween 80) for BBB delivery, demonstrating that surface modification is a feasible and efficient strategy for NPs made of biodegradable polymers to deliver therapeutic agents across the BBB (abstract; page 377).
Woodworth does not teach NPs with an average hydrodynamic diameter of 40–100 nm as measured by DLS, nor does Woodworth specifically teach the incorporation of PS80 during nanoparticle formation. Li fails to specifically teach a surfactant concentration of 0.001–0.2% (w/v). Accordingly, Li and Kulkarni are applied to supply these missing features.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the nanoparticle composition of Woodworth by incorporating PS80 during nanoparticle formation and optimizing the surfactant amount, in order to enhance cellular uptake of the NPs across the blood-brain barrier, as taught by Li and Kulkarni. One of ordinary skill in the art would have been motivated to make this modification because Li and Kulkarni both demonstrate that PS80-coated PLGA NPs improve transport across the BBB and increase delivery specificity. One of ordinary skill in the art would have had a reasonable expectation of success because all three references are directed to PLGA-based nanoparticle compositions for delivery of therapeutic agents across the blood-brain barrier in the treatment of brain diseases and disorders. It is obvious to combine prior art elements according to known methods to yield predictable results. See MPEP 2141 (III)(A)–(G).
Regarding claims 63 and 64, Woodworth teaches methods for treating physical disorders of the brain including brain injury, trauma (¶ 0009, claim 25), penetrating head trauma associated with risk of epilepsy (¶ 0080), and cancer (¶ 0046).
Regarding claims 67 and 74, Woodworth teaches nanoparticles having a hydrodynamic diameter between 4 nm and 200 nm (¶ 0008), and specifically between 50 nm and 100 nm as measured by dynamic light scattering (¶ 0049). The Woodworth range of 50–100 nm overlaps with and is largely encompassed within the claimed range of 40–100 nm. The claimed 55 nm specific value is within Woodworth’s range.
Regarding claim 68, Woodworth teaches nanoparticles having an average molecular weight of 5–15 kDa (¶ 0102), which overlaps with the claimed range of 7–31 kDa.
Regarding claims 71 and 72, Woodworth teaches pharmaceutical compositions formulated for delivery to the brain comprising plasmid (¶ 0209), shRNA (¶ 0209), antisense oligonucleotides (¶ 0146), aptamers (¶ 0108, claim 15), and siRNA (¶ 0413) as nucleic acid therapeutic agents.
Regarding claim 73, Woodworth teaches a pharmaceutical composition comprising PLGA at 25 mg/mL (¶ 0174), which overlaps with the claimed range of 0.5–50 mg/mL.
Regarding claim 29 (component iii), as further support, Li teaches PLGA NPs with TPGS enhanced cellular uptake efficiency 1.5-fold compared to PVA-emulsified NPs after 2 h incubation, and that PS80-coated PLGA NPs showed enhanced cellular uptake (21%) versus unmodified NPs (page 23, top). Li further demonstrates that surface-functionalized PLGA NPs aided brain uptake (page 23, middle), and that PS80 displays a specific role in brain targeting (page 22, 2nd ¶). Li also discloses a double emulsion preparation method with PLGA and PS80 (page 52, ¶ 2.3.2.2), which is relevant to the claimed incorporation during nanoparticle formation (claims 78–81).
Li fails to specifically teach a surfactant concentration of 0.001–0.2% (w/v).
Regarding claims 29, 63–65, 67, 68, 71–81, Kulkarni teaches a pharmaceutical composition for BBB delivery comprising PLGA NPs surface-modified with TPGS or PS80 (Tween 80) and a therapeutic agent (page 377). Kulkarni demonstrates that surface modification with appropriate surfactants overcomes elimination of NPs by the mononuclear phagocyte system and improves transport of drugs across the BBB (page 378, left column, last ¶), and that PS80-coated poly(butyl cyanoacrylate) NPs were more efficient at delivering drug to the brain than free drug (page 377, right column). Thus, the limitation of a pharmaceutical composition for brain delivery comprising a therapeutic agent, PLGA, and a surfactant (PS80 or TPGS) is taught.
Regarding claim 65, Kulkarni teaches NPs incubated in a 0.5% (w/v) surfactant solution (T80, F68, or F127) to prepare surface-coated PLGA NPs (page 379, left column, Preparation of NPs ¶). It would have been obvious to a PHOSITA to optimize the surfactant amount to improve transport of therapeutic agents across the BBB and increase delivery specificity, thereby arriving at the claimed range of 0.001–0.2% (w/v) through routine optimization. See In re Aller, 220 F.2d 454 (CCPA 1955) (optimization of a recognized result-effective variable is prima facie obvious).
Regarding claims 78–81 (method of fabricating PLGA nanoparticles), the claimed fabrication steps of: (a) dissolving PLGA in an organic phase; (b) dissolving a nucleic acid therapeutic and PS80 surfactant in an aqueous phase; (c) mixing the organic and aqueous phases to form NPs; and (d) collecting NPs having an average hydrodynamic diameter of 40–100 nm by DLS are rendered obvious by the combination of Li and Kulkarni. Li discloses a double emulsion preparation method involving an organic PLGA phase and an aqueous phase containing PS80 (page 52, ¶ 2.3.2.2), which corresponds to incorporating PS80 during nanoparticle formation. Kulkarni confirms that NP formation methods using TPGS or PS80 during emulsion yield surface-modified PLGA NPs suitable for brain delivery (abstract; page 379). It would have been obvious to a PHOSITA to prepare PLGA NPs by the double emulsion technique taught by Li, incorporating PS80 during formation as taught by both Li and Kulkarni, and to collect NPs of 40–100 nm, which falls within the size ranges taught by Woodworth (¶¶ 0008, 0049).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to modify the nanoparticle composition by incorporating PS80 during nanoparticle formation and optimizing the amount of surfactant, in order to enhance cellular uptake of the NPs across the blood-brain barrier, as taught by Woodworth, Li, and Kulkarni. One of ordinary skill in the art would have been motivated to improve the pharmaceutical composition for brain delivery by making these modifications because doing so would improve transport of therapeutic agents across the BBB, increase specificity of delivery, and enhance targeting, as taught by the cited references. One of ordinary skill in the art would have had a reasonable expectation of success because all references are directed to pharmaceutical compositions comprising PLGA-based nanoparticles capable of crossing the blood-brain barrier, loaded with therapeutic agents, for the treatment of various brain diseases and disorders. It is obvious to combine prior art elements according to known methods to yield predictable results. See MPEP 2141 (III)(A)–(G).
Response to Arguments
In view of Applicants’ claim amendments, the rejection under 35 U.S.C. 103 as being obvious over Woodworth in view of Li and further in view of Kulkarni is hereby maintained.
Applicant’s argument re: cancellation of claims 60, 61, 66, 69, 70. Noted. The cancellation of those claims moots the rejection as to those claims. The rejection is maintained as to all remaining pending claims.
Applicant’s argument re: Woodworth being silent on PS80. The Examiner acknowledges that Woodworth does not specifically teach PS80. However, Woodworth’s silence on PS80 does not defeat the rejection, because the combination of Li and Kulkarni supplies this feature. Li explicitly teaches PS80-coated PLGA NPs for brain delivery and PS80’s specific role in brain targeting (page 22, 2nd ¶; page 23). Kulkarni confirms the advantage of PS80 modification for BBB transport (page 377). The motivation to add PS80 to Woodworth’s formulation is provided by Li and Kulkarni. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007).
Applicant’s argument re: PS80 “incorporated during nanoparticle formation” not taught. The Examiner respectfully disagrees. Li discloses a double emulsion preparation method in which PLGA is dissolved in an organic phase and PS80 is included in the aqueous phase, such that PS80 is present during NP formation (page 52, ¶ 2.3.2.2). This is incorporation during formation, not post-synthesis coating. The Examiner acknowledges that Kulkarni’s primary preparation method (incubation of pre-formed NPs with surfactant, page 379) constitutes post-synthesis surface modification; however, Li’s double emulsion method with PS80 in the aqueous phase during NP formation is sufficient to teach or suggest the claimed incorporation step. A PHOSITA would have been motivated to use Li’s formation method given the demonstrated benefit of PS80 inclusion for brain delivery.
Applicant’s argument re: nanoparticle size (40–100 nm) not taught. The Examiner notes that Woodworth teaches NPs of 50–100 nm as measured by dynamic light scattering (¶ 0049), which substantially overlaps the claimed range of 40–100 nm. The difference between 40–49 nm (not explicitly disclosed in Woodworth) and 50 nm is a difference of degree, not kind. Woodworth further discloses a broader range of 4–200 nm (¶ 0008), encompassing the claimed range in its entirety. A PHOSITA would have been motivated to select NP sizes within the claimed range based on the teachings of Woodworth. Applicant’s Declaration evidence directed to size-dependent BBB crossing is acknowledged; however, Woodworth itself discloses NPs of 50–100 nm for BBB crossing, and no critical distinction has been established between the sub-range of 40–49 nm and the disclosed 50–100 nm range that would establish unexpected results sufficient to rebut prima facie obviousness. See In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) (overlapping ranges establish prima facie obviousness).
Applicant’s argument re: Kulkarni and Li being directed to small molecules only. The Examiner acknowledges that Li and Kulkarni do not specifically describe nucleic acid therapeutics as the cargo. However, Woodworth explicitly teaches nucleic acid (siRNA, shRNA, antisense oligonucleotides, plasmid) as the therapeutic agent in PLGA NPs for brain delivery (¶¶ 0043, 0099, 0146, 0209, 0413). Li and Kulkarni are relied upon only for the surfactant component (PS80 and its incorporation method), not for the identity of the therapeutic agent. A PHOSITA would have found it obvious to apply the PS80 surfactant modification taught by Li and Kulkarni to the nucleic acid–loaded PLGA NPs of Woodworth. The combination does not require any reformulation beyond substituting or adding a known surfactant to a known nanoparticle system for the same purpose.
Response to Amendment / Declaration
The declaration under 37 CFR 1.132 filed 5/11/2026 is insufficient to overcome the rejection of claim 29, 63-65, 67, 68, 71-81 based upon prior art Li and Kulkarni as set forth in the last Office action because of the following reasons below:
Applicant’s argument re: unexpected results / Declaration of Dr. Joshi. The Declaration of Dr. Nitin Joshi (¶¶ 2–5) presents experimental data showing that (1) NPs of 45, 70, and 90 nm showed significantly higher brain accumulation than 110 nm NPs, with ~70 nm performing best, and (2) NPs prepared with PS80 incorporated during formation showed higher brain accumulation than NPs coated post-synthesis. The Examiner has considered this evidence. However, the Declaration does not compare the claimed NPs to the closest prior art formulations (i.e., PS80-modified PLGA NPs of comparable sizes already disclosed by Li and Kulkarni). The Declaration compares PS80-incorporated NPs against PEG-coated NPs (per the specification) and against post-synthesis PS80-coated NPs. To establish unexpected results sufficient to rebut prima facie obviousness, the comparison must be made against the closest prior art, not merely against structurally distinct or admittedly inferior formulations. See In re Baxter Travenol Labs., 952 F.2d 388 (Fed. Cir. 1991). Accordingly, the Declaration evidence is insufficient to overcome the prima facie case of obviousness.
Therefore, a prima facie case is properly established and the rejection is maintained.
Conclusion
No claims are allowed.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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